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Low cerebrospinal fluid pressure headache
Opinion statement��\\u000a \\u000a \\u000a \\u000a \\u000a ��\\u000a \\u000a Alterations in cerebrospinal fluid (CSF) pressure lead to neurologic symptoms, the most common clinical manifestation of which\\u000a is headache. Typically, the headache is orthostatic and related to traction on pain-sensitive intracranial and meningeal structures,\\u000a distention on periventricular pain-sensitive areas, and direct pressure on pain conveying cranial nerves.\\u000a \\u000a \\u000a \\u000a \\u000a ��\\u000a \\u000a Low CSF headache is a distinct and familiar syndrome
Christine M. Lay
Immunoglobulin Levels in the Cerebrospinal Fluid
The immunoglobulins G, A, M, and D have been measured in the cerebrospinal fluid of 207 patients with neurological disease. Raised levels of IgG, expressed as a percentage of total cerebrospinal fluid (C.S.F.) protein, were found in 62% of 45 cases of multiple sclerosis compared with 14% of 160 cases with various other neurological disorders. Thus measurement of the IgG level is probably a useful confirmatory investigation in multiple sclerosis. IgA and IgM were found only in the C.S.F. of patients with a raised protein level, and IgD was not detected. PMID:4190842
Riddoch, D.; Thompson, R. A.
Malignancy markers in the cerebrospinal fluid
The specificity and sensitivity of malignancy marker determinations in cerebrospinal fluid (CSF) are often insufficient. Even at the subclinical stage of the disease the marker should be present. The effect of therapy should be monitored and relapses noted. Thus high standards of methodology are required. There are many substances that may indicate a malignant process in the central nervous system.
M. Koskiniemi
[Pneumomyelography with regard to cerebrospinal fluid replacement].
Spinal arachnoidal space was investigated with cerebrospinal fluid drained and replaced with air. Some adequate parameters of the CSF replacement with gases were calculated according to rules derived from 140 pneumomyelographic investigations in patients with lumbar osteochondrosis: baseline CSF pressure, its withdrawal time and total volume. These parameters reflect the volume of arachnoidal space and its conductivity. Due account of these data allowed to determine the beginning of gas insufflation and its total amount. PMID:2633563
Samodurov, A I
Cerebrospinal Fluid Otorrhea Caused by Arachnoid Granulation
Cerebrospinal fluid (CSF) leakage otorrhea may be congenital or can be caused by trauma, surgery, cholesteatoma, and tumors. Spontaneous CSF leakage through the middle ear without a secondary cause is a relatively rare disease. The pathophysiology of CSF otorrhea has not been clear yet. However, there are two theories of the pathophysiology of spontaneous CSF otorrhea have been studied in the medical field: one based on the congenital defect; the other about the arachnoid granulation which causes bone erosion. Herein, we examine and report a case of CSF otorrhea caused by arachnoid granulation. Literatures pertaining to the disorder will be reviewed and characteristics of the disorder also will be discussed. PMID:24653893
Kim, Sang Woo
Human neuroglobin protein in cerebrospinal fluid.
BACKGROUND: Neuroglobin is a hexacoordinated member of the globin family of proteins. It is predominantly localized to various brain regions and retina where it may play a role in protection against ischemia and nitric oxide-induced neural injury. Cerebrospinal fluid was collected from 12 chronic regional or systemic pain and 5 control subjects. Proteins were precipitated by addition of 50% 0.2 N acetic acid, 50% ethanol, 0.02% sodium bisulfite. The pellet was extensively digested with trypsin. Peptides were separated by capillary liquid chromatography using a gradient from 95% water to 95% acetonitrile in 0.2% formic acid, and eluted through a nanoelectrospray ionization interface into a quadrapole - time-of-flight dual mass spectrometer (QToF2, Waters, Milford, MA). Peptides were sequenced (PepSeq, MassLynx v3.5) and proteins identified using MASCOT (R). RESULTS: Six different neuroglobin peptides were identified in various combinations in 3 of 9 female pain subjects, but none in male pain, or female or male control subjects. CONCLUSION: This is the first description of neuroglobin in cerebrospinal fluid. The mechanism(s) leading to its release in chronic pain states remain to be defined. PMID:15730566
Casado, Begona; Pannell, Lewis K; Whalen, Gail; Clauw, Daniel J; Baraniuk, James N
Cerebrospinal Fluid Biomarker Candidates for Parkinsonian Disorders
The Parkinsonian disorders are a large group of neurodegenerative diseases including idiopathic Parkinson�s disease (PD) and atypical Parkinsonian disorders (APD), such as multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies. The etiology of these disorders is not known although it is considered to be a combination of genetic and environmental factors. One of the greatest obstacles for developing efficacious disease-modifying treatment strategies is the lack of biomarkers. Reliable biomarkers are needed for early and accurate diagnosis, to measure disease progression, and response to therapy. In this review several of the most promising cerebrospinal biomarker candidates are discussed. Alpha-synuclein seems to be intimately involved in the pathogenesis of synucleinopathies and its levels can be measured in the cerebrospinal fluid and in plasma. In a similar way, tau protein accumulation seems to be involved in the pathogenesis of tauopathies. Urate, a potent antioxidant, seems to be associated to the risk of developing PD and with its progression. Neurofilament light chain levels are increased in APD compared with PD and healthy controls. The new �omics� techniques are potent tools offering new insights in the patho-etiology of these disorders. Some of the difficulties encountered in developing biomarkers are discussed together with future perspectives. PMID:23346074
Constantinescu, Radu; Mondello, Stefania
newsletter | contact Share | Stasis Ulcer Information for adults A A A This image displays a patient with chronic leg swelling with stasis dermatitis and a stasis ulcer. Overview A stasis ulcer is a breakdown of ...
A new look at cerebrospinal fluid circulation.
According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation. PMID:24817998
Brinker, Thomas; Stopa, Edward; Morrison, John; Klinge, Petra
A new look at cerebrospinal fluid circulation
According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation. PMID:24817998
Imhotep and the Discovery of Cerebrospinal Fluid
Herbowski (2013) suggested recently the Egyptian Imhotep from the 3rd dynasty in Egypt to be the discoverer of cerebrospinal fluid. There are, however, no sources within the first 2000 years after Imhotep suggesting him to be in any way connected with the field of medicine. Over the course of three millennia Imhotep evolves into the sage who besides architecture also masters the arts of medicine, magic, astronomy, and astrology, at the same time as him being transformed from man to demi-God, and finally to a God. The identification of Imhotep as a doctor has thus little to do with facts and it is unlikely that he had anything to do with the Edwin-Smith papyrus from a much later period where CSF is first mentioned. PMID:24744920
Blomstedt, Patric
Imhotep and the discovery of cerebrospinal fluid.
Herbowski (2013) suggested recently the Egyptian Imhotep from the 3rd dynasty in Egypt to be the discoverer of cerebrospinal fluid. There are, however, no sources within the first 2000 years after Imhotep suggesting him to be in any way connected with the field of medicine. Over the course of three millennia Imhotep evolves into the sage who besides architecture also masters the arts of medicine, magic, astronomy, and astrology, at the same time as him being transformed from man to demi-God, and finally to a God. The identification of Imhotep as a doctor has thus little to do with facts and it is unlikely that he had anything to do with the Edwin-Smith papyrus from a much later period where CSF is first mentioned. PMID:24744920
Blomstedt, Patric
Anatomy and physiology of cerebrospinal fluid.
The cerebrospinal fluid (CSF) is contained in the brain ventricles and the cranial and spinal subarachnoid spaces. The mean CSF volume is 150 ml, with 25 ml in the ventricles and 125 ml in subarachnoid spaces. CSF is predominantly, but not exclusively, secreted by the choroid plexuses. Brain interstitial fluid, ependyma and capillaries may also play a poorly defined role in CSF secretion. CSF circulation from sites of secretion to sites of absorption largely depends on the arterial pulse wave. Additional factors such as respiratory waves, the subject's posture, jugular venous pressure and physical effort also modulate CSF flow dynamics and pressure. Cranial and spinal arachnoid villi have been considered for a long time to be the predominant sites of CSF absorption into the venous outflow system. Experimental data suggest that cranial and spinal nerve sheaths, the cribriform plate and the adventitia of cerebral arteries constitute substantial pathways of CSF drainage into the lymphatic outflow system. CSF is renewed about four times every 24 hours. Reduction of the CSF turnover rate during ageing leads to accumulation of catabolites in the brain and CSF that are also observed in certain neurodegenerative diseases. The CSF space is a dynamic pressure system. CSF pressure determines intracranial pressure with physiological values ranging between 3 and 4 mmHg before the age of one year, and between 10 and 15 mmHg in adults. Apart from its function of hydromechanical protection of the central nervous system, CSF also plays a prominent role in brain development and regulation of brain interstitial fluid homeostasis, which influences neuronal functioning. PMID:22100360
Sakka, L; Coll, G; Chazal, J
Quantitative proteomics of delirium cerebrospinal fluid.
Delirium is a common cause and complication of hospitalization in older people, being associated with higher risk of future dementia and progression of existing dementia. However relatively little data are available on which biochemical pathways are dysregulated in the brain during delirium episodes, whether there are protein expression changes common among delirium subjects and whether there are any changes which correlate with the severity of delirium. We now present the first proteomic analysis of delirium cerebrospinal fluid (CSF), and one of few studies exploring protein expression changes in delirium. More than 270 proteins were identified in two delirium cohorts, 16 of which were dysregulated in at least 8 of 17 delirium subjects compared with a mild Alzheimer's disease neurological control group, and 31 proteins were significantly correlated with cognitive scores (mini-mental state exam and acute physiology and chronic health evaluation III). Bioinformatics analyses revealed expression changes in several protein family groups, including apolipoproteins, secretogranins/chromogranins, clotting/fibrinolysis factors, serine protease inhibitors and acute-phase response elements. These data not only provide confirmatory evidence that the inflammatory response is a component of delirium, but also reveal dysregulation of protein expression in a number of novel and unexpected clusters of proteins, in particular the granins. Another surprising outcome of this work is the level of similarity of CSF protein profiles in delirium patients, given the diversity of causes of this syndrome. These data provide additional elements for consideration in the pathophysiology of delirium as well as potential biomarker candidates for delirium diagnosis. PMID:25369144
Poljak, A; Hill, M; Hall, R J; MacLullich, A M; Raftery, M J; Tai, J; Yan, S; Caplan, G A
Cerebrospinal Fluid Space Alterations in Melancholic Depression
Melancholic depression is a biologically homogeneous clinical entity in which structural brain alterations have been described. Interestingly, reports of structural alterations in melancholia include volume increases in Cerebro-Spinal Fluid (CSF) spaces. However, there are no previous reports of CSF volume alterations using automated whole-brain voxel-wise approaches, as tissue classification algorithms have been traditionally regarded as less reliable for CSF segmentation. Here we aimed to assess CSF volumetric alterations in melancholic depression and their clinical correlates by means of a novel segmentation algorithm (�new segment�, as implemented in the software Statistical Parametric Mapping-SPM8), incorporating specific features that may improve CSF segmentation. A three-dimensional Magnetic Resonance Image (MRI) was obtained from seventy patients with melancholic depression and forty healthy control subjects. Although imaging data were pre-processed with the �new segment� algorithm, in order to obtain a comparison with previous segmentation approaches, tissue segmentation was also performed with the �unified segmentation� approach. Melancholic patients showed a CSF volume increase in the region of the left Sylvian fissure, and a CSF volume decrease in the subarachnoid spaces surrounding medial and lateral parietal cortices. Furthermore, CSF increases in the left Sylvian fissure were negatively correlated with the reduction percentage of depressive symptoms at discharge. None of these results were replicated with the �unified segmentation� approach. By contrast, between-group differences in the left Sylvian fissure were replicated with a non-automated quantification of the CSF content of this region. Left Sylvian fissure alterations reported here are in agreement with previous findings from non-automated CSF assessments, and also with other reports of gray and white matter insular alterations in depressive samples using automated approaches. The reliable characterization of CSF alterations may help in the comprehensive characterization of brain structural abnormalities in psychiatric samples and in the development of etiopathogenic hypotheses relating to the disorders. PMID:22761673
Via, Esther; Cardoner, Narcis; Pujol, Jesus; Martinez-Zalacain, Ignacio; Hernandez-Ribas, Rosa; Urretavizacaya, Mikel; Lopez-Sola, Marina; Deus, Joan; Menchon, Jose Manuel; Soriano-Mas, Carles
Cerebrospinal fluid may mediate CNS ischemic injury
Background The central nervous system (CNS) is extremely vulnerable to ischemic injury. The details underlying this susceptibility are not completely understood. Since the CNS is surrounded by cerebrospinal fluid (CSF) that contains a low concentration of plasma protein, we examined the effect of changing the CSF in the evolution of CNS injury during ischemic insult. Methods Lumbar spinal cord ischemia was induced in rabbits by cross-clamping the descending abdominal aorta for 1 h, 2 h or 3 h followed by 7 d of reperfusion. Prior to ischemia, rabbits were subjected to the following procedures; 1) CSF depletion, 2) CSF replenishment at 0 mmHg intracranial pressure (ICP), and 3) replacement of CSF with 8% albumin- or 1% gelatin-modified artificial CSF, respectively. Motor function of the hind limbs and histopathological changes of the spinal cord were scored. Post-ischemic microcirculation of the spinal cord was visualized by fluorescein isothiocyanate (FITC) albumin. Results The severity of histopathological damage paralleled the neurological deficit scores. Paraplegia and associated histopathological changes were accompanied by a clear post-ischemic deficit in blood perfusion. Spinal cord ischemia for 1 h resulted in permanent paraplegia in the control group. Depletion of the CSF significantly prevented paraplegia. CSF replenishment with the ICP reduced to 0 mmHg, did not prevent paraplegia. Replacement of CSF with albumin- or gelatin-modified artificial CSF prevented paraplegia in rabbits even when the ICP was maintained at 10�15 mmHg. Conclusion We conclude that the presence of normal CSF may contribute to the vulnerability of the spinal cord to ischemic injury. Depletion of the CSF or replacement of the CSF with an albumin- or gelatin-modified artificial CSF can be neuroprotective. PMID:16174300
Wang, Yanming F; Gwathmey, Judith K; Zhang, Guorong; Soriano, Sulpicio G; He, Shunli; Wang, Yanguang
Application of transport phenomena analysis technique to cerebrospinal fluid.
The study of hydrocephalus and the modeling of cerebrospinal fluid flow have proceeded in the past using mathematical analysis that was very capable of prediction phenomenonologically but not well in physiologic parameters. In this paper, the basis of fluid dynamics at the physiologic state is explained using first established equations of transport phenomenon. Then, microscopic and molecular level techniques of modeling are described using porous media theory and chemical kinetic theory and then applied to cerebrospinal fluid (CSF) dynamics. Using techniques of transport analysis allows the field of cerebrospinal fluid dynamics to approach the level of sophistication of urine and blood transport. Concepts such as intracellular and intercellular pathways, compartmentalization, and tortuosity are associated with quantifiable parameters that are relevant to the anatomy and physiology of cerebrospinal fluid transport. The engineering field of transport phenomenon is rich and steeped in architectural, aeronautical, nautical, and more recently biological history. This paper summarizes and reviews the approaches that have been taken in the field of engineering and applies it to CSF flow. PMID:24091435
Lam, C H; Hansen, E A; Hall, W A; Hubel, A
More Than the Brain's Drain: Does Cerebrospinal Fluid Help the Brain Convey Messages?
ERIC Educational Resources Information Center
Examines the role of cerebrospinal fluid (CSF), a clear, colorless liquid that constantly bathes the brain and spinal cord. Scientists argue that cerebrospinal fluid carries important signals for sleep, appetite, and sex. Evaluates past and current research documenting the purpose of cerebrospinal fluid in the brain. (CCM)
Travis, John
Aging and superoxide dismutase activity in cerebrospinal fluid
We investigated superoxide dismutase (SOD) activity in human cerebrospinal fluid (CSF) as an index of the aging process in the central nervous system (CNS). The subjects were 61 individuals aged 21�77 years, comprising 24 men and 37 women without organic disorders of the nervous system. SOD activity in CSF was measured by the nitrite method modified by Oyanagui. The results
Takashi Okabe; Katsuhiko Hamaguchi; Tetsuya Inafuku; Motohiko Hara
Effects of alcohol on cerebrospinal fluid norepinephrine in rhesus monkeys
Alcohol (1�3 g\\/kg) significantly increased the concentration of cerebrospinal fluid (CSF) norepinephrine (NE) in rhesus monkeys. This effect is consistent with the previously demonstrated activational and possible antidepressant effect of low doses of alcohol. The greatest increase was observed in subjects with low baseline levels of CSF NE. Individual differences in activation or euphoria could be related to differential increases
Gary W. Kraemer; C. Raymond Lake; Michael H. Ebert; William T. McKinney
Entamoeba histolytica meningoencephalitis diagnosed by trophozoites in cerebrospinal fluid
Entamoeba histolytica meningoencephalitis has not been described in the modern literature, which is distinct from that caused by free-living amoebae. We report the first case of E.�histolytica meningoencephalitis without liver or brain abscesses. Cerebrospinal fluid revealed 2�+ very motile trophozoites. Our patient was successfully treated with intravenous metronidazole.
Goh, L M L; Marrone, J R
Management of Pregnant Women with Cerebrospinal Fluid Shunts
As more women with cerebrospinal fluid shunts reach child-bearing age, neurosurgeons, obstetricians and other health care providers will increasingly be called upon to care for them once they become pregnant. A review of the literature reveals that these patients may develop symptoms of shunt malfunction as uterine size increases. In most cases, symptoms can be managed conservatively during pregnancy and
Michael D. Cusimano; Filomena M. Meffe; Fred Gentili; Mathew Sermer
A mathematical model of blood, cerebrospinal fluid and brain dynamics
Using first principles of fluid and solid mechanics a comprehensive model of human intracranial dynamics is proposed. Blood,\\u000a cerebrospinal fluid (CSF) and brain parenchyma as well as the spinal canal are included. The compartmental model predicts\\u000a intracranial pressure gradients, blood and CSF flows and displacements in normal and pathological conditions like communicating\\u000a hydrocephalus. The system of differential equations of first
Andreas A. Linninger; Michalis Xenos; Brian Sweetman; Sukruti Ponkshe; Xiaodong Guo; Richard Penn
A new look at cerebrospinal fluid movement.
Brinker et al. extensively reviewed recent findings about CSF circulation in a recent article: "A new look at cerebrospinal circulation", but did not analyze some important available data in sufficient detail. For example, our findings as well as some clinical data and experimental results obtained from different animal species, do not support unidirectional CSF circulation but strongly suggest that there are cardiac cycle-dependent systolic-diastolic to-and-fro cranio-spinal CSF movements. These are based on: a) physiological oscillations of arterial and venous blood during cranio-spinal blood circulation; b) respiratory activity, and c) body activity and posture. That kind of complex CSF movement could explain the observed distribution of many different substances in all directions along the CSF system and within central nervous system tissue. It seems that efflux transport systems at capillary endothelium may be more important for brain homeostasis than the removal of metabolites by CSF flow. Thus, when discussing the CSF dynamics we suggest that a more appropriate term would be CSF movement rather than CSF circulation. PMID:25089184
Ore�kovi?, Darko; Klarica, Marijan
cerebrospinal fluid of patients with HIV-associated neurological diseases
Matrix metalloproteinases (MMPs) have been identified as mediators of brain injury in HIV-associated neurological diseases. The activity of the 72 kDa gelatinase A (MMP-2) and 92 kDa gelatinase B (MMP-9) was detected by zymography in the cerebrospinal fluid (CSF) of 138 HIV-infected patients (40 with AIDS dementia, 83 with brain opportunistic infections and 15 neurologically asymptomatic), 26 HIV-seronegative individuals with
Grazia M Liuzzi; Claudio M Mastroianni; Maria P Santacroce; Margherita Fanelli; Claudia D'Agostino; Vincenzo Vullo; Paolo Riccio
Endoscopic Repair of Lateral Sphenoid Recess Cerebrospinal Fluid Leaks
Endoscopic repair of anterior cranial base has been widely reported. However there is still no uniformity in the technique\\u000a of endoscopic repair of lateral sphenoid cerebrospinal fluid (CSF) leaks. To highlight the management of CSF leak or encephalocele\\u000a in the lateral sphenoid recess and relate our experiences. We retrospectively reviewed the medical records of all our patients\\u000a who underwent an
Milind V. Kirtane; Abhineet Lall; Kashmira Chavan; Dhruv Satwalekar
Sleep deprivation increases oleoylethanolamide in human cerebrospinal fluid
This study investigated the role of two fatty acid ethanolamides, the endogenous cannabinoid anandamide and its structural\\u000a analog oleoylethanolamide in sleep deprivation of human volunteers. Serum and cerebrospinal fluid (CSF) samples were obtained\\u000a from 20 healthy volunteers before and after a night of sleep deprivation with an interval of about 12�months. We found increased\\u000a levels of oleoylethanolamide in CSF (P�=�0.011)
Dagmar Koethe; Daniela Schreiber; Andrea Giuffrida; Christian Mauss; Johannes Faulhaber; Bernd Heydenreich; Martin Hellmich; Rudolf Graf; Joachim Klosterk�tter; Daniele Piomelli; F. Markus Leweke
Aging effects on cerebral blood and cerebrospinal fluid flows
Phase-contrast magnetic resonance imaging (PC-MRI) is a noninvasive reliable technique, which enables quantification of cerebrospinal fluid (CSF) and total cerebral blood flows (tCBF). Although it is used to study hydrodynamic cerebral disorders in the elderly group (hydrocephalus), there is no published evaluation of aging effects on both tCBF and CSF flows, and on their mechanical coupling. Nineteen young (mean age
Souraya Stoquart-ElSankari; Olivier Bal�dent; Catherine Gondry-Jouet; Malek Makki; Olivier Godefroy; Marc-Etienne Meyer
Metabolomics of Human Cerebrospinal Fluid Identifies Signatures of Malignant Glioma*
Cerebrospinal fluid is routinely collected for the diagnosis and monitoring of patients with neurological malignancies. However, little is known as to how its constituents may change in a patient when presented with a malignant glioma. Here, we used a targeted mass-spectrometry based metabolomics platform using selected reaction monitoring with positive/negative switching and profiled the relative levels of over 124 polar metabolites present in patient cerebrospinal fluid. We analyzed the metabolic profiles from 10 patients presenting malignant gliomas and seven control patients that did not present malignancy to test whether a small sample size could provide statistically significant signatures. We carried out multiple unbiased forms of classification using a series of unsupervised techniques and identified metabolic signatures that distinguish malignant glioma patients from the control patients. One subtype identified contained metabolites enriched in citric acid cycle components. Newly diagnosed patients segregated into a different subtype and exhibited low levels of metabolites involved in tryptophan metabolism, which may indicate the absence of an inflammatory signature. Together our results provide the first global assessment of the polar metabolic composition in cerebrospinal fluid that accompanies malignancy, and demonstrate that data obtained from high throughput mass spectrometry technology may have suitable predictive capabilities for the identification of biomarkers and classification of neurological diseases. PMID:22240505
Locasale, Jason W.; Melman, Tamar; Song, Susan; Yang, Xuemei; Swanson, Kenneth D.; Cantley, Lewis C.; Wong, Eric T.; Asara, John M.
A mathematical model of blood, cerebrospinal fluid and brain dynamics.
Using first principles of fluid and solid mechanics a comprehensive model of human intracranial dynamics is proposed. Blood, cerebrospinal fluid (CSF) and brain parenchyma as well as the spinal canal are included. The compartmental model predicts intracranial pressure gradients, blood and CSF flows and displacements in normal and pathological conditions like communicating hydrocephalus. The system of differential equations of first principles conservation balances is discretized and solved numerically. Fluid-solid interactions of the brain parenchyma with cerebral blood and CSF are calculated. The model provides the transitions from normal dynamics to the diseased state during the onset of communicating hydrocephalus. Predicted results were compared with physiological data from Cine phase-contrast magnetic resonance imaging to verify the dynamic model. Bolus injections into the CSF are simulated in the model and found to agree with clinical measurements. PMID:19219605
Linninger, Andreas A; Xenos, Michalis; Sweetman, Brian; Ponkshe, Sukruti; Guo, Xiaodong; Penn, Richard
Immunoglobulins in the cerebrospinal fluid of patients with late syphilis.
The concentrations of immunoglobulins G, A, and M were measured in 62 samples of cerebrospinal fluid from 35 patients with asymptomatic neurosyphilis, 18 with symptomatic neurosyphilis, and nine with late syphilis of other organs. The most frequent and highest increase in IgG and IgA occurred in patients with symptomatic neurosyphilis. IgM was found in only five patients, but its presence, together with an increase in IgG and IgA concentrations, appears to indicate activity of the pathological process and a poor prognosis for the course of the disease. PMID:7470831
Gibowski, M; Macho?ko, T
Spontaneous cerebrospinal fluid rhinorrhea secondary to anterior fossa osteoradionecrosis.
Osteoradionecrosis (ORN) after radiation therapy of head and neck or brain tumor most often presents in the mandible, followed by the maxillary bone. This case report describes a patient who presented with spontaneous cerebrospinal fluid (CSF) rhinorrhea 12 months after conventional external beam radiotherapy for frontotemporal anaplastic astrocytoma, and was diagnosed with anterior fossa ORN. Osteolysis in the anterior fossa on CT scan confirmed the diagnosis. A prompt temporal muscle graft with pericranial flap seal treated both the ORN and the CSF rhinorrhea, but observation would have been a suitable conservative option if ORN presented without CSF rhinorrhea. PMID:23517671
Hu, Zhebin; Godoy, Bruno L; Zadeh, Gelareh
Cerebrospinal fluid immunoglobulins and complement in meningococcal meningitis.
Cerebrospinal fluid (CSF) immunoglobulins (IgA, IgG, IgM) were measured in 107 patients with meningococcal meningitis. Levels were correlated significantly with CSF total protein, and both CSF immunoglobulin and protein increased with age. C3 was measured in the CSF of 38 patients and was also closely correlated with the CSF protein level. C3 breakdown products were found in all six CSFs tested. The CSF immunoglobulin and complement were thought to have leaked from the plasma due to inflammation of the meninges and had little value in diagnosis or prognosis. PMID:599185
Whittle, H C; Greenwood, B M
Cerebrospinal Fluid Otorrhea Treated by Extended Subtotal Petrosectomy with Obliteration
Extended subtotal petrosectomy as a treatment for stubborn cerebrospinal fluid (CSF) otorrhea is presented. Nine patients were successfully operated on by this technique, all previously having undergone surgery for brain or base of skull lesions, other interventions used had failed to seal the fistula. The retrosigmoid cells, facial cells, and internal auditory canal were found in our study to be the most commonly involved during pervious neurosurgery and so constituted the usual path for CSF leakage. Total exenteration of middle ear and mastoid cell tracts, skeletization of sigmoid sinus, jugular bulb and facial nerve, drilling out of the semicircular canals, vestibulum, and cochlea, and skeletization of the internal auditory canal are the main steps of this approach. PMID:17170807
Kronenberg, J.; Findler, G.; Braham, J.
Acetylcholinesterase activity in the cerebrospinal fluid of dogs with seizures.
Recent studies in animal models have focused on the role of cholinergic elements, mainly acetylcholinesterase (AChE) and the 'readthrough' acetylcholinesterase isoform (AChE-R), in seizures. A prospective double-masked study was conducted to assess the activity of AChE and AChE-R in cerebrospinal fluid (CSF) of 26 dogs post-seizure, 28 dogs with intervertebral disc disease (IVDD) and 16 healthy dogs. AChE was also measured in the serum in the post-seizure and IVDD groups. The results showed no significant differences in CSF AChE among the three groups. AChE-R was not detected in any dog and AChE in the serum was similar between groups. This preliminary study provides new information on AChE and AChE-R in the CSF and sera of dogs following naturally-occurring seizures. PMID:23988333
Chai, Orit; Sommer, Adi; Zimmerman, Gabriel; Soreq, Hermona; Friedman, Alon; Bdolah-Abram, Tali; Aroch, Itamar; Shamir, Merav H
Orbital cerebrospinal fluid accumulation after complicated pterional-orbitozygomatic craniotomy.
: We describe 2 patients who developed postoperative orbital cerebrospinal fluid (CSF) collection after orbitozygomatic pterional craniotomy. An 18-year-old woman underwent exploratory pterional-orbitozygomatic craniotomy. Five days postoperatively, after removal of a lumbar drain, proptosis and a compressive optic neuropathy developed. Computed tomography demonstrated a CSF collection contiguous with the craniotomy site. Resolution followed percutaneous aspiration and replacement of the lumbar drain. A 57-year-old woman underwent a pterional-orbitozygomatic craniotomy for removal of a left anterior clinoid meningioma, complicated by a large left hemorrhagic stroke requiring decompressive hemicraniectomy. Extracranial CSF collections accumulated in both the orbit and subgaleal spaces. Resolution followed placement of an external ventricular drain. Based on these cases, the mechanism seems to be the combination of iatrogenic formation of a communication with the subarachnoid space and elevated intracranial pressure. Resolution was achieved by normalizing intracranial pressure. PMID:24699141
Yoon, Michael K; Piluek, Wachirapon Jordan; Ruggiero, Jason P; McDermott, Michael W; McCulley, Timothy J
Cerebrospinal fluid biomarkers of Alzheimer's disease in cognitively healthy elderly
Numerous studies have shown that Alzheimer�s Disease (AD) pathology begins before the onset of clinical symptoms. Because therapies are likely to be more effective if they are implemented early in the disease progression, it is necessary to identify reliable biomarkers to detect AD pathology in the early stages of the disease, ideally in presymptomatic individuals. Recent research has identified three candidate cerebrospinal fluid (CSF) biomarkers that reflect AD pathology: amyloid beta (A�42), total tau protein (t-tau), and tau protein phosphorylated at AD-specific epitopes (p-tau). They are useful in supporting the AD diagnosis and have predictive value for AD when patients are in the stage of mild cognitive impairment (MCI). However, their predictive utility in cognitively healthy subjects is still being evaluated. We conducted a review of studies published between 1993 and 2011 and summarized their findings on the role of CSF biomarkers for AD in healthy elderly. PMID:23747874
Randall, Catherine; Mosconi, Lisa; de Leon, Mony; Glodzik, Lidia
Cerebrospinal Fluid Aquaporin-4 Antibody Levels in Neuromyelitis Optica Attacks
To elucidate immunopathogenetic roles of aquaporin-4 antibodies in the cerebrospinal fluid (CSF) of neuromyelitis optica spectrum disorders (NMOSD), we analyzed aquaporin-4 antibody titers, cellular and inflammatory markers in the CSF collected from 11 aquaporin-4 antibody seropositive patients. The CSF aquaporin-4 antibody levels during attacks (but not in sera) closely correlated with pleocytosis, inflammatory cytokines including interleukin-6 that can regulate antibody-producing plasmablasts, and glial fibrillary acidic protein levels in the CSF. The amount of aquaporin-4 antibodies present in the central nervous system may have therapeutic implications, as it is associated with astrocyte injury and inflammatory responses during NMOSD attacks. Ann Neurol 2014;76:305�309 PMID:24977390
Sato, Douglas Kazutoshi; Callegaro, Dagoberto; de Haidar Jorge, Frederico M; Nakashima, Ichiro; Nishiyama, Shuhei; Takahashi, Toshiyuki; Simm, Renata Faria; Apostolos-Pereira, Samira Luisa; Misu, Tatsuro; Steinman, Lawrence; Aoki, Masashi; Fujihara, Kazuo
A dissociation between fever and prostaglandin concentration in cerebrospinal fluid.
1. Sustained fever has been induced in conscious rabbits by I.V. injection and infusion of endogenous pyrogen. 2. Cerebrospinal fluid (e.s.f.) was sampled from the cisterna magna at hourly intervals. The concentration of prostaglandin increased in parallel with rectal temperature. The prostaglandin was identified as one of the E series. 3. When sodium salicylate (1-5 m-mole followed by a continuous infusion of 9 mumole/min) was started 1 hr before endogenous pyrogen, the febrile response to the pyrogen was not significantly diminished but no rise of prostaglandin concentration was detected in c.s.f. 4. This dissociation between fever and prostaglandin concentration means that changes in cisternal prostaglandin concentration cannot be accepted as evidence that prostaglandin mediates the febrile response. PMID:1214227
Cranston, W I; Hellon, R F; Mitchell, D
Treponemicidal levels of amoxicillin in cerebrospinal fluid after oral administration.
Seven patients in various stages of syphilis were treated by oral administration of amoxicillin (6 g daily) and probenecid (2 g daily) for 15 days. The treponemicidal level of amoxicillin was studied by a Treponema pallidum immobilization assay and found to be 0.070 micrograms/ml, as compared with 0.003 micrograms of penicillin/ml. Taking into account the WHO-recommended level of 0.018 micrograms/ml of penicillin, the minimal level of amoxicillin was estimated as 0.42 micrograms/ml. This level was obtained in serum and cerebrospinal fluid (CSF) of all patients treated with the above mentioned oral combination. It is concluded that treponemicidal levels of amoxicillin can be obtained in CSF after oral administration. The amoxicillin regimen described may be a valuable alternative to single-dose parenteral penicillin in the treatment of syphilitic patients with suspected CNS involvement, provided that reasonable compliance can be obtained. PMID:6359492
Faber, W R; Bos, J D; Rietra, P J; Fass, H; Van Eijk, R V
Agitation in Dementia: Relation to Core Cerebrospinal Fluid Biomarker Levels
Background The objective of this study was to examine the associations of agitation with the cerebrospinal fluid dementia biomarkers total-tau (T-tau), phosphorylated-tau (P-tau) and A?1-42. Methods One hundred patients (mean age � SD, 78.6 � 7.5 years) with dementia and neuropsychiatric symptoms, of whom 67% were female, were included. Agitation was measured using the Cohen-Mansfield Agitation Inventory (CMAI; 46.5 � 11.8 points). Results Total CMAI correlated with T-tau [rs (31) = 0.36, p = 0.04] and P-tau [rs (31) = 0.35, p = 0.05] in patients with Alzheimer's disease (AD; n = 33) but not in the total dementia population (n = 95). Conclusions Our results suggest that tau-mediated pathology including neurofibrillary tangles and the intensity of the disease process might be associated with agitation in AD.
Bloniecki, Victor; Aarsland, Dag; Cummings, Jeffrey; Blennow, Kaj; Freund-Levi, Yvonne
Embryonic blood-cerebrospinal fluid barrier formation and function
During embryonic development and adult life, brain cavities and ventricles are filled with cerebrospinal fluid (CSF). CSF has attracted interest as an active signaling medium that regulates brain development, homeostasis and disease. CSF is a complex protein-rich fluid containing growth factors and signaling molecules that regulate multiple cell functions in the central nervous system (CNS). The composition and substance concentrations of CSF are tightly controlled. In recent years, it has been demonstrated that embryonic CSF (eCSF) has a key function as a fluid pathway for delivering diffusible signals to the developing brain, thus contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the expansion and patterning of the brain. From fetal stages through to adult life, CSF is primarily produced by the choroid plexus. The development and functional activities of the choroid plexus and other blood�brain barrier (BBB) systems in adults and fetuses have been extensively analyzed. However, eCSF production and control of its homeostasis in embryos, from the closure of the anterior neuropore when the brain cavities become physiologically sealed, to the formation of the functional fetal choroid plexus, has not been studied in as much depth and remains open to debate. This review brings together the existing literature, some of which is based on experiments conducted by our research group, concerning the formation and function of a temporary embryonic blood�CSF barrier in the context of the crucial roles played by the molecules in eCSF. PMID:25389383
Bueno, David; Parvas, Maryam; Hermelo, Ismail; Garcia-Fernandez, Jordi
Cerebrospinal fluid flow dynamics in the central nervous system.
Cine-phase-contrast-MRI was used to measure the three-dimensional cerebrospinal fluid (CSF) flow field inside the central nervous system (CNS) of a healthy subject. Image reconstruction and grid generation tools were then used to develop a three-dimensional fluid-structure interaction model of the CSF flow inside the CNS. The CSF spaces were discretized using the finite-element method and the constitutive equations for fluid and solid motion solved in ADINA-FSI 8.6. Model predictions of CSF velocity magnitude and stroke volume were found to be in excellent agreement with the experimental data. CSF pressure gradients and amplitudes were computed in all regions of the CNS. The computed pressure gradients and amplitudes closely match values obtained clinically. The highest pressure amplitude of 77�Pa was predicted to occur in the lateral ventricles. The pressure gradient between the lateral ventricles and the lumbar region of the spinal canal did not exceed 132�Pa (~1�mmHg) at any time during the cardiac cycle. The pressure wave speed in the spinal canal was predicted and found to agree closely with values previously reported in the literature. Finally, the forward and backward motion of the CSF in the ventricles was visualized, revealing the complex mixing patterns in the CSF spaces. The mathematical model presented in this article is a prerequisite for developing a mechanistic understanding of the relationships among vasculature pulsations, CSF flow, and CSF pressure waves in the CNS. PMID:20737291
Sweetman, Brian; Linninger, Andreas A
Highly potent soluble amyloid-? seeds in human Alzheimer brain but not cerebrospinal fluid.
The soluble fraction of brain samples from patients with Alzheimer's disease contains highly biologically active amyloid-? seeds. In this study, we sought to assess the potency of soluble amyloid-? seeds derived from the brain and cerebrospinal fluid. Soluble Alzheimer's disease brain extracts were serially diluted and then injected into the hippocampus of young, APP transgenic mice. Eight months later, seeded amyloid-? deposition was evident even when the hippocampus received subattomole amounts of brain-derived amyloid-?. In contrast, cerebrospinal fluid from patients with Alzheimer's disease, which contained more than 10-fold higher levels of amyloid-? peptide than the most concentrated soluble brain extracts, did not induce detectable seeding activity in vivo. Similarly, cerebrospinal fluid from aged APP-transgenic donor mice failed to induce cerebral amyloid-? deposition. In comparison to the soluble brain fraction, cerebrospinal fluid largely lacked N-terminally truncated amyloid-? species and exhibited smaller amyloid-?-positive particles, features that may contribute to the lack of in vivo seeding by cerebrospinal fluid. Interestingly, the same cerebrospinal fluid showed at least some seeding activity in an in vitro assay. The present results indicate that the biological seeding activity of soluble amyloid-? species is orders of magnitude greater in brain extracts than in the cerebrospinal fluid. PMID:25212850
Fritschi, Sarah K; Langer, Franziska; Kaeser, Stephan A; Maia, Luis F; Portelius, Erik; Pinotsi, Dorothea; Kaminski, Clemens F; Winkler, David T; Maetzler, Walter; Keyvani, Kathy; Spitzer, Philipp; Wiltfang, Jens; Kaminski Schierle, Gabriele S; Zetterberg, Henrik; Staufenbiel, Matthias; Jucker, Mathias
Cerebrospinal fluid (CSF) overproduction results from either CSF infection or choroid plexus hypertrophy or tumor, with only a single idiopathic case described so far. We report a unique case of a male infant with Crouzon syndrome who presented with intracranial hypertension, caused by up to 4-fold increase in CSF daily production. Conditions related to CSF overproduction, namely central nervous system infections and choroid plexus hypertrophy or tumor, were ruled out by repeated magnetic resonance imaging and CSF samples. Medical therapy failed to reduce CSF production and the patient underwent several shunting procedures, cranial expansion, and endoscopic coagulation of the choroid plexus. This article thoroughly reviews pertinent literature on CSF production mechanisms and possible therapeutic implications. PMID:25165051
Trevisi, Gianluca; Frassanito, Paolo; Di Rocco, Concezio
Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics.
Axonal damage is a prominent cause of disability and yet its pathogenesis is incompletely understood. Using a xenogeneic system, here we define the bioenergetic changes induced in rat neurons by exposure to cerebrospinal fluid samples from patients with multiple sclerosis compared to control subjects. A first discovery cohort of cerebrospinal fluid from 13 patients with multiple sclerosis and 10 control subjects showed that acute exposure to cerebrospinal fluid from patients with multiple sclerosis induced oxidative stress and decreased expression of neuroprotective genes, while increasing expression of genes involved in lipid signalling and in the response to oxidative stress. Protracted exposure of neurons to stress led to neurotoxicity and bioenergetics failure after cerebrospinal fluid exposure and positively correlated with the levels of neurofilament light chain. These findings were validated using a second independent cohort of cerebrospinal fluid samples (eight patients with multiple sclerosis and eight control subjects), collected at a different centre. The toxic effect of cerebrospinal fluid on neurons was not attributable to differences in IgG content, glucose, lactate or glutamate levels or differences in cytokine levels. A lipidomic profiling approach led to the identification of increased levels of ceramide C16:0 and C24:0 in the cerebrospinal fluid from patients with multiple sclerosis. Exposure of cultured neurons to micelles composed of these ceramide species was sufficient to recapitulate the bioenergetic dysfunction and oxidative damage induced by exposure to cerebrospinal fluid from patients with multiple sclerosis. Therefore, our data suggest that C16:0 and C24:0 ceramides are enriched in the cerebrospinal fluid of patients with multiple sclerosis and are sufficient to induce neuronal mitochondrial dysfunction and axonal damage. PMID:24893707
Vidaurre, Oscar G; Haines, Jeffery D; Katz Sand, Ilana; Adula, Kadidia P; Huynh, Jimmy L; McGraw, Corey A; Zhang, Fan; Varghese, Merina; Sotirchos, Elias; Bhargava, Pavan; Bandaru, Veera Venkata Ratnam; Pasinetti, Giulio; Zhang, Weijia; Inglese, Matilde; Calabresi, Peter A; Wu, Gang; Miller, Aaron E; Haughey, Norman J; Lublin, Fred D; Casaccia, Patrizia
BACKGROUND: The central nervous system develops around a fluid filled compartment. Recently, attention has turned to the potential role of the fluid (cerebrospinal fluid, CSF) in the developmental process. In particular, the cerebral cortex develops from the germinal epithelium adjacent to the CSF with regulation of cell proliferation and differentiation provided by cells adjacent to the fluid-filled subarachnoid space. METHODS:
Jaleel A Miyan; Mahjiub Zendah; Farhad Mashayekhi; P Jane Owen-Lynch
We report the annotated genome sequence of a Mycobacterium tuberculosis clinical isolate from the cerebrospinal fluid of a tuberculous meningitis patient admitted to the Central India Institute of Medical Sciences, Nagpur, India. PMID:25146143
Bhullar, Shradha S.; More, Ravi P.; Puranik, Sampada; Taori, Girdhar M.; Daginawala, Hatim F.
Levodopa and 3-O-methyldopa in cerebrospinal fluid after levodopa-carbidopa association.
Since motor fluctuations in Parkinsonian patients might be, at least in part, explained by an antagonism between levodopa (LD) and its metabolite 3-O-methyldopa (3-OMD) at blood-brain-barrier (BBB), we decided to study LD and 3-OMD plasma and cerebrospinal fluid (CSF) levels in subjects undergoing lumbar puncture for diagnostic purposes. After informed consent, 70 subjects took a tablet of carbidopa-levodopa association (Sinemet or Sinemet-CR) 0.5, 1, 2, 4, 8, 12 h before blood and lumbar cerebrospinal fluid collection. LD and 3-OMD were determined by an HPLC-electrochemical method. The subjects treated with Sinemet-CR had lower LD cerebrospinal fluid concentrations along with lower LD and higher 3-OMD plasma concentrations. This pattern of LD cerebrospinal fluid concentrations may be explained by means of a transport competition between LD and 3-OMD at blood brain barrier level. PMID:9264047
Benetello, P; Furlanut, M; Fortunato, M; Pea, F; Baraldo, M
Serum procalcitonin and cerebrospinal fluid cytokines level in children with meningitis.
AIMS: To determine the level of serum procalcitonin and cerebrospinal fluid cytokines in children with bacterial or viral meningitis and to document the use of these parameters in differential diagnosis. RESULTS: Before the start of antibiotic treatment, serum procalcitonin and tumor necrosis factor alpha levels were found to be higher in acute bacterial meningitis compared with viral meningitis and with the control group. Similarly, cerebrospinal fluid interleukin-6 levels were found to be significantly higher in children with acute bacterial meningitis compared with viral meningitis. However, no significant difference was determined between groups in respect to the cerebrospinal fluid interleukin-8 level. CONCLUSION: Serum procalcitonin and cerebrospinal fluid tumor necrosis factor alpha levels can be used in the early diagnosis of bacterial meningitis. Similarly, they may be useful adjuncts in differential diagnosis of bacterial and viral meningitis. PMID:15545058
Taskin, Erdal; Turgut, Mehmet; Kilic, Mehmet; Akbulut, Handan; Aygun, A Denizmen
Invasive Candida infections associated with medical devices are very difficult to cure without device removal. We present a case of neonatal cerebrospinal fluid shunt-associated Candida meningitis, in which removal of the device was precluded, that was successfully treated with caspofungin. Pharmacokinetic assessment of caspofungin concentrations in cerebrospinal fluid showed that exposure was adequate in the presence of a high systemic exposure. In complex cases of neonatal Candida infections involving medical devices, the addition of caspofungin might be beneficial. PMID:23439643
Jans, Jop; Br�ggemann, Roger J M; Christmann, V; Verweij, Paul E; Warris, Adilia
Detection of free endotoxin in cerebrospinal fluid by the Limulus lysate test.
We used a rabbit model of Escherichia coli meningitis to study the basis for positive Limulus lysate tests in infected cerebrospinal fluid. The results indicated that positive Limulus tests are due to endotoxins in cerebrospinal fluid and not to leukocyte proteases or other possible activators of the Limulus clotting system. The results also suggest that bacteria-free endotoxin may be present in localized gram-negative bacterial infections. PMID:6378802
Munford, R S; Hall, C L; Grimm, L
Human Neurocysticercosis: Comparison of Different Diagnostic Tests Using Cerebrospinal Fluid ?
Neurocysticercosis (NC), caused by the larval stage of Taenia solium, is one of the most common parasitic diseases of the central nervous system. The diagnosis of NC is mostly based on costly brain neuroimaging (computed tomography and/or nuclear magnetic resonance), which is rarely accessible in most affected areas. The most sensitive and specific tools for NC diagnosis are imagery techniques. The identification of specific antibodies and antigens is currently used only to support NC diagnosis due to their limited specificity and sensitivity. This study was performed to compare immunodiagnostic assays (antibody detection by enzyme-linked immunosorbent assay [ELISA] and enzyme-linked immunoelectrotransfer blotting [EITB] and HP10 antigen detection by ELISA) with the detection of parasite DNA by PCR amplification of a repetitive element of the parasite genome in the cerebrospinal fluid (CSF) of 121 radiologically and clinically characterized NC patients. Patients were divided into six groups according to the stage of the parasites and their localization. The CSF cellularity of each patient was also recorded. When all patients were considered, PCR exhibited the highest sensitivity (95.9%) and variable specificity (80% or 100%) depending on the controls used. The sensitivities of antibody detection by ELISA and EITB were not significantly different, and ELISA identified HP10 antigen mostly when vesicular cysticerci were located in the subarachnoideal basal cisterns. These results can help in the selection of different individual assays or combinations of assays to be used in NC diagnosis according to different requirements. PMID:21068283
Michelet, Lorraine; Fleury, Agnes; Sciutto, Edda; Kendjo, Eric; Fragoso, Gladis; Paris, Luc; Bouteille, Bernard
CNS tumours: oligoclonal immunoglobulin D in cerebrospinal fluid and serum.
Oligoclonal immunoglobulin D bands were detected by isoelectric focusing in 7 out of 25 unconcentrated cerebrospinal fluid (CSF) samples obtained from patients with tumours of the central nervous system (CNS). The tumours were confirmed by clinical and histological findings. Two patients with CNS malignancy had intrathecal synthesis of oligoclonal bands both IgD and IgG. Four patients with a variety of CNS tumours had a systemic IgD immune response but no oligoclonal IgG bands. One patient with the most malignant tumour histology had a systemic IgD response as well as local synthesis of IgG. The study reveals several new aspects regarding CNS tumours: they are immunologically active and are capable of invoking oligoclonal immunoglobulin production both within the CNS and systemically. Multiple immunoglobulin activation can be found in malignant CNS tumours, and systemic IgD production may occur independently from IgG synthesis and may represent an immune response to a neoantigen produced in the CNS compartment. PMID:10442454
Mavra, M; Drulovic, J; Levic, Z; Stojsavljevic, N; Grujicic, D; Janicijevic, M; Thompson, E J
99mTc-sodium pertechnetate permeation into cerebrospinal fluid.
The integrity of the blood-brain barrier may be reflected by the blood and cerebrospinal fluid (CSF) if these two compartments are sampled at an appropriate interval after the administration of certain substances. After reading through the controversial literature, this study was undertaken to determine the frequency with which 99mTc-sodium pertechnetate entered the CSF to an abnormal extent, and to see whether this was related to any particular pathology. The plasma-to-CSF ratios were determined in 51 patients 4 hours following the intravenous administration of 0.5-10 mCi 99mTc-sodium pertechnetate. In 23 patients with active CNS tuberculosis, the mean value of the pertechnetate plasma-to-CSF ration was 32.12. In contradistinction, the plasma-to-CSF pertechnetate in 28 nontuberculous subjects was considerably higher (144.63). For the purpose of correlation, a 82Br partition test was also done on each subject 48 hours following the oral administration of NH82Br. The 48-hour study in each of these cases was generally in agreement with the pertechnetate studies: the plasma-to-CSF ratio mean value was 1.25 in patients with active CNS tuberculosis, while for the nontuberculous patients it was 3.32. PMID:466905
Borkar, A; DaCosta, H
Cerebrospinal Fluid Proteome of Patients with Acute Lyme Disease
Acute Lyme disease results from transmission of and infection by the bacterium Borrelia burgdorferi following a tick bite. During acute infection, bacteria can disseminate to the central nervous system (CNS) leading to the development of Lyme meningitis. Here we have analyzed pooled cerebrospinal fluid (CSF) allowing for a deep view into the proteome for a cohort of patients with early-disseminated Lyme disease and CSF inflammation leading to the identification of proteins that reflect host responses, which are distinct for subjects with acute Lyme disease. Additionally, we analyzed individual patient samples and quantified changes in protein abundance employing label-free quantitative mass spectrometry based methods. The measured changes in protein abundances reflect the impact of acute Lyme disease on the CNS as presented in CSF. We have identified 89 proteins that differ significantly in abundance in patients with acute Lyme disease. A number of the differentially abundant proteins have been found to be localized to brain synapse and thus constitute important leads for better understanding of the neurological consequence of disseminated Lyme disease.
Angel, Thomas E.; Jacobs, Jon M.; Smith, Robert P.; Pasternack, Mark S.; Elias, Susan; Gritsenko, Marina A.; Shukla, Anil K.; Gilmore, Edward C.; McCarthy, Carol; Camp, David G.; Smith, Richard D.
Embryonic cerebrospinal fluid in brain development: neural progenitor control.
Due to the effort of several research teams across the world, today we have a solid base of knowledge on the liquid contained in the brain cavities, its composition, and biological roles. Although the cerebrospinal fluid (CSF) is among the most relevant parts of the central nervous system from the physiological point of view, it seems that it is not a permanent and stable entity because its composition and biological properties evolve across life. So, we can talk about different CSFs during the vertebrate life span. In this review, we focus on the CSF in an interesting period, early in vertebrate development before the formation of the choroid plexus. This specific entity is called "embryonic CSF." Based on the structure of the compartment, CSF composition, origin and circulation, and its interaction with neuroepithelial precursor cells (the target cells) we can conclude that embryonic CSF is different from the CSF in later developmental stages and from the adult CSF. This article presents arguments that support the singularity of the embryonic CSF, mainly focusing on its influence on neural precursor behavior during development and in adult life. PMID:25165044
Gato, Angel; Alonso, M Isabel; Mart�n, Cristina; Carnicero, Estela; Moro, Jos� Antonio; De la Mano, An�bal; Fern�ndez, Jos� M F; Lamus, Francisco; Desmond, Mary E
Intravenous physostigmine increases cerebrospinal fluid neuropeptide-Y.
The ability to measure directly central nervous system (CNS) neurotransmitter changes after an acute pharmacological challenge would be a useful clinical tool in psychiatric research. As one approach to this possibility, we attempted to measure cerebrospinal fluid (CSF) neuropeptide changes produced by an intravenous infusion of the indirect cholinergic agonist physostigmine. Six rhesus monkeys, with indwelling CSF catheters, had serial CSF samples removed before and after a 15 micrograms/kg physostigmine infusion. Five of six monkeys studied showed at least a 50% increase in CSF neuropeptide-Y (NPY) levels. Normal human subjects (n = 27) had CSF sampled before and 15, 30, and 45 min after an acute intravenous infusion of physostigmine (either 0, 5, or 15 micrograms/kg). An Analysis of Variance revealed a significant (p = 0.04) dose-time interaction, suggesting that physostigmine increased CSF NPY at the 15 micrograms/kg dose. CSF levels of seven other neuropeptides remained unchanged. These results suggest that the pharmacological challenge paradigm can be adapted to CSF neuropeptides, providing new measures of CNS stimulus-induced response beyond the peripheral plasma determinations usually employed. PMID:2790099
Berrettini, W H; Garrick, N A; Nurnberger, J I; Simmons-Alling, S; Gelernter, J; Gold, P W; Rubinow, D R; Murphy, D L
Dynamic oxygen-enhanced MRI of cerebrospinal fluid.
Oxygen causes an increase in the longitudinal relaxation rate of tissues through its T1-shortening effect owing to its paramagnetic properties. Due to such effects, MRI has been used to study oxygen-related signal intensity changes in various body parts including cerebrospinal fluid (CSF) space. Oxygen enhancement of CSF has been mainly studied using MRI sequences with relatively longer time resolution such as FLAIR, and T1 value calculation. In this study, fifteen healthy volunteers were scanned using fast advanced spin echo MRI sequence with and without inversion recovery pulse in order to dynamically track oxygen enhancement of CSF. We also focused on the differences of oxygen enhancement at sulcal and ventricular CSF. Our results revealed that CSF signal after administration of oxygen shows rapid signal increase in both sulcal CSF and ventricular CSF on both sequences, with statistically significant predominant increase in sulcal CSF compared with ventricular CSF. CSF is traditionally thought to mainly form from the choroid plexus in the ventricles and is absorbed at the arachnoid villi, however, it is also believed that cerebral arterioles contribute to the production and absorption of CSF, and controversy remains in terms of the precise mechanism. Our results demonstrated rapid oxygen enhancement in sulcal CSF, which may suggest inhaled oxygen may diffuse into sulcal CSF space rapidly probably due to the abundance of pial arterioles on the brain sulci. PMID:24956198
Mehemed, Taha M; Fushimi, Yasutaka; Okada, Tomohisa; Yamamoto, Akira; Kanagaki, Mitsunori; Kido, Aki; Fujimoto, Koji; Sakashita, Naotaka; Togashi, Kaori
Primary spontaneous cerebrospinal fluid leaks located at the clivus
Transclival meningoceles and primary spontaneous cerebrospinal fluid (CSF) leaks at the clivus are extremely rare lesions and only few of them have been reported in the literature. We report here six cases of transclival primary spontaneous CSF leaks through the clivus. A retrospective case study was performed. We reviewed six cases involving sinonasal CSF leaks located at the clivus treated between 1997 and 2009. Presenting symptoms, duration of symptoms, defect size, site of defect, surgical approach and technique of defect closure, intraoperative complications, postoperative complications, and recurrences are discussed. All CSF leaks were located in the upper central part of the clivus. two of six patients showed signs of increased intracranial pressure (ICP) including arachnoid pits and/or empty sella. For three patients a purely transnasal approach was used with multilayer reconstruction using a nonvascularized graft, and three patients underwent a transnasal transseptal approach with a multilayer reconstruction, with nasoseptal flap. No recurrences of CSF leaks at clivus or other sites were observed to date with a mean follow-up of 10.3 years (range, 3�15 years). Spontaneous CSF rhinorrhea located at the clivus is an extremely rare condition. To date, only eight cases have been described. Here, we report the largest group of six consecutive cases. Irrespective of the used reconstruction technique in all cases a 100% closure rate was achieved. However, identification of increased ICP is an essential aspect and this condition should be treated either medically or surgically. PMID:24124635
Kitice, Adriano; Vellutini, Eduardo; Balsalobre, Leonardo; Stamm, Aldo
Fibrinolytic Activity of Human Brain and Cerebrospinal Fluid
Fibrinolytic activity (FA) of brain tissue, meninges and choroid plexus from 41 human cadavers without intracranial disorders was studied by Astrup's biochemical method and Todd's histochemical method. FA of cerebrospinal fluid (CSF) before and after pneumoencephalography (PEG) was also studied by Astrup's method. FA of human brain was higher in the adults than in the newborn and infants, and increased with ageing in infants. No significant difference was found among age groups in the adults. There was no detectable difference of FA in various regions of the brain. Higher FA was recognized in meninges and choroid plexus. Liquefaction of the extravasated blood in the subarachnoid space was considered to be produced by the high fibrinolytic activity of the meninges. The lysed zones on fibrin plate by Todd's method were found at the vessels of the brain tissue and meninges, especially at small blood vessels. FA was found to be localized at the vascular endothelial cells. The lytic areas in the adult brain were relatively larger than those in the newborn brain at the same incubation time. CSF produced small lysed zones on human fibrin plate. CSF and plasma after PEG showed larger lysed zones than those before PEG, and plasminogen activator and/or proactivator in CSF and plasma seemed to be increased after PEG. Plasmin activity was not found in CSF before and after PEG. ImagesFigs. 2-5 PMID:4243674
Takashima, S.; Koga, M.; Tanaka, K.
Pharmacokinetics of florfenicol in cerebrospinal fluid and plasma of calves.
Florfenicol, a fluorinated analog of thiamphenicol, is of great value in veterinary infectious diseases that formerly responded favorably to chloramphenicol. In view of the treatment of meningitis in calves, we studied its pharmacokinetics in the cerebrospinal fluid (CSF) and plasma of six animals. To this end, a new high-performance liquid chromatography method was developed which, unlike previous ones, uses solid-phase instead of double-phase extraction to isolate the drug. After a single intravenous dose of 20 mg/kg of body weight, a maximum concentration in CSF of 4.67 +/- 1.51 microg/ml (n = 6) was reached, with a mean residence time of 8.7 h. The decline of florfenicol in both CSF and plasma fitted a biexponential model with elimination half-lives of 13.4 and 3.2 h, respectively. Florfenicol penetrated well into CSF, as evidenced from an availability of 46% +/- 3% relative to plasma. The levels remained above the MIC for Haemophilus somnus over a 20-h period. Our results provide evidence indicating the effectiveness of florfenicol in the treatment of bacterial meningitis of calves. PMID:9303399
de Craene, B A; Deprez, P; D'Haese, E; Nelis, H J; Van den Bossche, W; De Leenheer, P
Phantom model of physiologic intracranial pressure and cerebrospinal fluid dynamics.
We describe herein a novel life-size phantom model of the intracranial cavity and its validation. The cerebrospinal fluid (CSF) domains including ventricular, cysternal, and subarachnoid spaces were derived via magnetic resonance imaging. Brain mechanical properties and cranio-spinal compliance were set based on published data. Both bulk and pulsatile physiologic CSF flow were modeled. Model validation was carried out by comparisons of flow and pressure measurements in the phantom with published in vivo data of healthy subjects. Physiologic intracranial pressure with 10 mmHg mean and 0.4 mmHg peak pulse amplitude was recorded in the ventricles. Peak CSF flow rates of 0.2 and 2 ml/s were measured in the cerebral aqueduct and subarachnoid space, respectively. The phantom constitutes a first-of-its-kind approach to modeling physiologic intracranial dynamics in vitro. Herein, we describe the phantom design and manufacturing, definition and implementation of its operating parameters, as well as the validation of the modeled dynamics. PMID:22333981
Bottan, Simone; Poulikakos, Dimos; Kurtcuoglu, Vartan
Insights into cerebrospinal fluid and cerebral blood flows in infants and young children.
This study investigates the craniospinal flows of blood and cerebrospinal fluid using phase-contrast magnetic resonance imaging (MRI) on 23 control neonates and infants (5 d-68 mo old). Mean arterial cerebral blood flow increased with age of infant from 180 mL/min after birth to 1330 mL/min around 6 years of age. This corresponds to 51 mL/min/100 g and 95 mL/min/100 g, respectively. Cervical cerebrospinal fluid stroke volume increased from 38 � 10(-3) mL to 752 � 10(-3) mL per cardiac cycle. After arterial systolic blood inflow, we observed a delay of the venous outflow that was always preceded by cerebrospinal fluid flushing out through the spinal canal. These results highlighted the importance of compliance of the spinal compartment and the interaction of blood and cerebrospinal fluid dynamics. The capacity of the spinal compartment to receive intracranial cerebrospinal fluid in presence of fontanels was demonstrated. We provide reference values to understand the physiology of cerebrospinal fluid and cerebral blood. PMID:24346313
Capel, Cyrille; Makki, Malek; Gondry-Jouet, Catherine; Bouzerar, Roger; Courtois, V�ronique; Krejpowicz, B�n�dicte; Bal�dent, Olivier
The blood-brain barrier, the blood-cerebrospinal fluid barrier (BCB) and other specialized brain barriers are increasingly recognized as a major obstacle to the treatment of most brain disorders. The impairment of these barriers has been implicated in neuropathology of several diseases, such as autism, ischemia, multiple sclerosis and Alzheimer disease. This dual function of the blood-neural barriers points out the importance and need for the development of techniques that can evaluate the nature and level of their integrity. Here we report the discovery of CSF secretory Ca(2+)-dependent phospholipase A2 (sPLA2) activity as a measure of BCB permeability. Lumbar CSF from BCB impaired (n=26), multiple sclerosis (n=18) and healthy control (n=32) cases was analyzed using both a newly developed continuous fluorescence assay for CSF sPLA2 activity and CSF/Serum albumin ratio (Q(Alb)), the most common and established method to evaluate BCB permeability. While both measurements showed no significant differences between multiple sclerosis and age-matched normal healthy cases, they were highly correlated. Though the CSF sPLA2 activity and Q(Alb) had over 95% agreement, the former was found to be more sensitive than the latter in measuring low levels of BCB impairment. PMID:20470866
Chalbot, Sonia; Zetterberg, Henrik; Blennow, Kaj; Fladby, Tormod; Grundke-Iqbal, Inge; Iqbal, Khalid
Previously there have been no methods for directly tracing the flow of cerebrospinal fluid (CSF) under physiological conditions, and the circulation of CSF has therefore been studied and visualized by injecting a radioactively labeled tracer or contrast medium visible in x-ray images. The newly developed Time-Spatial Inversion Pulse (Time-SLIP) method makes it possible to directly visualize the flow of CSF using magnetic resonance imaging (MRI), permitting CSF dynamics to be depicted in a certain time frame. The CSF dynamics visualized using Time-SLIP has been found to differ markedly from the classical CSF circulation theory described in medical textbooks. It can be said that research on CSF dynamics has advanced to the next stage with the use of this innovative imaging method. Obtaining a more accurate understanding of normal CSF physiology and pathophysiology should lead to improved diagnostic accuracy, permit the identification of new etiological factors in a variety of diseases, and promote the development of new therapeutic approaches. PMID:25165048
Yamada, Shinya
Previously there have been no methods for directly tracing the flow of cerebrospinal fluid (CSF) under physiological conditions, and the circulation of CSF has therefore been studied and visualized by injecting a radioactively labeled tracer or contrast medium visible in x-ray images. The newly developed Time-Spatial Inversion Pulse (Time-SLIP) method makes it possible to directly visualize the flow of CSF using magnetic resonance imaging (MRI), permitting CSF dynamics to be depicted in a certain time frame. The CSF dynamics visualized using Time-SLIP has been found to differ markedly from the classical CSF circulation theory described in medical textbooks. It can be said that research on CSF dynamics has advanced to the next stage with the use of this innovative imaging method. Obtaining a more accurate understanding of normal CSF physiology and pathophysiology should lead to improved diagnostic accuracy, permit the identification of new etiological factors in a variety of diseases, and promote the development of new therapeutic approaches. PMID:25165048
Yamada, Shinya
Cerebrospinal fluid flow dynamics were evaluated by /sup 111/In-diethylenetriamine pentaacetic acid (/sup 111/In-DTPA) ventriculography in 27 patients with neoplastic meningitis. Nineteen patients (70 percent) had evidence of cerebrospinal fluid flow disturbances. These occurred as ventricular outlet obstructions, abnormalities of flow in the spinal canal, or flow distrubances over the cortical convexities. Tumor histology, physical examination, cerebrospinal fluid analysis, myelograms, and computerized axial tomographic scans were not sufficient to predict cerebrospinal fluid flow patterns. These data indicate that cerebrospinal fluid flow abnormalities are common in patients with neoplastic meningitis and that /sup 111/In-DTPA cerebrospinal fluid flow imaging is useful in characterizing these abnormalities. This technique provides insight into the distribution of intraventricularly administered chemotherapy and may provide explanations for treatment failure and drug-induced neurotoxicity in patients with neoplastic meningitis.
Grossman, S.A.; Trump, D.L.; Chen, D.C.; Thompson, G.; Camargo, E.E.
Cerebrospinal Fluid Biomarker Candidates Associated with Human WNV Neuroinvasive Disease
During the last decade, the epidemiology of WNV in humans has changed in the southern regions of Europe, with high incidence of West Nile fever (WNF) cases, but also of West Nile neuroinvasive disease (WNND). The lack of human vaccine or specific treatment against WNV infection imparts a pressing need to characterize indicators associated with neurological involvement. By its intimacy with central nervous system (CNS) structures, modifications in the cerebrospinal fluid (CSF) composition could accurately reflect CNS pathological process. Until now, few studies investigated the association between imbalance of CSF elements and severity of WNV infection. The aim of the present study was to apply the iTRAQ technology in order to identify the CSF proteins whose abundances are modified in patients with WNND. Forty-seven proteins were found modified in the CSF of WNND patients as compared to control groups, and most of them are reported for the first time in the context of WNND. On the basis of their known biological functions, several of these proteins were associated with inflammatory response. Among them, Defensin-1 alpha (DEFA1), a protein reported with anti-viral effects, presented the highest increasing fold-change (FC>12). The augmentation of DEFA1 abundance in patients with WNND was confirmed at the CSF, but also in serum, compared to the control individual groups. Furthermore, the DEFA1 serum level was significantly elevated in WNND patients compared to subjects diagnosed for WNF. The present study provided the first insight into the potential CSF biomarkers associated with WNV neuroinvasion. Further investigation in larger cohorts with kinetic sampling could determine the usefulness of measuring DEFA1 as diagnostic or prognostic biomarker of detrimental WNND evolution. PMID:24695528
Fraisier, Christophe; Papa, Anna; Granjeaud, Samuel; Hintzen, Rogier; Martina, Byron; Camoin, Luc; Almeras, Lionel
Preoperative cerebrospinal fluid ?-Amyloid/Tau ratio and postoperative delirium
Objective The neuropathogenesis of postoperative delirium remains unknown. Low cerebrospinal fluid (CSF) ?-amyloid protein (A?) and high CSF Tau levels are associated with Alzheimer's disease. We, therefore, assessed whether lower preoperative CSF A?/Tau ratio was associated with higher incidence and greater severity of postoperative delirium. Methods One hundred and fifty-three participants (71���5�years, 53% men) who had total hip/knee replacement under spinal anesthesia were enrolled. CSF was obtained during initiation of spinal anesthesia. The incidence and severity of postoperative delirium were determined by Confusion Assessment Method (CAM) and Memorial Delirium Assessment Scale (MDAS) on postoperative day 1 and 2. A?40, A?42, and Tau levels in the CSF were measured by enzyme-linked immunosorbent assay. The relationships among these variables were determined, adjusting for age and gender. Results Participants in the lowest quartile of preoperative CSF A?40/Tau and A?42/Tau ratio had higher incidence (32% vs. 17%, P�=�0.0482) and greater symptom severity of postoperative delirium (A?40/Tau ratio: 4 vs. 3, P�=�0.034; A?42/Tau ratio: 4 vs. 3, P�=�0.062, the median of the highest MDAS score) as compared to the combination of the rest of the quartiles. The preoperative CSF A?40/Tau or A?42/Tau ratio was inversely associated with MDAS score (A?40/Tau ratio: ?0.12���0.05, P�=�0.014, adj. ?0.12���0.05, P�=�0.018; A?42/Tau ratio: ?0.65���0.26, P�=�0.013, adj. ?0.62���0.27, P�=�0.022). Interpretation Lower CSF A?/Tau ratio could be associated with postoperative delirium, pending confirmation of our preliminary results in further studies. These findings suggest potential roles of A? and/or Tau in postoperative delirium neuropathogenesis. PMID:24860840
Xie, Zhongcong; Swain, Celeste A; Ward, Sarah A P; Zheng, Hui; Dong, Yuanlin; Sunder, Neelakantan; Burke, Dennis W; Escobar, Diana; Zhang, Yiying; Marcantonio, Edward R
Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections.
The cerebrospinal fluid (CSF) biomarker profile in Alzheimer's disease (AD) is characterized by decreased beta amyloid (A?(1-42)), increased total and hyperphosphorylated tau (t-tau and p-tau, respectively), which is a useful diagnostic tool and gives insight in the pathogenesis of AD. It is of importance to study how these biomarkers react in other CNS diseases; therefore, we decided to analyse amyloid and tau biomarkers in different CNS infections. We also included analysis of soluble amyloid precursor proteins (sAPP? and -?). CSF A?(1-42), sAPP? and -?, t-tau and p-tau were analysed in bacterial meningitis (n = 12), Lyme neuroborreliosis (n = 13), herpes simplex virus type 1 (HSV-1) encephalitis (n = 10), HIV-associated dementia (HAD) (n = 21), AD (n = 21) and healthy controls (n = 42). Concurrent with AD, A?(1-42) was decreased in all groups except neuroborreliosis compared to controls. HSV-1 encephalitis, bacterial meningitis and HAD showed lower concentrations of sAPP? and -? compared to AD. T-tau was increased in AD and HSV-1 encephalitis compared to all other groups. P-tau was higher in AD and HSV-1 encephalitis compared to bacterial meningitis, HAD and control. Decreased CSF A?(1-42), sAPP? and -? in various CNS infections imply an effect of neuroinflammation on amyloid metabolism which is similar in regard to AD concerning A?(1-42), but differs concerning sAPP? and -?. These results clearly indicate different pathologic pathways in AD and infectious CNS disease and may provide help in the differential biomarker diagnostics. Increased p-tau in HSV-1 encephalitis probably reflect acute neuronal damage and necrosis. PMID:23052602
Krut, Jan Jessen; Zetterberg, Henrik; Blennow, Kaj; Cinque, Paola; Hagberg, Lars; Price, Richard W; Studahl, Marie; Gissl�n, Magnus
Cerebrospinal Fluid PKR Level Predicts Cognitive Decline in Alzheimer's Disease
The cerebrospinal fluid (CSF) levels of the proapoptotic kinase R (PKR) and its phosphorylated PKR (pPKR) are increased in Alzheimer�s disease (AD), but whether CSF PKR concentrations are associated with cognitive decline in AD patients remain unknown. In this study, 41 consecutive patients with AD and 11 patients with amnestic mild cognitive impairment (aMCI) from our Memory Clinic were included. A lumbar puncture was performed during the following month of the clinical diagnosis and Mini-Mental State Examination (MMSE) evaluations were repeated every 6 months during a mean follow-up of 2 years. In AD patients, linear mixed models adjusted for age and sex were used to assess the cross-sectional and longitudinal associations between MMSE scores and baseline CSF levels of A? peptide (A? 1-42), Tau, phosphorylated Tau (p-Tau 181), PKR and pPKR. The mean (SD) MMSE at baseline was 20.5 (6.1) and MMSE scores declined over the follow-up (-0.12 point/month, standard error [SE]?=?0.03). A lower MMSE at baseline was associated with lower levels of CSF A? 1�42 and p-Tau 181/Tau ratio. pPKR level was associated with longitudinal MMSE changes over the follow-up, higher pPKR levels being related with an exacerbated cognitive deterioration. Other CSF biomarkers were not associated with MMSE changes over time. In aMCI patients, mean CSF biomarker levels were not different in patients who converted to AD from those who did not convert.These results suggest that at the time of AD diagnosis, a higher level of CSF pPKR can predict a faster rate of cognitive decline. PMID:23320095
Lapalus, Pauline; Prevot, Magali; Laplanche, Jean-Louis
Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum
AIMTo investigate the diagnostic potential of herpes simplex virus (HSV) DNA in cerebrospinal fluid and serum; to correlate the findings with outcome in the child and with type of maternal infection.METHODSCerebrospinal fluid and serum specimens from 36 children with verified neonatal HSV infections, diagnosed between 1973 and 1996, were examined using the polymerase chain reaction technique (PCR).RESULTSIn 21 children for
G Malm; M Forsgren
Levofloxacin Disposition in Cerebrospinal Fluid in Patients with External Ventriculostomy
In vitro levofloxacin exhibits both potent or intermediate activity against most of the pathogens frequently responsible for acute bacterial meningitis and synergistic activity with some beta-lactams. Since levofloxacin was shown to penetrate the cerebrospinal fluid (CSF) during meningeal inflammation both in animals and in humans, the disposition of levofloxacin in CSF was studied in 10 inpatients with external ventriculostomy because of communicating hydrocephalus related to subarachnoid occlusion due to cerebral accidents who were treated with 500 mg of levofloxacin intravenously twice a day because of extracerebral infections. Plasma and CSF concentration-time profiles and pharmacokinetics were assessed at steady state. Plasma and CSF levofloxacin concentrations were analyzed by high-pressure liquid chromatography. The peak concentration of levofloxacin at steady state (Cmax ss)was 10.45 mg/liter in plasma and 4.06 mg/liter in CSF, respectively, with the ratio of the Cmax ss in CSF to the Cmax ss in plasma being 0.47. The areas under the concentration-time curves during the 12-h dosing interval (AUC0-?s) were 47.69 mg?�?h/liter for plasma and 33.42 mg?�?h/liter for CSF, with the ratio of the AUC0-? for CSF to the AUC0-? for plasma being 0.71. The terminal-phase half-life of levofloxacin in CSF was longer than that in plasma (7.02 � 1.57 and 5.51 � 1.36 h, respectively; P = 0.034). The ratio of the levofloxacin concentration in CSF to the concentration in plasma progressively increased with time, from 0.30 immediately after dosing to 0.99 at the end of the dosing interval. In the ventricular CSF of patients with uninflamed meninges, levofloxacin was shown to provide optimal exposure, which approximately corresponded to the level of exposure of the unbound drug in plasma. The findings provide support for trials of levofloxacin with twice-daily dosing in combination with a reference beta-lactam for the treatment of bacterial meningitis in adults. This cotreatment could be useful both for overcoming Streptococcus pneumoniae resistance and for enabling optimal exposure of the CSF to at least one antibacterial agent for the overall treatment period. PMID:14506016
Pea, Federico; Pavan, Federica; Nascimben, Ennio; Benetton, Claudio; Scotton, Pier Giorgio; Vaglia, Alberto; Furlanut, Mario
Antibodies against equine herpesvirus 1 in the cerebrospinal fluid in the horse.
Neutralizing antibodies against equine herpesvirus 1 were measured in serum and cerebrospinal fluid of 16 horses and ponies from a closed herd both before and after vaccination with modified live equine herpesvirus 1. These titers were also measured in 22 neurologically normal and 15 neurologically abnormal horses at a teaching hospital. Animals from the closed herd had prevaccination serum titers up to 1:8 and postvaccination serum titers up to 1:128. Horses from the teaching hospital had serum titers up to 1:64. Cerebrospinal fluid titers were not detected in the vaccinated horses or the neurologically normal horses but a low titer (1:8) was noted in one neurologically abnormal horse. This titer probably resulted from hemorrhage into the cerebrospinal fluid following trauma. PMID:17422553
Blythe, L L; Mattson, D E; Lassen, E D; Craig, A M
A lady in her late 20s was admitted with a history of headaches and intermittent focal neurological symptoms which were greatly exacerbated by catheter angiography of the cerebral circulation. Cerebrospinal fluid analysis demonstrated a lymphocytic pleocytosis. She subsequently made a spontaneous recovery, without neurological sequelae. Her presentation fits the diagnostic criteria for the previously described syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL). HaNDL is a probably underdiagnosed nosological entity, characterised by often dramatic clinical manifestations but ultimately a good prognosis. PMID:22700346
Cifelli, A; Vaithianathar, L
A lady in her late 20s was admitted with a history of headaches and intermittent focal neurological symptoms which were greatly exacerbated by catheter angiography of the cerebral circulation. Cerebrospinal fluid analysis demonstrated a lymphocytic pleocytosis. She subsequently made a spontaneous recovery, without neurological sequelae. Her presentation fits the diagnostic criteria for the previously described syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL). HaNDL is a probably underdiagnosed nosological entity, characterised by often dramatic clinical manifestations but ultimately a good prognosis. PMID:22700346
Cifelli, A; Vaithianathar, L
Abdominal cerebrospinal fluid pseudocyst due to infection with enterococcus faecalis. A case report.
Abdominal cerebrospinal fluid pseudocyst is a rare complication of ventriculo-peritoneal shunt occurring as a result of non-absorption of cerebrospinal fluid from the abdominal cavity due to inflammation. Usual presentations include abdominal symptoms; abdominal distention, pain, nausea, vomiting and symptoms of raised intracranial pressure like headache due to shunt dysfunction. The diagnosis may be delayed in severely handicapped patients due to poor communicability, multiple associated complications or co-morbidities. Radiological modalities are used for diagnosis as well as treatment. PMID:24148340
Muttikkal, T J E; Dashti, K; Muqim, A T; Ben Nakhi, A; Hayat, A
In order to address the significance of apolipoprotein E (apoE) in the pathogenesis as well as the clinical diagnosis of Alzheimer�s disease (AD), we measured its level in cerebrospinal fluid (CSF) from randomly selected Japanese control subjects at various ages (n = 36), which included 14 age-matched controls, and from AD patients including early-onset (n = 11, EOAD) and late-onset
Ryuichi Fukuyama; Toshiki Mizuno; Satoru Mori; Katsuhiko Yanagisawa; Kenji Nakajima; Shinji Fushiki
National Technical Information Service (NTIS)
In this study, we present a method to perform a numerical simulation of the flow dynamics of the Cerebrospinal Fluid (CSF) based on anatomical Magnetic Resonance Images (MRI). The Computational Fluid Dynamics (CFD) software, written in language C, integra...
L. Fin, R. Grebe, O. Baledent, I. Idy-Peretti
ARTCEREB, an irrigation and perfusion solution (Artcereb), is a preparation intended for the irrigation and perfusion of the cerebral ventricles, and it is therefore important to evaluate its effects on cerebrospinal fluid (CSF) and on the surrounding cerebrospinal parenchyma. To confirm the kinetics of the perfusion fluid component, we performed whole body autoradiography and examined glucose balance during ventriculocisternal perfusion with (14)C-glucose labeled Artcereb in the rat model, which simulates ventricular irrigation or ventriculocisternal perfusion in clinical neurosurgery. We also performed ventriculocisternal perfusion with Artcereb, lactated Ringer's solution, or normal saline, and observed the effect of these solutions on animal condition and on brain tissue morphology. In the kinetic study, diffusion of (14)C-glucose from the perfused Artcereb to the cerebrospinal tissue was seen on whole body autoradiography, and almost 90% of the glucose in the perfusion fluid was distributed to the cerebrospinal tissue and the systemic circulation. These data indicated that the perfusion fluid interacted actively with the CSF, surrounding parenchyma and the systemic circulation, and suggested that the formation of perfusion fluid affected CSF composition and cerebrospinal tissue functions. Animals perfused with normal saline were associated with serious symptoms including tonic convulsions and death, and exhibited neuronal death in the cerebrum. However, these severe changes were not observed in animals perfused with Artcereb or lactated Ringer's solution. We therefore propose that during neurosurgery, it is extremely important to use a physiological solution like Artcereb which closely resembles normal human CSF, in order to maintain cerebrospinal function and to alleviate postoperative adverse events. PMID:19797859
Doi, Kazuhisa; Morioka, Yujiro; Nishimura, Masuhiro; Kawano, Takeshi; Harada, Daisuke; Naito, Shinsaku; Yamauchi, Aiko
Metal Concentrations in Plasma and Cerebrospinal Fluid in Patients with Alzheimer�s Disease
Background\\/Aims: The homeostasis of essential metals such as copper, iron, selenium and zinc may be altered in the brain of subjects with Alzheimer�s disease (AD). Methods: Concentrations of metals (magnesium, calcium, vanadium, manganese, iron, cobalt, nickel, copper, zinc, selenium, rubidium, strontium, molybdenum, cadmium, tin, antimony, cesium, mercury and lead) were determined in plasma and cerebrospinal fluid (CSF) by inductively coupled
Lars Gerhardsson; Thomas Lundh; Lennart Minthon; Elisabet Londos
Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia
Schizophrenia is a serious brain disease of uncertain etiology. A role for retroviruses in the etiopathogenesis of some cases of schizophrenia has been postulated on the basis of clinical and epidemiological observations. We found sequences homologous to retroviral pol genes in the cell-free cerebrospinal fluids (CSFs) of 10 of 35 (29%) individuals with recent-onset schizophrenia or schizoaffective disorder. Retroviral sequences
H�kan Karlsson; Silke Bachmann; Johannes Schroder; Justin McArthur; E. Fuller Torrey; Robert H. Yolken
Increase in ?-Amyloid Levels in Cerebrospinal Fluid of Children with Down Syndrome
Background: Individuals with Down syndrome (DS) invariably develop Alzheimer�s disease (AD) during their life span. It is therefore of importance to study young DS patients when trying to elucidate early events in AD pathogenesis. Aim: To investigate how levels of different amyloid-? (A?) peptides, as well as tau and phosphorylated tau, in cerebrospinal fluid (CSF) from children with DS change
Hillevi Englund; G�ran Anner�n; Jan Gustafsson; Ulrika Wester; Jens Wiltfang; Lars Lannfelt; Kaj Blennow; Kina H�glund
Introduction: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate. Methods:
Stacey Berg; Baruti Serabe; Aleksander Aleksic; Lisa Bomgaars; Leticia McGuffey; Robert Dauser; John Durfee; Jed Nuchtern; Susan Blaney
Huntington's disease (HD) is a progressive neurodegenerative disease caused by an unstable CAG trinucleotide repeat expansion. The need for biomarkers of onset and progression in HD is imperative, since currently reliable outcome measures are lacking. We used two-dimensional electrophoresis and mass spectrometry to analyze the proteome profiles in cerebrospinal fluid (CSF) of 6 pairs of HD patients and controls. Prothrombin,
Yen-Chu Huang; Yih-Ru Wu; Mu-Yun Tseng; Yi-Chun Chen; Sen-Yung Hsieh; Chiung-Mei Chen; Mark Smith
In this study, the use of neurochemical markers in patients with aseptic and tuberculous meningitis has been investigated. The cerebrospinal fluid levels of amino acids, nitrite (a metabolite of nitric oxide), vitamin B12 and homocysteine were quantitated in both groups of patients. Among the amino acids, aspartic acid and glutamic acid both excitatory amino acid, GABA, glycine and tryptophan were
G. Ali Qureshi; Shahid M Baig; Ivan Bednar; Ammar Halawa; S. H Parvez
Objective: Despite the use of various strategies for the prevention of spinal cord ischemia, paraplegia and paraparesis continue to occur after thoracoabdominal aortic aneurysm (TAAA) repair. Although cerebrospinal fluid drainage (CSFD) is often used as an adjunct for spinal cord protection, its benefit remains unproven. The purpose of this randomized clinical trial was to evaluate the impact of CSFD on
Joseph S. Coselli; Scott A. LeMaire; C�neyt K�ksoy; Zachary C. Schmittling; Patrick E. Curling
Previous findings from our laboratory demonstrated that some clonally expanded cerebrospinal fluid (CSF) B cells from MS patients exhibit diminished mutation targeting patterns in comparison to typical B cells selected in the context of germinal centers (GCs). In order to determine whether the overall CSF B cell repertoires adhered to mutation patterns typical of GC-selected B cells, we analyzed the
Christopher Harp; Jane Lee; Doris Lambracht-Washington; Elizabeth Cameron; Gregory Olsen; Elliot Frohman; Michael Racke; Nancy Monson
Corticotropin-releasing hormone (CRH) in cerebrospinal fluid (CSF) is regarded as index of brain endocrine and behavioral functioning. We investigated the acute effects of intravenous cortisol (100mg) vs. placebo on serial CSF CRH in ten healthy men. CSF CRH concentrations were not significantly suppressed by cortisol within 3h. The origin and regulation of CSF CRH need further research. PMID:23896353
Kellner, Michael; Salzwedel, Cornelie; Wortmann, Viola; Urbanowicz, Tatiana; Boelmans, Kai; Yassouridis, Alexander; Stalla, G�nter K; Wiedemann, Klaus
This study was designed to investigate whether myelin basic protein (MBP) in cerebrospinal fluid (CSF) can be a predictive marker of delayed encephalopathy from carbon monoxide (CO) poisoning. Five patients with CO poisoning were included in the study. The CSF was serially sampled to determine the MBP concentration. All patients were classified into group DE or group non-DE according to
Toshimitsu Ide; Yoshito Kamijo
BACKGROUND: The neurofilament is a major structural component of myelinated axons. Increased cerebrospinal fluid (CSF) concentrations of the light chain of the neurofilament protein (NFL) can serve as a sensitive indicator of central nervous system (CNS) injury. To assess whether interrupting antiretroviral treatment of HIV infection might have a deleterious effect on the CNS, we measured NFL levels in HIV-infected
Magnus Gissl�n; Lars Rosengren; Lars Hagberg; Steven G Deeks; Richard W Price
Glutamine transport at the blood�brain and blood�cerebrospinal fluid barriers
Glutamine has multiple physiological and pathophysiological roles in the brain. Because of their position at the interface between blood and brain, the cerebral capillaries and the choroid plexuses that form the blood�brain barriers (BBB) and blood�cerebrospinal fluid (CSF) barriers, have the potential to influence brain glutamine concentrations. Despite this, there has been a paucity of data on the mechanisms and
Jianming Xiang; Steven R. Ennis; Galaleldin E. Abdelkarim; Mutsuo Fujisawa; Nobuyuki Kawai; Richard F. Keep
Cerebrospinal Fluid Pleocytosis In Children with Pneumonia but Lacking Evidence Of Meningitis
Headache, nuchal rigidity, positive Kernig's sign, and even convulsions may be observed during severe bacterial infections such as pneumonia, pyelonephritis, typhoid fever, and bacillary dysentery. In such cases, meningitis can be excluded only by documentation of normal cerebrospinal fluid (CSF).1 The authors describe four children with lobar pneumonia in whom the clinical signs of meningeal irritation wene associated with a
Moshe Nussinovitch; Herman A. Cohen; Moshe Frydman; Itzhak Varsano
Neurotransmitter amino acid in cerebrospinal fluid of patients with dementia with Lewy bodies
Summary. The purpose of the present study was to compare neurotransmitter amino acid concentrations in the cerebrospinal fluid (CSF) and CSF\\/plasma ratios in 21 patients with dementia with Lewy bodies (DLB) and 26 matched controls. To this purpose, we used an ion-exchange chromatographic method. DLB patients exhibit higher CSF concentrations of asparagine (+25%) and glycine (+21%) compared to a control
J. A. Molina; P. G�mez; C. Vargas; S. Ortiz; S. P�rez-Rial; L. Urig�en; J. M. Oliva; C. Villanueva; J. Manzanares
There are reports of failure of extended-spectrum cephalosporin treatment in pneumococcal meningitis. On the basis of in vitro and animal experimental studies, the addition of vancomycin or rifampin to an extended- spectrum cephalosporin has been recommended for empiric treatment of these patients. Cerebrospinal fluid (CSF) was taken from 31 children with bacterial meningitis randomized to receive ceftriaxone alone (n 511),
Treponema pallidum subsp. pallidum can invade the central nervous system (CNS) at various stages of the disease (2, 11). CNS invasion by T. pallidum is determined by a positive syph- ilis serologic test, abnormal cerebrospinal fluid (CSF) cell count and protein level, and\\/or a positive CSF Venereal Dis- ease Research Laboratory (VDRL) test. Despite the high specificity of the CSF
Transferrin, radiolabeled with In-111, can be coinjected into glioblastoma multiforme lesions, and subsequent scintigraphic imaging can demonstrate the biokinetics of the cytotoxic transferrin. The administration of [sup 111]In transferrin into a brain tumor results in distribution of radioactivity in the brain, brain tumor, and the cerebrospinal fluid (CSF). Information about absorbed radiation doses to these regions, as well as other
Jeff F. Evans; J. B. Stubbs
5-Hydroxyindolacetic acid and homovanillic acid in cerebrospinal fluid in manic-depressive psychosis
Cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid and homovanillic acid were determined in 37 depressed and 47 manic patients, in 30 other psychiatric patients and in 54 healthy controls. There were no differences in the concentrations of 5-hydroxyindoleacetic acid between the four groups. Manic patients had higher concentrations of homovanillic acid than the other three groups. After loading with probenecid (5
R. Sj�str�m; B.-E. Roos
Summary The developmental change of dopamine �-hydroxylase (DBH) activity in cerebrospinal fluid (CSF) of epileptic children was studied. Non-epileptic children showed lower DBH activity in CSF than adult, and its activity increased with age. In contrast, epileptic children showed no increase in DBH activity with age. DBH in CSF may be a good index of noradrenergic function in child brain.
H. Suzuki; M. Shimohira; Y. Iwakawa; T. Nagatsu
Cerebrospinal fluid levels of thiamine in patients with Alzheimer's disease
Summary.�� Thiamine is an essential cofactor for several important enzymes involved in brain oxidative metabolism, such as the alpha-ketoglutarate\\u000a dehydrogenase complex (KGDHC), pyruvate-dehydrogenase complex (PDHC), and transketolase. Some investigators reported decreased\\u000a thiamine-diphosphate levels and decreased activities of KGDHC, pyruvate-dehydrogenase complex and transketolase in the brain\\u000a tissue of Alzheimer's disease (AD) patients. We measured cerebrospinal (CSF) levels of thiamine-diphosphate, thiamine-monophosphate,\\u000a free
J. A. Molina; F. J. Jim�nez-Jim�nez; A. Hern�nz; E. Fern�ndez-Vivancos; S. Medina; F. de Bustos; C. G�mez-Escalonilla; Y. Sayed
Introduction CyberKnife� radiation is an effective treatment for unresectable skull base tumors because it can deliver a highly conformational dose distribution to the complex shapes of tumor extensions. There have been few reports of severe complications with this treatment. This is the first published case report to our knowledge of cerebrospinal fluid leakage induced by CyberKnife� radiotherapy. Case presentation A skull base tumor was identified on magnetic resonance imaging in a 78-year-old Asian woman with a headache in her forehead. An endoscopic transnasal tumor resection was performed; however, the tumor, invading into the cavernous sinuses and optic canal, was not completely removed. During the subtotal resection of the tumor, no cerebrospinal fluid leakage was observed. Osteosarcoma was histologically diagnosed, and CyberKnife� radiation was performed to the residual tumor considering the aggressive feature of the tumor with a molecular immunology Borstel-1 index of 15%. Five months after the treatment, magnetic resonance imaging showed definite tumor shrinkage, and the patient had been living her daily life without any troubles. After another month, the patient was transferred to our clinic because of coma with high fever, and computed tomography demonstrated severe pneumocephalus. Rhinorrhea was definitely identified on admission; therefore, emergency repair of the cerebrospinal fluid leakage was performed using an endoscope. Dural defects at the bottom of the sella turcica were identified under careful endoscopic observation and fat tissue was patched to the dural defects. Follow-up computed tomography proved complete disappearance of air from the cisterns 2 weeks after the surgery, and the patient was discharged from our hospital without any neurological deficits. Conclusion CyberKnife� radiation is one of the effective treatments for skull base tumors; however, the risk of cerebrospinal fluid leakage should be considered when tumor invasion to the dura mater is suspected. Emergency surgical treatment is required when cerebrospinal fluid leakage is induced by the radiotherapy because the leakage is not expected to be healed by palliative treatments. PMID:23622107
Monoaminc and metabolite levels in the cerebrospinal fluid of hibernating and euthermic marmots.
Cerebrospinal fluid from yellow-bellied marmots, Marmota flaviventris, was analysed for monoamine and monoamine metabolite content during euthermia and deep hibernation. Dopamine (DA) levels were decreased, while DA metabolite levels, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were dramatically increased in hibernating marmots. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5HIAA) levels were also greatly enhanced during hibernation while norepinephrine (NE) levels were only moderately increased. These findings demonstrate that cerebrospinal monoamine levels are dynamically altered during hibernation, such that DA versus 5-HT and NE levels undergo opposite changes. Therefore, these data indicate that DA, 5-HT and NE neuronal systems are differentially altered during hibernation in mammals. PMID:10607025
Reid; Kilduff; Romero; Florant; Dement; Heller
Beta2-Microglobulin as a Diagnostic Marker in Cerebrospinal Fluid: A Follow-Up Study
Beta2-Microglobulin (?2-m) is a low molecular weight protein occurring in all body fluids. Its concentration increases in various pathologies. Increased values in cerebrospinal fluid (CSF) are ascribed to an activation of immune system. Using immunoturbidimetry, we examined concentrations of beta2-microglobulin in cerebrospinal fluid in a large group of 6274 patients with defined neurological diseases. Cell counts, total protein, albumin, glucose, lactic acid, immunoglobulins concentrations, and isofocusing (IEF) were also evaluated. We found substantial changes of CSF ?2-m concentrations in purulent meningitis, leptomeningeal metastasis, viral meningitis/encephalitis, and neuroborreliosis, while in multiple sclerosis these changes were not significant. Intrathecal synthesis and immune activation were present in these clinical entities. A new normative study enables better understanding of beta2-microglobulin behavior in CSF. PMID:24895473
Svatonova, Jana; Borecka, Klara; Adam, Pavel; Lanska, Vera
Neurodegenerative diseases, such as multiple sclerosis represent global health issues. Accordingly, there is an urgent need to understand the pathogenesis of this and other central nervous system disorders, so that more effective therapeutics can be developed. Cerebrospinal fluid is a potential source of important reporter molecules released from various cell types as a result of central nervous system pathology. Here, we report the development of an unbiased approach for the detection of reactive cerebrospinal fluid molecules and target brain proteins from patients with multiple sclerosis. To help identify molecules that may serve as clinical biomarkers for multiple sclerosis, we have biotinylated proteins present in the cerebrospinal fluid and tested their reactivity against brain homogenate as well as myelin and myelin-axolemmal complexes. Proteins were separated by two-dimensional gel electrophoresis, blotted onto membranes and probed separately with biotinylated unprocessed cerebrospinal fluid samples. Protein spots that reacted to two or more multiple sclerosis-cerebrospinal fluids were further analyzed by matrix assisted laser desorption ionization-time-of-flight time-of-flight mass spectrometry. In addition to previously reported proteins found in multiple sclerosis cerebrospinal fluid, such as ?? crystallin, enolase, and 14-3-3-protein, we have identified several additional molecules involved in mitochondrial and energy metabolism, myelin gene expression and/or cytoskeletal organization. These include aspartate aminotransferase, cyclophilin-A, quaking protein, collapsin response mediator protein-2, ubiquitin carboxy-terminal hydrolase L1, and cofilin. To further validate these findings, the cellular expression pattern of collapsin response mediator protein-2 and ubiquitin carboxy-terminal hydrolase L1 were investigated in human chronic-active MS lesions by immunohistochemistry. The observation that in multiple sclerosis lesions phosphorylated collapsin response mediator protein-2 was increased, whereas Ubiquitin carboxy-terminal hydrolase L1 was down-regulated, not only highlights the importance of these molecules in the pathology of this disease, but also illustrates the use of our approach in attempting to decipher the complex pathological processes leading to multiple sclerosis and other neurodegenerative diseases. PMID:21421798
Menon, Krishnakumar N; Steer, David L; Short, Martin; Petratos, Steven; Smith, Ian; Bernard, Claude C A
Authors report a rare case of acute intracranial subdural and intraventricular hemorrhage that were caused by intracranial hypotension resulted from cerebrospinal fluid leakage through an unidentified dural tear site during spinal surgery. The initial brain computed tomography image showed acute hemorrhages combined with preexisting asymptomatic chronic subdural hemorrhage. One burr hole was made over the right parietal skull to drain intracranial hemorrhages and subsequent drainage of cerebrospinal fluid induced by closure of the durotomy site. Among various methods to treat cerebrospinal fluid leakage through unidentified dural injury site, primary repair and spinal subarachnoid drainage are well known treatment options. The brain imaging study to diagnose intracranial hemorrhage should be taken before selecting the treatment method, especially for spinal subarachnoid drainage. Similar mechanism to its spinal counterpart, cranial cerebrospinal fluid drainage has not been mentioned in previous article and could be another treatment option to seal off an unidentified dural tear in particular case of drainage of intracranial hemorrhage is needed. PMID:23439677
Summary��Alzheimer's disease (AD) is the most common disease causing dementia. Today the clinical diagnosis of AD is made by way of exclusion, and no biochemical markers are available to assist the clinical diagnosis. We examined the potential of neuron-specific enolase (NSE) in cerebrospinal fluid (CSF) as a diagnostic marker for AD. NSE was determined with a monoclonal antibody two-site immunoradiometric
K. Blennow; A. Wallin; R. Ekman
Alternative cleavage of the amyloid precursor protein (APP) results in generation and secretion of both soluble APP (sAPP) and ?-amyloid (A?). A? is the main component of the amyloid depositions in the brains of Alzheimer's disease (AD) patients. Using Western blotting, we compared the levels of ?-secretase cleaved sAPP, ?-secretase cleaved sAPP and total sAPP, in cerebrospinal fluid (CSF) from
Kristina Sennvik; Johan Fastbom; Mari Blomberg; Lars-Olof Wahlund; Bengt Winblad; Eirikur Benedikz
Sugar Chains of Cerebrospinal Fluid Transferrin as a New Biological Marker of Alzheimer�s Disease
Background\\/Aims: Alzheimer�s disease (AD) is a well-known type of dementia. However, it remains difficult to identify AD in the early stage and to distinguish it from other dementing disorders. We examined glycoproteins in cerebrospinal fluid (CSF) as potential biological markers of AD. Methods: CSF samples were collected from AD, other dementia and nondemented patients. Glycoproteins in CSF were detected by
Miyako Taniguchi; Yuka Okayama; Yuki Hashimoto; Miki Kitaura; Daiki Jimbo; Yosuke Wakutani; Kenji Wada-Isoe; Kenji Nakashima; Hiroyasu Akatsu; Katsutoshi Furukawa; Hiroyuki Arai; Katsuya Urakami
Background and Purpose�Copper-zinc superoxide dismutase (CuZnSOD) is expressed intracellularly, while extracel- lular SOD (EC-SOD) is released from cells. The purpose of this study was to determine whether gene transfer of CuZnSOD increases SOD activity predominantly in tissues, and gene transfer of EC-SOD increases SOD activity in cerebrospinal fluid (CSF). We also determined whether heparin or dextran sulfate releases EC-SOD into
Hiroshi Nakane; Yi Chu; Frank M. Faraci; Larry W. Oberley; Donald D. Heistad
The penetration of the active metabolites of Cyclophosphamide(CP) and ifosfamide (IF) into cerebrospinal fluid (CSF) was determined in rhesus monkeys following an i.v. infusion of 1 gm\\/m2 of CP and IF. Active metabolites were measured using a high-performance liquid chro- matography assay with fluorometric detection following derivatization with m-aminophenol. CSF to blood ratios of the active metabolites of CP and
Carola A. S. Arndt; Frank M. Balis; Cynthia Lester McCully; O. Michael Colvin; David G. Poplack
Factors Influencing the Measurement of Lysosomal Enzymes Activity in Human Cerebrospinal Fluid
Measurements of the activities of lysosomal enzymes in cerebrospinal fluid have recently been proposed as putative biomarkers for Parkinson's disease and other synucleinopathies. To define the operating procedures useful for ensuring the reliability of these measurements, we analyzed several pre-analytical factors that may influence the activity of ?-glucocerebrosidase, ?-mannosidase, ?-mannosidase, ?-galactosidase, ?-fucosidase, ?-hexosaminidase, cathepsin D and cathepsin E in cerebrospinal fluid. Lysosomal enzyme activities were measured by well-established fluorimetric assays in a consecutive series of patients (n?=?28) with different neurological conditions, including Parkinson's disease. The precision, pre-storage and storage conditions, and freeze/thaw cycles were evaluated. All of the assays showed within- and between-run variabilities below 10%. At ?20�C, only cathepsin D was stable up to 40 weeks. At ?80�C, the cathepsin D, cathepsin E, and ?-mannosidase activities did not change significantly up to 40 weeks, while ?-glucocerebrosidase activity was stable up to 32 weeks. The ?-galactosidase and ?-fucosidase activities significantly increased (+54.9�38.08% after 4 weeks and +88.94�36.19% after 16 weeks, respectively). Up to four freeze/thaw cycles did not significantly affect the activities of cathepsins D and E. The ?-glucocerebrosidase activity showed a slight decrease (?14.6%) after two freeze/thaw cycles. The measurement of lysosomal enzyme activities in cerebrospinal fluid is reliable and reproducible if pre-analytical factors are accurately taken into consideration. Therefore, the analytical recommendations that ensue from this study may contribute to the establishment of actual values for the activities of cerebrospinal fluid lysosomal enzymes as putative biomarkers for Parkinson's disease and other neurodegenerative disorders. PMID:24983953
Parnetti, Lucilla; Eusebi, Paolo; Paciotti, Silvia; De Carlo, Claudia; Codini, Michela; Tambasco, Nicola; Rossi, Aroldo; Agnaf, Omar M. El.; Calabresi, Paolo; Beccari, Tommaso
Cerebrospinal fluid biomarkers in parkinsonian conditions: an update and future directions
Parkinsonian diseases comprise a heterogeneous group of neurodegenerative disorders, which show significant clinical and pathological overlap. Accurate diagnosis still largely relies on clinical acumen; pathological diagnosis remains the gold standard. There is an urgent need for biomarkers to diagnose parkinsonian disorders, particularly in the early stages when diagnosis is most difficult. In this review, several of the most promising cerebrospinal fluid candidate markers will be discussed. Their strengths and limitations will be considered together with future developments in the field. PMID:24691581
Magdalinou, Nadia; Lees, Andrew J; Zetterberg, Henrik
Biomarkers of Folate and Vitamin B12 Are Related in Blood and Cerebrospinal Fluid
Background: B-vitamins (folate, B12) are important mi- cronutrients for brain function and essential cofactors for homocysteine (HCY) metabolism. Increased HCY has been related to neurological and psychiatric disor- ders. We studied the role of the B-vitamins in HCY metabolism in the brain. Methods: We studied blood and cerebrospinal fluid (CSF) samples from 72 patients who underwent lumbar puncture. We measured
Rima Obeid; Panagiotis Kostopoulos; Jean-Pierre Knapp; Mariz Kasoha; George Becker; Klaus Fassbender; Wolfgang Herrmann
Pediatric Neurosurgical Practice Patterns Designed to Prevent Cerebrospinal Fluid Shunt Infection
Background\\/Aims: Various factors have been associated with cerebrospinal fluid (CSF) shunt infection risk, leading to many recommendations intended to reduce that risk. We sought to assess current North American pediatric neurosurgical practice patterns in this regard via a web-based survey. Particular attention was paid to the use of antibiotic-impregnated materials and prophylactic perioperative antibiotics. Methods: The membership of the section
Thomas J. Gruber; Sara Riemer; Curtis J. Rozzelle
A randomized, double-blind, placebo-controlled trial of perioperative rifampin-trimethoprim was undertaken at the Hospital for Sick Children from March 1984 to October 1987, in which 243 patients undergoing 300 cerebrospinal fluid (CSF) shunting procedures were randomized into groups including treatment with rifampin\\/trimethoprim and placebo, and then followed for a minimum of 2 years. Patients were stratified prior to randomization into those
Beverly C. Walters; Liliana Goumnerova; Harold J. Hoffman; E. Bruce Hendrick; Robin P. Humphreys; Carey Levinton
Cerebrospinal fluid of Alzheimer patients promotes ?-amyloid fibril formation in vitro
Cerebral deposition of amyloid ?-peptide (A?) is an invariant feature of Alzheimer's disease (AD). To answer why soluble A? does not aggregate to ?-amyloid fibrils (fA?) in the brain of normal humans, we examined the influence of cerebrospinal fluid (CSF) obtained from AD and non-AD patients on the formation of fA?(1�40) and fA?(1�42) in vitro, by using fluorescence spectroscopy with
Kenjiro Ono; Moeko Noguchi; Yasuko Matsumoto; Daisuke Yanase; Kazuo Iwasa; Hironobu Naiki; Masahito Yamada
This report describes treatment with cervical epidural blood patch of low cerebrospinal fluid (CSF) pressure headache resulting from spontaneous CSF leak via a tear in a cervical dural cuff. The leak was diagnosed by a dynamic computed tomography (CT)-myelography study followed by gadolinium enhanced magnetic res- onance imaging(MRI)-scan. The epidural needle was inserted with the aid of image intensifier and
Michael J. Cousins; David Brazier; Raymond Cook
Passage of neuropeptides from the cerebrospinal fluid to circulation depends upon cisternal pressure. When cisternal collecting pressure was kept at -20 cm, plasma levels of gastrin-17 and somatostatin-14 remained at basal values despite perfusion of high doses of the peptides into the cerebro-ventricular system. Progressive reduction of this pressure above -15 cm results in a progressive rise of the peripheral concentration of the peptides. Discrimination between central and peripheral action of centrally administered neuropeptides is, therefore, possible. PMID:6145499
Chang, T M; Passaro, E; Debas, H; Yamada, T; Oldendorf, W H
8 male schizophrenic patients participated in a double-blind, cross over study of the extrapyramidal side-effects of haloperidol and clozapine (acute dystonia, Parkinsonism and tardive dyskinesia), together with their effect on homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). Haloperidol (9 mg\\/day) caused Parkinsonism, reduced tardive dyskinesias and increased the HVA concentration in the CSF. Clozapine (225
J. Gerlach; K. Thorsen; R. Fog
Background: Some important clinical differences exist between human immunodeficiency virus (HIV)-seropositive and HIV-seronegative patients. Alterations in the cerebrospinal fluid (CSF) cytokines and matrix metalloproteinase have been noted in tuberculous meningitis. In HIV-infected patients, the immunopathogenesis is expected to be different. Materials and Methods: In this study, 64 patients of tuberculous meningitis (28 HIV seropositive and 36 seronegative) were included. The patients were followed up for six months. Cerebrospinal fluid (CSF) samples of tuberculous meningitis patients and 20 controls were subjected to tissue necrosis factor (TNF)-?, interleukin (IL)-1?, interferon (IFN)-?, IL-10, matrix metalloproteinase (MMP)-2, and MMP-9 estimations. The levels were correlated with the patients� baseline clinical characteristics, CSF parameters, neuroimaging findings, and the outcome. The outcome was assessed and modified with the Barthel index. Results: The CSF cytokines and MMP levels were significantly elevated in tuberculous meningitis when compared with the controls. There was no significant difference seen between HIV seropositive and seronegative tuberculous meningitis, except for the IL-1? level, which was significantly lower in the HIV-infected patients. The cytokine and MMP levels did not correlate with the baseline clinical characteristics, disease severity, cerebrospinal fluid characteristics, neuroimaging findings, and outcome. Conclusion: In conclusion, HIV infection did not affect a majority of the CSF cytokines and MMP levels in tuberculous meningitis except for IL-1? level. None of the estimated inflammatory parameters correlated with the outcome. PMID:25024567
Rai, Dheeraj; Garg, Ravindra Kumar; Mahdi, Abbas Ali; Jain, Amita; Verma, Rajesh; Tripathi, Anil Kumar; Singh, Maneesh Kumar; Malhotra, Hardeep Singh; Singh, Gyan Prakash; Ahmad, Mohammad Kaleem
Demonstration of the exact site of the dural fistula in cerebrospinal fluid rhinorrhea is difficult. Previous reports present the methods of metrizamide cisternography combined with both hypocycloid tomography and computed tomography. But in these methods, direct, dynamic, actual and real-time visualization of the fistula with minimal dose of metrizamide is rather difficult. By using digital video subtraction system (Philips DVI-2CV), we could visualize the direct, dynamic and actual site of fistula with small amount of metrizamide instilled into the suboccipital subarachnoid space with the patient prone position. We report a successful case of traumatic cerebrospinal fluid rhinorrhea drained through the bony defect at the planum sphenoid into the posterior ethmoid sinus. This is the first report to deal with the usefulness of digital video subtraction system for exact localization of cerebrospinal fluid rhinorrhea. We emphasize the usefulness of metrizamide cisternography by the digital video subtraction system combined with the metrizamide computed tomographic cisternography for the precise localization of dural fistula. PMID:3320800
Takahashi, T; Mutsuga, N; Aoki, T; Handa, T
Development of a theoretical framework for analyzing cerebrospinal fluid dynamics
Background To date hydrocephalus researchers acknowledge the need for rigorous but utilitarian fluid mechanics understanding and methodologies in studying normal and hydrocephalic intracranial dynamics. Pressure volume models and electric circuit analogs introduced pressure into volume conservation; but control volume analysis enforces independent conditions on pressure and volume. Previously, utilization of clinical measurements has been limited to understanding of the relative amplitude and timing of flow, volume and pressure waveforms; qualitative approaches without a clear framework for meaningful quantitative comparison. Methods Control volume analysis is presented to introduce the reader to the theoretical background of this foundational fluid mechanics technique for application to general control volumes. This approach is able to directly incorporate the diverse measurements obtained by clinicians to better elucidate intracranial dynamics and progression to disorder. Results Several examples of meaningful intracranial control volumes and the particular measurement sets needed for the analysis are discussed. Conclusion Control volume analysis provides a framework to guide the type and location of measurements and also a way to interpret the resulting data within a fundamental fluid physics analysis. PMID:19772652
Cohen, Benjamin; Voorhees, Abram; Vedel, S?ren; Wei, Timothy
Application of Control Volume Analysis to Cerebrospinal Fluid Dynamics
NASA Astrophysics Data System (ADS)
Hydrocephalus is among the most common birth defects and may not be prevented nor cured. Afflicted individuals face serious issues, which at present are too complicated and not well enough understood to treat via systematic therapies. This talk outlines the framework and application of a control volume methodology to clinical Phase Contrast MRI data. Specifically, integral control volume analysis utilizes a fundamental, fluid dynamics methodology to quantify intracranial dynamics within a precise, direct, and physically meaningful framework. A chronically shunted, hydrocephalic patient in need of a revision procedure was used as an in vivo case study. Magnetic resonance velocity measurements within the patient's aqueduct were obtained in four biomedical state and were analyzed using the methods presented in this dissertation. Pressure force estimates were obtained, showing distinct differences in amplitude, phase, and waveform shape for different intracranial states within the same individual. Thoughts on the physiological and diagnostic research and development implications/opportunities will be presented.
Wei, Timothy; Cohen, Benjamin; Anor, Tomer; Madsen, Joseph
Cerebrospinal fluid flow imaging by using phase-contrast MR technique
Cerebrospinal fluid (CSF) spaces include ventricles and cerebral and spinal subarachnoid spaces. CSF motion is a combined effect of CSF production rate and superimposed cardiac pulsations. Knowledge of CSF dynamics has benefited considerably from the development of phase-contrast (PC) MRI. There are several disorders such as communicating and non-communicating hydrocephalus, Chiari malformation, syringomyelic cyst and arachnoid cyst that can change the CSF dynamics. The aims of this pictorial review are to outline the PC MRI technique, CSF physiology and cerebrospinal space anatomy, to describe a group of congenital and acquired disorders that can alter the CSF dynamics, and to assess the use of PC MRI in the assessment of various central nervous system abnormalities. PMID:21586507
Battal, B; Kocaoglu, M; Bulakbasi, N; Husmen, G; Tuba Sanal, H; Tayfun, C
Cerebrospinal fluid flow imaging by using phase-contrast MR technique.
Cerebrospinal fluid (CSF) spaces include ventricles and cerebral and spinal subarachnoid spaces. CSF motion is a combined effect of CSF production rate and superimposed cardiac pulsations. Knowledge of CSF dynamics has benefited considerably from the development of phase-contrast (PC) MRI. There are several disorders such as communicating and non-communicating hydrocephalus, Chiari malformation, syringomyelic cyst and arachnoid cyst that can change the CSF dynamics. The aims of this pictorial review are to outline the PC MRI technique, CSF physiology and cerebrospinal space anatomy, to describe a group of congenital and acquired disorders that can alter the CSF dynamics, and to assess the use of PC MRI in the assessment of various central nervous system abnormalities. PMID:21586507
Battal, B; Kocaoglu, M; Bulakbasi, N; Husmen, G; Tuba Sanal, H; Tayfun, C
Cerebrospinal fluid (CSF) flow dynamics, which supposedly have a strong relationship with chronic cerebrospinal venous insufficiency (CCSVI), might be expected to be affected in multiple sclerosis (MS) patients. In this study, CSF flow at the level of the cerebral aqueduct was evaluated quantitatively by phase contrast magnetic resonance imaging (PC-MRI) to determine whether CSF flow dynamics are affected in MS patients. We studied 40 MS patients and 40 healthy controls using PC-MRI. We found significantly higher caudocranial (p=0.010) and craniocaudal CSF flow volumes (p=0.015) and stroke volume (p=0.010) in the MS patients compared with the controls. These findings may support the venous occlusion theory, but may also be explained by atrophy-dependent ventricular dilatation independent of the venous theory in MS patients. PMID:22364942
Gorucu, Y; Albayram, S; Balci, B; Hasiloglu, Z I; Yenigul, K; Yargic, F; Keser, Z; Kantarci, F; Kiris, A
The management of cerebrospinal fluid rhinorrhea has historically plagued the neurosurgeon and the otolaryngologist-head and neck surgeon. Intracranial repair is still favored at many institutions, despite its inherent morbidity. Extracranial nonendoscopic techniques have been previously described but have not gained wide acceptance. More recently, several reports have been published describing a variety of endoscopic techniques in limited patient series used to manage cerebrospinal fluid rhinorrhea. We present our series of 29 patients with cerebrospinal fluid rhinorrhea, treated with endoscopic techniques between December 1989 and June 1993, with follow-up ranging from 3 to 43 months. This represents the largest reported series to date of patients treated with this technique. Our technique has evolved during this time period but centers around the use of free tissue grafts from various donor sites. The causes of the skull base defects in this series included neurosurgical procedures (9), functional endoscopic sinus surgery (8), and trauma (3). Defects occurred spontaneously in 9 cases. The fovea ethmoidalis and sphenoid sinus were the site in 11 and 12 cases, respectively, and the cribriform plate was involved in 6 cases. Cerebrospinal fluid rhinorrhea was documented by nasal endoscopy with or without intrathecal fluorescein, laboratory studies, computed tomography with or without contrast cisternography, and radioisotope cisternography in various combinations. Resolution of cerebrospinal fluid rhinorrhea was achieved in 22 of 29 patients (75.9%) with one endoscopic procedure and 25 of 29 patients (86.2%) after a second attempt. Four patients required neurosurgical intervention for recurrent cerebrospinal fluid rhinorrhea. Complications were minimal and were related primarily to the original pathology or procedure. Cerebrospinal fluid rhinorrhea can be managed safely and effectively with endoscopic techniques in a majority of cases, and the morbidity of open procedures can be avoided. PMID:7970798
Dodson, E E; Gross, C W; Swerdloff, J L; Gustafson, L M
To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt-Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study ('cerebrospinal fluid markers') we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-?(1-42)) and evaluated the specificity of 14-3-3 in Creutzfeldt-Jakob disease diagnosis for the years 1998-2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt-Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt-Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt-Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95-97%) and non-neurological conditions (91-97%). We observed lower specificity in the differential diagnoses of acute neurological diseases (82-87%). A marked and constant increase in cerebrospinal fluid test referrals per year in all centres did not influence 14-3-3 test specificity and no change in spectrum of differential diagnosis was observed. Cerebrospinal fluid protein 14-3-3 detection remains an important test in the diagnosis of Creutzfeldt-Jakob disease. Due to a loss in specificity in acute neurological events, the interpretation of positive 14-3-3 results needs to be performed in the clinical context. The spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions such as inflammatory diseases and non-neurological origin. PMID:23012332
Stoeck, Katharina; Sanchez-Juan, Pascual; Gawinecka, Joanna; Green, Alison; Ladogana, Anna; Pocchiari, Maurizio; Sanchez-Valle, Raquel; Mitrova, Eva; Sklaviadis, Theodor; Kulczycki, Jerzy; Slivarichova, Dana; Saiz, Albert; Calero, Miguel; Knight, Richard; Aguzzi, Adriano; Laplanche, Jean-Louis; Peoc'h, Katell; Schelzke, Gabi; Karch, Andre; van Duijn, Cornelia M; Zerr, Inga
To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt�Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study (�cerebrospinal fluid markers�) we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-?1�42) and evaluated the specificity of 14-3-3 in Creutzfeldt�Jakob disease diagnosis for the years 1998�2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt�Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt�Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt�Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95�97%) and non-neurological conditions (91�97%). We observed lower specificity in the differential diagnoses of acute neurological diseases (82�87%). A marked and constant increase in cerebrospinal fluid test referrals per year in all centres did not influence 14-3-3 test specificity and no change in spectrum of differential diagnosis was observed. Cerebrospinal fluid protein 14-3-3 detection remains an important test in the diagnosis of Creutzfeldt�Jakob disease. Due to a loss in specificity in acute neurological events, the interpretation of positive 14-3-3 results needs to be performed in the clinical context. The spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions such as inflammatory diseases and non-neurological origin. PMID:23012332
Sanchez-Juan, Pascual; Gawinecka, Joanna; Green, Alison; Ladogana, Anna; Pocchiari, Maurizio; Sanchez-Valle, Raquel; Mitrova, Eva; Sklaviadis, Theodor; Kulczycki, Jerzy; Slivarichova, Dana; Saiz, Albert; Calero, Miguel; Knight, Richard; Aguzzi, Adriano; Laplanche, Jean-Louis; Peoc'h, Katell; Schelzke, Gabi; Karch, Andre; van Duijn, Cornelia M.; Zerr, Inga
Background Currently, there are no consistently effective chemotherapies for recurrent and inoperable meningiomas. Recently, cucurbitacin I (JSI-124), a naturally occurring tetracyclic triterpenoid compound used as folk medicines has been found to have cytoxic and anti-proliferative properties in several malignancies thru inhibition of activator of transcription (STAT3) activation. Previously, we have found STAT3 to be activated in meningiomas, particularly higher grade tumors. Methods Primary leptomeningeal cultures were established from 17, 20 and 22�week human fetuses and meningioma cell cultures were established from 6 World Health Organization (WHO) grade I or II meningiomas. Cells were treated with cerebrospinal fluid from patients without neurologic disease. The effects of cucurbitacin I on cerebrospinal fluid stimulation of meningioma cell DNA synthesis phosphorylation/activation of JAK1, STAT3, pMEK1/2, p44/42MAPK, Akt, mTOR, Rb and caspase 3 activation were analyzed in human leptomeningeal and meningioma cells. Results Cerebrospinal fluid significantly stimulated DNA synthesis in leptomeningeal cells. Co-administration of cucurbitacin I (250?nM) produces a significant blockade of this effect. Cucurbitacin I alone also produced a significant reduction in basal DNA synthesis. In grade I and II meningiomas, cerebrospinal fluid also significantly stimulated DNA synthesis. Co-administration of cucurbitacin I (250?nM) blocked this effect. In the leptomeningeal cultures, cerebrospinal fluid stimulated STAT3 phosphorylation but not p44/42MAPK, Akt or mTOR. Cucurbitacin I had no effect on basal STAT3 phosphorylation but co-administration with cerebrospinal fluid blocked cerebrospinal fluid stimulation of STAT3 phosphorylation in each. In the grade I meningiomas, cerebrospinal fluid stimulated phosphorylation of STAT3 and decreased MEK1/2 and cucurbitacin I had no effect on basal STAT3, p44/42MAPK, Akt, JAK1, mTOR, or Rb phosphorylation. In the grade II meningiomas, cerebrospinal fluid stimulated STAT3 phosphorylation in all and reduced phosphorylation of MEK1/2 in all and p44/42MAPK in one. Cucurbitacin I had no effect on basal phosphorylation of STAT3 but reduced phorphorylated p44/42 MAPK in 2 grade II meningioma cells lines. Conclusions These studies raise the possibility that cucurbitacin I might have value as an adjunct chemotherapy. Additional studies are warranted to evaluate the effects of cucurbitacin I on meningiomas in vivo. PMID:24188277
Bipolar disorder is a psychiatric disorder characterized by recurrent episodes of mania/hypomania and depression. Progressive cognitive dysfunction such as impairments in executive function and verbal memory is common in euthymic bipolar patients. The cerebrospinal fluid has previously been used to study neurodegenerative processes in Alzheimer's disease, from which changes in three core biomarkers have emerged as indicative of degeneration: amyloid ?, total tau, and hyperphosphorylated tau. Here, neurodegeneration in bipolar disorder was investigated by assessing the association between bipolar disorder and cerebrospinal fluid biomarkers for neurodegenerative processes. Cerebrospinal fluid was obtained from 139 bipolar disorder patients and 71 healthy controls. Concentrations of total and phosphorylated tau, amyloid ?1-42, amyloid ?38/?40/?42, and the soluble forms of amyloid precursor protein were measured in patients vs controls. The concentrations of the soluble forms of amyloid precursor protein were significantly lower in bipolar patients compared with controls. The amyloid ?42/amyloid ?38 and the amyloid ?42/amyloid ?40 ratios were higher in bipolar patients than controls. There were no discernible differences in the concentrations of total/phosphorylated tau, amyloid ?1-42, or amyloid ?38/?40/?42. The concentrations of the biomarkers within the bipolar patient group were further associated with different ongoing medical treatments and diagnostic subgroups. The findings suggest that the amyloid precursor protein metabolism is altered in bipolar disorder. The results may have implications for the understanding of the pathophysiology of bipolar disorder and for the development of treatment strategies. Importantly, there were no signs of an Alzheimer-like neurodegenerative process among bipolar patients. PMID:23212456
Jakobsson, Joel; Zetterberg, Henrik; Blennow, Kaj; Johan Ekman, Carl; Johansson, Anette G M; Landen, Mikael
Cerebrospinal fluid and serum cytokine profiles in narcolepsy with cataplexy: a case-control study.
Recent advances in the identification of susceptibility genes and environmental exposures provide strong support that narcolepsy-cataplexy is an immune-mediated disease. Only few serum cytokine studies with controversial results were performed in narcolepsy and none in the cerebrospinal fluid. We measured a panel of 12 cytokines by a proteomic approach in the serum of 35 patients with narcolepsy-cataplexy compared to 156 healthy controls, and in the cerebrospinal fluid of 34 patients with narcolepsy-cataplexy compared to 17 non-narcoleptic patients; and analyzed the effect of age, duration and severity of disease on the cytokine levels. After multiple adjustments we reported lower serum IL-2, IL-8, TNF-?, MCP-1 and EGF levels, and a tendency for higher IL-4 level in narcolepsy compared to controls. Significant differences were only found for IL-4 in cerebrospinal fluid, being higher in narcolepsy. Positive correlations were found in serum between IL-4, daytime sleepiness, and cataplexy frequency. The expression of some pro-inflammatory cytokines (MCP-1, VEGF, EGF, IL2, IL-1?, IFN-?) in either serum or CSF was negatively correlated with disease severity and duration. No correlation was found for any specific cytokine in 18 of the patients with narcolepsy with peripheral and central samples collected the same day. Significant decreased pro/anti-inflammatory cytokine profiles were found at peripheral and central levels in narcolepsy, together with a T helper 2/Th1 serum cytokine secretion imbalance. To conclude, we showed some evidence for alterations in the cytokine profile in patients with narcolepsy-cataplexy compared to controls at peripheral and central levels, with the potential role of IL-4 and significant Th1/2 imbalance in the pathophysiology of narcolepsy. PMID:24394344
Dauvilliers, Yves; Jaussent, Isabelle; Lecendreux, Michel; Scholz, Sabine; Bayard, Sophie; Cristol, Jean Paul; Blain, Hubert; Dupuy, Anne-Marie
Spectrophotometric study of total protein-albumin methods applied to cerebrospinal fluid.
A spectrophotometric study was carried out for three proteins assays when modification of their serum procedures using bromcresol green, bromcresol purple and biuret reagents were applied to the determinations of total proteins and albumin in cerebrospinal fluids. A novel concentration device wherein the sample itself was used as the primary diluent for the three reagents concentrated to contain the proper amounts of chemicals in smaller volumes than suggested in their serum procedures allowed reasonable absorbance signals to be obtained. Low molecular weight molecules were separated from the albumin and globulins of the fluids by centrifugal ultrafiltration using a 25K cutoff and spectra were obtained for both high and low molecular weight fractions. Some materials were obtained in the separated ultrafiltrates which gave reactions with all three reagents, reactions which either overlapped the spectra of the albumin reactions or superimposed the spectra obtained with the total protein reaction. A screening procedure for cerebrospinal fluid total proteins or centrifugally ultrafiltered albumin appears reasonable as an inference from studies made, although further elucidation of the low molecular weight fractions in needed as a confirmation device. PMID:7237740
Artiss, J D; Thibert, R J; Zak, B
Cerebrospinal fluid protein changes in multiple sclerosis after dental amalgam removal.
A relationship between multiple sclerosis (MS) and dental silver-mercury fillings has been suggested by some investigators, but never proven. This study documents objective biochemical changes following the removal of these fillings along with other dental materials, utilizing a new health care model of multidisciplinary planning and treatment. The dramatic changes in photolabeling of cerebrospinal fluid (CSF) proteins following these dental interventions suggest CSF photolabeling may serve as an objective biomarker for monitoring MS. The clear-cut character of these changes should also encourage more research to better define this possible association between dental mercury and MS. PMID:9727079
Huggins, H A; Levy, T E
Mondini dysplasia is a congenital malformation of the inner ear, which is characterized by a short and large cochlear canal of 1.5 turn rather than 2.5 turns and an apical region with cystic dilatation. Patients present with congenital deafness, when both cochlea are affected. Unilateral disease may cause recurrent meningitis, otorrhea or rhinorrhea. In this article, we report a three-year-old pediatric case with a history of meningitis and cerebrospinal fluid otorrhea following tympanostomy tube placement for serous otitis media. PMID:23521415
I?eri, Mete; U�ar, Sel�uk; Derin, Serhan; Ust�nda?, Emre
Transclival cerebrospinal fluid fistula in a patient with Marfan�s syndrome
Summary��Marfan�s syndrome is a disease associated with reduced structural integrity of connective tissues. We report a 36-year-old\\u000a patient with Marfan�s syndrome who presented with rhinorrhoea, occipital headache and vomiting. Physical examination revealed\\u000a typical Marfan�s syndrome features including dolicocephalous, mandibular micrognathia, tall stature, disproportionately long\\u000a limbs and digits, and hypermobility of the joints. A high-resolution CT scan demonstrated pneumoencephalous, cerebrospinal\\u000a fluid
A. Ramos; J. Garc�a-Ur�a; L. Ley; G. Saucedo
Cerebrospinal fluid CXCL13 is a prognostic marker for aseptic meningitis.
In exceptional cases, patients with aseptic meningitis eventually develop aseptic meningoencephalitis. To find a candidate marker for the development of aseptic meningoencephalitis in adult patients diagnosed with aseptic meningitis, we compared 12 different cytokines/chemokines in cerebrospinal fluid (CSF) from 5 patients with aseptic meningoencephalitis, 8 patients with aseptic meningitis, and 8 patients with control disease. Only the CXCL13 concentration was significantly elevated in the CSF of the group with aseptic meningoencephalitis compared with the group with aseptic meningitis. Thus, CSF CXCL13 may be a useful marker for predicting the prognosis of aseptic meningitis. PMID:24907903
Fujimori, Juichi; Nakashima, Ichiro; Kuroda, Hiroshi; Fujihara, Kazuo; Aoki, Masashi
Digital PCR technology detects brain-tumor-associated mutation in cerebrospinal fluid
Researchers from the Massachusetts General Hospital (a component of the Dana-Farber Cancer Institute) and their colleagues have used digital versions of a standard molecular biology tool to detect a common tumor-associated mutation in the cerebrospinal fluid (CSF) of patients with brain tumors. In their report being published in the open-access journal Molecular Therapy � Nucleic Acids, the investigators describe using advanced forms of the gene-amplification technology polymerase chain reaction (PCR) to analyze bits of RNA carried in membrane-covered sacs called extracellular vesicles for the presence of a tumor-associated mutation in a gene called IDH1.
N-Acetylaspartic and N-acetylaspartylglutamic acid concentrations in human ventricular, subarachnoid and lumbar cerebrospinal fluid were measured by combined gas chromatography-mass spectrometry using selected ion monitoring with deuterated internal standards. N-Acetylaspartate concentrations were in the range 55, 9, and 1 microM, respectively; N-acetylaspartylglutamate concentrations in the same fluids were in the range 8, 3 and 4 microM, respectively. There did not appear to be any difference in lumbar fluid concentrations of either compound between control subjects, schizophrenic patients, Alzheimer's disease patients and a pooled group of patients with neurological degeneration. Ventricular concentrations of both compounds were greatly increased in deceased patients suggesting that maintenance of their intracellular concentrations is probably energy dependent. The concentrations of these compounds in lumbar cerebrospinal fluid from living, and ventricular cerebrospinal fluid from deceased subjects were weakly correlated with one another. In lumbar fluid neither compound appeared to be correlated with age. Analysis of serially collected lumbar samples from two subjects showed a weak concentration gradient for both compounds. Neither antipsychotic medication nor the acid transport inhibitor probenecid had any effect on lumbar concentrations of either compound. Attempts to use anion exchange high pressure liquid chromatography with UV detection for measurement of the low concentrations of N-acetylaspartate found in cerebrospinal fluid from living subjects were unsuccessful. PMID:10492520
Faull, K F; Rafie, R; Pascoe, N; Marsh, L; Pfefferbaum, A
This study is a review of 1,040 significant positive blood cultures from 415 patients, and 44 positive cerebrospinal fluid cultures from 44 patients treated at the Meir General Hospital during the period 1976-78. The most frequent isolates from blood cultures were Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae. The most frequent isolates from cerebrospinal fluid cultures were Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis, which were present in similar proportions. E. coli was predominant in the division of medicine, Staph. aureus in the division of pediatrics and Klebsiella in the division of surgery. Fifty percent of the E. coli isolates were sensitive to ampicillin and carbenicillin; about 80%, to cephalothin and sulfamethoxazole-trimethoprim; and 100%, to gentamicin. Only 7% of the Klebsiella isolates were sensitive to apicillin; 72% were sensitive to cephalothin and 87%, to gentamicin. Only 18% of Staph. aureus isolates were sensitive to penicillin, but about 95% were sensitive to methicillin or cephalothin. Two of 10 salmonellae isolates and 13% of H. influenzae were resistant to ampicillin. PMID:6772597
Nitzan, Y; Maayan, M; Drucker, M
Because normal cerebrospinal fluid (CSF) has almost no natural Doppler scatterers, patency testing of ventriculoperitoneal cerebrospinal fluid shunts (small silastic tubing with lumen diameter of approximately 1 mm draining excessive CSF from the brain) cannot be performed by Doppler ultrasound. We have developed a low-frequency bubble excitation system that generates microbubble scatterers in both distilled water and CSF. Doppler ultrasound can then be used for flow measurement in a ventriculoperitoneal shunt. By using low duty-cycle (approximately 10%), low-frequency (approximately 30 kHz), and low-amplitude (approximately 30 kPa) ultrasound, a population of microbubbles can be maintained for sufficiently long times (>10 min) for Doppler ultrasound measurement, although bubble initiation is inconsistent. The minimum pressure needed for bubble maintenance was found to decrease with increasing burst length and duty cycle. It has been possible to detect the presence of CSF shunt flow down to a mean flow rate of 3 mL/h (mean velocity approximately 0.6 mm/s). The bubble maintenance scheme developed satisfies the safety parameters specified by the American Institute of Ultrasound in Medicine (AIUM) and the US Food and Drug Administration (FDA). Results from both in vitro and in vivo (externalized shunts) experiments indicate the feasibility of this scheme for determining realistic CSF shunt flows, though some practical problems remain before the technique will be ready for clinical use. PMID:10374981
Lam, K W; Drake, J M; Cobbold, R S
In inflammatory disease of the central nervous system (CNS), oligoclonal bands of immunoglobulin with restricted heterogeneity can often be observed in cerebrospinal fluid (CSF) samples. These antibodies can be directed against the disease inducing pathogen or might be autoreactive and involved in the process of brain inflammation and demyelination. We used a molecular biology approach to characterize these antibody responses in patients with Lyme disease. This disorder is caused by infections with the spirochete Borrelia burgdorferi which is transmitted by ticks. Lyme disease can be associated with neurological symptoms due to inflammation of the central and peripheral nervous system. Phage lambda gtll expression libraries from B. burgdorferi and human brain were screened with cerebrospinal fluid antibody probes from patients with Lyme disease. We obtained recombinant phage clones encoding antigenic proteins from both B. burgdorferi and human CNS libraries. Thus, in this study two patients with chronic Lyme disease produced antibodies against recombinant B. burgdorferi as well as against CNS proteins, and the generation of this transient autoimmune response might be essential to the development of demyelinating disease. PMID:2491615
Schluesener, H J; Martin, R; Sticht-Groh, V
The olfactory route for cerebrospinal fluid drainage into the peripheral lymphatic system.
Drainage of the cerebrospinal fluid through the olfactory nerves into the nasal lymphatics has been suggested repeatedly. To investigate precisely the morphology of this pathway, India ink was injected into the subarachnoidal space of the rat brain, and samples including the olfactory bulbs, olfactory tracts and the nasal mucosa were observed by light and electron microscopy. Under the dissecting microscope, ink particles were found within the subarachnoid space and along the olfactory nerves. At the nasal mucosa, a lymphatic network stained in black was identified near the olfactory nerves, which finally emptied into the superficial and deep cervical lymph nodes. Light microscopically, ink particles were found in the subarachnoid space, partially distributed around the olfactory nerves and within the lymphatic vessels. By electron microscopy, the subarachnoid space often formed a pocket-like space in the entrance of the fila olfactoria. The olfactory nerves were partially surrounded by ink particles within the space between perineurial cells and epineurial fibroblasts. At the nasal mucosa, the lymphatics were frequently located close to the nerves. These results indicate that the cerebrospinal fluid drains from the subarachnoid space along the olfactory nerves to the nasal lymphatics, which in turn, empties into the cervical lymph nodes. This anatomical communication, thus, allows the central nervous system to connect with the lymphatic system. The presence of this route may play an important role in the movement of antigens from the subarachnoidal space to the extracranial lymphatic vessels, resulting in inducement of an immune response of the central nervous system. PMID:16866984
Walter, B A; Valera, V A; Takahashi, S; Ushiki, T
Subarachnoid haemorrhage constitutes a neurological emergency. In most cases the diagnosis is easy to establish by cerebral computed tomography or cerebrospinal fluid tap. However, in rare cases verification of the diagnosis is more difficult and a residual uncertainty remains. We describe three patients supposed to have a subarachnoid haemorrhage without pathological findings in both cerebral computed tomography and cerebrospinal fluid. In these cases vasospasm or cerebral aneurysm were detected by means of transcranial Doppler sonography and/or conventional angiography. We comment on the special features of this rare presentation of a severe acute neurological emergency, and we discuss diagnostic work-up and differential diagnoses. PMID:21128197
Burghaus, L; Liu, W; Fink, G R; Eggers, C
ABSTRACT Epilepsy is a common neurological disorder with seizures, but diagnostic approaches in veterinary clinics remain limited. Cerebrospinal fluid (CSF) is a body fluid used for diagnosis in veterinary medicine. In this study, we explored canine epilepsy diagnostic biomarkers using gas chromatography-mass spectrometry (GC-MS)-based metabolic profiling of CSF and multivariate data analysis. Profiles for subjects with idiopathic epilepsy differed significantly from those of healthy controls and subjects with symptomatic epilepsy. Among 60 identified metabolites, the levels of 20 differed significantly among the three groups. Glutamic acid was significantly increased in idiopathic epilepsy, and some metabolites including ascorbic acid were changed in both forms of epilepsy. These findings show that metabolic profiles of CSF differ between idiopathic and symptomatic epilepsy and that metabolites including glutamic acid and ascorbic acid in CSF may be useful for diagnosis of canine epilepsy. PMID:24334864
HASEGAWA, Tetsuya; SUMITA, Maho; HORITANI, Yusuke; TAMAI, Reo; TANAKA, Katsuhiro; KOMORI, Masayuki; TAKENAKA, Shigeo
Oropouche fever is the second most frequent arboviral infection in Brazil, surpassed only by dengue. Oropouche virus (OROV) causes large and explosive outbreaks of acute febrile illness in cities and villages in the Amazon and Central-Plateau regions. Cerebrospinal fluid (CSF) samples from 110 meningoencephalitis patients were analyzed. The RNA extracted from fluid was submitted to reverse transcription-polymerase chain reaction and sequencing to identify OROV. Three CSF samples showed the presence of OROV causing infection in the central nervous system (CNS). These patients are adults. Two of the patients had other diseases affecting CNS and immune systems: neurocysticercosis and acquired immunodeficiency syndrome, respectively. Nucleotide sequence analysis showed that the OROV from the CSF of these patients belonged to genotype I. We show here that severe Oropouche disease is occurring during outbreaks of this virus in Brazil. PMID:22492162
Bastos, Michele de Souza; Figueiredo, Luiz Tadeu Moraes; Naveca, Felipe Gomes; Monte, Rossicleia Lins; Lessa, Nat�lia; Pinto de Figueiredo, Regina Maria; Gimaque, Jo�o Bosco de Lima; Pivoto Jo�o, Guilherme; Ramasawmy, Rajendranath; Mour�o, Maria Paula Gomes
Acute myeloid leukemia (AML) can affect not only bone marrow (BM) and peripheral blood (PB), but also the compartment of cerebrospinal fluid (CSF). Besides standard chemotherapy, specific and non-specific immunotherapy has been employed synergistically to treat AML patients. Here we report on a patient who received standard chemotherapy, unspecific immunotherapy with interleukin-2, as well as later specific CD8+ T-cell stimulation by RHAMM-R3 peptide vaccination. The patient maintained a complete remission in BM and PB, while he developed recurrent relapses in the CSF. Moreover, the patient developed a chloroma in the vicinity of neuronal sheaths during hematological CR, but high leukemia cell numbers within the CSF spaces over a long time period. This rare observation demonstrates several aspects. There is a previously unknown site of leukemia cell distribution, namely the peripheral cerebrospinal outflow pathway (PCOP). This demonstrates the ineffective therapy of this previously unknown mechanism of leukemia cell spread. The hypothesis that the PCOP is a site of physiological CSF-T-cell trafficking, and the lumen of the PCOP should be considered as an extension of the subarachnoidal spaces without closed anatomical borders is supported by this observation. The CSF spaces, but possibly specifically the PCOP, may represent a previously unknown survival niche of tumor cells within intrathecal spaces. PMID:21737662
Schmitt, Michael; Neubauer, Andreas; Greiner, Jochen; Xu, Xun; Barth, Thomas F E; Bechter, Karl
Different pre-treatment methods have been compared for two-dimensional mapping of individual rat cerebrospinal fluid samples based on acetone, trichloroacetic acid\\/acetone and methanol\\/acetone precipitation of proteins. Acetone precipitation following incubation with DTT gave the highest protein recovery (72%) and the largest number of protein spots (92���4) as well as minimizing the time taken.
Sonia Garcia-Rodriguez; Sandro Arg�elles Castilla; Alberto Machado; Antonio Ayala
Laboratory evidence for tuberculous meningitis is difficult to acquire due to the low numbers of organisms present in cerebrospinal fluid (CSF) and the presence of nucleic acid amplification inhibitors. The Amplified Mycobacterium tuberculosis Direct Test (MTD) is sensitive and specific for the direct detection of M. tuberculosis complex in respiratory samples but has not been approved for CSF. We evaluated
Joann L. Cloud; Cheryl Shutt; Wade Aldous; Gail Woods
Distinguishing corticobasal degeneration (CBD) from progressive supranuclear palsy (PSP) is clinically and pathologically difficult, and a useful biological marker to discriminative these two diseases has been a subject of clinical interest. In the present study, we assessed tau protein levels in cerebrospinal fluids by sandwich ELISA to distinguish CBD from PSP. The subjects consisted of 27 cases of CBD, 30
K. Urakami; K. Wada; H. Arai; H. Sasaki; M. Kanai; M. Shoji; H. Ishizu; K. Kashihara; M. Yamamoto; K. Tsuchiya-Ikemoto; M. Morimatsu; H. Takashima; M. Nakagawa; K. Kurokawa; H. Maruyama; Y. Kaseda; S. Nakamura; K. Hasegawa; H. Oono; C. Hikasa; K. Ikeda; K. Yamagata; Y. Wakutani; T. Takeshima; K. Nakashima
Purpose: This study was conducted to evaluate the role of cerebrospinal fluid (CSF) drainage and distal aortic perfusion (DAP) in the prevention of postoperative neurologic complications for high-risk patients who had undergone type I and type II thoracoabdominal aortic aneurysm (TAAA) repair.Methods: CSF drainage and DAP were used as an adjunct in the treatment of 94 patients with TAAA (31
Hazim J. Safi; Kenneth R. Hess; Mark Randel; Dimitrios C. Iliopoulos; John C. Baldwin; Ravi K. Mootha; Salwa S. Shenaq; Roy Sheinbaum; Thomas Greene
Previous studies have reported elevated concentrations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) in patients with major depression. Elevations of CSF CRF have also been reported in adult laboratory animals exposed to the stress of brief maternal deprivation or maternal neglect in the neonatal or preweaning period. The present study was designed to determine whether major depression and a history
Linda L Carpenter; Audrey R Tyrka; Christopher J McDougle; Robert T Malison; Michael J Owens; Charles B Nemeroff; Lawrence H Price
Deposition of ?-synuclein (?S) aggregates inside brain cells is a pathological hallmark of several neurodegenerative diseases, including Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Recently, extracellular ?S was detected in cerebrospinal fluid (CSF) and plasma of humans. We investigated whether CSF influences ?S aggregation in vitro using fluorescence spectroscopy with thioflavin S and electron microscopy. We found that
Kenjiro Ono; Moeko Noguchi-Shinohara; Mitsuhiro Yoshita; Hironobu Naiki; Masahito Yamada
Cytokines are involved in nerve regeneration by modulating the synthesis of neurotrophic factors. The role played by interleukin-6 (IL-6) in promoting nerve growth factor (NGF) after brain injury was investigated by monitoring the release of IL-6 and NGF in ventricular cerebrospinal fluid (CSF) of 22 patients with severe traumatic brain injuries. IL-6 was found in the CSF of all individuals
Thomas Kossmann; Volkmar Hans; Hans-Georg Imhof; Otmar Trentz; Maria Cristina Morganti-Kossmann
PURPOSE: To evaluate MR imaging and lumbar cerebrospinal fluid enzymes as potential sensitive indicators of cerebral injury after open-heart valve replacement surgery. METHODS: Thirty-four patients with cardiac valvular disease were prospectively entered into this study and then under- went valve replacement or repair under cardiopulmonary bypass using a membrane oxygenator. In 26 patients, MR head images were obtained 12 to
Gary K. Steinberg; R. Scott Mitchell; Teresa E. Bell; Gregory W. Albers
The Guillain-Barr� syndrome is often preceded by a herpes virus infection. Herpes simplex virus, however, has rarely been observed as the causative agent. A patient is described with a herpes simplex virus infection followed by a Guillain-Barr� syndrome. Immunoblotting was used to detect herpes simplex virus-specific antibodies in serum and cerebrospinal fluid. Images PMID:2545828
Bernsen, H J; Van Loon, A M; Poels, R F; Verhagen, W I; Frenken, C W
Mass spectral measurements of the apoHDL in horse (Equus caballus) cerebrospinal fluid.
As a continuation of our proteogenomic studies of equine apolipoproteins, we have obtained molecular masses for several of the apolipoproteins associated with the HDL in horse cerebrospinal fluid (CSF). Using electrospray-ionization mass spectrometry (ESI-MS), we report on values for apolipoproteins, A-I and A-II, as well as acylated apoA-I. In comparison with our previously published data on equine plasma apolipoproteins, there appears to be a higher percentage of acylated apoA-I in the CSF than in plasma. As was the case in plasma, apoA-II circulates as a homodimer. These studies also revealed a protein with a mass of 34,468Da that we are speculating is the value for horse apoE. PMID:22377539
Puppione, Donald L; Della Donna, Lorenza; Bassilian, Sara; Souda, Puneet; MacDonald, Melinda H; Whitelegge, Julian P
Catabolites of purine nucleotides were measured in the cerebrospinal fluid (CSF) of newborn infants with sepsis, seizures and hydrocephalus using isocratic reversed-phase HPLC. The inosine levels in the CSF of the infants with any of the illnesses were significantly higher when compared with the controls. There was a tendency for hypoxanthine levels to be higher in the group of children with hydrocephalus. No significant differences in the concentrations of xanthine, adenine and uric acid were found. The inosine concentration in the CSF is proposed to be a more sensitive indicator of brain injury than the levels of other CSF purines. The levels of all purine metabolites measured in the CSF showed large individual variations. The ratio between hypoxanthine (as an indicator of ATP breakdown) and uric acid (as a scavenger of oxygen free radicals) concentration is proposed as a new criterion to be used in the evaluation of brain injury. PMID:8568608
Schmidt, H; Siems, W G; Grune, T; Grauel, E L
A Window into the Heterogeneity of Human Cerebrospinal Fluid A? Peptides
The initiating event in Alzheimer's disease (AD) is an imbalance in the production and clearance of amyloid beta (A?) peptides leading to the formation of neurotoxic brain A? assemblies. Cerebrospinal Fluid (CSF), which is a continuum of the brain, is an obvious source of markers reflecting central neuropathologic features of brain diseases. In this review, we provide an overview and update on our current understanding of the pathobiology of human CSF A? peptides. Specifically, we focused our attention on the heterogeneity of the CSF A? world discussing (1) basic research studies and what has been translated to clinical practice, (2) monomers and other soluble circulating A? assemblies, and (3) communication modes for A? peptides and their microenvironment targets. Finally, we suggest that A? peptides as well as other key signals in the central nervous system (CNS), mainly involved in learning and hence plasticity, may have a double-edged sword action on neuron survival and function. PMID:21876644
Ghidoni, Roberta; Paterlini, Anna; Albertini, Valentina; Stoppani, Elena; Binetti, Giuliano; Fuxe, Kjell; Benussi, Luisa; Agnati, Luigi F.
Resistance to outflow of cerebrospinal fluid after central infusions of angiotensin
NASA Technical Reports Server (NTRS)
Infusions of artificial cerebrospinal fluid (CSF) into the cerebroventricles of conscious rats can raise CSF pressure (CSFp). This response can be modified by some neuropeptides. One of these, angiotensin, facilitates the rise in CSFp. We measured CSFp in conscious rats with a computerized system and evaluated resistance to CSF outflow during infusion of artificial CSF, with or without angiotensin, from the decay kinetics of superimposed bolus injections. Angiotensin (10 ng/min) raised CSFp (P less than 0.05) compared with solvent, but the resistance to CSF outflow of the two groups was similar (P greater than 0.05). Because CSFp was increased by angiotensin without an increase in the outflow resistance, a change in some volume compartment is likely. Angiotensin may raise CSFp by increasing CSF synthesis; this possibility is supported, since the choroid plexuses contain an intrinsic isorenin-angiotensin system. Alternatively, angiotensin may dilate pial arteries, leading to an increased intracranial blood volume.
Morrow, B. A.; Keil, L. C.; Severs, W. B.
Blood flow in the cerebral gray matter was measured in normal pressure hydrocephalus and Alzheimer disease by 133Xe inhalation. Flow values in the frontal and temporal gray matter increased after lowering cerebrospinal fluid (CSF) pressure by lumbar puncture in normal pressure hydrocephalus (p less than 0.05) and also after shunting. One case with cerebral complications did not improve clinically. In Alzheimer disease the reverse (decreases in flow in the gray matter) occurred after removal of CSF. Normal pressure hydrocephalus was associated with impaired cerebral vasomotor responsiveness during 100% oxygen and 5% carbon dioxide inhalation. This complication was restored toward normal after CSF removal and/or shunting. Cerebral blood flow measurements appear to be useful for confirming the diagnosis of normal pressure hydrocephalus and predicting the clinical benefit from shunting.
Meyer, J.S.; Tachibana, H.; Hardenberg, J.P.; Dowell, R.E. Jr.; Kitagawa, Y.; Mortel, K.F.
Secondary hydrocephalus communicans after traumatic upper cervical spine injuries with leakage of cerebrospinal fluid is a rare and hardly described complication. A case of a 75-year-old woman sustained a type II dens axis without other injuries, especially without evidence of a hydrocephalus in the primary CT scan. Dorsal atlanto-axial fusion was performed. Postoperative drainage was prolonged and positive for ?2-transferrin. Wound revision with an attempt to seal the leakage was not successful. Secondary CT scans of the brain were performed due to neurological deterioration and showed a hydrocephalus with typical EEG findings. No anatomical reason for a circulative obstruction was found in the CT scan. After application of a ventriculo-peritoneal shunt the neurological status improved and the patient could be discharged to neurological rehabilitation. PMID:22752831
Mica, Ladislav; Neuhaus, Valentin; Poschmann, Enrico; Konu-Leblebicioglu, Dilek; Schwarz, Urs; Wanner, Guido A; Werner, Clement ML; Simmen, Hans-Peter
A highly sensitive and fast reversed-phase liquid chromatographic (LC) method combined with pulsed electrochemical detection (PED) was developed for the direct quantification of the aminoglycoside antibiotic amikacin in cerebrospinal fluid (CSF). The limit of quantification obtained was 0.06 microg/ml and linearity was established over the concentration range 0.06-4.00 microg/ml. The recovery was found to be close to 100%. This method was developed in order to study CSF pharmacokinetics of amikacin in neonates. The narrow therapeutic range calls for monitoring to ensure optimal therapy and to minimize the risk of toxic side effects such as nephro- and ototoxicity, especially in populations like preterm neonates at birth, where the predictability of amikacin clearance is limited. Typical problems to be solved were the low amikacin concentrations and the limited sample volume of CSF. PMID:18396112
Brajanoski, Gordana; Hoogmartens, Jos; Allegaert, Karel; Adams, Erwin
Cerebrospinal fluid can be used for HIV genotyping when it fails in blood
Blood plasma specimens are the clinical standard for HIV-1 pol gene genotyping from viral populations; however, it is not always successful, often from low viral loads or the presence of polymerase chain reaction (PCR) inhibitors. Objective To describe the successful of HIV-1 genotyping in two samples of cerebrospinal fluid (CSF), after genotype procedures failed from blood. Method Two HIV-infected patients enrolled in a neurocognitive research study were evaluated when standard HIV-1 genotyping failed from blood plasma samples. Genotyping was performed using the commercial system TRUGENE� HIV-1 Genotyping Kit and the OpenGene� DNA Sequencing System (Siemens Healthcare Diagnostics, Tarrytown, NY, USA). Results CSF genotyping was performed via the same commercial platform and was successful in both cases. Conclusion This report demonstrates that CSF could be used as an alternate clinical specimen for HIV-1 genotyping when it fails from blood. PMID:25054982
Rotta, Indianara; Raboni, Sonia Mara; Ribeiro, Clea Elisa Lopes; Riedel, Maristela; Winhescki, Maria da Graca; Smith, Davey M.; Ellis, Ronald J.; de Almeida, Sergio Monteiro
A 38-year-old woman presented with repeated episodes of meningitis. She had undergone transsphenoidal tumor removal followed by gamma knife irradiation in 1994. Complete remission was achieved. Intermittent cerebrospinal fluid (CSF) leakage began in 2004, and transsphenoidal surgery was performed for direct repair of the skull base defect. Operative findings showed that the sellar floor was uncovered, and CSF continuously escaped through the cyanoacrylate polymer framework of the previous repair. Reconstruction used autologous muscle pieces and cyanoacrylate polymer adhesive. The CSF leakage was presumably due to delayed radiation damage to the mucous membrane of the skull base. Several methods for reconstruction of the sellar floor have been proposed, which all rely on tissue regeneration including the arachnoid, dura mater, and mucus membrane of the sphenoidal sinus. Preservation of the arachnoid membrane and minimizing removal of the mucous membrane are essential, especially if postoperative irradiation is anticipated. PMID:17965568
Ogawa, Yoshikazu; Tominaga, Teiji
Three-dimensional computational prediction of cerebrospinal fluid flow in the human brain.
A three-dimensional model of the human cerebrospinal fluid (CSF) spaces is presented. Patient-specific brain geometries were reconstructed from magnetic resonance images. The model was validated by comparing the predicted flow rates with Cine phase-contrast MRI measurements. The model predicts the complex CSF flow patterns and pressures in the ventricular system and subarachnoid space of a normal subject. The predicted maximum rostral to caudal CSF flow in the pontine cistern precedes the maximum rostral to caudal flow in the ventricles by about 10% of the cardiac cycle. This prediction is in excellent agreement with the subject-specific flow data. The computational results quantify normal intracranial dynamics and provide a basis for analyzing diseased intracranial dynamics. PMID:21215965
Sweetman, Brian; Xenos, Michalis; Zitella, Laura; Linninger, Andreas A
Background: Increasingly, older patients with severe spinal stenosis/instability undergo multiple unnecessary preoperative epidural spinal injections (ESI), despite their risks and lack of long-term benefits. Here we add to the list of risks by showing how often preoperative ESI lead to punctate cerebrospinal fluid (CSF) fistulas documented during subsequent surgery (e.g. multilevel laminectomies with non-instrumented fusions). Methods: A series of 39 patients with spinal stenosis/instability prospectively underwent multilevel laminectomy/non-instrumented fusion utilizing lamina autograft and NanOss Bioactive. We asked how often preoperative ESI were performed in this population and how frequently they contributed to operatively confirmed punctate cerebrospinal fluid (CSF) fistulas. Notably, CSF leaks were clearly attributed to ESI, as they were located centrally/paracentrally at the L4-L5 level, just below hypertrophied/ossified yellow ligament (OYL), and were the exact size of a Tuohy needle with clean edges. Results: An average of 4.1 (range 2-12) preoperative ESI were performed in 33 of 39 patients undergoing average 4.3 level laminectomies and 1.3 level non-instrumented fusions; 6 (18.2%) patients exhibited operatively confirmed, punctate CSF fistulas attributed to these ESI. The most recent injections were administered between 2 and 5 weeks prior to surgery (average 3.9 weeks). Fistulas were primarily repaired with 7-0 GORE-TEX sutures and fibrin Sealant (Tisseel). Conclusions: Of 33 patients undergoing multilevel laminectomies with non-instrumented fusions receiving preoperative ESI, 6 (18.2%) had operatively confirmed punctate CSF fistulas due to preoperative ESI performed an average of 4.1 times per patient.
Epstein, Nancy E.
Efavirenz (EFV) is one of the most commonly prescribed antiretrovirals for use in the treatment of human immunodeficiency virus (HIV) infection. EFV is extensively metabolized by cytochrome P450 to a number of oxygenated products; however, the pharmacologic activity and distribution of these metabolites in anatomic compartments have yet to be explored. The systemic distribution of EFV oxidative metabolites was examined in blood plasma, seminal plasma, and cerebrospinal fluid from subjects on an EFV-based regimen. The 8-hydroxy EFV metabolite was detected in blood plasma, seminal plasma, and cerebrospinal fluid, with median concentrations of 314.5 ng/ml, 358.5 ng/ml, and 3.37 ng/ml, respectively. In contrast, 7-hydroxy and 8,14-hydroxy EFV were only detected in blood plasma and seminal plasma with median concentrations of 8.84 ng/ml and 10.23 ng/ml, and 5.63 ng/ml and 5.43 ng/ml, respectively. Interestingly, protein-free concentrations of metabolites were only detectable in seminal plasma, where a novel dihdyroxylated metabolite of EFV was also detected. This accumulation of protein-free EFV metabolites was demonstrated to be the result of differential protein binding in seminal plasma compared with that of blood plasma. In addition, the oxidative metabolites of EFV did not present with any significant pharmacologic activity toward HIV-1 as measured using an HIV green fluorescent protein single-round infectivity assay. This study is the first to report the physiologic distribution of metabolites of an antiretroviral into biologic compartments that the virus is known to distribute and to examine their anti-HIV activity. These data suggest that the male genital tract may be a novel compartment that should be considered in the evaluation of drug metabolite exposure. PMID:23166317
Avery, Lindsay B.; VanAusdall, Jennifer L.; Hendrix, Craig W.
Neurological outcomes of preterm infants with posthemorrhagic hydrocephalus are among the worst in newborn medicine. There remains no consensus regarding the diagnosis or treatment of posthemorrhagic hydrocephalus, and the pathological pathways leading to the adverse neurological sequelae are poorly understood. In the current study, we developed an innovative approach to simultaneously identify potential diagnostic markers of posthemorrhagic hydrocephalus and investigate novel pathways of posthemorrhagic hydrocephalus-related neurological disability. Tandem multi-affinity fractionation for specific removal of plasma proteins from the hemorrhagic cerebrospinal fluid samples was combined with high resolution label-free quantitative proteomics. Analysis of cerebrospinal fluid obtained from infants with posthemorrhagic hydrocephalus demonstrated marked differences in the levels of 438 proteins when compared with cerebrospinal fluid from age-matched control infants. Amyloid precursor protein, neural cell adhesion molecule-L1, neural cell adhesion molecule-1, brevican and other proteins with important roles in neurodevelopment showed profound elevations in posthemorrhagic hydrocephalus cerebrospinal fluid compared with control. Initiation of neurosurgical treatment of posthemorrhagic hydrocephalus resulted in resolution of these elevations. The results from this foundational study demonstrate the significant promise of tandem multi-affinity fractionation-proteomics in the identification and quantitation of protein mediators of neurodevelopment and neurological injury. More specifically, our results suggest that cerebrospinal fluid levels of proteins such as amyloid precursor protein or neural cell adhesion molecule-L1 should be investigated as potential diagnostic markers of posthemorrhagic hydrocephalus. Notably, dysregulation of the levels these and other proteins may directly affect ongoing neurodevelopmental processes in these preterm infants, providing an entirely new hypothesis for the developmental disability associated with posthemorrhagic hydrocephalus. PMID:22186713
Morales, Diego M.; Townsend, R. Reid; Malone, James P.; Ewersmann, Carissa A.; Macy, Elizabeth M.; Inder, Terrie E.; Limbrick, David D.
Objectives: Despite many hypotheses, the pathophysiology of syringomyelia is still not well understood. In this report, the authors propose a hypothesis based on analysis of cerebrospinal fluid dynamics in the spine. Methods: An electric circuit model of the CSF dynamics of the spine was constructed based on a technique of computational fluid mechanics. With this model, the authors calculated how a pulsatile CSF wave coming from the cranial side is propagated along the spinal cord. Results: Reducing the temporary fluid storage capacity of the cisterna magna dramatically increased the pressure wave propagated along the central canal. The peak of this pressure wave resided in the mid-portion of the spinal cord. Conclusions: The following hypotheses are proposed. The cisterna magna functions as a shock absorber against the pulsatile CSF waves coming from the cranial side. The loss of shock absorbing capacity of the cisterna magna and subsequent increase of central canal wall pressure leads to syrinx formation in patients with Chiari I malformation. PMID:12588922
Chang, H; Nakagawa, H
The brain is a vital organ and because it is well shielded from the outside environment, possibilities for noninvasive analysis are often limited. Instead, fluids taken from the spinal cord or circulatory system are preferred sources for the discovery of candidate markers within neurological diseases. In the context of multiple sclerosis (MS), we applied an affinity proteomic strategy and screened 22 plasma samples with 4595 antibodies (3450 genes) on bead arrays, then defined 375 antibodies (334 genes) for targeted analysis in a set of 172 samples and finally used 101 antibodies (43 genes) on 443 plasma as well as 573 cerebrospinal spinal fluid (CSF) samples. This revealed alteration of protein profiles in relation to MS subtypes for IRF8, IL7, METTL14, SLC30A7, and GAP43. Respective antibodies were subsequently used for immunofluorescence on human post-mortem brain tissue with MS pathology for expression and association analysis. There, antibodies for IRF8, IL7, and METTL14 stained neurons in proximity of lesions, which highlighted these candidate protein targets for further studies within MS and brain tissue. The affinity proteomic translation of profiles discovered by profiling human body fluids and tissue provides a powerful strategy to suggest additional candidates to studies of neurological disorders. PMID:25231264
Bystr�m, Sanna; Ayoglu, Burcu; H�ggmark, Anna; Mitsios, Nicholas; Hong, Mun-Gwan; Drobin, Kimi; Forsstr�m, Bj�rn; Fredolini, Claudia; Khademi, Mohsen; Amor, Sandra; Uhl�n, Mathias; Olsson, Tomas; Mulder, Jan; Nilsson, Peter; Schwenk, Jochen M
The interthalamic adhesion is a unique feature of the third ventricle in the brain. It differs in shape and size and its location varies between individuals. In this study, computational fluid dynamics was performed on 4 three-dimensional models of the cerebral ventricular system with the interthalamic adhesion modeled in different locations in the third ventricle. Cerebrospinal fluid (CSF) was modeled as incompressible Newtonian fluid and flow was assumed laminar. The periodic motion of CSF flow as a function of the cardiac cycle starting from diastole was prescribed as the inlet boundary condition at the foramen of Monroe. Results from this study show how the location of the interthalamic adhesion influences the pattern of pressure distribution in the cerebral ventricles. In addition, the highest CSF pressure in the third ventricle can vary by approximately 50% depending on the location of the interthalamic adhesion. We suggest that the interthalamic adhesion may have functional implications on the development of hydrocephalus and it is important to model this anatomical feature in future studies. PMID:19896132
Cheng, Shaokoon; Tan, Kristy; Bilston, Lynne E
Effects of irregular cerebrospinal fluid production rate in human brain ventricular system
NASA Astrophysics Data System (ADS)
Hydrocephalus is an abnormal accumulation of fluid in the ventricles and cavities in the brain. It occurs when the cerebrospinal fluid (CSF) flow or absorption is blocked or when excessive CSF is secreted. The excessive accumulation of CSF results in an abnormal widening of the ventricles. This widening creates potentially harmful pressure on the tissues of the brain. In this study, flow analysis of CSF was conducted on a three-dimensional model of the third ventricle and aqueduct of Sylvius, derived from MRI scans. CSF was modeled as Newtonian Fluid and its flow through the region of interest (ROI) was done using EFD. Lab software. Different steady flow rates through the Foramen of Monro, classified by normal and hydrocephalus cases, were modeled to investigate its effects. The results show that, for normal and hydrocephalus cases, the pressure drop of CSF flow across the third ventricle was observed to be linearly proportionally to the production rate increment. In conclusion, flow rates that cause pressure drop of 5 Pa was found to be the threshold for the initial sign of hydrocephalus.
Hadzri, Edi Azali; Shamsudin, Amir Hamzah; Osman, Kahar; Abdul Kadir, Mohammed Rafiq; Aziz, Azian Abd
Stasis: Flexible Transactional Storage
An increasing range of applications requires robust support for atomic, durable and concurrent transactions. Databases provide the default solution, but force appli- cations to interact via SQL and to forfeit control over data layout and access mechanisms. We argue there is a gap between DBMSs and file systems that limits design- ers of data-oriented applications. Stasis is a storage framework
Russell Sears; Eric A. Brewer
Coordinated stasis: An overview
Coordinated stasis, as defined herein, represents an empirical pattern, common in the fossil record, wherein groups of coexisting species lineages display concurrent stability over extended intervals of geologic time separated by episodes of relatively abrupt change. In marine benthic fossil assemblages, where the pattern was first recognized, the majority of species lineages (60 to more than 80%) are present in
Carlton E. Brett; Linda C. Ivany; Kenneth M. Schopf
Quantification of the cerebrospinal fluid from a new whole body MRI sequence
NASA Astrophysics Data System (ADS)
Our work aims to develop a biomechanical model of hydrocephalus both intended to perform clinical research and to assist the neurosurgeon in diagnosis decisions. Recently, we have defined a new MR imaging sequence based on SPACE (Sampling Perfection with Application optimized Contrast using different flip-angle Evolution). On these images, the cerebrospinal fluid (CSF) appears as a homogeneous hypersignal. Therefore such images are suitable for segmentation and for volume assessment of the CSF. In this paper we present a fully automatic 3D segmentation of such SPACE MRI sequences. We choose a topological approach considering that CSF can be modeled as a simply connected object (i.e. a filled sphere). First an initial object which must be strictly included in the CSF and homotopic to a filled sphere, is determined by using a moment-preserving thresholding. Then a priority function based on an Euclidean distance map is computed in order to control the thickening process that adds "simple points" to the initial thresholded object. A point is called simple if its addition or its suppression does not result in change of topology neither for the object, nor for the background. The method is validated by measuring fluid volume of brain phantoms and by comparing our volume assessments on clinical data to those derived from a segmentation controlled by expert physicians. Then we show that a distinction between pathological cases and healthy adult people can be achieved by a linear discriminant analysis on volumes of the ventricular and intracranial subarachnoid spaces.
Lebret, Alain; Petit, Eric; Durning, Bruno; Hodel, J�r�me; Rahmouni, Alain; Decq, Philippe
The role of cerebrospinal fluid pressure in glaucoma and other ophthalmic diseases: A review.
Glaucoma is one of the most common causes of blindness in the world. Well-known risk factors include age, race, a positive family history and elevated intraocular pressures. A newly proposed risk factor is decreased cerebrospinal fluid pressure (CSFP). This concept is based on the notion that a pressure differential exists across the lamina cribrosa, which separates the intraocular space from the subarachnoid fluid space. In this construct, an increased translaminar pressure difference will occur with a relative increase in elevated intraocular pressure or a reduction in CSFP. This net change in pressure is proposed to act on the tissues within the optic nerve head, potentially contributing to glaucomatous optic neuropathy. Similarly, patients with ocular hypertension who have elevated CSFPs, would enjoy a relatively protective effect from glaucomatous damage. This review will focus on the current literature pertaining to the role of CSFP in glaucoma. Additionally, the authors examine the relationship between glaucoma and other known CSFP-related ophthalmic disorders. PMID:24227969
Fleischman, David; Allingham, R Rand
Chronic metabolic alkalosis was induced in rats by combining a low K+ diet with a 0.2 M NaHCO3 solution as drinking fluid for either 15 or 27 days. Local cerebral blood flow and local cerebral glucose utilization were measured in 31 different structures of the brain in conscious animals by means of the iodo-(14C)antipyrine and 2-(14C)deoxy-D-glucose method. The treatment induced moderate (15 days, base excess (BE) 16 mM) to severe (27 days, BE 25 mM) hypochloremic metabolic alkalosis and K+ depletion. During moderate metabolic alkalosis no change in cerebral glucose utilization and blood flow was detectable in most brain structures when compared with controls. Cerebrospinal fluid (CSF) K+ and H+ concentrations were significantly decreased. During severe hypochloremic alkalosis, cerebral blood flow was decreased by 19% and cerebral glucose utilization by 24% when compared with the control values. The decrease in cerebral blood flow during severe metabolic alkalosis is attributed mainly to the decreased cerebral metabolism and to a lesser extent to a further decrease of the CSF H+ concentration. CSF K+ concentration was not further decreased. The results show an unaltered cerebral blood flow and glucose utilization together with a decrease in CSF H+ and K+ concentrations at moderate metabolic alkalosis and a decrease in cerebral blood flow and glucose utilization together with a further decreased CSF H+ concentration at severe metabolic alkalosis.
Schroeck, H.K.; Kuschinsky, W. (Univ. of Bonn (Germany, F.R.))
The role of cerebrospinal fluid pressure in glaucoma and other ophthalmic diseases: A review
Glaucoma is one of the most common causes of blindness in the world. Well-known risk factors include age, race, a positive family history and elevated intraocular pressures. A newly proposed risk factor is decreased cerebrospinal fluid pressure (CSFP). This concept is based on the notion that a pressure differential exists across the lamina cribrosa, which separates the intraocular space from the subarachnoid fluid space. In this construct, an increased translaminar pressure difference will occur with a relative increase in elevated intraocular pressure or a reduction in CSFP. This net change in pressure is proposed to act on the tissues within the optic nerve head, potentially contributing to glaucomatous optic neuropathy. Similarly, patients with ocular hypertension who have elevated CSFPs, would enjoy a relatively protective effect from glaucomatous damage. This review will focus on the current literature pertaining to the role of CSFP in glaucoma. Additionally, the authors examine the relationship between glaucoma and other known CSFP-related ophthalmic disorders. PMID:24227969
Fleischman, David; Allingham, R. Rand
While there is growing experimental evidence that cerebrospinal fluid (CSF) flow induced by the beating of ependymal cilia is an important factor for neuronal guidance, the respective contribution of vascular pulsation-driven macroscale oscillatory CSF flow remains unclear. This work uses computational fluid dynamics to elucidate the interplay between macroscale and cilia-induced CSF flows and their relative impact on near-wall dynamics. Physiological macroscale CSF dynamics are simulated in the ventricular space using subject-specific anatomy, wall motion and choroid plexus pulsations derived from magnetic resonance imaging. Near-wall flow is quantified in two subdomains selected from the right lateral ventricle, for which dynamic boundary conditions are extracted from the macroscale simulations. When cilia are neglected, CSF pulsation leads to periodic flow reversals along the ventricular surface, resulting in close to zero time-averaged force on the ventricle wall. The cilia promote more aligned wall shear stresses that are on average two orders of magnitude larger compared with those produced by macroscopic pulsatile flow. These findings indicate that CSF flow-mediated neuronal guidance is likely to be dominated by the action of the ependymal cilia in the lateral ventricles, whereas CSF dynamics in the centre regions of the ventricles is driven predominantly by wall motion and choroid plexus pulsation. PMID:24621815
Siyahhan, Bercan; Knobloch, Verena; de Z�licourt, Diane; Asgari, Mahdi; Schmid Daners, Marianne; Poulikakos, Dimos; Kurtcuoglu, Vartan
Cerebrospinal fluid mitochondrial DNA: a novel DAMP in pediatric traumatic brain injury.
Danger-associated molecular patterns (DAMPs) are nuclear or cytoplasmic proteins that are released from the injured tissues and activate the innate immune system. Mitochondrial DNA (mtDNA) is a novel DAMP that is released into the extracellular milieu subsequent to cell death and injury. We hypothesized that cell death within the central nervous system in children with traumatic brain injury (TBI) would lead to the release of mtDNA into the cerebrospinal fluid (CSF) and has the potential to predict the outcome after trauma. Cerebrospinal fluid was collected from children with severe TBI who required intracranial pressure monitoring with Glasgow Coma Scale (GCS) scores of 8 or less via an externalized ventricular drain. Control CSF was obtained in children without TBI or meningoencephalitis who demonstrated no leukocytes in the diagnostic lumbar puncture. The median age for patients with TBI was 6.3 years, and 62% were male. The common mechanisms of injury included motor vehicle collision (35.8%), followed by falls (21.5%) and inflicted TBI (19%); six children (14.2%) died during their intensive care unit course. The mean CSF mtDNA concentration was 1.10E+05 � 2.07E+05 and 1.63E+03 � 1.80E+03 copies/?L in the pediatric TBI and control populations, respectively. Furthermore, the mean CSF mtDNA concentration in pediatric patients who later died or had severe disability was significantly higher than that of the survivors (1.63E+05 � 2.77E+05 vs. 5.05E+04 � 6.21E+04 copies/?L) (P < 0.0001). We found a significant correlation between CSF mtDNA and high mobility group box 1, another prototypical DAMP, concentrations (? = 0.574, P < 0.05), supporting the notion that both DAMPs are increased in the CSF after TBI. Our data suggest that CSF mtDNA is a novel DAMP in TBI and appears to be a useful biomarker that correlates with neurological outcome after TBI. Further inquiry into the components of mtDNA that modulate the innate immune response will be helpful in understanding the mechanism of local and systemic inflammation after TBI. PMID:24667615
Walko, Thomas D; Bola, R Aaron; Hong, John D; Au, Alicia K; Bell, Michael J; Kochanek, Patrick M; Clark, Robert S B; Aneja, Rajesh K
We surveyed the T cell receptor repertoire in three separate compartments (brain, cerebrospinal fluid, and blood) of two multiple sclerosis patients who initially had diagnostic brain biopsies to clarify their unusual clinical presentation but were subsequently confirmed to have typical multiple sclerosis. One of the brain biopsy specimens had been previously investigated by microdissection and single-cell PCR to determine the clonal composition of brain-infiltrating T cells at the single-cell level. Using complementarity-determining region 3 spectratyping, we identified several identical, expanded CD8+ (but not CD4+) T cell clones in all three compartments. Some of the expanded CD8+ T cells also occurred in sorted CD38+ blood cells, suggesting that they were activated. Strikingly, some of the brain-infiltrating CD8+ T cell clones persisted for >5 years in the cerebrospinal fluid and/or blood and may thus contribute to the progression of the disease. PMID:14983026
Skulina, Christian; Schmidt, Stephan; Dornmair, Klaus; Babbe, Holger; Roers, Axel; Rajewsky, Klaus; Wekerle, Hartmut; Hohlfeld, Reinhard; Goebels, Norbert
Background\\/Aims: In this study, metal concentrations were related to the levels of well-known Alzheimer markers in cerebrospinal fluid (CSF), such as amyloid-beta (A?), total tau (T-tau) and phosphorylated-tau (P-tau). Methods: Concentrations of 19 metals (Mg, Ca, V, Mn, Fe, Co, Ni, Cu, Zn, Se, Rb, Sr, Mo, Cd, Sn, Sb, Cs, Hg and Pb by inductively coupled plasma-mass spectrometry) and
Lars Gerhardsson; Kaj Blennow; Thomas Lundh; Elisabet Londos; Lennart Minthon
Background\\/Aims\\/Methods: This is a follow-up study from a recent randomized controlled trial conducted at the Women and Children�s Hospital of Buffalo that investigated the use of antimicrobial sutures (AMS) for wound closure during cerebrospinal fluid shunting procedures. Our purpose was to determine the average cost of shunt infections at our institution and estimate the healthcare savings associated with reduced infection
Jonathan Stone; Thomas J. Gruber; Curtis J. Rozzelle
Epstein-Barr virus DNA load in cerebrospinal fluid and plasma of patients with AIDS-related lymphoma
Detection of Epstein-Barr virus (EBV) DNA in the cerebrospinal fluid (CSF) is associated with acquired immunodeficiency syndrome\\u000a (AIDS)-related brain lymphoma. Real-time polymerase chain reaction (PCR) was performed to quantify EBV DNA in CSF and plasma\\u000a from 42 patients with AIDS-related non-Hodgkin�s lymphoma (NHL). Twenty patients had primary central nervous system lymphoma\\u000a (PCNSL) and 22 systemic NHL, including 12 with central
Simona Bossolasco; Paola Cinque; Maurilio Ponzoni; Maria Grazia Vigano; Adriano Lazzarin; Annika Linde; Kerstin I. Falk
Several lines of evidence suggest that d-serine, an endogenous agonist of the glycine site on the NMDA receptors, might play a role in the pathophysiology of schizophrenia. The purpose of this study was to determine whether levels of d- and l-serine or d-serine ratio (d-serine\\/total serine) in cerebrospinal fluid (CSF) were altered in first episode and drug-naive schizophrenic patients. The
Kenji Hashimoto; G�ran Engberg; Eiji Shimizu; Conny Nordin; Leif H. Lindstr�m; Masaomi Iyo
BACKGROUND: In 70-80% of cases, neuromyelitis optica (NMO) is associated with highly specific serum auto-antibodies to aquaporin-4 (termed AQP4-Ab or NMO-IgG). Recent evidence strongly suggests that AQP4-Ab are directly involved in the immunopathogenesis of NMO. OBJECTIVE: To assess the frequency, syndrome specificity, diagnostic relevance, and origin of cerebrospinal fluid (CSF) AQP4-Ab in patients with NMO spectrum disorders (NMOSD). METHODS: 87
Diego Franciotta; Friedemann Paul; Klemens Ruprecht; Roberto Bergamaschi; Paulus S Rommer; Reinhard Reuss; Christian Probst; Wolfgang Kristoferitsch; Klaus Peter Wandinger; Brigitte Wildemann
Escherichia coli is a major cause of enteric\\/diarrheal diseases, urinary tract infections, and sepsis. E. coli K1 is the leading gram-negative organism causing neonatal meningitis, but the microbial basis of E. coli K1 meningitis is incompletely understood. Here we employed comparative genomic hybridization to investigate 11 strains of E. coli K1 isolated from the cerebrospinal fluid (CSF) of patients with
Yufeng Yao; Yi Xie; K. S. Kim
Here we report a hypersomnolent girl with extensive hypothalamic damage after removal of a craniopharyngioma. The presence of a short sleep latency, sleep onset REM periods during a multiple sleep latency test (MSLT) and negative HLA DQB1*0602 typing suggested a diagnosis of symptomatic narcolepsy. Low cerebrospinal fluid hypocretin-1 level indicated destruction of hypocretin-producing neurons in the hypothalamus. An increased amount
Naoko Tachibana; Masako Taniike; Takeshi Okinaga; Beth Ripley; Emmanuel Mignot; Seiji Nishino
The antigen detectable by counter-current immunoelectrophoresis in the cerebrospinal fluid and sera of patients with group A meningococcal meningitis was found to be a high molecular weight polysaccharide. Its composition was deduced from its immunochemical identity with a known group A meningococcal polysaccharide which has previously been shown to be a polymer of N-acetyl, O-acetyl mannosamine phosphate. PMID:4219838
Greenwood, B. M.; Whittle, H. C.
We report a rare case of cerebrospinal fluid (CSF) leakage after radiosurgery for skull base metastasis from renal cell carcinoma. A mass invading the left petrous bone and sphenoid sinus was treated with gamma knife radiosurgery, and CSF rhinorrhea developed 4 months after the procedure. The CSF leak was successfully controlled by endoscopic sinus surgery. CSF leakage may develop as a rare complication after radiosurgery for skull base lesions, and the endoscopic repair technique is a useful therapeutic method. PMID:18797420
Kim, Chang-Hyun; Chung, Seung-Kyu; Dhong, Hun-Jong; Lee, Jung-Il
The kinetics of changes in the eotaxin concentration in the serum and cerebrospinal fluid (CSF) of BALB\\/c mice after infection with Angiostrongylus cantonensis and the correlation between the concentration of eotaxin and worm recovery were investigated. The mean concentration of eotaxin in serum of infected mice gradually increased from 46.3�6.5�pg\\/ml at week�0 to 104.9�44.8�pg\\/ml at week�3 after infection, while the
EddyEssen Chang; Lee-Yi Chung; Chuan-Min Yen
Apolipoprotein E ?4 allele (APOE ?4) increases the apolipoprotein E (apoE) protein levels in Alzheimer's disease (AD) cerebrospinal fluid (CSF). Thus, we hypothesized that apoE levels were also associated with the APOE genotype, and amyloid-? (A?)-associated clinical, functional, and imaging parameters in patients with Lewy body-associated disorders (LBD). Indeed, similar to AD, patients with LBD displayed high CSF apoE levels (greatest in patients with dementia with LBD), and this was linked to APOE ?4. High CSF apoE protein correlated positively with CSF soluble amyloid precursor protein, total tau, and cortical and striatal Pittsburgh compound B retention; and correlated negatively with CSF A?42, cognitive tests scores, and glucose uptake ratio in the temporal and parietal cortices. APOE ?4-triggered accumulation of apoE in CSF is related to A?-associated clinical and functional imaging parameters in LBD. Accordingly, therapeutic strategies aimed at reducing apoE levels in the brain should be explored not only in AD but also in LBD, particularly when accompanied with dementia. PMID:23978325
Vijayaraghavan, Swetha; Maetzler, Walter; Reimold, Matthias; Lithner, Christina Unger; Liepelt-Scarfone, Inga; Berg, Daniela; Darreh-Shori, Taher
Oligomers of the amyloid-? peptide (A?) are thought to be the most toxic form of A? and are linked to the development of Alzheimer's disease (AD). Here, we used a flow cytometric approach for the detection and assessment of oligomers in cerebrospinal fluid (CSF) from AD patients and other neurological disorders. 30 CSF samples from patients suffering from AD (n = 14), non-demented controls (n = 12), and other neurological disorders (dementia with Lewy bodies, n = 2; vascular dementia, n = 1; primary progressive aphasia, n = 1) were analyzed for the presence of A?-oligomers by flow cytometry. The CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-? (A?)42 were determined using ELISA. CSF A?-oligomer levels in AD patients were elevated in comparison to the non-AD group (p = 0.073). The ratio A?-oligomers/A?42 was significantly elevated in AD subjects compared to non-AD subjects (p = 0.001). Most important, there was a negative correlation between the amount of A?-oligomers and the Mini-Mental Status Exam score (r = -0.65; p = 0.013) in AD patients. The detection of A?-oligomers using flow cytometry analysis seems to be useful in assessing the stage of AD. This is a novel and important finding as none of the currently used CSF biomarkers are clearly associated with dementia severity. PMID:22214781
Santos, Alexander Navarrete; Ewers, Michael; Minthon, Lennart; Simm, Andreas; Silber, Rolf-Edgar; Blennow, Kaj; Prvulovic, David; Hansson, Oskar; Hampel, Harald
Visualization of cerebrospinal fluid (CSF), that flow in the brain and spinal cord, plays an important role to detect neurodegenerative diseases such as Alzheimer's disease. This is performed by measuring the substantial changes in the CSF flow dynamics, volume and/or pressure gradient. Magnetic resonance imaging (MRI) technique has become a prominent tool to quantitatively measure these changes and image segmentation method has been widely used to distinguish the CSF flows from the brain tissues. However, this is often hampered by the presence of partial volume effect in the images. In this paper, a new hybrid evolutionary spatial fuzzy clustering method is introduced to overcome the partial volume effect in the MRI images. The proposed method incorporates Expectation Maximization (EM) method, which is improved by the evolutionary operations of the Genetic Algorithm (GA) to differentiate the CSF from the brain tissues. The proposed improvement is incorporated into a spatial-based fuzzy clustering (SFCM) method to improve segmentation of the boundary curve of the CSF and the brain tissues. The proposed method was validated using MRI images of Alzheimer's disease patient. The results presented that the proposed method is capable to filter the CSF regions from the brain tissues more effectively compared to the standard EM, FCM, and SFCM methods. PMID:24110448
Abdullah, Afnizanfaizal; Hirayama, Akihiro; Yatsushiro, Satoshi; Matsumae, Mitsunori; Kuroda, Kagayaki
Over the last years there has been an increased focus on the importance of knowing the effect of pre-analytical influence on the proteomes under study, particularly in the field of biomarker discovery. We present three proteomics studies examining the effect of blood contamination and the rostro-caudal gradient (RCG) on the cerebrospinal fluid (CSF) proteome, in addition to plasma/CSF protein ratios. The studies showed that the central nervous system (CNS) derived proteins appeared to be unaffected by the RCG, while the plasma-derived proteins showed an increase in concentration towards the lumbar area. This implies that the concentration of the plasma-derived proteins in CSF will vary depending on the volume of CSF that is collected. In the CSF samples spiked with blood, 262 of 814 quantified proteins showed an abundance increase of more than 1.5 fold, while 403 proteins had a fold change of less than 1.2 and appeared to be unaffected by blood contamination. Proteins with a high plasma/CSF ratio appeared to give the largest effect on the CSF proteome upon blood contamination. The results give important background information on how factors like blood contamination, RCG and blood-CNS-barrier influences the CSF proteome. This information is particularly important in the field of biomarker discovery, but also for routine clinical measurements. The data from the blood contamination and RCG discovery studies have been deposited to the ProteomeXchange with identifier PXD000401. PMID:24599184
Aaseb?, Elise; Opsahl, Jill Anette; Bj?rlykke, Yngvild; Myhr, Kjell-Morten; Kroksveen, Ann Cathrine; Berven, Frode S.
A novel peptidomics approach to detect markers of Alzheimer's disease in cerebrospinal fluid.
Sensitive and specific diagnosis and monitoring of disease progression are of prime importance to develop new therapies for Alzheimer's disease patients. Although the diagnostic accuracy, verified by pathological examination is high, it is currently not possible to diagnose Alzheimer's disease with a high degree of certainty until relatively late in the disease process. Here, we have undertaken a peptidome analysis of postmortem cerebrospinal fluid of neuropathologically confirmed Alzheimer's disease patients and non-demented controls using a combination of methods and technologies. This includes novel sample preparation based on the enrichment of endogenous, proteolytically derived peptides as well as peptides non-covalently bound to abundant proteins. We observed differences in peptide profiles associated with Alzheimer's disease in the endogenous peptide fraction and in the protein-bound peptide fraction. The discriminating peptides in the unbound peptide fraction were identified as VGF nerve growth factor inducible precursor, and complement C4 precursor, whereas the discriminating peptides in the protein-bound fraction were identified as VGF nerve growth factor inducible precursor, and alpha-2-HS-glycoprotein. PMID:22465281
Wijte, Dorien; McDonnell, Liam A; Balog, Crina I A; Bossers, Koen; Deelder, Andr� M; Swaab, Dick F; Verhaagen, Joost; Mayboroda, Oleg A
Background The cerebrospinal fluid (CSF) biomarkers total tau, abnormally phosphorylated tau and amyloid ? 1-42 are strongly associated with Alzheimer's disease (AD). Apart from the pathologic hallmarks that these biomarkers represent, other processes such as inflammation and microglial activation are present in the brains of patients with AD. New biomarkers related to these processes could be valuable for the diagnosis and follow-up of AD patients and for the evaluation of inflammation-related pathologies. Aim The aim of this study was to evaluate the association of inflammatory CSF biomarkers with AD. Methods Twenty-five AD patients and 25 controls who had a pathological and normal CSF profile of the core AD biomarkers, respectively, were included in this study. CSF levels of chitotriosidase, YKL-40 (also known as chitinase-3-like protein 1) and monocyte chemoattractant protein-1 (MCP-1) were quantified and the levels compared between the groups. Results AD patients had increased CSF levels of chitotriosidase and YKL-40 (both approximately twice higher than in controls), while the levels of MCP-1 were similar in the AD and control groups. Conclusion The results indicate that chitotriosidase and YKL-40 may be helpful for the evaluation of cerebral inflammatory activity in AD patients.
Rosen, Christoffer; Andersson, Carl-Henrik; Andreasson, Ulf; Molinuevo, Jose L.; Bjerke, Maria; Rami, Lorena; Llado, Albert; Blennow, Kaj; Zetterberg, Henrik
We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome and other unclassified forms. In seven patients, spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities. PMID:22929030
Reinstein, Eyal; Pariani, Mitchel; Bannykh, Serguei; Rimoin, David L; Schievink, Wouter I
Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs. PMID:24694925
Jakobsson, Joel; Bjerke, Maria; Ekman, Carl Johan; Sellgren, Carl; Johansson, Anette G M; Zetterberg, Henrik; Blennow, Kaj; Land�n, Mikael
Determination of metabolic organic acids in cerebrospinal fluid by microchip electrophoresis.
A new MCE method for the determination of oxalic, citric, glycolic, lactic, and 2- and 3-hydroxybutyric acids, indicators of some metabolic and neurological diseases, in cerebrospinal fluid (CSF) was developed. MCE separations were performed on a PMMA microchip with coupled channels at lower pH (5.5) to prevent proteins interference. A double charged counter-ion, BIS-TRIS propane, was very effective in resolving the studied organic acids. The limits of detection (S/N = 3) ranging from 0.1 to 1.6 ?M were obtained with the aid of contact conductivity detector implemented directly on the microchip. RSDs for migration time and peak area of organic acids in artificial and CSF samples were <0.8 and <9.7%, respectively. Recoveries of organic acids in untreated CSF samples on the microchip varied from 91 to 104%. Elimination of chloride interference, a major anionic constituent of CSF, has been reached by two approaches: (i) the use of coupled channels microchip in a column switching mode when approximately 97-99% of chloride was removed electrophoretically in the first separation channel and (ii) the implementation of micro-SPE with silver-form resin prior to the MCE analysis, which selectively removed chloride from undeproteinized CSF samples. PMID:24431209
Dan?, Ladislav; Bodor, R�bert; Tro�ka, Peter; Hor?i?iak, Michal; Mas�r, Mari�n
Dosimetric model for antibody targeted radionuclide therapy of tumor cells in cerebrospinal fluid
Although encouraging results have been obtained using systemic radioimmunotherapy in the treatment of cancer, it is likely that regional applications may prove more effective. One such strategy is the treatment of central nervous system leukemia in children by intrathecal instillation of targeting or nontargeting beta particle emitting radionuclide carriers. The beta particle dosimetry of the spine is assessed, assuming that the spinal cord and the cerebrospinal fluid compartment can be adequately represented by a cylindrical annulus. The radionuclides investigated were {sup 90}Y, {sup 131}I, {sup 67}Cu, and {sup 199}Au. It is shown that the radiation dose to the cord can be significantly reduced using short range beta particle emitters and that there is little advantage in using targeting carriers with these radionuclides. {sup 199}Au and {sup 67}Cu also have the advantage of having a suitable gamma emission for imaging, permitting pretherapy imaging and dosimetric calculations to be undertaken prior to therapy. If these methods prove successful, it may be possible to replace the external beam component used in the treatment of central nervous system leukemia in children by intrathecal radionuclide therapy, thus reducing or avoiding side effects such as growth and intellectual impairment.
Millar, W.T.; Barrett, A. (Univ. of Glasgow, Scotland (England))
Detection of disease-associated ?-synuclein in the cerebrospinal fluid: a feasibility study.
With the aim to evaluate the significance and reliability of detecting disease-specific ?-synuclein in the cerebrospinal fluid (CSF) we developed an ELISA and bead-assay. We used a commercial antibody (5G4) that does not bind to the physiological monomeric form of ?-synuclein, but is highly specific for the disease-associated forms, including high molecular weight fraction of ?-sheet rich oligomers. We applied both tests in CSF from a series of neuropathologically confirmed ?-synucleinopathy cases, including Parkinson' disease dementia (PDD) and dementia with Lewy bodies (DLB) (n = 7), as well as Alzheimer' disease (n = 6), and control patients without neurodegenerative pathologies (n = 9). Disease-specific ?-synuclein was detectable in the CSF in a subset of patients with ?-synuclein pathology in the brain. When combined with the analysis of total ?-synuclein, the bead-assay for disease-specific ?-synuclein was highly specific for PDD/DLB. Detection of disease-associated ?synuclein combined with the total levels of ?-synuclein is a promising tool for the in-vivo diagnosis of ?-synucleinopathies, including PDD and LBD. PMID:25131945
Unterberger, Ursula; Lachmann, Ingolf; Voigtl�nder, Till; Pirker, Walter; Berghoff, Anna S; Flach, Katharina; Wagner, Uta; Geneste, Aline; Perret-Liaudet, Armand; Kovacs, Gabor G
Simultaneous determination of all forms of biopterin and neopterin in cerebrospinal fluid.
In humans, genetic defects of the synthesis or regeneration of tetrahydrobiopterin (BH4), an essential cofactor in hydroxylation reactions, are associated with severe neurological disorders. The diagnosis of these conditions relies on the determination of BH4, dihydrobiopterin (BH2), and dihydroneopterin (NH2) in cerebrospinal fluid (CSF). As MS/MS is less sensitive than fluorescence detection (FD) for this purpose, the most widely used method since 1980 involves two HPLC runs including two differential off-line chemical oxidation procedures aiming to transform the reduced pterins into their fully oxidized fluorescent counterparts, biopterin (B) and neopterin (N). However, this tedious and time-consuming two-step indirect method underestimates BH4, BH2, and NH2 concentrations. Direct quantification of BH4 is essential for studying its metabolism and for monitoring the efficacy of BH4 supplementation in patients with genetic defects. Here we describe a single step method to simultaneously measure BH4, BH2, B, NH2, and N in CSF by HPLC coupled to FD after postcolumn coulometric oxidation. All target pterins were quantified in CSF with a small volume (100 ?L), and a single filtration step for sample preparation and analysis. As compared to the most widely used method in more than 100 CSF samples, this new assay is the easiest route for accurately determining in a single run BH4, BH2, and NH2 in CSF in deficit situations as well as for monitoring the efficacy of the treatment. PMID:24650440
Guibal, Pierre; L�v�que, Nathalie; Doummar, Diane; Giraud, Nicolas; Roze, Emmanuel; Rodriguez, Diana; Couderc, R�my; Billette De Villemeur, Thierry; Moussa, Fathi
Adhesion of staphylococci to polymers with and without immobilized heparin in cerebrospinal fluid.
Infections of cerebrospinal fluid (CSF) shunts constitute a serious clinical problem. The role of adhesion by coagulase negative staphylococci, the most common etiological agent, was examined in vitro to polyvinyl chloride (PVC), silicone, and to PVC and silicone with end-point attached (EPA) heparin. These are flexible materials commonly used in neurosurgical implants. Bacterial adhesion was quantitated by bioluminescence. The bacterial adhesion to biomaterial surfaces increased with increasing concentrations of bacterial cells. Scatchard plot analysis showed continuous negative (concave) slopes, indicating multiple interactions between biomaterial and bacteria. The thermodynamic studies showed a positive value of the standard entropy change at 37 degrees C, which indicates that hydrophobic interactions are important in bacterial adhesion to polymers. Incubation with CSF for 1 h decreased bacterial adhesion in 75% of the samples compared to incubation in buffer. Thus, the contribution of CSF proteins, like fibronectin, for the initial bacterial adhesion might be small. Heparinization of silicone and PVC decreased the numbers of adhered bacteria by 23 to 54% and 0 to 43% compared to unheparinized surfaces. Among putative inhibitors tested, suramin, chondroitin sulfate, and fucoidan inhibited adhesion to 81 +/- 19, 78 +/- 22, and 64 +/- 7%, respectively. These findings indicate that hydrophobic interactions play an important role, and heparinization rendering the biomaterial surface hydrophilic is therefore effective to reduce bacterial adhesion. Heparinized polymers incubated with putative inhibitors may be the optimal way to prevent shunt infections. PMID:9086415
Nomura, S; Lundberg, F; Stollenwerk, M; Nakamura, K; Ljungh, A
Monoclonal 2C3 specific to ?-amyloid (A?) oligomers (A?Os) enabled us to test our hypothesis that the alteration of lipoprotein-A? interaction in the central nervous system (CNS) initiates and/or accelerates the cascade favoring A? assembly. Immunoprecipitation of frontal cortex employing 2C3 unequivocally detected soluble 4-, 8-, and 12-mers in Alzheimer's disease (AD) brains. Immunoblot analysis of the entorhinal cortex employing 2C3 revealed that the accumulation of soluble 12-mers precedes the appearance of neuronal loss or cognitive impairment and is enhanced as the Braak neurofibrially tangle (NFT) stages progress. The dissociation of soluble A? from lipoprotein particles occurs in cerebrospinal fluid (CSF), and the presence of lipoprotein-free oligomeric 2C3 conformers (4- to 35-mers) was evident, which mimic CNS environments. Such CNS environments may strongly affect conformation of soluble A? peptides, resulting in the conversion of soluble A?(42) monomers into soluble A?(42) assembly. The findings suggest that functionally declined lipoproteins may accelerate the generation of metabolic conditions leading to higher levels of soluble A?(42) assembly in the CNS. PMID:21394760
Takamura, Ayumi; Kawarabayashi, Takeshi; Yokoseki, Tatsuki; Shibata, Masao; Morishima-Kawashima, Maho; Saito, Yuko; Murayama, Shigeo; Ihara, Yasuo; Abe, Koji; Shoji, Mikio; Michikawa, Makoto; Matsubara, Etsuro
Neuropathology is the most reliable criterion for diagnosing Alzheimer's disease (AD). A well-established system for staging the spread of neuropathological changes in AD is available. The clinical use of a biomarker that reflects the neuropathological change occurring in brain tissue has not yet been established. Melatonin is a product that plays not only a major role in the regulation of the circadian rhythms but may also exert neuroprotective effects in AD. Melatonin levels were determined in ventricular postmortem cerebrospinal fluid (CSF) of 121 subjects. Braak staging and a modified Braak staging for cortex (MBSC) were used to evaluate the severity of AD neuropathology. The present study revealed that not only the Braak stages of AD, but also the MBSC were negatively correlated with CSF melatonin levels. By using MBSC, we now demonstrate for the first time that CSF melatonin levels were significantly decreased in the aged individuals with early neuropathological changes in the temporal cortex, where the AD process starts. Those individuals that did not have any neurofibrillary tangle (NFT) or neuritic plaque (NP) in the temporal cortex, had much higher melatonin levels (287 +/- 68 and 280 +/- 64 pg/mL, respectively) than those individuals that had a few NFTs and NPs (82 +/- 4 and 39 +/- 8 pg/mL, respectively) in the temporal cortex. These results suggest that the decrease in CSF melatonin levels may be an early event in the development of AD possibly occurring even before the clinical symptoms. PMID:12887656
Zhou, Jiang-Ning; Liu, Rong-Yu; Kamphorst, Wouter; Hofman, Michel A; Swaab, Dick F
Neuronal and Glia-Related Biomarkers in Cerebrospinal Fluid of Patients with Acute Ischemic Stroke
BACKGROUND Cerebral ischemia promotes morphological reactions of the neurons, astrocytes, oligodendrocytes, and microglia in experimental studies. Our aim was to examine the profile of CSF (cerebrospinal fluid) biomarkers and their relation to stroke severity and degree of white matter lesions (WML). METHODS A total of 20 patients (mean age 76 years) were included within 5�10 days after acute ischemic stroke (AIS) onset. Stroke severity was assessed using NIHSS (National Institute of Health stroke scale). The age-related white matter changes (ARWMC) scale was used to evaluate the extent of WML on CT-scans. The concentrations of specific CSF biomarkers were analyzed. RESULTS Patients with AIS had significantly higher levels of NFL (neurofilament, light), T-tau, myelin basic protein (MBP), YKL-40, and glial fibrillary acidic protein (GFAP) compared with controls; T-Tau, MBP, GFAP, and YKL-40 correlated with clinical stroke severity, whereas NFL correlated with severity of WML (tested by Mann�Whitney test). CONCLUSIONS Several CSF biomarkers increase in AIS, and they correlate to clinical stroke severity. However, only NFL was found to be a marker of degree of WML. PMID:24932109
Hjalmarsson, Clara; Bjerke, Maria; Andersson, Bjorn; Blennow, Kaj; Zetterberg, Henrik; Aberg, N David; Olsson, Bob; Eckerstrom, Carl; Bokemark, Lena; Wallin, Anders
The measurement of ?-aminobutyric acid (GABA) is suitable for investigating various neurological disorders. In this study, a sensitive and selective method for free GABA quantification in cerebrospinal fluid (CSF) has been standardised. This method is based on CE with LIF detection using 4-fluoro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-F) as a derivatisating agent. The reaction conditions (NBD-F concentration, pH, temperature and reaction time) and the electrophoretic parameters (run buffer composition and pH and separation voltage) were optimised to obtain the maximum derivatisation efficiency and electrophoretic resolution. The best resolution was obtained using 200 mM sodium borate, 10 mM SDS, 8.5 mM ?-CD, pH 10 and 20 kV voltage. The method was linear in the concentration range of 2.5-1000 nM with good inter- and intra-assay precision values. The effects of CSF handling on free GABA concentrations were also evaluated. Our results show that the time delay between CSF collection and freezing strongly increases the CSF GABA values. Age-related reference values were established in 55 paediatric controls. The influence of antiepileptic therapy on free CSF GABA was studied in 38 neuropaediatric patients. Significantly, higher GABA values were obtained in patients taking valproic acid or vigabatrin therapy, which are antiepileptic drugs that modulate GABA metabolism. PMID:24338894
Casado, Mercedes; Molero, Marta; Sierra, Cristina; Garc�a-Cazorla, Angels; Ormazabal, Aida; Artuch, Rafael
Previous findings from our laboratory demonstrated that some clonally expanded cerebrospinal fluid (CSF) B cells from MS patients exhibit diminished mutation targeting patterns in comparison to typical B cells selected in the context of germinal centers (GCs). In order to determine whether the overall CSF B cell repertoires adhered to mutation patterns typical of GC-selected B cells, we analyzed the immunoglobulin repertoires from CSF B cells of 8 MS patients for mutation characteristics typical of GC-derived B cells. Mutation targeting was preserved. Thus, clonal expansion of some CSF B cells may occur independently of GC, but the CSF B cell pool is governed by typical GC selection. Interestingly, the heavy chain CDR3�s of CSF B cells from MS patients had a net acidic charge, similar to GC-derived B cells, but a tendency towards longer CDR3�s, consistent with autoreactive B cells. How these findings may support current hypotheses regarding the origin of CSF B cells is discussed. PMID:17169437
Harp, Christopher; Lee, Jane; Lambracht-Washington, Doris; Cameron, Elizabeth; Olsen, Gregory; Frohman, Elliot; Racke, Michael; Monson, Nancy
Diagnosis of acute leukemia in cerebrospinal fluid (CSF-acute leukemia).
Cerebrospinal fluid-acute leukemia (CSF-acute leukemia) is a frequent and serious complication in patients with acute leukemia. One of the major problems of this complication is the diagnosis process itself. CSF cytology is currently considered the gold standard for establishing the diagnosis, a technique which presents various processing limitations, seriously impacting the predictive values. In the last 11 years, studies of CSF flow cytometry analysis done in patients with acute leukemia have demonstrated superiority in comparison with CSF cytology. Although comparative studies between these two techniques have been reported since 2001, no new consensus or formal changes to the gold standard have been established for the CSF acute leukemia diagnosis. The evidence suggests that positive flow cytometry cases, considered as indeterminate cases, will behave like disease in the central nervous system (CNS). Nevertheless, we think there are some variables and considerations that must be first evaluated under research protocols before CNS relapse can be established with only one positive flow cytometry analysis in the setting of indeterminate CSF samples. This paper proposes a diagnostic algorithm and complementary strategies. PMID:22639108
Crespo-Solis, Erick; L�pez-Karpovitch, Xavier; Higuera, Jes�s; Vega-Ramos, Beatriz
European cerebrospinal fluid consensus group--a TeamRoom (Lotus Notes)-based communication network.
A group of clinical neurochemists from all over Europe used TeamRoom to share information and to trace their discussions in a computer network. TeamRoom is a Lotus Notes based groupware tool enabling collaboration amongst geographically dispersed teams. As a result of this work a picture is emerging in the virtual TeamRoom space that represents a new kind of consensus in the use of cerebrospinal fluid analysis for diagnosis of neurological diseases. This kind of consensus differs from the conventional written report in giving a more complex and potentially richer representation of the field, in which both common views and minority perspectives are revealed. If direct access to this work is made available to other clinical neurochemists for consultation via a website, they may see their own practice in a wider context. This approach to improving different evolving traditions is more suitable for a global multicultural environment than a singular view of best practice produced by a more traditional process of group discussion. We refer to the benefits of a mixture of face to face meetings, collaboration in TeamRoom and teleconferencing for work in a non-hierarchical, multicultural and multilingual group. We suggest that the TeamRoom concept is a valuable model for enhancing self-organized harmonization across the developing European Union. PMID:11071068
Shaw, P; Reiber, H; Brennan, C
PACAP has well-known neuroprotective potential including traumatic brain injury (TBI). Its level is up-regulated following various insults of the CNS in animal models. A few studies have documented alterations of PACAP levels in human serum. The time course of post-ictal PACAP levels, for example, show correlation with migraine severity. Very little is known about the course of PACAP levels following CNS injury in humans and the presence of PACAP has not yet been detected in cerebrospinal fluid (CSF) of subjects with severe TBI (sTBI). The aim of the present study was to determine whether PACAP occurs in the CSF and plasma (Pl) of patients that suffered sTBI and to establish a time course of PACAP levels in the CSF and Pl. Thirty eight subjects with sTBI were enrolled with a Glasgow Coma Scale ?8 on admission. Samples were taken daily, until the time of death or for maximum 10 days. Our results demonstrated that PACAP was detectable in the CSF, with higher concentrations in patients with TBI. PACAP concentrations markedly increased in both Pl and CSF in the majority of patients 24-48h after the injury stayed high thereafter. In cases of surviving patients, Pl and CSF levels displayed parallel patterns, which may imply the damage of the blood-brain barrier. However, in patients, who died within the first week, Pl levels were markedly higher than CSF levels, possibly indicating the prognostic value of high Pl PACAP levels. PMID:25017241
Bukovics, Peter; Czeiter, Endre; Amrein, Krisztina; Kovacs, Noemi; Pal, Jozsef; Tamas, Andrea; Bagoly, Terez; Helyes, Zsuzsanna; Buki, Andras; Reglodi, Dora
Objective Determine if antiretroviral (ARV) regimens with good central nervous system (CNS) penetration control HIV in cerebrospinal fluid (CSF) and improve cognition. Design Multi-site longitudinal observational study. Setting Research clinics. Subjects 101 individuals with advanced HIV beginning or changing a new potent ARV regimen. Data for 79 subjects were analyzed. Participants underwent structured history and neurological examination, venipuncture, lumbar puncture, neuropsychological tests at entry, 24 and 52 weeks. Intervention ARV regimens were categorized as CNS penetration effectiveness (CPE) rank ? 2 or < 2. Generalized estimating equations were used to examine associations over the course of the study. Main Outcome Measures Concentration of HIV RNA in CSF and blood, neuropsychological test scores. Results Odds of suppression of CSF HIV RNA were higher when CPE rank ? 2 compared to < 2. Odds of suppression of plasma HIV RNA were not associated with CPE rank. Among subjects with impaired neuropsychological performance at entry, those prescribed regimens with a CPE rank ? 2 or more ARVs had lower NPZ4 over the course of the study. Conclusions ARV regimens with good CNS penetration, as assessed by CPE rank, are more effective in controlling CSF (and presumably CNS) viral replication than regimens with poorer penetration. In this study, ARVs with good CNS penetration were associated with poorer neurocognitive performance. A larger, controlled trial is required before any conclusions regarding the influence of specific ARVs on neurocognitive performance should be made. PMID:19424052
Marra, Christina M.; Zhao, Yu; Clifford, David B.; Letendre, Scott; Evans, Scott; Henry, Katherine; Ellis, Ronald J.; Rodriguez, Benigno; Coombs, Robert W.; Schifitto, Giovanni; McArthur, Justin C.; Robertson, Kevin
Detectable human immunodeficiency virus (HIV) RNA in the cerebrospinal fluid (CSF) is associated with central nervous system (CNS) complications. We developed the CSF HIV risk score through prediction modeling to estimate the risk of detectable CSF HIV RNA (threshold >50 copies/mL) to help identify persons who might benefit most from CSF monitoring. We used baseline data from 1,053 participants receiving combination antiretroviral therapy who were enrolled in the 6-center, US-based CNS HIV Antiretroviral Therapy Effects Research (CHARTER) prospective cohort in 2004-2007. Plasma HIV RNA, CNS penetration effectiveness, duration of combination antiretroviral therapy, medication adherence, race, and depression status were retained correlates of CSF HIV RNA, displaying good discrimination (C statistic = 0.90, 95% confidence interval (CI): 0.87, 0.93) and calibration (Hosmer-Lemeshow P = 0.85). The CSF HIV risk score ranges from 0 to 42 points, with a mean of 15.4 (standard deviation, 7.3) points. At risk scores greater than 25, the probability of detecting CSF HIV RNA was at least 42.9% (95% CI: 36.6, 49.6). For each 1-point increase, the odds of detecting CSF HIV RNA increased by 26% (odds ratio = 1.26, 95% CI: 1.21, 1.31; P < 0.01). The risk score correlates with detection of CSF HIV RNA. It represents an advance in HIV management and monitoring of CNS effects, providing a potentially useful tool for clinicians. PMID:24966216
Hammond, Edward R; Crum, Rosa M; Treisman, Glenn J; Mehta, Shruti H; Marra, Christina M; Clifford, David B; Morgello, Susan; Simpson, David M; Gelman, Benjamin B; Ellis, Ronald J; Grant, Igor; Letendre, Scott L; McArthur, Justin C
Background: Brain arteriovenous malformations (AVMs) produce circulatory and functional disturbances in adjacent as well as in remote areas of the brain, but their physiological effect on the cerebrospinal fluid (CSF) pressure is not well known. Methods: The hypothesis of an intrinsic disease mechanism leading to increased CSF pressure in all patients with brain AVM is outlined, based on a theory of hemodynamic control of intracranial pressure that asserts that CSF pressure is a fraction of the systemic arterial pressure as predicted by a two-resistor series circuit hydraulic model. The resistors are the arteriolar resistance (that is regulated by vasomotor tonus), and the venous resistance (which is mechanically passive as a Starling resistor). This theory is discussed and compared with the knowledge accumulated by now on intravasal pressures and CSF pressure measured in patients with brain AVM. Results: The theory provides a basis for understanding the occurrence of pseudotumor cerebri syndrome in patients with nonhemorrhagic brain AVMs, for the occurrence of local mass effect and brain edema bordering unruptured AVMs, and for the development of hydrocephalus in patients with unruptured AVMs. The theory also contributes to a better appreciation of the pathophysiology of dural arteriovenous fistulas, of vein of Galen aneurismal malformation, and of autoregulation-related disorders in AVM patients. Conclusions: The hydraulic hypothesis provides a comprehensive frame to understand brain AVM hemodynamics and its effect on the CSF dynamics. PMID:23607064
Rossitti, Sandro
Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span
Adequate central nervous system noradrenergic activity enhances cognition, but excessive noradrenergic activity may have adverse effects on cognition. Previous studies have also demonstrated that noradrenergic activity is higher in older than younger adults. We aimed to determine relationships between cerebrospinal fluid (CSF) norepinephrine (NE) concentration and cognitive performance by using data from a CSF bank that includes samples from 258 cognitively normal participants aged 21�100 years. After adjusting for age, gender, education, and ethnicity, higher CSF NE levels (units of 100 pg/mL) are associated with poorer performance on tests of attention, processing speed, and executive function (Trail Making A: regression coefficient 1.5, standard error [SE] 0.77, p = 0.046; Trail Making B: regression coefficient 5.0, SE 2.2, p = 0.024; Stroop Word-Color Interference task: regression coefficient 6.1, SE 2.0, p = 0.003). Findings are consistent with the earlier literature relating excess noradrenergic activity with cognitive impairment. PMID:23639207
Wang, Lucy Y.; Murphy, Richard R.; Hanscom, Brett; Li, Ge; Millard, Steven P.; Petrie, Eric C.; Galasko, Douglas R.; Sikkema, Carl; Raskind, Murray A.; Wilkinson, Charles W.; Peskind, Elaine R.
The objective of this work is to quantify age-related differences in the characteristics and coupling of cerebral arterial inflow and cerebrospinal fluid (CSF) dynamics. To this end, 3T phase-contrast magnetic resonance imaging blood and CSF flow data of eleven young ( years) and eleven elderly subjects ( years) with a comparable sex-ratio were acquired. Flow waveforms and their frequency composition, transfer functions from blood to CSF flows and cross-correlations were analyzed. The magnitudes of the frequency components of CSF flow in the aqueduct differ significantly between the two age groups, as do the frequency components of the cervical spinal CSF and the arterial flows. The males' aqueductal CSF stroke volumes and average flow rates are significantly higher than those of the females. Transfer functions and cross-correlations between arterial blood and CSF flow reveal significant age-dependence of phase-shift between these, as do the waveforms of arterial blood, as well as cervical-spinal and aqueductal CSF flows. These findings accentuate the need for age- and sex-matched control groups for the evaluation of cerebral pathologies such as hydrocephalus. PMID:22666360
Schmid Daners, Marianne; Knobloch, Verena; Soellinger, Michaela; Boesiger, Peter; Seifert, Burkhardt; Guzzella, Lino; Kurtcuoglu, Vartan
Alzheimer's disease (AD), the most common type of dementia among older people, is characterized by the accumulation of ?-amyloid (A?) senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF) production, associated with the increased expression of Na(+)-K(+) ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of A?, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis. PMID:21660211
Wostyn, Peter; Van Dam, Debby; Audenaert, Kurt; De Deyn, Peter Paul
The aim of this exploratory investigation was to determine if genetic variation within amyloid precursor protein (APP) or its processing enzymes correlates with APP cleavage product levels: APP?, APP? or A?42, in cerebrospinal fluid (CSF) of cognitively normal subjects or Alzheimer's disease (AD) patients. Cognitively normal control subjects (n = 170) and AD patients (n = 92) were genotyped for 19 putative regulatory tagging SNPs within 9 genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the APP processing pathway. SNP genotypes were tested for their association with CSF APP?, APP?, and A?42, AD risk and age-at-onset while taking into account age, gender, race and APOE ?4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APP? levels. In controls, the rs514049 CC genotype had higher APP? levels than the CA, AA collapsed genotype, whereas the opposite effect was seen in AD patients. These results suggest that genetic variation within ADAM10, an APP processing gene, influences CSF APP? levels in an AD specific manner. PMID:21196064
Bekris, L M; Galloway, N M; Millard, S; Lockhart, D; Li, G; Galasko, D R; Farlow, M R; Clark, C M; Quinn, J F; Kaye, J A; Schellenberg, G D; Leverenz, J B; Seubert, P; Tsuang, D W; Peskind, E R; Yu, C E
Objectives?To describe our departmental experience in the surgical repair of tegmen tympani defects using a combined transmastoid/minicraniotomic approach. Design?Retrospective review of videos from surgery and patients' charts. Setting?Tertiary university referral center. Participants?Twenty-two patients who underwent surgical repair of tegmen defects associated with cerebrospinal fluid (CSF) leakage and/or meningocele/meningoencephalocele by a combined transmastoid/minicraniotomic approach. Main Outcome Measures?A retrospective review of videos of surgery and charts of patients with tegmen tympani or tegmen antri defects and CSF leakage, temporal lobe encephalocele, and/or meningoencephalocele. Results?All patients underwent the combined approach and had their defects closed, without significant intraoperative or postoperative complications. Conclusions?Mastoidectomy with temporal minicraniotomy represents an effective approach in patients with tegmen tympani dehiscence; the advantages of this technique are the control of the floor of the middle cranial fossa and the possibility to reach bony defects located anteriorly without manipulation of the ossicular chain and temporal lobe. PMID:25093152
Marchioni, Daniele; Bonali, Marco; Alicandri-Ciufelli, Matteo; Rubini, Alessia; Pavesi, Giacomo; Presutti, Livio
Volume transmission of beta-endorphin via the cerebrospinal fluid; a review
There is increasing evidence that non-synaptic communication by volume transmission in the flowing CSF plays an important role in neural mechanisms, especially for extending the duration of behavioral effects. In the present review, we explore the mechanisms involved in the behavioral and physiological effects of ?-endorphin (?-END), especially those involving the cerebrospinal fluid (CSF), as a message transport system to reach distant brain areas. The major source of ?-END are the pro-opio-melano-cortin (POMC) neurons, located in the arcuate hypothalamic nucleus (ARH), bordering the 3rd ventricle. In addition, numerous varicose ?-END-immunoreactive fibers are situated close to the ventricular surfaces. In the present paper we surveyed the evidence that volume transmission via the CSF can be considered as an option for messages to reach remote brain areas. Some of the points discussed in the present review are: release mechanisms of ?-END, independence of peripheral versus central levels, central ?-END migration over considerable distances, behavioral effects of ?-END depend on location of ventricular administration, and abundance of mu and delta opioid receptors in the periventricular regions of the brain. PMID:22883598
Kynurenic acid (KYNA) is implicated in cognitive functions. Altered concentrations of the compound are found in serum and cerebrospinal fluid (CSF) of patients with Alzheimer�s disease (AD). Further studies to determine whether KYNA serves as a biomarker for cognitive decline and dementia progression are required. In this study, we measured CSF KYNA levels in AD patients (n = 19), patients with dementia with Lewy bodies (DLB) (n = 18), and healthy age-matched controls (Ctrls)) (n = 20) to further explore possible correlations between KYNA levels, cognitive decline, and well-established AD and inflammatory markers. Neither DLB patients nor AD patients showed significantly altered CSF KYNA levels compared to Ctrls. However, female AD patients displayed significantly higher KYNA levels compared to male AD patients, a gender difference not seen in the Ctrl or DLB group. Levels of KYNA significantly correlated with the AD-biomarker P-tau and the inflammation marker soluble intercellular adhesion molecule-1 (sICAM-1) in the AD patient group. No associations between KYNA and cognitive functions were found. Our study shows that, although KYNA was not associated with cognitive decline in AD or DLB patients, it may be implicated in AD-related hyperphosphorylation of tau and inflammation. Further studies on larger patient cohorts are required to understand the potential role of KYNA in AD and DLB. PMID:24855376
Wennstrom, Malin; Nielsen, Henrietta M; Orhan, Funda; Londos, Elisabet; Minthon, Lennart; Erhardt, Sophie
The objective of this study was to measure changes in cerebrospinal fluid (CSF) pressure and cerebrovascular hemodynamics following acoustic neuroma surgery. The subjects were 32 patients undergoing translabyrinthine or retrosigmoid excision of acoustic neuroma. CSF pressure and the amplitude of the CSF pressure pulse wave were measured using lumbar catheters, and all variables were recorded minute by minute on a microcomputer. Transcranial doppler (TCD) was used to measure flow velocity in the middle cerebral artery in 10 patients to monitor changes in cerebral hemodynamics. In the 24 hours after surgery, all patients showed a statistically significant rise in CSF pressure from 11.4 mm Hg (standard deviation [SD] 6.1) to 19.6 mm Hg (SD 5.2) and a corresponding fall in the compliance of the CSF compartment. These changes were reversed within 48 hours, and the CSF pressure fell below the preoperative level over the next 4 days without any drainage of CSF. The results of this study demonstrate a transient increase in CSF pressure and decrease in craniospinal compliance that is provoked by surgery. The most plausible explanation for this disturbance is impaired CSF absorption, which resolves rapidly in most patients without therapeutic CSF drainage. PMID:17171145
Laing, Rodney J.; Smielewski, Piotr; Czosnyka, Marek; Quaranta, Nicola; Moffat, David A.
Cerebrospinal fluid�based kinetic biomarkers of axonal transport in monitoring neurodegeneration
Progress in neurodegenerative disease research is hampered by the lack of biomarkers of neuronal dysfunction. We here identified a class of cerebrospinal fluid�based (CSF-based) kinetic biomarkers that reflect altered neuronal transport of protein cargo, a common feature of neurodegeneration. After a pulse administration of heavy water (2H2O), distinct, newly synthesized 2H-labeled neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct 2H-cargo proteins displayed delayed appearance and disappearance kinetics in the CSF, suggestive of aberrant transport kinetics. Microtubule-modulating pharmacotherapy normalized CSF-based kinetics of affected 2H-cargo proteins and ameliorated neurodegenerative symptoms in mice. After 2H2O labeling, similar neuronal transport deficits were observed in CSF of patients with Parkinson�s disease (PD) compared with non-PD control subjects, which indicates that these biomarkers are translatable and relevant to human disease. Measurement of transport kinetics may provide a sensitive method to monitor progression of neurodegeneration and treatment effects. PMID:22922254
Fanara, Patrizia; Wong, Po-Yin A.; Husted, Kristofor H.; Liu, Shanshan; Liu, Victoria M.; Kohlstaedt, Lori A.; Riiff, Timothy; Protasio, Joan C.; Boban, Drina; Killion, Salena; Killian, Maudi; Epling, Lorrie; Sinclair, Elisabeth; Peterson, Julia; Price, Richard W.; Cabin, Deborah E.; Nussbaum, Robert L.; Br�hmann, J�rg; Brandt, Roland; Christine, Chadwick W.; Aminoff, Michael J.; Hellerstein, Marc K.
Cerebrospinal fluid-based kinetic biomarkers of axonal transport in monitoring neurodegeneration.
Progress in neurodegenerative disease research is hampered by the lack of biomarkers of neuronal dysfunction. We here identified a class of cerebrospinal fluid-based (CSF-based) kinetic biomarkers that reflect altered neuronal transport of protein cargo, a common feature of neurodegeneration. After a pulse administration of heavy water (2H2O), distinct, newly synthesized 2H-labeled neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct 2H-cargo proteins displayed delayed appearance and disappearance kinetics in the CSF, suggestive of aberrant transport kinetics. Microtubule-modulating pharmacotherapy normalized CSF-based kinetics of affected 2H-cargo proteins and ameliorated neurodegenerative symptoms in mice. After 2H2O labeling, similar neuronal transport deficits were observed in CSF of patients with Parkinson's disease (PD) compared with non-PD control subjects, which indicates that these biomarkers are translatable and relevant to human disease. Measurement of transport kinetics may provide a sensitive method to monitor progression of neurodegeneration and treatment effects. PMID:22922254
Fanara, Patrizia; Wong, Po-Yin A; Husted, Kristofor H; Liu, Shanshan; Liu, Victoria M; Kohlstaedt, Lori A; Riiff, Timothy; Protasio, Joan C; Boban, Drina; Killion, Salena; Killian, Maudi; Epling, Lorrie; Sinclair, Elisabeth; Peterson, Julia; Price, Richard W; Cabin, Deborah E; Nussbaum, Robert L; Br�hmann, J�rg; Brandt, Roland; Christine, Chadwick W; Aminoff, Michael J; Hellerstein, Marc K
A standardized protocol for flow cytometric analysis of cells isolated from cerebrospinal fluid.
Flow cytometry (FC) is an useful tool for the analysis of subpopulations in complex cell suspensions. When applying this method to the cerebrospinal fluid (CSF), some characteristic properties of this cell type must be taken into consideration: there are only few cells which decay rapidly in their native medium and during centrifugation. One aim of the immunostaining procedure preceding flow cytometric analysis must be to minimize cell loss in order to get an undistorted picture of 'true' CSF cell populations. Consequently, morphological flow cytometric plots of high resolution are an indispensable precondition for reliable determination of subpopulations defined by monoclonal antibody (Mab) binding. We describe a standardized protocol for the flow cytometric examination of CSF cells which minimizes undesired cell loss. By the use of a 'quality control' the extent of cell loss could be monitored. Examples of morphological flow cytometric plots are given. The subsequent determination of Mab binding subpopulations is critical when fluorescence intensities of antigen positive and negative cells are non-disjunct. A statistical test was developed for these cases often seen when cell surface determinants are expressed at low levels only. PMID:7510788
Dux, R; Kindler-R�hrborn, A; Annas, M; Faustmann, P; Lennartz, K; Zimmermann, C W
We conducted a study to assess the efficacy of the dipstick leukocyte esterase test (LET) in the detection of cerebrospinal fluid (CSF) leukocytosis as a quick screen for bacterial meningitis. Nine hundred forty-two CSF samples were collected from 800 patients. The LET was compared in a double-blinded fashion with routine cell count determinations and cultures. We reviewed the clinical courses of all patients with positive cultures to assess the significance of culture isolates. Statistical analysis revealed LET sensitivity of 84.4% and specificity of 98.1% for clinical presentations of bacterial meningitis for which initiation of therapy is currently recommended. The LET identified culture-proven cases of meningitis with sensitivity of 73% and specificity of 95%. We propose the LET as an adjunct to, but not a replacement for, CSF cell count and chemistry determination in the initial laboratory assessment of bacterial meningitis. It is a reasonable screen that allows rapid initiation of treatment and directs the laboratory technician to devote extra attention to examination of a CSF specimen with a higher likelihood of pathology. PMID:2683900
DeLozier, J S; Auerbach, P S
Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood-Cerebrospinal Fluid Barrier
The subarachnoid space, where cerebrospinal fluid (CSF) flows over the brain and spinal cord, is lined on one side by arachnoid barrier (AB) cells that form part of the blood-CSF barrier. However, despite the fact that drugs are administered into the CSF and CSF drug concentrations are used as a surrogate for brain drug concentration following systemic drug administration, the tight-junctioned AB cells have never been examined for whether they express drug transporters that would influence CSF and central nervous system drug disposition. Hence, we characterized drug transporter expression and function in AB cells. Immunohistochemical analysis showed P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in mouse AB cells but not other meningeal tissue. The Gene Expression Nervous System Atlas (GENSAT) database and the Allen Mouse Brain Atlas confirmed these observations. Microarray analysis of mouse and human arachnoidal tissue revealed expression of many drug transporters and some drug-metabolizing enzymes. Immortalized mouse AB cells express functional P-gp on the apical (dura-facing) membrane and BCRP on both apical and basal (CSF-facing) membranes. Thus, like blood-brain barrier cells and choroid plexus cells, AB cells highly express drug transport proteins and likely contribute to the blood-CSF drug permeation barrier. PMID:23298861
Yasuda, Kazuto; Cline, Cynthia; Vogel, Peter; Onciu, Mihaela; Fatima, Soghra; Sorrentino, Brian P.; Thirumaran, Ranjit K.; Ekins, Sean; Urade, Yoshihiro; Fujimori, Ko
In Vivo Imaging of Lymphatic Drainage of Cerebrospinal Fluid in Mouse
Background Mouse models are commonly used to study central nervous system disorders, in which cerebrospinal fluid (CSF) drainage may be disturbed. However, mouse CSF drainage into lymphatics has not been thoroughly characterized. We aimed to image this using an in vivo approach that combined quantum dot fluorescent nanoparticles with hyperspectral imaging. Findings Quantum dot 655 was injected into the CSF of the cisterna magna in seven mice and visualized by in vivo hyperspectral imaging at time points 20 and 40�min, 1, 2, and 6�h after injection. In controls (n?=?4), quantum dots were applied directly onto intact dura mater covering the cisterna magna. After imaging, lymph nodes in the neck were harvested and processed post-mortem for histological analysis. After injection into the CSF, quantum dot signal was detected in vivo in submandibular lymph nodes of all mice studied as early as 20�min, but not in controls. Post-mortem gross and histological examination of lymph nodes confirmed in vivo observations. Conclusions Non-invasive in vivo hyperspectral imaging is a useful tool to study CSF lymphatic drainage and is relevant to understanding this pathway in CNS disease models. PMID:24360130
ABSTRACT Acute central nervous system (CNS) infections cause substantial morbidity and mortality, but the etiology remains unknown in a large proportion of cases. We identified and characterized the full genome of a novel cyclovirus (tentatively named cyclovirus-Vietnam [CyCV-VN]) in cerebrospinal fluid (CSF) specimens of two Vietnamese patients with CNS infections of unknown etiology. CyCV-VN was subsequently detected in 4% of 642 CSF specimens from Vietnamese patients with suspected CNS infections and none of 122 CSFs from patients with noninfectious neurological disorders. Detection rates were similar in patients with CNS infections of unknown etiology and those in whom other pathogens were detected. A similar detection rate in feces from healthy children suggested food-borne or orofecal transmission routes, while high detection rates in feces from pigs and poultry (average, 58%) suggested the existence of animal reservoirs for such transmission. Further research is needed to address the epidemiology and pathogenicity of this novel, potentially zoonotic virus. PMID:23781068
Tan, Le Van; van Doorn, H. Rogier; Nghia, Ho Dang Trung; Chau, Tran Thi Hong; Tu, Le Thi Phuong; de Vries, Michel; Canuti, Marta; Deijs, Martin; Jebbink, Maarten F.; Baker, Stephen; Bryant, Juliet E.; Tham, Nguyen Thi; BKrong, Nguyen Thi Thuy Chinh; Boni, Maciej F.; Loi, Tran Quoc; Phuong, Le Thi; Verhoeven, Joost T. P.; Crusat, Martin; Jeeninga, Rienk E.; Schultsz, Constance; Chau, Nguyen Van Vinh; Hien, Tran Tinh; van der Hoek, Lia; Farrar, Jeremy; de Jong, Menno D.
ID3 contributes to cerebrospinal fluid seeding and poor prognosis in medulloblastoma
Background The inhibitor of differentiation (ID) genes have been implicated as promoters of tumor progression and metastasis in many human cancers. The current study investigated the expression and functional roles of ID genes in seeding and prognosis of medulloblastoma. Methods ID gene expression was screened in human medulloblastoma tissues. Knockdown of ID3 gene was performed in medulloblastoma cells in vitro. The expression of metastasis-related genes after ID3 knockdown was assessed. The effect of ID3 knockdown on tumor seeding was observed in an animal model in vivo. The survival of medulloblastoma patients was plotted according to the ID3 expression levels. Results Significantly higher ID3 expression was observed in medulloblastoma with cerebrospinal fluid seeding than tumors without seeding. Knockdown of ID3 decreased proliferation, increased apoptosis, and suppressed the migration of D283 medulloblastoma cells in vitro. In a seeding model of medulloblastoma, ID3 knockdown in vivo with shRNA inhibited the growth of primary tumors, prevented the development of leptomeningeal seeding, and prolonged animal survival. High ID3 expression was associated with shorter survival of medulloblastoma patients, especially in Group 4 medulloblastomas. Conclusions High ID3 expression is associated with medullolbastoma seeding and is a poor prognostic factor, especially in patients with Group 4 tumors. ID3 may represent the metastatic/ aggressive phenotype of a subgroup of medulloblastoma. PMID:23768125
To determine the involvement of oxidative stress in the pathogenesis of acute encephalopathy associated with human herpesvirus-6 (HHV-6) infection, we measured the levels of oxidative stress markers 8-hydroxy-2?-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct (HEL), tau protein, and cytokines in cerebrospinal fluid (CSF) obtained from patients with HHV-6-associated acute encephalopathy (HHV-6 encephalopathy) (n = 16) and complex febrile seizures associated with HHV-6 (HHV-6 complex FS) (n = 10). We also examined changes in CSF-8OHdG and CSF-HEL levels in patients with HHV-6 encephalopathy before and after treatment with edaravone, a free radical scavenger. CSF-8-OHdG levels in HHV-6 encephalopathy and HHV-6 complex FS were significantly higher than in control subjects. In contrast, CSF-HEL levels showed no significant difference between groups. The levels of total tau protein in HHV-6 encephalopathy were significantly higher than in control subjects. In six patients with HHV-6 infection (5 encephalopathy and 1 febrile seizure), the CSF-8-OHdG levels of five patients decreased after edaravone treatment. Our results suggest that oxidative DNA damage is involved in acute encephalopathy associated with HHV-6 infection. PMID:25294958
Tanuma, Naoyuki; Miyata, Rie; Nakajima, Keisuke; Okumura, Akihisa; Kubota, Masaya; Hamano, Shin-ichiro; Hayashi, Masaharu
Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer disease.
Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid ?1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed. PMID:25165049
Babi?, Mirjana; Svob �trac, Dubravka; M�ck-�eler, Dorotea; Pivac, Nela; Stani?, Gabrijela; Hof, Patrick R; Simi?, Goran
We studied adenosine deaminase (ADA) activity in cerebrospinal fluid (CSF) of 16 cases of tuberculous meningitis, 4 cases of cryptococcal meningitis, 5 cases of bacterial meningitis, 12 cases of eosinophilic meningitis, 26 cases of aseptic meningitis, 6 cases of carcinomatous meningitis and 108 cases with normal CSF. The mean CSF ADA values for the different groups were: 39.44 +/- 41.46, 13.00 +/- 7.43, 34.20 +/- 40.81, 3.17 +/- 4.82, 10.03 +/- 9.23, 8.67 +/- 13.60, and 2.58 +/- 2.90 U/I, respectively. Comparing the ADA activity between patients with tuberculous meningitis and non-tuberculous meningitis, the receiver-operating characteristic (ROC) curve identified a CSF ADA level of 15.5 U/I as the best cut-off value to differentiate between the two, with a sensitivity of 75% and a specificity of 93%, with an area under the curve of 0.92. When tuberculous meningitis was compared with aseptic and carcinomatous meningitis, the ROC curve identified a CSF ADA level of 19.0 U/I as the best cut-off value for differentiation, with a sensitivity of 69% and a specificity of 94%, with an area under the curve of 0.83. The level of CSF ADA may be useful as a complementary tool in the early diagnosis of tuberculous meningitis. PMID:17333738
Chotmongkol, Verajit; Teerajetgul, Yaovalak; Yodwut, Chattanong
CXCL13 as a Cerebrospinal Fluid Marker for Neurosyphilis in HIV-infected Patients with Syphilis
Background Asymptomatic neurosyphilis is more difficult to diagnose in HIV-infected patients because HIV itself can cause cerebrospinal fluid (CSF) pleocytosis. The proportion of CSF lymphocytes that are B cells is elevated in neurosyphilis, suggesting that the CSF concentration of the B cell chemoattractant, chemokine (C-X-C motif) ligand 13 (CXCL13) concentration may also be elevated. Methods CSF and blood were collected from 199 HIV-infected patients with syphilis and neurosyphilis. Serum and CSF CXCL13 concentrations were determined. Results Patients with neurosyphilis had higher CSF and serum CXCL13 concentrations compared to patients with syphilis but not neurosyphilis. The odds of having symptomatic neurosyphilis were increased by 2.23 fold for every log increase in CSF CXCL13 concentration and were independent of CSF WBC and plasma HIV RNA concentrations, peripheral blood CD4+ T cell count and use of antiretroviral medications. A cut-off of 10 pg/mL CSF CXCL13 had high sensitivity and a cut-off of 250 pg/mL or evidence of intrathecal synthesis of CXCL13 had high specificity for diagnosis of both symptomatic and asymptomatic neurosyphilis. CSF concentrations of CXCL13 declined after treatment for neurosyphilis. Conclusions CSF CXCL13 concentration may be particularly useful for diagnosis of neurosyphilis in HIV-infected patients because it is independent of CSF pleocytosis and markers of HIV disease. PMID:20393380
Marra, Christina M.; Tantalo, Lauren C.; Sahi, Sharon K.; Maxwell, Clare L.; Lukehart, Sheila A.
The objective of this work is to quantify age-related differences in the characteristics and coupling of cerebral arterial inflow and cerebrospinal fluid (CSF) dynamics. To this end, 3T phase-contrast magnetic resonance imaging blood and CSF flow data of eleven young (24 � 3 years) and eleven elderly subjects (70 � 5 years) with a comparable sex-ratio were acquired. Flow waveforms and their frequency composition, transfer functions from blood to CSF flows and cross-correlations were analyzed. The magnitudes of the frequency components of CSF flow in the aqueduct differ significantly between the two age groups, as do the frequency components of the cervical spinal CSF and the arterial flows. The males' aqueductal CSF stroke volumes and average flow rates are significantly higher than those of the females. Transfer functions and cross-correlations between arterial blood and CSF flow reveal significant age-dependence of phase-shift between these, as do the waveforms of arterial blood, as well as cervical-spinal and aqueductal CSF flows. These findings accentuate the need for age- and sex-matched control groups for the evaluation of cerebral pathologies such as hydrocephalus. PMID:22666360
Schmid Daners, Marianne; Knobloch, Verena; Soellinger, Michaela; Boesiger, Peter; Seifert, Burkhardt; Guzzella, Lino; Kurtcuoglu, Vartan
HIV migration between blood and cerebrospinal fluid or semen over time.
Previous studies reported associations between neuropathogenesis and human immunodeficiency virus (HIV) compartmentalization in cerebrospinal fluid (CSF) and between sexual transmission and human immunodeficiency virus type 1 (HIV) compartmentalization in semen. It remains unclear, however, how compartmentalization dynamics change over time. To address this, we used statistical methods and Bayesian phylogenetic approaches to reconstruct temporal dynamics of HIV migration between blood and CSF and between blood and the male genital tract. We investigated 11 HIV-infected individuals with paired semen and blood samples and 4 individuals with paired CSF and blood samples. Aligned partial HIV env sequences were analyzed by (1) phylogenetic reconstruction, using a Bayesian Markov-chain Monte Carlo approach; (2) evaluation of viral compartmentalization, using tree-based and distance-based methods; and (3) analysis of migration events, using a discrete Bayesian asymmetric phylogeographic approach of diffusion with Markov jump counts estimation. Finally, we evaluated potential correlates of viral gene flow across anatomical compartments. We observed bidirectional replenishment of viral compartments and asynchronous peaks of viral migration from and to blood over time, suggesting that disruption of viral compartment is transient and directionally selected. These findings imply that viral subpopulations in anatomical sites are an active part of the whole viral population and that compartmental reservoirs could have implications in future eradication studies. PMID:24302756
Chaillon, Antoine; Gianella, Sara; Wertheim, Joel O; Richman, Douglas D; Mehta, Sanjay R; Smith, David M
Serotonin metabolites in the cerebrospinal fluid in sudden infant death syndrome.
Forensic biomarkers are needed in sudden infant death syndrome (SIDS) to help identify this group among other sudden unexpected deaths in infancy. Previously, we reported multiple serotonergic (5-HT) abnormalities in nuclei of the medulla oblongata that help mediate protective responses to homeostatic stressors. As a first step toward their assessment as forensic biomarkers of medullary pathology, here we test the hypothesis that 5-HT-related measures are abnormal in the cerebrospinal fluid (CSF) of SIDS infants compared with those of autopsy controls. Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the degradative products of 5-HT and dopamine, respectively, were measured by high-performance liquid chromatography in 52 SIDS and 29 non-SIDS autopsy cases. Tryptophan (Trp) and tyrosine (Tyr), the substrates of 5-HT and dopamine, respectively, were also measured. There were no significant differences in 5-HIAA, Trp, HVA, or Tyr levels between the SIDS and non-SIDS groups. These data preclude the use of 5-HIAA, HVA, Trp, or Tyr measurements as CSF autopsy biomarkers of 5-HT medullary pathology in infants who have died suddenly and unexpectedly. They do, however, provide important information about monoaminergic measurements in human CSF at autopsy and their developmental profile in infancy that is applicable to multiple pediatric disorders beyond SIDS. PMID:24423636
Rognum, Ingvar J; Tran, Hoa; Haas, Elisabeth A; Hyland, Keith; Paterson, David S; Haynes, Robin L; Broadbelt, Kevin G; Harty, Brian J; Mena, Othon; Krous, Henry F; Kinney, Hannah C
Approach to Cerebrospinal Fluid (CSF) Biomarker Discovery and Evaluation in HIV Infection
Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previouslydefined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.
Price, Richard W.; Peterson, Julia; Fuchs, Dietmar; Angel, Thomas E.; Zetterberg, Henrik; Hagberg, Lars; Spudich, Serena S.; Smith, Richard D.; Jacobs, Jon M.; Brown, Joseph N.; Gisslen, Magnus
Abstract Background. The Sysmex XE-5000 offers automated quantification of red blood cells and white blood cells (WBCs) in body fluids, with differentiation of polymorphonuclear cells (PMNs) and mononuclear cells (MNCs). Methods. We evaluated automated WBC counting in cerebrospinal fluid (CSF) using the body fluid mode on the Sysmex XE-5000, comparing it with flow cytometry as the reference method, and also with manual counting by microscopy. Experimental analysis for linearity and limit of detection was performed by diluting isolated WBCs in cell-free CSF. To study the ability to discriminate between PMNs and MNCs, samples were spiked using MNCs separated from peripheral blood. Comparison of WBC counts between a counting chamber and the XE-5000 was performed for 198 CSF samples. Results. In the experimental set-up, within-run (CV 19%) and between-day imprecision (CV 15.3%) in quantitating total number of WBC on XE-5000 was acceptable for WBC counts ? 25 � 10(6)/L. Compared with expected cell counts, mean bias was + 2.6% for flow cytometry, + 5.5% for XE-5000 and - 73.2% for manual counting. Differentiation between PMNs and MNCs was in concordance with flow cytometry. In comparisons of clinical CSF samples, overall agreement between the XE-5000 and manual counting was observed in 81% of the samples, but mean difference in WBC differentiation was higher for PMN (51.1 � 10(6)/L) than for MNC (7.95 � 10(6)/L). Conclusion. Despite limited precision at low WBC counts, XE-5000 could be a favourable alternative to the labour-intensive, time-consuming and less reliable manual counting and cuts turnaround times in routine CSF-based diagnosis. PMID:25180445
Li, Aihong; Gr�nlund, Elisabeth; Brattsand, G�ran
Nearly all bodily processes exhibit circadian rhythmicity. As a consequence, the pharmacokinetic and pharmacodynamic properties of a drug may also vary with time of day. The objective of this study was to investigate diurnal variation in processes that regulate drug concentrations in the brain, focusing on P-glycoprotein (P-gp). This efflux transporter limits the distribution of many drugs in the brain. To this end, the exposure to the P-gp substrate quinidine was determined in the plasma and brain tissue after intravenous administration in rats at six different time points over the 24-h period. Our results indicate that time of administration significantly affects the exposure to quinidine in the brain. Upon inhibition of P-gp, exposure to quinidine in brain tissue is constant over the 24-h period. To gain more insight into processes regulating brain concentrations, we used intracerebral microdialysis to determine the concentration of quinidine in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) after intravenous administration at two different time points. The data were analyzed by physiologically based pharmacokinetic modeling using NONMEM. The model shows that the variation is due to higher activity of P-gp-mediated transport from the deep brain compartment to the plasma compartment during the active period. Furthermore, the analysis reveals that CSF flux is higher in the resting period compared to the active period. In conclusion, we show that the exposure to a P-gp substrate in the brain depends on time of administration, thereby providing a new strategy for drug targeting to the brain. PMID:24917180
Kervezee, Laura; Hartman, Robin; van den Berg, Dirk-Jan; Shimizu, Shinji; Emoto-Yamamoto, Yumi; Meijer, Johanna H; de Lange, Elizabeth C M
Prion-Seeding Activity in Cerebrospinal Fluid of Deer with Chronic Wasting Disease
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a uniformly fatal family of neurodegenerative diseases in mammals that includes chronic wasting disease (CWD) of cervids. The early and ante-mortem identification of TSE-infected individuals using conventional western blotting or immunohistochemistry (IHC) has proven difficult, as the levels of infectious prions in readily obtainable samples, including blood and bodily fluids, are typically beyond the limits of detection. The development of amplification-based seeding assays has been instrumental in the detection of low levels of infectious prions in clinical samples. In the present study, we evaluated the cerebrospinal fluid (CSF) of CWD-exposed (n=44) and na�ve (n=4) deer (n=48 total) for CWD prions (PrPd) using two amplification assays: serial protein misfolding cyclic amplification with polytetrafluoroethylene beads (sPMCAb) and real-time quaking induced conversion (RT-QuIC) employing a truncated Syrian hamster recombinant protein substrate. Samples were evaluated blindly in parallel with appropriate positive and negative controls. Results from amplification assays were compared to one another and to obex immunohistochemistry, and were correlated to available clinical histories including CWD inoculum source (e.g. saliva, blood), genotype, survival period, and duration of clinical signs. We found that both sPMCAb and RT-QuIC were capable of amplifying CWD prions from cervid CSF, and results correlated well with one another. Prion seeding activity in either assay was observed in approximately 50% of deer with PrPd detected by IHC in the obex region of the brain. Important predictors of amplification included duration of clinical signs and time of first tonsil biopsy positive results, and ultimately the levels of PrPd identified in the obex by IHC. Based on our findings, we expect that both sPMCAb and RT-QuIC may prove to be useful detection assays for the detection of prions in CSF. PMID:24282599
Haley, Nicholas J.; Van de Motter, Alexandra; Carver, Scott; Henderson, Davin; Davenport, Kristen; Seelig, Davis M.; Mathiason, Candace; Hoover, Edward
A computational model of cerebrospinal fluid production and reabsorption driven by Starling forces.
Experimental evidence has cast doubt on the classical model of river-like cerebrospinal fluid (CSF) flow from the choroid plexus to the arachnoid granulations. We propose a novel model of water transport through the parenchyma from the microcirculation as driven by Starling forces. This model investigates the effect of osmotic pressure on water transport between the cerebral vasculature, the extracellular space (ECS), the perivascular space (PVS), and the CSF. A rigorous literature search was conducted focusing on experiments which alter the osmolarity of blood or ventricles and measure the rate of CSF production. Investigations into the effect of osmotic pressure on the volume of ventricles and the flux of ions in the blood, choroid plexus epithelium, and CSF are reviewed. Increasing the osmolarity of the serum via a bolus injection completely inhibits nascent fluid flow production in the ventricles. A continuous injection of a hyperosmolar solution into the ventricles can increase the volume of the ventricle by up to 125%. CSF production is altered by 0.231 ?L per mOsm in the ventricle and by 0.835 ?L per mOsm in the serum. Water flux from the ECS to the CSF is identified as a key feature of intracranial dynamics. A complete mathematical model with all equations and scenarios is fully described, as well as a guide to constructing a computational model of intracranial water balance dynamics. The model proposed in this article predicts the effects the osmolarity of ECS, blood, and CSF on water flux in the brain, establishing a link between osmotic imbalances and pathological conditions such as hydrocephalus and edema. PMID:25358881
Buishas, Joel; Gould, Ian G; Linninger, Andreas A
Visualisation of cerebrospinal fluid flow patterns in albino Xenopus larvae in vivo
Background It has long been known that cerebrospinal fluid (CSF), its composition and flow, play an important part in normal brain development, and ependymal cell ciliary beating as a possible driver of CSF flow has previously been studied in mammalian fetuses in vitro. Lower vertebrate animals are potential models for analysis of CSF flow during development because they are oviparous. Albino Xenopus laevis larvae are nearly transparent and have a straight, translucent brain that facilitates the observation of fluid flow within the ventricles. The aim of these experiments was to study CSF flow and circulation in vivo in the developing brain of living embryos, larvae and tadpoles of Xenopus laevis using a microinjection technique. Methods The development of Xenopus larval brain ventricles and the patterns of CSF flow were visualised after injection of quantum dot nanocrystals and polystyrene beads (3.1 or 5.8 ?m in diameter) into the fourth cerebral ventricle at embryonic/larval stages 30-53. Results The fluorescent nanocrystals showed the normal development of the cerebral ventricles from embryonic/larval stages 38 to 53. The polystyrene beads injected into stage 47-49 larvae revealed three CSF flow patterns, left-handed, right-handed and non-biased, in movement of the beads into the third ventricle from the cerebral aqueduct (aqueduct of Sylvius). In the lateral ventricles, anterior to the third ventricle, CSF flow moved anteriorly along the outer wall of the ventricle to the inner wall and then posteriorly, creating a semicircle. In the cerebral aqueduct, connecting the third and fourth cerebral ventricles, CSF flow moved rostrally in the dorsal region and caudally in the ventral region. Also in the fourth ventricle, clear dorso-ventral differences in fluid flow pattern were observed. Conclusions This is the first visualisation of the orchestrated CSF flow pattern in developing vertebrates using a live animal imaging approach. CSF flow in Xenopus albino larvae showed a largely consistent pattern, with the exception of individual differences in left-right asymmetrical flow in the third ventricle. PMID:22534239
A one-dimensional model of the spinal cerebrospinal-fluid compartment.
Modeling of the cerebrospinal fluid (CSF) system in the spine is strongly motivated by the need to understand the origins of pathological conditions such as the emergence and growth of fluid-filled cysts in the spinal cord. In this study, a one-dimensional (1D) approximation for the flow in elastic conduits was used to formulate a model of the spinal CSF compartment. The modeling was based around a coaxial geometry in which the inner elastic cylinder represented the spinal cord, middle elastic tube represented the dura, and the outermost tube represented the vertebral column. The fluid-filled annuli between the cord and dura, and the dura and vertebral column, represented the subarachnoid and epidural spaces, respectively. The system of governing equations was constructed by applying a 1D form of mass and momentum conservation to all segments of the model. The developed 1D model was used to simulate CSF pulse excited by pressure disturbances in the subarachnoid and epidural spaces. The results were compared to those obtained from an equivalent two-dimensional finite element (FE) model which was implemented using a commercial software package. The analysis of linearized governing equations revealed the existence of three types of waves, of which the two slower waves can be clearly related to the wave modes identified in previous similar studies. The third, much faster, wave emanates directly from the vertebral column and has little effect on the deformation of the spinal cord. The results obtained from the 1D model and its FE counterpart were found to be in good general agreement even when sharp spatial gradients of the spinal cord stiffness were included; both models predicted large radial displacements of the cord at the location of an initial cyst. This study suggests that 1D modeling, which is computationally inexpensive and amenable to coupling with the models of the cranial CSF system, should be a useful approach for the analysis of some aspects of the CSF dynamics in the spine. The simulation of the CSF pulse excited by a pressure disturbance in the epidural space, points to the possibility that regions of the spinal cord with abnormally low stiffness may be prone to experiencing large strains due to coughing and sneezing. PMID:22482672
Cirovic, Srdjan; Kim, Minsuok
The pathogenesis of syringomyelia in association with Chiari malformation (CM) is unclear. Studies of patients with CM have shown alterations in the CSF velocity profile and these could contribute to syrinx development or enlargement. Few studies have considered the fluid mechanics of CM patients with and without syringomyelia separately. Three subject-specific CFD models were developed for a normal participant, a CM patient with syringomyelia and a CM patient without syringomyelia. Model geometries, CSF flow rate data and CSF velocity validation data were collected from MRI scans of the 3 subjects. The predicted peak CSF pressure was compared for the 3 models. An extension of the study performed geometry and flow substitution to investigate the relative effects of anatomy and CSF flow profile on resulting spinal CSF pressure. Based on 50 monitoring locations for each of the models, the CM models had significantly higher magnitude (p<0.01) peak CSF pressure compared with normal. When using the same CSF input flow waveform, changing the upper spinal geometry changed the magnitude of the CSF pressure gradient, and when using the same upper spinal geometry, changing the input flow waveform changed the timing of the peak pressure. This study may assist in understanding syringomyelia mechanisms and relative effects of CSF velocity profile and spinal geometry on CSF pressure. PMID:23769174
Clarke, Elizabeth C; Fletcher, David F; Stoodley, Marcus A; Bilston, Lynne E
The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 � 23.7 ?g/ml. A CSF maximum (CmaxCSF) of 0.63 � 0.50 ?g/ml (mean � standard deviation) was observed 4.1 � 2.6 h after the end of the infusion. CmaxCSF and the area under the curve for CSF (AUCCSF) depended on the AUC for serum (AUCS), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at ? phase [t1/2?] of 7.36 � 2.89 h in CSF versus t1/2? of 1.69 � 0.60 h in serum). The AUCCSF/AUCS ratio for meropenem, as a measure of overall CSF penetration, was 0.047 � 0.022. The AUCCSF/AUCS ratio for meropenem was similar to that for other ?-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa. PMID:9687399
Nau, Roland; Lassek, Christoph; Kinzig-Schippers, Martina; Thiel, Andreas; Prange, Hilmar W.; Sorgel, Fritz
Cerebrospinal fluid (CSF) analysis is an important tool in the diagnostic work-up of many neurological disorders, but reference ranges for CSF glucose, CSF/plasma glucose ratio and CSF lactate based on studies with large numbers of CSF samples are not available. Our aim was to define age-specific reference values. In 1993 The Nijmegen Observational CSF Study was started. Results of all CSF samples that were analyzed between 1993 and 2008 at our laboratory were systematically collected and stored in our computerized database. After exclusion of CSF samples with an unknown or elevated erythrocyte count, an elevated leucocyte count, elevated concentrations of bilirubin, free hemoglobin, or total protein 9,036 CSF samples were further studied for CSF glucose (n?=?8,871), CSF/plasma glucose ratio (n?=?4,516) and CSF lactate values (n?=?7,614). CSF glucose, CSF/plasma glucose ratio and CSF lactate were age-, but not sex dependent. Age-specific reference ranges were defined as 5�95th percentile ranges. CSF glucose 5th percentile values ranged from 1.8 to 2.9 mmol/L and 95th percentile values from 3.8 to 5.6 mmol/L. CSF/plasma glucose ratio 5th percentile values ranged from 0.41 to 0.53 and 95th percentile values from 0.82 to 1.19. CSF lactate 5th percentile values ranged from 0.88 to 1.41 mmol/L and 95th percentile values from 2.00 to 2.71 mmol/L. Reference ranges for all three parameters were widest in neonates and narrowest in toddlers, with lower and upper limits increasing with age. These reference values allow a reliable interpretation of CSF results in everyday clinical practice. Furthermore, hypoglycemia was associated with an increased CSF/plasma glucose ratio, whereas hyperglycemia did not affect the CSF/plasma glucose ratio. PMID:22880096
Leen, Wilhelmina G.; Willemsen, Michel A.; Wevers, Ron A.; Verbeek, Marcel M.
Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia
Schizophrenia is a serious brain disease of uncertain etiology. A role for retroviruses in the etiopathogenesis of some cases of schizophrenia has been postulated on the basis of clinical and epidemiological observations. We found sequences homologous to retroviral pol genes in the cell-free cerebrospinal fluids (CSFs) of 10 of 35 (29%) individuals with recent-onset schizophrenia or schizoaffective disorder. Retroviral sequences also were identified in the CSFs of 1 of 20 individuals with chronic schizophrenia. However, retroviral sequences were not identified in any of the CSFs obtained from 22 individuals with noninflammatory neurological diseases or from 30 individuals without evidence of neurological or psychiatric diseases (?2 = 19.25, P < 0.001). The nucleotide sequences identified in the CSFs of the individuals with schizophrenia or schizoaffective disorder were related to those of the human endogenous retroviral (HERV)-W family of endogenous retroviruses and to other retroviruses in the murine leukemia virus genus. Transcription of RNA homologous to members of the HERV-W family of retroviruses also was found to be up-regulated differentially in the frontal cortex regions of brains obtained postmortem from individuals with schizophrenia, as compared with corresponding tissue from individuals without psychiatric diseases. The transcriptional activation of certain retroviral elements within the central nervous system may be associated with the development of schizophrenia in at least some individuals. The further characterization of retroviral elements within the central nervous system of individuals with schizophrenia might lead to improved methods for the diagnosis and management of this disorder. PMID:11296294
Karlsson, Hakan; Bachmann, Silke; Schroder, Johannes; McArthur, Justin; Torrey, E. Fuller; Yolken, Robert H.
The central nervous system (CNS) develops from the neural tube, a hollow structure filled with embryonic cerebrospinal fluid (eCSF) and surrounded by neuroepithelial cells. Several lines of evidence suggest that the eCSF contains diffusible factors regulating the survival, proliferation, and differentiation of the neuroepithelium, although these factors are only beginning to be uncovered. One possible candidate as eCSF morphogenetic molecule is SCO-spondin, a large glycoprotein whose secretion by the diencephalic roof plate starts at early developmental stages. In vitro, SCO-spondin promotes neuronal survival and differentiation, but its in vivo function still remains to be elucidated. Here we performed in vivo loss of function experiments for SCO-spondin during early brain development by injecting and electroporating a specific shRNA expression vector into the neural tube of chick embryos. We show that SCO-spondin knock down induces an increase in neuroepithelial cells proliferation concomitantly with a decrease in cellular differentiation toward neuronal lineages, leading to hyperplasia in both the diencephalon and the mesencephalon. In addition, SCO-spondin is required for the correct morphogenesis of the posterior commissure and pineal gland. Because SCO-spondin is secreted by the diencephalon, we sought to corroborate the long-range function of this protein in vitro by performing gain and loss of function experiments on mesencephalic explants. We find that culture medium enriched in SCO-spondin causes an increased neurodifferentiation of explanted mesencephalic region. Conversely, inhibitory antibodies against SCO-spondin cause a reduction in neurodifferentiation and an increase of mitosis when such explants are cultured in eCSF. Our results suggest that SCO-spondin is a crucial eCSF diffusible factor regulating the balance between proliferation and differentiation of the brain neuroepithelial cells. PMID:23761733
Vera, A.; Stanic, K.; Montecinos, H.; Torrejon, M.; Marcellini, S.; Caprile, T.
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination and neurodegeneration throughout the CNS, which lead over time to a condition of irreversible functional decline known as progressive MS. Currently, there are no satisfactory treatments for this condition because the mechanisms that underlie disease progression are not well understood. This is partly due to the lack of a specific animal model that represents progressive MS. We investigated the effects of intracerebroventricular injections of cerebrospinal fluid (CSF) derived from untreated primary progressive (PPMS), secondary progressive (SPMS), and relapsing/remitting (RRMS) MS patients into mice. We found discrete inflammatory demyelinating lesions containing macrophages, B cell and T cell infiltrates in the brains of animals injected with CSF from patients with progressive MS. These lesions were rarely found in animals injected with RRMS-CSF and never in those treated with control-CSF. Animals that developed brain lesions also presented extensive inflammation in their spinal cord. However, discrete spinal cord lesions were rare and only seen in animals injected with PPMS-CSF. Axonal loss and astrogliosis were seen within the lesions following the initial demyelination. In addition, Th17 cell activity was enhanced in the CNS and in lymph nodes of progressive MS-CSF injected animals compared to controls. Furthermore, CSF derived from MS patients who were clinically stable following therapy had greatly diminished capacity to induce CNS lesions in mice. Finally, we provided evidence suggesting that differential expression of pro-inflammatory cytokines present in the progressive MS CSF might be involved in the observed mouse pathology. Our data suggests that the agent(s) responsible for the demyelination and neurodegeneration characteristic of progressive MS is present in patient CSF and is amenable to further characterization in experimental models of the disease. PMID:25111532
Cristofanilli, Massimiliano; Rosenthal, Hannah; Cymring, Barbara; Gratch, Daniel; Pagano, Benjamin; Xie, Boxun; Sadiq, Saud A
Altered Cerebrospinal Fluid Concentrations of TGF?1 in Patients with Drug-Resistant Epilepsy.
Transforming growth factor beta (TGF?) signaling participates in pathogenesis of epilepsy. TGF?1, as a transmitter of TGF? signaling, might be a useful marker for predicting the prognosis of patients with epilepsy. The present study aimed to measure TGF?1 level in the cerebrospinal fluid (CSF) of patients with drug-resistant epilepsy and non-resistant epilepsy. A total of 43 patients with epilepsy were recruited, 28 were non-resistant epilepsy subgroup, 15 drug-resistant epilepsy subgroup. 11 patients with intracranial infection and 11 individuals with primary headache were used as controls. The concentration of CSF and serum TGF?1 was measured by enzyme-linked immunosorbent assay. The concentration of CSF-TGF?1 was 209.26���81.07�pg/ml in the drug-resistant epilepsy subgroup, 121.80���40.32�pg/ml in the non-resistant epilepsy subgroup, 552.17���456.20�pg/ml in intracranial infection control, 133.80���68.55�pg/ml in headache control, respectively. TGF?1 level was significantly increased in the drug-resistant epilepsy subgroup compared to the non-resistant epilepsy subgroup. TGF?1 level in intracranial infection control was higher than that in the non-resistant epilepsy subgroup. There was no statistically difference of CSF-TGF?1 between the non-resistant epilepsy subgroup and headache controls, between the resistant epilepsy subgroup and intracranial infection controls. TGF? levels are increased in the CSF of patients with drug-resistant epilepsy. High CSF-TGF?1 levels may be a potential screening biomarker of antiepileptic drug resistance in patients with epilepsy. PMID:25161078
Yu, Weihua; Zou, Yan; Du, Yingshi; Luo, Jing; Zhang, Man; Yang, Wenxiu; Wang, Xuefeng; L�, Yang
The brainstem is well recognized as a critical site for integrating descending modulatory systems that both inhibit and facilitate pain at the level of the spinal cord. The cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) distributes and localizes in the ventral periaqueductal central gray of the brainstem. Although emerging lines of evidence suggest that the CSF-contacting nucleus may be closely linked to transduction and regulation of pain signals, the definitive role of the CSF-contacting nucleus in pain modulation remains poorly understood. In the present study, we determined the role of the CSF-contacting nucleus in rat nocifensive behaviors after persistent pain by targeted ablation of the CSF-contacting nucleus in the brainstem using the cholera toxin subunit B-saporin (CB-SAP), a cytotoxin coupled to cholera toxin subunit B. Compared with CB/SAP, CB-SAP induced complete ablation of the CSF-contacting nucleus, and the CB-SAP-treated rats showed hypersensitivity in responses to acute nociceptive stimulation, and exacerbated spontaneous nocifensive responses induced by formalin, thermal hyperalgesia and mechanical allodynia induced by plantar incision. Furthermore, immunohistochemical experiments showed that the CSF-contacting nucleus was a cluster of 5-HT-containing neurons in the brainstem, and the spinal projection of serotonergic axons originating from the CSF-contacting nucleus constituted the descending 5-HT pathway to the spinal cord. CB-SAP induced significant downregulation of 5-HT in the spinal dorsal horn, and intrathecal injection of 5-HT significantly reversed hypersensitivity in responses to acute nociceptive stimulation in the CB-SAP-treated rats. These results indicate that the CSF-contacting nucleus 5-HT pathway is an important component of the endogenous descending inhibitory system in the control of spinal nociceptive transmission. PMID:25108066
Liu, He; Yan, Wei-Wei; Lu, Xiao-Xing; Zhang, Xiu-Li; Wei, Jing-Qiu; Wang, Xiao-Yu; Wang, Tiao; Wu, Tong; Cao, Jing; Shao, Cui-Jie; Zhou, Fang; Zhang, Hong-Xing; Zhang, Peng; Zang, Ting; Lu, Xian-Fu; Cao, Jun-Li; Ding, Hai-Lei; Zhang, Li-Cai
Amyloid-beta peptide and oligomers in the brain and cerebrospinal fluid of aged canines.
The study of Alzheimer's disease (AD) pathogenesis requires the use of animal models that develop some amount of amyloid pathology in the brain. Aged canines (beagles) naturally accumulate human-type amyloid-beta peptide (Abeta) and develop parallel declines in cognitive function. However, the type and quantity of biochemically extracted Abeta in brain and cerebrospinal fluid (CSF), its link to aging, and similarity to human aging has not been examined systematically. Thirty beagles, aged 4.5-15.7 years, were studied. Abeta40 and Abeta42 were measured in CSF by ELISA, and from SDS and formic acid extracted prefrontal cortex. A sample of the contralateral hemisphere, used to assess immunohistochemical amyloid load, was used for comparison. In the brain, increases in Abeta42 were detected at a younger age, prior to increases in Abeta40, and were correlated with an increased amyloid load. In the CSF, Abeta42 decreased with age while Abeta40 levels remained constant. The CSF Abeta42/40 ratio was also a good predictor of the amount of Abeta in the brain. The amount of soluble oligomers in CSF was inversely related to brain extractable Abeta, whereas oligomers in the brain were correlated with SDS soluble Abeta42. These findings indicate that the Abeta in the brain of the aged canine exhibits patterns that mirror Abeta deposited in the human brain. These parallels support the idea that the aged canine is a useful intermediate between transgenic mice and humans for studying the development of amyloid pathology and is a potentially useful model for the refinement of therapeutic interventions. PMID:20164551
Head, Elizabeth; Pop, Viorela; Sarsoza, Floyd; Kayed, Rakez; Beckett, Tina L; Studzinski, Christa M; Tomic, Jennifer L; Glabe, Charles G; Murphy, M Paul
The Alzheimer�s Association external quality control program for cerebrospinal fluid biomarkers
Background The cerebrospinal fluid (CSF) biomarkers amyloid ? (A?)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer�s disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer�s Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program. Methods The program is open for laboratories using commercially available kits for A?, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Molndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples. Results Forty laboratories participated. Twenty-six used INNOTESTenzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure A?-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the A? triplex (A?N-42, A?N-40, and A?N-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories. Conclusions Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers. PMID:21784349
Mattsson, Niklas; Andreasson, Ulf; Persson, Staffan; Arai, Hiroyuki; Batish, Sat Dev; Bernardini, Sergio; Bocchio-Chiavetto, Luisella; Blankenstein, Marinus A.; Carrillo, Maria C.; Chalbot, Sonia; Coart, Els; Chiasserini, Davide; Cutler, Neal; Dahlfors, Gunilla; Duller, Stefan; Fagan, Anne M.; Forlenza, Orestes; Frisoni, Giovanni B.; Galasko, Douglas; Galimberti, Daniela; Hampel, Harald; Handberg, Aase; Heneka, Michael T.; Herskovits, Adrianna Z.; Herukka, Sanna-Kaisa; Holtzman, David M.; Humpel, Christian; Hyman, Bradley T.; Iqbal, Khalid; Jucker, Mathias; Kaeser, Stephan A.; Kaiser, Elmar; Kapaki, Elisabeth; Kidd, Daniel; Klivenyi, Peter; Knudsen, Cindy S.; Kummer, Markus P.; Lui, James; Llad�, Albert; Lewczuk, Piotr; Li, Qiao-Xin; Martins, Ralph; Masters, Colin; McAuliffe, John; Mercken, Marc; Moghekar, Abhay; Molinuevo, Jos� Luis; Montine, Thomas J.; Nowatzke, William; O�Brien, Richard; Otto, Markus; Paraskevas, George P.; Parnetti, Lucilla; Petersen, Ronald C.; Prvulovic, David; de Reus, Herman P. M.; Rissman, Robert A.; Scarpini, Elio; Stefani, Alessandro; Soininen, Hilkka; Schr�der, Johannes; Shaw, Leslie M.; Skinningsrud, Anders; Skrogstad, Brith; Spreer, Annette; Talib, Leda; Teunissen, Charlotte; Trojanowski, John Q.; Tumani, Hayrettin; Umek, Robert M.; Van Broeck, Bianca; Vanderstichele, Hugo; Vecsei, Laszlo; Verbeek, Marcel M.; Windisch, Manfred; Zhang, Jing; Zetterberg, Henrik; Blennow, Kaj
Cellular Composition of Cerebrospinal Fluid in HIV-1 Infected and Uninfected Subjects
In order to characterize the cellular composition of cerebrospinal fluid (CSF) in a healthy state and in the setting of chronic pleocytosis associated with HIV-1 (HIV) infection, multi-parameter flow cytometry was used to identify and quantitate cellular phenotypes in CSF derived from HIV-uninfected healthy controls and HIV-infected subjects across a spectrum of disease and treatment. CD4+ T cells were the most frequent CSF population and the CD4:CD8 ratio was significantly increased in the CSF compared to blood (p?=?0.0232), suggesting preferential trafficking of CD4+ over CD8+ T cells to this compartment. In contrast, in HIV-infection, CD8+ T cells were the major cellular component of the CSF and were markedly increased compared to HIV-uninfected subjects (p<0.001). As with peripheral blood, the CSF CD4:CD8 ratio was reversed in HIV-infected subjects compared to HIV-uninfected subjects. Monocytes, B cells and NK cells were rare in the CSF in both groups, although absolute counts of CSF NK cells and B cells were significantly increased in HIV-infected subjects (p<0.05). Our studies show that T cells are the major cellular component of the CSF in HIV-infected and uninfected subjects. The CSF pleocytosis characteristic of HIV infection involves all lymphocyte subsets we measured, except for CD4+ T cells, but is comprised primarily of CD8+ T cells. The reduced proportion of CD4+ T cells in the CSF may reflect both HIV-related peripheral loss and changes in trafficking patterns in response to HIV infection in the central nervous system. PMID:23822975
Ho, Emily L.; Ronquillo, Rollie; Altmeppen, Hermann; Spudich, Serena S.; Price, Richard W.; Sinclair, Elizabeth
Cobalamin as a regulator of serum and cerebrospinal fluid levels of normal prions.
We have previously demonstrated that the concentration of normal prion proteins (PrP(C)) is increased in the serum and cerebrospinal fluid (CSF) of rats deficient in vitamin B(12) (cobalamin, Cbl). In this study, we investigated whether similar increases also occur in the serum and CSF of patients deficient in Cbl (Cbl-D), and whether the increase in serum levels can be corrected by Cbl therapy. The study involved two sample populations. The first consisted of 45 patients (13 patients with pernicious anemia [PA], 19 with other forms of anemia, and 13 healthy controls); and the second, 68 patients (five with subacute combined degeneration [SCD], 18 with amyotrophic lateral sclerosis, 22 with multiple sclerosis [MS], and 23 neurological controls). Serum PrP(C) levels were measured using an enzyme-linked-immunosorbent-assay before as well as after Cbl therapy. The mean serum PrP(C) levels in patients with PA were significantly higher than those of the controls (p=0.0017) but normalized after Cbl therapy; there was no significant change in the patients with other forms of anemia. Mean CSF PrP(C) levels in the patients with SCD were significantly higher than in the neurological controls (p<0.03). The serum and CSF PrP(C) levels of patients with PA and those with SCD were correlated significantly with serum (p=0.004) and CSF (p=0.0018) Cbl levels. In patients with MS, CSF PrP(C) concentrations were significantly lower than those of the controls regardless of their CSF Cbl levels. We found a correlation between Cbl and PrP(C) levels in the serum and CSF of Cbl-D patients, which suggests that Cbl may regulate the PrP(C) levels in the serum and CSF in humans. PMID:23146213
Scalabrino, Giuseppe; Veber, Daniela; Briani, Chiara; Milani, Silvano; Terralavoro, Antonietta; Brenna, Sergio; Valenti, Luca; Silani, Vincenzo; Morelli, Claudia; Peracchi, Maddalena
Introduction The neuronal loss in Alzheimer disease (AD) has been described to affect grey matter in the cerebral cortex. However, in the elderly, AD pathology is likely to occur together with subcortical axonal degeneration on the basis of cerebrovascular disease. Therefore, we hypothesized that biomarkers for AD and subcortical axonal degeneration would correlate in patients undergoing testing for dementia biomarkers, particularly in older age groups. Methods We performed correlation and cluster analyses of cerebrospinal fluid (CSF) biomarker data from 5,542 CSF samples analyzed in our routine clinical neurochemistry laboratory in 2010 through 2012 for the established CSF AD biomarkers total tau (T-tau), phosphorylated-tau (P-tau), amyloid ?1-42 (A?42), and for neurofilament light (NFL), which is a protein expressed in large-caliber myelinated axons, the CSF levels of which correlate with subcortical axonal injury. Results A?42, T-tau, and P-tau correlated with NFL. By cluster analysis, we found a bimodal data distribution in which a group with a low A?42/P-tau ratio (suggesting AD pathology) had high levels of NFL. High levels of NFL also correlated with the presence of an AD biomarker pattern defined by A?42/P-tau and T-tau. Only 29% of those with an AD biomarker signature had normal NFL levels. Age was a possible confounding factor for the associations between NFL and established AD biomarkers, but in a logistic regression analysis, both age and NFL independently predicted the AD biomarker pattern. Conclusions The association between an AD-like signature using the established biomarkers A?42, T-tau, and P-tau with increased levels of NFL provides in vivo evidence of an association between AD and subcortical axonal degeneration in this uniquely large dataset of CSF samples tested for dementia biomarkers. PMID:24479774
D-Amino Acid Aberrations in Cerebrospinal Fluid and Plasma of Smokers
The glutamatergic neurotransmission system and the N-methyl-D-aspartate receptor (NMDAR) have been implicated in smoking and alcohol consumption behavior. Preclinical studies have demonstrated that nicotine and ethanol influence NMDAR functionality, which may have a role in tendencies to consume these substances. Nonetheless, little is known about concentrations of NMDAR coagonists in the cerebrospinal fluid (CSF) and plasma of individuals who smoke or consume alcohol. Glycine and L- and D-stereoisomers of alanine, serine, and proline were therefore measured using ultra-high-performance liquid chromatography-tandem mass spectrometry in 403 healthy subjects. Nicotine and alcohol consumption were quantified using questionnaires. Possible differences in NMDAR coagonist concentrations in plasma and CSF were investigated using ANCOVA with age, body mass index, and storage duration as covariates. The significance threshold was Bonferroni corrected (?=0.00625). Compared with non-smokers, smokers displayed lower levels of D-proline in plasma (p=0.0027, Cohen's d=?0.41) and D-proline in CSF (p=0.0026, Cohen's d=?0.43). D-Serine in CSF was higher in smokers than in non-smokers (p=0.0052, Cohen's d=0.41). After subdividing participants based on smoking quantity, dose-dependent decreases were demonstrated in smokers for D-proline in plasma (F=5.65, p=0.0039) and D-proline in CSF (F=5.20, p=0.0060). No differences in NMDAR coagonist levels between alcohol consumption groups were detected. To our knowledge, this is the first report to implicate D-amino acids in smoking behavior of humans. Whether such concentration differences lie at the root of or result from smoking habits may be addressed in prospective studies. PMID:23615666
Luykx, Jurjen J; Bakker, Steven C; van Boxmeer, Loes; Vinkers, Christiaan H; Smeenk, Hanne E; Visser, Wouter F; Verhoeven-Duif, Nanda M; Strengman, Eric; Buizer-Voskamp, Jacobine E; de Groene, Lizzy; van Dongen, Eric PA; Borgdorff, Paul; Bruins, Peter; de Koning, Tom J; Kahn, Rene S; Ophoff, Roel A
Peroxiredoxin VI oxidation in cerebrospinal fluid correlates with traumatic brain injury outcome.
Traumatic brain injury (TBI) patients would benefit from the identification of reliable biomarkers to predict outcomes and treatment strategies. In our study, cerebrospinal fluid (CSF) from patients with severe TBI was evaluated for oxidant stress-mediated damage progression after hospital admission and subsequent ventriculostomy placement. Interestingly, substantial levels of peroxiredoxin VI (Prdx6), a major antioxidant enzyme normally found in astrocytes, were detected in CSF from control and TBI patients and were not associated with blood contamination. Functionally, Prdx6 and its associated binding partner glutathione S-transferase Pi (GSTP1-1, also detected in CSF) act in tandem to detoxify lipid peroxidation damage to membranes. We found Prdx6 was fully active in CSF of control patients but becomes significantly inactivated (oxidized) in TBI. Furthermore, significant and progressive oxidation of "buried" protein thiols in CSF of TBI patients (compared to those of nontrauma controls) was detected over a 24-h period after hospital admission, with increased oxidation correlating with severity of trauma. Conversely, recovery of Prdx6 activity after 24h indicated more favorable patient outcome. Not only is this the first report of an extracellular form of Prdx6 but also the first report of its detection at a substantial level in CSF. Taken together, our data suggest a meaningful correlation between TBI-initiated oxidation of Prdx6, its specific phospholipid hydroperoxide peroxidase activity, and severity of trauma outcome. Consequently, we propose that Prdx6 redox status detection has the potential to be a biomarker for TBI outcome and a future indicator of therapeutic efficacy. PMID:24726861
Manevich, Y; Hutchens, S; Halushka, P V; Tew, K D; Townsend, D M; Jauch, E C; Borg, K
Computed tomography-guided epidural patching of postoperative cerebrospinal fluid leaks.
Object Cerebrospinal fluid leaks due to unrecognized durotomy during spinal surgery are often managed with a second surgery for dural closure. CT-guided percutaneous patching targeted to the dural defect offers an alternative to surgery since it can be performed in a minimally invasive fashion without the need for general anesthesia. This case series describes the authors' experience using targeted CT-guided percutaneous patching to repair incidental durotomies incurred during spinal surgery. Methods This investigation is a retrospective case series involving patients who underwent CT-guided percutaneous patching of surgical incidental durotomies and were referred between January 2007 and June 2013. Their presenting clinical history, myelographic findings, and clinical outcomes, including the need for eventual surgical duraplasty, were reviewed. Results Nine cases were identified, including 7 durotomies incurred during lumbar discectomy, one due to a medial transpedicular screw breach, and one incurred during vertebrectomy for spinal osteosarcoma. All patients who had favorable outcomes with percutaneous intervention alone had 2 common features: dural defect of 4 mm or smaller and absence of a pseudomeningocele. Patients with CSF leaks complicated by pseudomeningocele and those with a dural defect of 6 mm or more all required eventual surgical management. Conclusions The authors' results suggest that findings on CT myelography may help predict which patients with postsurgical durotomy can be treated with percutaneous intervention. In particular, CT-guided patching may be more likely to be successful in those patients with dural defects of less than 5 mm and without pseudomeningocele. In patients with larger dural defects or pseudomeningoceles, percutaneous blood patching alone is unlikely to be successful. PMID:25127431
Mihlon, Frank; Kranz, Peter G; Gafton, Andreia Roxana; Gray, Linda
The Gen-Probe Amplified Mycobacterium tuberculosis Direct Test (MTD) was adapted to be used for cerebrospinal fluid (CSF) and a large variety of other nonrespiratory specimens. Standardized with artificially spiked dilution series of CSF, the modified MTD procedure consists of (i) increasing the amount of sample 10-fold, (ii) pretreating the specimen with a detergent, and (iii) increasing the amplification time from 2 to 3 h. Performance of MTD in a clinical mycobacteriology laboratory was tested over an extended period of time, involving a total of 322 nonrespiratory as well as 1,117 respiratory specimens from 998 patients. Results from MTD were compared with those from microscopy, culture, analysis of tuberculostearic acid by gas-liquid chromatography-mass spectrometry (CSF only), and the final clinical diagnosis. When MTD results were compared with resolved data, the sensitivity, specificity, and positive and negative predictive values for MTD were 93.1, 97.7, 90.0, and 98.5%, respectively, for nonrespiratory specimens and 86.6, 96.4, 76.8, and 98.1%, respectively, for respiratory specimens. Our data demonstrate that (i) MTD is a robust, highly sensitive and specific technique for the rapid detection of M. tuberculosis complex in all types of clinical specimens, (ii) there was no statistically significant difference (P > 0.005) in sensitivity and specificity for nonrespiratory compared with respiratory specimens, and (iii) repeating all MTDs which yield a result between 30,000 and 200,000 relative light units would help prevent a large number of false positives and, thus, enhance test specificity. PMID:8815093
Pfyffer, G E; Kissling, P; Jahn, E M; Welscher, H M; Salfinger, M; Weber, R
Pre-analytical factors influencing the stability of cerebrospinal fluid proteins.
Cerebrospinal fluid (CSF) is a potential source for new biomarkers due to its proximity to the brain. This study aimed to clarify the stability of the CSF proteome when undergoing pre-analytical factors. We investigated the effects of repeated freeze/thaw cycles, protease inhibitors and delayed storage for 4h, 24h or 14 days at -20�C, 4�C and room temperature (RT) after centrifugation compared with our standard practice of two hours at RT before placing the samples in an -80�C environment. The results were obtained using immunoassays for amyloid-beta 1-42 (A?42), tau, phosphorylated tau (P-tau) and cystatin C and using surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) mass spectrometry for proteomic profiling. Tau and P-tau were susceptible to repeated freeze/thaw cycles while SELDI-TOF analysis produced eight significant peaks and additional artefact peaks from samples with added protease inhibitors. Delayed storage for different durations and in different temperatures produced six significant SELDI-TOF peaks. A?42 and tau were susceptible to increased temperatures and the duration before storage, whereas P-tau and cystatin C were not. Transthyretin and several of its isoforms were found using SELDI-TOF and were susceptible to freeze/thaw cycles and to increased temperature and length of time prior to storage. We recommend that CSF should be collected and centrifuged immediately after sampling and prior to storage at -80�C without the addition of protease inhibitors. Freeze/thawing should be avoided because of the instability of tau, P-tau and transthyretin. Standardised CSF sampling, handling and storage for biomarker research are essential for accurately comparing the results obtained by different studies and institutions. PMID:23537933
Simonsen, Anja H; Bahl, Justyna M C; Danborg, Pia B; Lindstrom, Veronica; Larsen, Severin O; Grubb, Anders; Heegaard, Niels H H; Waldemar, Gunhild
Plaques and tangles may be manifestations of a more substantial underlying cause of Alzheimer's disease (AD). Disease-related changes in the clearance of amyloid-? (A?) and other metabolites suggest this cause may involve cerebrospinal fluid (CSF) flow through the interstitial spaces of the brain, including an archaic route through the olfactory system that predates neocortical expansion by three hundred million years. This olfactory CSF conduit (OCC) runs from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone, and down the olfactory tract to the olfactory bulb, where CSF seeps through the cribriform plate to the nasal submucosa. Olfactory dysfunction is common in AD and could be related to alterations in CSF flow along the OCC. Further, reductions in OCC flow may impact CSF hydrodynamics upstream in the MTL and basal forebrain, resulting in less efficient A? removal from those areas-among the first affected by neuritic plaques in AD. Factors that reduce CSF drainage across the cribriform plate and slow the clearance of metabolite-laden CSF could include aging-related bone changes, head trauma, inflammation of the nasal epithelium, and toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis-all of which have been linked to AD risk. Problems with CSF-mediated clearance could also provide a link between these seemingly disparate factors and familial AD mutations that induce plaque and tangle formation. I hypothesize that disruptions of CSF flow across the cribriform plate are important early events in AD, and I propose that restoring this flow will enhance the drainage of A? oligomers and other metabolites from the MTL. PMID:24769627
Ethell, Douglas W
[Detection of malignant B lymphocytes in cerebrospinal fluid by using BIOMED-2 PCR].
The purpose of this study was to develop a sensitive method for the detection of malignant B lymphocytes in cerebrospinal fluid (CSF) from patients with diffuse large B-cell lymphoma (DLBCL) who were considered as risk of central nervous system (CNS) involvement. Nine CSF samples were collected and then centrifuged. The cell precipitate was lysed directly. The supernatant was used to detect immunoglobulin heavy chain (IgH) gene rearrangement (characteristic changes of malignant B lymphocytes ) by BIOMED-2 PCR. The sensitivity of this method was compared with that of cytology defection and flow cytometry. In addition, through a series of quantity/concentration of tumor cells, the sensitivity differences caused by two sample handling methods (direct cell lysis vs traditional DNA extraction) were analyzed, and the sensitivity of direct cell lysis combined with BIOMED-2 PCR was evaluated. The results showed that the positive clonality of IgH gene rearrangement were detected by BIOMED-2 PCR in 5 cases, but the positive were detected by cytology defection/flow cytometry only in 2 cases, which indicated that the BIOMED-2 PCR assay gives a better yield. In addition, when combined with BIOMED-2 PCR, direct cell lysis produced sensitivity much higher than DNA extraction. The former can enable clonality detection from a minimum of 0.1%/20 tumor cells. It is concluded the method of direct cell lysis combined with BIOMED-2 PCR is sensitive and suitable for paucicellular CSF detection. It may aid the diagnosis of CNS involvement in patients with DLBCL. PMID:24156428
Liu, Li-Xiao; Zhao, Hui; Zhang, Wei-Wei; Yue, Dong-Mei; Zhou, Jin
We aimed to identify cerebrospinal fluid (CSF) biomarkers associated with neurodegeneration in individuals with and without CSF evidence of Alzheimer pathology. We investigated 287 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects (age=74.9�6.9; 22/48/30% with Alzheimer's disease/mild cognitive impairment/controls) with CSF multiplex analyte data and serial volumetric MRI. We calculated brain and hippocampal atrophy rates, ventricular expansion and Mini Mental State Examination decline. We used false discovery rate corrected regression analyses to assess associations between CSF variables and atrophy rates in individuals with and without amyloid pathology, adjusting in stages for tau, baseline volume, p-tau, age, sex, ApoE4 status and diagnosis. Analytes showing statistically significant independent relationships were entered into reverse stepwise analyses. Adjusting for tau, baseline volume, p-tau, age, sex and ApoE4, 4/83 analytes were significantly independently associated with brain atrophy rate, 1/83 with ventricular expansion and 2/83 with hippocampal atrophy. The strongest CSF predictor for the three atrophy measures was low trefoil factor 3 (TFF3). High cystatin C (CysC) was associated with higher whole brain atrophy and hippocampal atrophy rates. Lower levels of vascular endothelial growth factor and chromogranin A (CrA) were associated with higher whole brain atrophy. In exploratory reverse stepwise analyses, lower TFF3 was associated with higher rates of whole brain, hippocampal atrophy and ventricular expansion. Lower levels of CrA were associated with higher whole brain atrophy rate. The relationship between low TFF3 and increased hippocampal atrophy rate remained after adjustment for diagnosis. We identified a series of CSF markers that are independently associated with rate of neurodegeneration in amyloid-positive individuals. TFF3, a substrate for NOTCH processing may be an important biomarker of neurodegeneration across the Alzheimer spectrum. PMID:25072324
Paterson, R W; Bartlett, J W; Blennow, K; Fox, N C; Shaw, L M; Trojanowski, J Q; Zetterberg, H; Schott, J M
Neuroinflammation may be involved in the pathophysiology of Parkinson's disease (PD) and specifically in non-motor symptoms such as depression, fatigue and cognitive impairment. The aim of this study was to measure inflammatory markers in cerebrospinal fluid (CSF) samples from PD patients and a reference group, and to investigate correlations between non-motor symptoms and inflammation. We quantified C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, eotaxin, interferon gamma-induced protein-10, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein 1-? in CSF samples from PD patients (N=87) and the reference group (N=33). Sixteen of the PD patients had a dementia diagnosis (PDD). We assessed symptoms of fatigue, depression, anxiety and cognitive function using the Functional Assessment of Chronic Illness Therapy-Fatigue, the Hospital Anxiety and Depression Scale, and the Mini Mental State Examination, respectively. There were no significant differences in mean levels of inflammatory markers between PD patients and the reference group. After controlling for age, gender and somatic illness, patients with PDD had significantly higher levels of CRP compared to non-demented PD patients (p=0.032) and the reference group (p=0.026). Increased levels of inflammatory markers in CSF were significantly associated with more severe symptoms of depression, anxiety, fatigue, and cognition in the entire PD group. After controlling for PD duration, age, gender, somatic illness and dementia diagnosis, high CRP levels were significantly associated with more severe symptoms of depression (p=0.010) and fatigue (p=0.008), and high MCP-1 levels were significantly associated with more severe symptoms of depression (p=0.032). Our results indicate that non-motor features of PD such as depression, fatigue, and cognitive impairment are associated with higher CSF levels of inflammatory markers. PMID:23911592
Lindqvist, Daniel; Hall, Sara; Surova, Yulia; Nielsen, Henrietta M; Janelidze, Shorena; Brundin, Lena; Hansson, Oskar
Soluble aggregated forms of amyloid-? protein (A?) have garnered significant attention recently for their role in Alzheimer�s disease (AD). Protofibrils are a subset of these soluble species and are considered intermediates in the aggregation pathway to mature A? fibrils. Biological studies have demonstrated that protofibrils exhibit both toxic and inflammatory activities. It is important in these in vitro studies to prepare protofibrils using solution conditions that are appropriate for cellular studies as well as conducive to biophysical characterization of protofibrils. Here we describe the preparation and characterization of A?(1�42) protofibrils in modified artificial cerebrospinal fluid (aCSF) and demonstrate their prominent binding and activation of microglial cells. A simple phosphate/bicarbonate buffer system was prepared that maintained the ionic strength and cell compatibility of F-12 medium but did not contain numerous supplements that interfere with spectroscopic analyses of A? protofibrils. Reconstitution of A?(1�42) in aCSF and isolation with size exclusion chromatography (SEC) revealed curvilinear ?-sheet protofibrils <100 nm in length and hydrodynamic radii of 21 nm. Protofibril concentration determination by BCA assay, which was not possible in F-12 medium, was more accurately measured in aCSF. Protofibrils formed and isolated in aCSF, but not monomers, markedly stimulated TNF? production in BV-2 and primary microglia and bound in significant amounts to microglial membranes. This report demonstrates the suitability of a modified aCSF system for preparing SEC-isolated A?(1�42) protofibrils and underscores the unique ability of protofibrils to functionally interact with microglia. PMID:23242692
Paranjape, Geeta S.; Terrill, Shana E.; Gouwens, Lisa K.; Ruck, Benjamin M.; Nichols, Michael R.
We developed PCR primers specific for the blaTEM and blaROB ampicillin resistance genes. The specificity of the primers was confirmed by testing a series of Escherichia coli isolates containing a variety of ampicillin resistance genes and a series of ampicillin-resistant and ampicillin-susceptible Haemophilus influenzae isolates. There was a perfect correlation between ampicillin MICs, the presence of beta-lactamase (as determined by the nitrocefin test), and the results with the blaTEM and blaROB primers. Isolates of H. influenzae and Streptococcus pneumoniae obtained from 25 frozen cerebrospinal fluid (CSF) specimens were also tested. Four of 14 H. influenzae isolates were positive with the blaTEM primers; none were positive with the blaROB primers. Ampicillin MICs were determined for the H. influenzae isolates, and penicillin MICs were determined for the S. pneumoniae isolates. Only the four PCR-positive H. influenzae isolates had elevated MICs of ampicillin and were beta-lactamase positive. None of the H. influenzae isolates contained the blaROB gene, and none of the S. pneumoniae isolates produced positive reactions with either primer set. We then used universal primers directed to conserved regions of rRNA and a Haemophilus detection probe to identify which of the 25 frozen samples of CSF contained H. influenzae. Fourteen of the 25 CSF specimens were positive for H. influenzae, which correlated with the number of organisms obtained by culture of the CSF samples. Four of the CSF samples were positive with the blaTEM primer set, and these correlated with the four H. influenzae isolates that were positive when tested directly by PCR. The blaTEM assay required the use of native Taq polymerase because Amplitaq preparations were contaminated with vector DNA that contained the blaTEM-1 gene. PMID:7852564
Tenover, F C; Huang, M B; Rasheed, J K; Persing, D H
We developed PCR primers specific for the blaTEM and blaROB ampicillin resistance genes. The specificity of the primers was confirmed by testing a series of Escherichia coli isolates containing a variety of ampicillin resistance genes and a series of ampicillin-resistant and ampicillin-susceptible Haemophilus influenzae isolates. There was a perfect correlation between ampicillin MICs, the presence of beta-lactamase (as determined by the nitrocefin test), and the results with the blaTEM and blaROB primers. Isolates of H. influenzae and Streptococcus pneumoniae obtained from 25 frozen cerebrospinal fluid (CSF) specimens were also tested. Four of 14 H. influenzae isolates were positive with the blaTEM primers; none were positive with the blaROB primers. Ampicillin MICs were determined for the H. influenzae isolates, and penicillin MICs were determined for the S. pneumoniae isolates. Only the four PCR-positive H. influenzae isolates had elevated MICs of ampicillin and were beta-lactamase positive. None of the H. influenzae isolates contained the blaROB gene, and none of the S. pneumoniae isolates produced positive reactions with either primer set. We then used universal primers directed to conserved regions of rRNA and a Haemophilus detection probe to identify which of the 25 frozen samples of CSF contained H. influenzae. Fourteen of the 25 CSF specimens were positive for H. influenzae, which correlated with the number of organisms obtained by culture of the CSF samples. Four of the CSF samples were positive with the blaTEM primer set, and these correlated with the four H. influenzae isolates that were positive when tested directly by PCR. The blaTEM assay required the use of native Taq polymerase because Amplitaq preparations were contaminated with vector DNA that contained the blaTEM-1 gene. Images PMID:7852564
Tenover, F C; Huang, M B; Rasheed, J K; Persing, D H
Objective Spinal dysraphism defects span wide spectrum. Wound dehiscence is a common postoperative complication, and is a challenge in the current management of cerebrospinal fluid (CSF) leaks and wound healing. The purpose of this study is to evaluate the risks of CSF-related morbidity in the surgical treatment of spinal dysraphism. Methods Ten patients with spinal dysraphism were included in this retrospective study. The median age of the cohort was 4.8 months. To assess the risk of CSF morbidity, we measured the skin lesion area and the percentage of the skin lesion area relative to the back surface for each patient. We then analyzed the relationship between morbidity and the measured skin lesion area or related factors. Results The overall median skin lesion area was 36.2 cm2 (n=10). The percentage of the skin lesion area relative to the back surface ranged from 0.6% to 18.1%. During surgical reconstruction, 4 patients required subsequent operations to repair CSF morbidity. The comparison of the mean area of skin lesions between the CSF morbidity group and the non-CSF morbidity group was statistically significant (average volume skin lesion of 64.4�32.5 cm2 versus 27.7�27.8 cm2, p<0.05). CSF morbidity tended to occur either when the skin lesion area was up to 44.2 cm2 or there was preexisting fibrosis before revision with an accompanying broad-based dural defect. Conclusion Measuring the lesion area, including the skin, dura, and related surgical parameters, offers useful information for predicting wound challenges and selecting appropriate reconstructive surgery methods. PMID:24278652
Lee, Byung-Jou; Han, Seong-Rok; Choi, Chan-Young; Lee, Dong-Joon; Kang, Jae Heon
Intraventricular colistin, administered as colistin methanesulfonate (CMS), is the last resource for the treatment of central nervous system infections caused by panresistant Gram-negative bacteria. The doses and daily regimens vary considerably and are empirically chosen; the cerebrospinal fluid (CSF) pharmacokinetics of colistin after intraventricular administration of CMS has never been characterized. Nine patients (aged 18 to 73 years) were treated with intraventricular CMS (daily doses of 2.61 to 10.44 mg). Colistin concentrations were measured using a selective high-performance liquid chromatography (HPLC) assay. The population pharmacokinetics analysis was performed with the P-Pharm program. The pharmacokinetics of colistin could be best described by the one-compartment model. The estimated values (means � standard deviations) of apparent CSF total clearance (CL/Fm, where Fm is the unknown fraction of CMS converted to colistin) and terminal half-life (t1/2?) were 0.033 � 0.014 liter/h and 7.8 � 3.2 h, respectively, and the average time to the peak concentration was 3.7 � 0.9 h. A positive correlation between CL/Fm and the amount of CSF drained (range 40 to 300 ml) was observed. When CMS was administered at doses of ?5.22 mg/day, measured CSF concentrations of colistin were continuously above the MIC of 2 ?g/ml, and measured values of trough concentration (Ctrough) ranged between 2.0 and 9.7 ?g/ml. Microbiological cure was observed in 8/9 patients. Intraventricular administration of CMS at doses of ?5.22 mg per day was appropriate in our patients, but since external CSF efflux is variable and can influence the clearance of colistin and its concentrations in CSF, the daily dose of 10 mg suggested by the Infectious Diseases Society of America may be more prudent. PMID:22687507
Cusato, Maria; Accetta, Giovanni; Marino, Valeria; Procaccio, Francesco; Del Gaudio, Alfredo; Iotti, Giorgio A.; Regazzi, Mario
Mutations in the leucine-rich repeat kinase 2 gene are the most common cause of autosomal dominant Parkinson�s disease (PD). To assess the cerebrospinal fluid (CSF) levels of ?-synuclein oligomers in symptomatic and asymptomatic leucine-rich repeat kinase 2 mutation carriers, we used enzyme-linked immunosorbent assays (ELISA) to investigate total and oligomeric forms of ?-synuclein in CSF samples. The CSF samples were collected from 33 Norwegian individuals with leucine-rich repeat kinase 2 mutations: 13 patients were clinically diagnosed with PD and 20 patients were healthy, asymptomatic leucine-rich repeat kinase 2 mutation carriers. We also included 35 patients with sporadic PD (sPD) and 42 age-matched healthy controls. Levels of CSF ?-synuclein oligomers were significantly elevated in healthy asymptomatic individuals carrying leucine-rich repeat kinase 2 mutations (n = 20; P < 0.0079) and in sPD group (n = 35; P < 0.003) relative to healthy controls. Increased ?-synuclein oligomers in asymptomatic leucine-rich repeat kinase 2 mutation carriers showed a sensitivity of 63.0% and a specificity of 74.0%, with an area under the curve of 0.66, and a sensitivity of 65.0% and a specificity of 83.0%, with an area under the curve of 0.74 for sPD cases. An inverse correlation between CSF levels of ?- synuclein oligomers and disease severity and duration was observed. Our study suggests that quantification of ?-synuclein oligomers in CSF has potential value as a tool for PD diagnosis and presymptomatic screening of high-risk individuals.
Aasly, Jan O.; Johansen, Krisztina K.; Br?nstad, Gunnar; War?, Bj?rg J.; Majbour, Nour K.; Varghese, Shiji; Alzahmi, Fatimah; Paleologou, Katerina E.; Amer, Dena A. M.; Al-Hayani, Abdulmonem; El-Agnaf, Omar M. A.
HIV-1 invades the central nervous system (CNS) in the context of acute infection, persists thereafter in the absence of treatment, and leads to chronic intrathecal immunoactivation that can be measured by the macrophage activation marker, neopterin, in cerebrospinal fluid (CSF). In this review we describe our experience with CSF neopterin measurements in 382 untreated HIV-infected patients across the spectrum of immunosuppression and HIV-related neurological diseases, in 73 untreated AIDS patients with opportunistic CNS infections, and in 233 treated patients. In untreated patients, CSF neopterin concentrations are almost always elevated and increase progressively as immunosuppression worsens and blood CD4 cell counts fall. However, patients with HIV dementia exhibit particularly high CSF neopterin concentrations, above those of patients without neurological disease, though patients with CNS opportunistic infections, including CMV encephalitis and cryptococcal meningitis, also exhibit high levels of CSF neopterin. Combination antiretroviral therapy, with its potent effect on CNS HIV infection and CSF HIV RNA, mitigates both intrathecal immunoactivation and lowers CSF neopterin. However, despite suppression of plasma and CSF HIV RNA to below the detection limits of clinical assays (<50 copies HIV RNA/mL), CSF neopterin often remains mildly elevated, indicating persistent low-level intrathecal immune activation and raising the important questions of whether this elevation is driven by continued CNS infection and whether it causes continued indolent CNS injury. Although nonspecific, CSF neopterin can serve as a useful biomarker in the diagnosis of HIV dementia in the setting of confounding conditions, in monitoring the CNS inflammatory effects of antiretroviral treatment, and give valuable information to the cause of ongoing brain injury. PMID:20525234
Methodological Aspects of ELISA Analysis of Thioredoxin 1 in Human Plasma and Cerebrospinal Fluid
Thioredoxin-1 (Trx1) is a protein antioxidant involved in major cellular processes. Increased plasma levels of Trx1 have been associated with human diseases suggesting that Trx1 is a marker for oxidative stress with putative clinical use. However, the reported mean levels of Trx1 in the control cohorts vary a hundred-fold between studies (0.8�87 ng/ml), possibly due to methodological differences between the capture ELISA used in the different studies. The aim of this study was to investigate methodological aspects related to the ELISA measurement of Trx1. ELISAs utilizing different capture and detection combinations of antibodies to Trx1 and as well as recombinant human (rh) Trx1 standards from two sources were characterized. The different ELISAs were subsequently used to measure Trx1 in human plasma and cerebrospinal fluid samples (CSF) from healthy donors and from patients with various neurological diagnoses. The Trx1 standards differed in their content of monomeric and oligomeric Trx1, which affected the ELISAs composed of different antibody combinations. Thus, the levels of Trx1 determined in human plasma and CSF samples varied depending on the antibody used in the ELISAs and on the rhTrx1 standard. Furthermore, the relevance of preventing interference by heterophilic antibodies (HA) in human plasma and CSF was investigated. The addition of a HA blocking buffer to human samples drastically reduced the ELISA signals in many samples showing that HA are likely to cause false positive results unless they are blocked. In conclusion, the study shows that the design of a Trx1 ELISA in regards to antibodies and standards used has an impact on the measured Trx1 levels. Importantly, analyses of human plasma and CSF without preventing HA interference may obscure the obtained data. Overall, the results of this study are crucial for the improvement of future studies on the association of Trx1 levels with various diseases. PMID:25075746
Lundberg, Mathias; Curbo, Sophie; Reiser, Kathrin; Masterman, Thomas; Braesch-Andersen, Sten; Arestrom, Irene; Ahlborg, Niklas
Reduced alpha-synuclein in cerebrospinal fluid in synucleinopathies: Evidence from a meta-analysis.
Alpha-synuclein plays a key role in the pathology of synucleinopathies including Parkinson's disease (PD) and multiple system atrophy (MSA). However, whether alpha-synuclein level in cerebrospinal fluid (CSF) could distinguish synucleinopathies from progressive supranuclear palsy (PSP) is still a contentious issue. A comprehensive literature search yielded nine eligible studies. We expressed the between-group difference of the concentration of alpha-synuclein in CSF as the standardized mean difference. The proportion of variation attributable to heterogeneity was computed and expressed as I(2) . Nine studies involved 537 controls, 843 PD, 130 MSA, and 98 PSP patients. The overall effect of PD on alpha-synuclein in CSF was significantly different from normal control or disease control (standardized mean difference = -0.67, P < 0.00001). These studies were heterogeneous (I(2) = 40%). Alpha-synuclein in CSF in MSA was significantly reduced relative to controls with heterogeneous studies (standardized mean difference = -0.75, P < 0.0001; I(2) = 62%). In contrast, no significant difference of alpha-synuclein in CSF was observed between PSP and controls with heterogeneous studies (standardized mean difference = -0.28, P = 0.13; I(2) = 53%). Alpha-synuclein in CSF was significantly reduced in synucleinopathies compared with PSP ("PD vs. PSP": standardized mean difference = -0.38, P = 0.001; "MSA vs. PSP": standardized mean difference = -0.66, P < 0.00001). The included studies were homogeneous (I(2) = 0%). Our study showed that alpha-synuclein levels in CSF in synucleinopathies was significantly lower than in PSP. This finding provides insights into the pathophysiological difference between synucleinopathies and PSP as well as possibility of development of a tool for differential diagnosis between MSA and PSP using enzyme-linked immunosorbent assay (ELISA) and similar methods. � 2014 International Parkinson and Movement Disorder Society. PMID:25258345
Sako, Wataru; Murakami, Nagahisa; Izumi, Yuishin; Kaji, Ryuji
The role of the serotonergic system in the pathogenesis of behavioral disorders such as depression, alcoholism, obsessive-compulsive disorder, and violence is not completely understood. Measurement of the concentration of neurotransmitters and their metabolites in cerebrospinal fluid (CSF) is considered among the most valid, albeit indirect, methods of assessing central nervous system function in man. However, most studies in humans have measured lumbar CSF concentrations only at single time points, thus not taking into account rhythmic or episodic variations in levels of neurotransmitters, precursors, or metabolites. We have continuously sampled lumbar CSF via subarachnoid catheter in 12 healthy volunteers, aged 20-65 years. One ml (every 10 min) CSF samples were collected at a rate of 0.1ml/min for 24-hour (h), and the levels of tryptophan (TRP) and 5-hydroxy indoleacetic acid (5-HIAA) were measured. Variability across all 12 subjects was significantly greater (P < 0.0001) than the variability seen in repeated analysis of a reference CSF sample for both 5-HIAA (32.0% vs 7.9%) and TRP (25.4% vs 7.0%), confirming the presence of significant biological variability during the 24-hr period examined. This variability could not be explained solely by meal related effects. Cosinor analysis of the 24-hr TRP concentrations from all subjects revealed a significant diurnal pattern in CSF TRP levels, whereas the 5-HIAA data were less consistent. These studies indicate that long-term serial CSF sampling reveals diurnal and biological variability not evident in studies based on single CSF samples. PMID:12137916
Kennedy, John S; Gwirtsman, Harry E; Schmidt, Dennis E; Johnson, Benjamin W; Fielstein, Elliot; Salomon, Ronald M; Shiavi, Richard G; Ebert, Michael H; Parris, Winston C V; Loosen, Peter T
Features of the Sinushunt(R) and its influence on the cerebrospinal fluid system
Objectives: A new cerebrospinal fluid (CSF) shunt system, Sinushunt�, has recently been introduced. CSF is shunted from the ventricles to the transverse sinus. The Sinushunt is not a classical differential pressure shunt; instead, it opens as soon as there is a positive pressure over the shunt and the flow is dependent on the resistance of the system, which is high compared with traditional CSF shunts. The objective of this study was to characterise the features of the Sinushunt and to evaluate its influence on the CSF system. Methods: Five brand new Sinushunts with distal catheters were tested. An automated, computerised experimental apparatus based on regulation of pressure, built into an incubator at 37 �C, was used. Opening pressure, resistance, and anti-reflux properties were determined. Results: The mean (SD) opening pressure was highly dependent on the pressure in the sinus: Popen = 1.3 (0.6) mm Hg with Psinus = 0.0 mm Hg, and Popen = 7.5 (0.6) mm Hg for Psinus = 6.5 mm Hg. The mean (SD) resistance of the shunts was 7.9 (0.3) mm Hg/ml/min and not clinically significantly affected by the sinus pressure. In one shunt there was reflux, and in another two shunts there was a very small, but similar, tendency. Conclusions: This study confirms that the resistance of the Sinushunt is comparable to the physiological values in humans. However, the optimal post-operative resistance for different hydrocephalus types is unknown, and randomised clinical trials are needed to confirm improved outcome and reduced complication rate for the Sinushunt compared with traditional low resistance ventriculoperitoneal shunts. A weakness of the anti-reflux system of the Sinushunt must be suspected and has to be further investigated. PMID:15258219
Eklund, A; Koskinen, L; Malm, J
Time-course of cerebrospinal fluid histamine in the wake-consolidated squirrel monkey.
Central nervous system (CNS) histamine is low in individuals with narcolepsy, a disease characterized by severe fragmentation of both sleep and wake. We have developed a primate model, the squirrel monkey, with which we can examine the role of the CNS in the wake-consolidation process, as these primates are day-active, have consolidated wake and sleep and have cerebrospinal fluid (CSF) that is readily accessible. Using this model and three distinct protocols, we report herein on the role of CNS histamine in the wake consolidation process. CSF histamine has a robust daily rhythm, with a mean of 24.9?�?3.29?pg?mL(-1) , amplitude of 31.7?�?6.46?pg?mL(-1) and a peak at 17:49?� 70.3?min (lights on 07:00-19:00?hours). These levels are not significantly affected by increases (up to 161?�?40.4% of baseline) or decreases (up to 17.2?�?2.50% of baseline) in locomotion. In direct contrast to the effects of sleep deprivation in non-wake-consolidating mammals, in whom CSF histamine increases, pharmacologically induced sleep (?-hydroxybutyrate) and wake (modafinil) have no direct effects on CSF histamine concentrations. These data indicate that the time-course of histamine in CSF in the wake-consolidated squirrel monkey is robust against variation in activity and sleep and wake-promoting pharmacological compounds, and may indicate that histamine physiology plays a role in wake-consolidation such as is present in the squirrel monkey and humans. PMID:21910776
Zeitzer, Jamie M; Kodama, Tohru; Buckmaster, Christine L; Honda, Yoshiko; Lyons, David M; Nishino, Seiji; Mignot, Emmanuel
Objective To identify cerebrospinal fluid (CSF) protein changes in persons who will develop familial Alzheimer disease (FAD) due to PSEN1 and APP mutations, using unbiased proteomics. Design We compared proteomic profiles of CSF from individuals with FAD who were mutation carriers (MCs) and related noncarriers (NCs). Abundant proteins were depleted and samples were analyzed using liquid chromatography� electrospray ionization�mass spectrometry on a high-resolution time-of-flight instrument. Tryptic peptides were identified by tandem mass spectrometry. Proteins differing in concentration between the MCs and NCs were identified. Setting A tertiary dementia referral center and a proteomic biomarker discovery laboratory. Participants Fourteen FAD MCs (mean age, 34.2 years; 10 are asymptomatic, 12 have presenilin-1 [PSEN1] gene mutations, and 2 have amyloid precursor protein [APP] gene mutations) and 5 related NCs (mean age, 37.6 years). Results Fifty-six proteins were identified, represented by multiple tryptic peptides showing significant differences between MCs and NCs (46 upregulated and 10 downregulated); 40 of these proteins differed when the analysis was restricted to asymptomatic individuals. Fourteen proteins have been reported in prior proteomic studies in late-onset AD, including amyloid precursor protein, transferrin, ?1?-glycoprotein, complement components, afamin precursor, spondin 1, plasminogen, hemopexin, and neuronal pentraxin receptor. Many other proteins were unique to our study, including calsyntenin 3, AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) 4 glutamate receptor, CD99 antigen, di-N-acetyl-chitobiase, and secreted phosphoprotein 1. Conclusions We found much overlap in CSF protein changes between individuals with presymptomatic and symptomatic FAD and those with late-onset AD. Our results are consistent with inflammation and synaptic loss early in FAD and suggest new presymptomatic biomarkers of potential usefulness in drug development. PMID:22232349
Ringman, John M.; Schulman, Howard; Becker, Chris; Jones, Ted; Bai, Yuchen; Immermann, Fred; Cole, Gregory; Sokolow, Sophie; Gylys, Karen; Geschwind, Daniel H.; Cummings, Jeffrey L.; Wan, Hong I.
Automatic segmentation of ventricular cerebrospinal fluid from ischemic stroke CT images.
Accurate segmentation of ventricular cerebrospinal fluid (CSF) regions in stroke CT images is important in assessing stroke patients. Manual segmentation is subjective, time consuming and error prone. There are currently no methods dedicated to extracting ventricular CSF regions in stroke CT images. 102 ischemic stroke CT scans (slice thickness between 3 and 6 mm, voxel size in the axial plane between 0.390 and 0.498 mm) were acquired. An automated template-based algorithm is proposed to extract ventricular CSF regions which accounts for the presence of ischemic infarct regions, image noise, and variations in orientation. First, template VT(2) is registered to the scan using landmark-based piecewise linear scaling and then template VT(1) is used to further refine the registration by partial segmentation of the fourth ventricle. A region of interest (ROI) is found using the registered VT(2). Automated thresholding is then applied to the ROI and the artifacts are removed in the final phase. Sensitivity, dice similarity coefficient, volume error, conformity and sensibility of segmentation results were 0.74?�?0.12, 0.8?�?0.09, 0.16?�?0.11, 0.45?�?0.39, 0.88?�?0.09, respectively. The processing time for a 512?�?512?�?30 CT scan takes less than 30 s on a 2.49 GHz dual core processor PC with 4 GB RAM. Experiments with clinical stroke CT scans showed that the proposed algorithm can generate acceptable results in the presence of noise, size variations and orientation differences of ventricular systems and in the presence of ischemic infarcts. PMID:22125015
Poh, L E; Gupta, V; Johnson, A; Kazmierski, R; Nowinski, W L
Cerebrospinal fluid activity of tissue plasminogen activator in patients with neurological diseases.
AIM: To study cerebrospinal fluid (CSF) activity of tissue plasminogen activator (tPA) in patients with neurological diseases. METHODS: CSF tPA and urokinase (uPA) activities were studied using an immunocapture assay and zymography in 44 patients with neurological disease and 20 reference subjects. The patient group comprised three patients with meningitis, 21 with encephalitis, nine with acute lymphoblastic (n = 7) and myeloid (n = 2) leukaemia, seven with multiple sclerosis, three with facial paresis, and one with polyradiculitis. RESULTS: Raised tPA activities were observed in patients with multiple sclerosis, leukaemia and encephalitis. In contrast, there were no differences in the mean activities of tPA in patients with meningitis or other diseases compared with the reference subjects. The highest tPA activities were found in patients with multiple sclerosis. The mean activity in patients with leukaemia was higher than in those with meningitis and polyradiculitis, but not encephalitis and facial paresis. Although the CSF tPA activity correlated positively with age in reference subjects, no correlation was observed in patients. Samples were qualitatively screened for both tPA and uPA activity by zymography and positive samples were quantitated. Some of the samples had quantifiable levels of uPA activity: three of seven multiple sclerosis samples, 10 of 21 samples from patients with encephalitis and five of nine leukaemic samples. The highest activities were recorded in patients with leukaemia. uPA was not detected in the CSF of the patients with meningitis, facial paresis or polyradiculitis. CONCLUSIONS: Plasminogen activator activity can be measured reliably in CSF and the assessment of tPA activity may be useful for studying the pathogenesis of neurological diseases. PMID:8813958
Akenami, F O; Siren, V; Koskiniemi, M; Siimes, M A; Teravainen, H; Vaheri, A
Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau(181)) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau(181) levels in two independent CSF series (P(combined) = 1.17 x 10(-05)). We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series (P(combined) = 1.17 x 10(-05)). Our analyses suggest that genetic variants associated with CSF ptau(181) levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF A?(42) levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF A?(42) levels. Finally, we believe genome-wide association studies of CSF tau/ptau(181) levels should identify novel genetic variants which will likely influence rate of progression of AD. PMID:20862329
Cruchaga, Carlos; Kauwe, John S K; Mayo, Kevin; Spiegel, Noah; Bertelsen, Sarah; Nowotny, Petra; Shah, Aarti R; Abraham, Richard; Hollingworth, Paul; Harold, Denise; Owen, Michael M; Williams, Julie; Lovestone, Simon; Peskind, Elaine R; Li, Ge; Leverenz, James B; Galasko, Douglas; Morris, John C; Fagan, Anne M; Holtzman, David M; Goate, Alison M
Background Multiple sclerosis (MS), an inflammatory disease of the central nervous system, manifests itself in numerous forms and stages. A number of brain metabolic alterations have been reported for MS patients vs. control subjects. However, metabolite profiles of cerebrospinal fluid (CSF) are not consistent among the published MS studies, most probably due to variations in the patient cohorts studied. We undertook the first investigation of highly homogeneous MS patient cohorts to determine characteristic effects of inflammatory MS plaques on the CSF metabolome, including only patients with clinically isolated syndrome (CIS) with or without inflammatory brain plaques, and controls. Methodology/Principal Findings CSF obtained by lumbar puncture was analyzed by proton magnetic resonance spectroscopy. 27 metabolites were quantified. Differences between groups of control subjects (n?=?10), CIS patients with (n?=?21) and without (n?=?12) inflammatory plaques were evaluated by univariate statistics and principal component analysis (PCA). Seven metabolites showed statistically significant inter-group differences (p<0.05). Interestingly, a significant increase in ?-hydroxyisobutyrate (BHIB) was detected in CIS with vs. without active plaques, but not when comparing either CIS group with control subjects. Moreover, a significant correlation was found, for the first time, between CSF lactate concentration and the number of inflammatory MS brain plaques. In contrast, fructose concentrations were equally enhanced in CIS with or without active plaques. PCA based on all 27 metabolites yielded group-specific clusters. Conclusions/Significance CSF metabolic profiles suggest a close link between MS plaque activity in CIS patients on the one hand and organic-acid metabolism on the other. Our detection of increased BHIB levels points to a hitherto unsuspected role for this compound in MS with active plaques, and serves as a basis for further investigation. The metabolic effects described in our study are crucial elements in the explanation of biochemical mechanisms involved in specific MS manifestations. PMID:17611627
Lutz, Norbert W.; Viola, Angele; Malikova, Irina; Confort-Gouny, Sylviane; Audoin, Bertrand; Ranjeva, Jean-Philippe; Pelletier, Jean; Cozzone, Patrick J.
Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid.
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized ?=0.32, P=4.92 � 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (?=0.21; P unadjusted=5.6 � 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes. PMID:23319000
Luykx, J J; Bakker, S C; Lentjes, E; Neeleman, M; Strengman, E; Mentink, L; DeYoung, J; de Jong, S; Sul, J H; Eskin, E; van Eijk, K; van Setten, J; Buizer-Voskamp, J E; Cantor, R M; Lu, A; van Amerongen, M; van Dongen, E P A; Keijzers, P; Kappen, T; Borgdorff, P; Bruins, P; Derks, E M; Kahn, R S; Ophoff, R A
Background Absence of clinical and radiological activity in relapsing�remitting multiple sclerosis (RRMS) is perceived as disease remission. We explored the role of persisting inflammation during remission in disease evolution. Methods Cerebrospinal fluid (CSF) levels of interleukin 1? (IL-1?), a major proinflammatory cytokine, were measured in 170 RRMS patients at the time of clinical and radiological remission. These patients were then followed up for at least 4�years, and clinical, magnetic resonance imaging (MRI) and optical coherence tomography (OCT) measures of disease progression were recorded. Results Median follow-up of RRMS patients was 5�years. Detection of CSF IL-1? levels at the time of remission did not predict earlier relapse or new MRI lesion formation. Detection of IL-1? in the CSF was instead associated with higher progression index (PI) and Multiple Sclerosis Severity Scale (MSSS) scores at follow-up, and the number of patients with sustained Expanded Disability Status Scale (EDSS) or Multiple Sclerosis Functional Composite worsening at follow-up was higher in individuals with detectable levels of IL-1?. Patients with undetectable IL-1? in the CSF had significantly lower PI and MSSS scores and a higher probability of having a benign MS phenotype. Furthermore, patients with undetectable CSF levels of IL-1? had less retinal nerve fiber layer thickness and macular volume alterations visualized by OCT compared to patients with detectable IL-1?. Conclusions Our results suggest that persistence of a proinflammatory environment in RRMS patients during clinical and radiological remission influences midterm disease progression. Detection of IL-1? in the CSF at the time of remission appears to be a potential negative prognostic factor in RRMS patients. PMID:24548694
Cytokine Concentrations in the Cerebrospinal Fluid of Great Danes with Cervical Spondylomyelopathy
Background Chronic inflammation is involved in the pathogenesis of human cervical spondylotic myelopathy and could also play a role in cervical spondylomyelopathy (CSM) in dogs. Hypothesis/Objectives That cerebrospinal fluid (CSF) cytokine concentrations would differ between clinically normal (control) and CSM-affected Great Danes (GDs), with affected GDs showing higher levels of inflammatory cytokines, such as interleukin (IL)-6 and monocyte chemoattractant protein-1/chemokine ligand 2 (MCP-1/CCL2). Animals Client-owned GDs: 15 control, 15 CSM-affected. Methods Prospective study. Dogs underwent cervical vertebral column magnetic resonance imaging and collection of CSF from the cerebellomedullary cistern. Cytokine concentrations were measured using a commercially available canine multiplex immunoassay. Cytokine concentrations were compared between groups. Associations with the administration of anti-inflammatory medications, disease duration and severity, severity of spinal cord (SC) compression, and SC signal changes were investigated in affected GDs. Results Affected GDs had significantly lower MCP-1/CCL2 (mean 138.03 pg/mL, 95% confidence interval [CI] = 114.85�161.20) than control GDs (212.89 pg/mL, 95% CI = 165.68�260.11, P = .028). In affected GDs, MCP-1/CCL2 concentrations correlated inversely with the severity of SC compression. There were no associations with administration of anti-inflammatory medications, disease duration, or disease severity. IL-6 concentrations were significantly higher (2.20 pg/mL, 95% CI = 1.92�2.47, P < .001) in GDs with SC signal changes. Conclusions and Clinical Importance Lower MCP-1/CCL2 in CSM-affected GDs might compromise clearance of axonal and myelin debris, delay axon regeneration, and affect recovery. Higher IL-6 in CSM-affected GDs with SC signal changes suggests more severe inflammation in this group. PMID:24965833
Martin-Vaquero, P.; da Costa, R.C.; Moore, S.A.; Gross, A.C.; Eubank, T.D.
Decreased cerebrospinal fluid secretogranin II concentrations in severe forms of bipolar disorder
Background Bipolar disorder is a common psychiatric mood disorder that is defined by recurrent episodes of abnormally elevated mood and depression. Progressive structural brain changes in individuals with bipolar disorder have been suggested to be associated with defects in the secretion of neurotrophic factors. We sought to assess how the regulated secretory pathway in the brain is affected in patients with bipolar disorder by measuring chromogranin B and secretogranin II, which are 2 cerebrospinal fluid (CSF) biological markers for this process. Methods We measured the concentrations of chromogranin B (peptide 439�451) and secretogranin II (peptide 154�165) in the CSF of patients with well-defined bipolar disorder and healthy controls. The lifetime severity of bipolar disorder was rated using the Clinical Global Impression (CGI) scale. Results We included 126 patients with bipolar disorder and 71 healthy controls in our analysis. Concentrations of secretogranin II were significantly lower in patients with bipolar disorder type I than in healthy controls. The reduction was most pronounced in patients with high CGI scores (i.e., severe disease). Limitations The cross-sectional design of the current study limits the ability to pinpoint the causalities behind the observed associations. Conclusion This study shows that the CSF marker secretogranin II has the potential to act as a biological marker for severe forms of bipolar disorder. Our findings indicate that patients with bipolar disorder possess defects in the regulatory secretory pathway, which may be of relevance to the progressive structural brain changes seen in those with severe forms of the disease. PMID:23415276
Jakobsson, Joel; Stridsberg, Mats; Zetterberg, Henrik; Blennow, Kaj; Ekman, Carl-Johan; Johansson, Anette G.M.; Sellgren, Carl; Landen, Mikael
Two investigational compounds (FRM-1, (R)-7-fluoro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and FRM-2, (R)-7-cyano-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide) resided in rat brain longer than in systemic circulation. In Caco-2 directional transport studies, they both showed good intrinsic passive permeability but differed significantly in efflux susceptibility (efflux ratio of <2 and ?7, respectively), largely attributed to P-glycoprotein (P-gp). Capitalizing on these interesting properties, we investigated how cerebrospinal fluid (CSF) concentration (CCSF) would be shaped by unbound plasma concentration (Cu,p) and unbound brain concentration (Cu,b) in disequilibrium conditions and at steady state. Following subcutaneous administration, FRM-1CCSF largely followed Cu,p initially and leveled between Cu,p and Cu,b. However, it gradually approached Cu,b and became lower than, but parallel to Cu,b at the terminal phase. In contrast, FRM-2CCSF temporal profile mostly paralleled the Cu,p but was at a much lower level. Upon intravenous infusion to steady state, FRM-1CCSF and Cu,b were similar, accounting for 61% and 69% of the Cu,p, indicating a case of largely passive diffusion-governed brain penetration where CCSF served as a good surrogate for Cu,b. On the contrary, FRM-2CCSF and Cu,b were remarkably lower than Cu,p (17% and 8% of Cu,p, respectively), suggesting that FRM-2 brain penetration was severely impaired by P-gp-mediated efflux and CCSF underestimated this impact. A semi-physiologically based pharmacokinetic (PBPK) model was constructed that adequately described the temporal profiles of the compounds in the plasma, brain and CSF. Our work provided some insight into the relative importance of blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) in modulating CCSF. PMID:25091561
Tang, Cuyue; Chen, Ting; Kapadnis, Sudarshan; Hodgdon, Hilliary; Tao, Yi; Chen, Xing; Wen, Melody; Costa, Don; Murphy, Deirdre; Nolan, Scott; Flood, Dorothy G; Welty, Devin F; Koenig, Gerhard
Active removal of inorganic phosphate from cerebrospinal fluid by the choroid plexus.
The P(i) concentration of mammalian cerebrospinal fluid (CSF) is about one-half that of plasma, a phenomenon also shown here in the spiny dogfish, Squalus acanthias. The objective of the present study was to characterize the possible role of the choroid plexus (CP) in determining CSF P(i) concentration. The large sheet-like fourth CP of the shark was mounted in Ussing chambers where unidirectional (33)P(i) fluxes revealed potent active transport from CSF to the blood side under short-circuited conditions. The flux ratio was 8:1 with an average transepithelial resistance of 87 � 17.9 ?�cm(2) and electrical potential difference of +0.9 � 0.17 mV (CSF side positive). Active P(i) absorption from CSF was inhibited by 10 mM arsenate, 0.2 mM ouabain, Na(+)-free medium, and increasing the K(+) concentration from 5 to 100 mM. Li(+) stimulated transport twofold compared with Na(+)-free medium. Phosphonoformic acid (1 mM) had no effect on active P(i) transport. RT-PCR revealed both P(i) transporter (PiT)1 and PiT2 (SLC20 family) gene expression, but no Na(+)-P(i) cotransporter II (SLC34 family) expression, in the shark CP. PiT2 immunoreactivity was shown by immunoblot analysis and localized by immunohistochemistry in (or near) the CP apical microvillar membranes of both the shark and rat. PiT1 appeared to be localized primarily to vascular endothelial cells. Taken together, these data indicate that the CP actively removes P(i) from CSF. This process has transport properties consistent with a PiT2, Na(+)-dependent transporter that is located in the apical region of the CP epithelium. PMID:24740787
Guerreiro, Pedro M; Bataille, Amy M; Parker, Sonda L; Renfro, J Larry
Intracranial pressure pulse waveform correlates with aqueductal cerebrospinal fluid stroke volume.
This study identifies a novel relationship between cerebrospinal fluid (CSF) stroke volume through the cerebral aqueduct and the characteristic peaks of the intracranial pulse (ICP) waveform. ICP waveform analysis has become much more advanced in recent years; however, clinical practice remains restricted to mean ICP, mainly due to the lack of physiological understanding of the ICP waveform. Therefore, the present study set out to shed some light on the physiological meaning of ICP morphological metrics derived by the morphological clustering and analysis of continuous intracranial pulse (MOCAIP) algorithm by investigating their relationships with a well defined physiological variable, i.e., the stroke volume of CSF through the cerebral aqueduct. Seven patients received both overnight ICP monitoring along with a phase-contrast MRI (PC-MRI) of the cerebral aqueduct to quantify aqueductal stroke volume (ASV). Waveform morphological analysis of the ICP signal was performed by the MOCAIP algorithm. Following extraction of morphological metrics from the ICP signal, nine temporal ICP metrics and two amplitude-based metrics were compared with the ASV via Spearman's rank correlation. Of the nine temporal metrics correlated with the ASV, only the width of the P2 region (ICP-Wi2) reached significance. Furthermore, both ICP pulse pressure amplitude and mean ICP did not reach significance. In this study, we showed the width of the second peak (ICP-Wi2) of an ICP pulse wave is positively related to the volume of CSF movement through the cerebral aqueduct. This finding is an initial step in bridging the gap between ICP waveform morphology research and clinical practice. PMID:22995390
Hamilton, Robert; Baldwin, Kevin; Fuller, Jennifer; Vespa, Paul; Hu, Xiao; Bergsneider, Marvin
miRNA Expression Profiles in Cerebrospinal Fluid and Blood of Patients with Acute Ischemic Stroke.
The aims of the study were (1) to determine whether miRNAs (microRNAs) can be detected in the cerebrospinal fluid (CSF) and blood of patients with ischemic stroke and (2) to compare these miRNA profiles with corresponding profiles from other neurological patients to address whether the miRNA profiles of CSF or blood have potential usefulness as diagnostic biomarkers of ischemic stroke. CSF from patients with acute ischemic stroke (n?=?10) and patients with other neurological diseases (n?=?10) was collected by lumbar puncture. Blood samples were taken immediately after. Expression profiles in the cell-free fractions of CSF and blood were analyzed by a microarray technique (miRCURY LNA� microRNA Array, Exiqon A/S, Denmark) using a quantitative PCR (qPCR) platform containing 378 miRNA primers. In total, 183 different miRNAs were detected in the CSF, of which two miRNAs (let-7c and miR-221-3p) were found upregulated in relation to stroke. In the blood, 287 different miRNAs were detected of which two miRNAs (miR-151a-3p and miR-140-5p) were found upregulated and one miRNA (miR-18b-5p) was found downregulated in the stroke group. Some miRNAs occurred exclusively in the CSF including miR-523-3p which was detected in 50�% of the stroke patients, whereas it was completely absent in controls. Our preliminary results demonstrate that it is possible to detect and profile miRNAs in CSF and blood from patients with neurological diseases. Some miRNAs appear differentially expressed in the CSF and others in the blood of stroke patients. Currently, we are validating our results in larger groups of patients. PMID:25127724
S�rensen, Sofie S�lvsten; Nygaard, Ann-Britt; Nielsen, Ming-Yuan; Jensen, Kai; Christensen, Thomas
Stasis Theory and Paleontology Discourse
ERIC Educational Resources Information Center
Stasis theory is a powerful tool for rhetorical analysis, recently under fresh consideration by rhetorical theorists (e.g. Gross) and scholars who identify its utility in the writing classroom (e.g. Carroll). In this study, the author applies stasis theory to a paleontological argument involving a controversial fossil, "Protoavis texensis."�
Northcut, Kathryn M.
L-serine-O-phosphate (L-SOP), the precursor of L-serine, is a potent agonist against the group III metabotropic glutamate receptors (mGluRs) and, thus, is of interest as a potential biomarker for monitoring modulation of neurotransmitter release. So far, no reports are available on the analysis of L-SOP in cerebrospinal fluid (CSF). Here a novel method is presented to determine L-SOP levels in CSF employing precolumn derivatization with (5-N-succinimidoxy-5-oxopentyl)triphenylphosphonium bromide (SPTPP) coupled to liquid chromatography/mass spectrometry (derivatization-LC/MS, d-LC/MS). PMID:24534252
McNaney, Colleen A; Benitex, Yulia; Luchetti, David; Labasi, Jeffrey M; Olah, Timothy V; Morgan, Daniel G; Drexler, Dieter M
Background��Brain plasticity in patients with periventricular leukomalacia (PVL) may suggest grey matter (GM) changes.\\u000a \\u000a \\u000a \\u000a Objective��To assess the volume of 116 GM areas and total volume of GM, white matter (WM) and cerebrospinal fluid (CSF) in preterm children\\u000a with PVL, using the Statistical Parametric Mapping (SPM5) and the Individual Brain Atlases Statistical Parametric Mapping\\u000a (IBASPM) toolboxes.\\u000a \\u000a \\u000a \\u000a Materials and methods��Ten preterm children
Loukia C. Tzarouchi; Loukas G. Astrakas; Anastasia Zikou; Vassilios Xydis; Paraskevi Kosta; Styliani Andronikou; Maria I. Argyropoulou
Purpose To examine characteristics of ocular hypertensive subjects and potential associations with estimated cerebrospinal fluid pressure (estCSFP). Methods The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6�9.8 years. Ocular hypertension was defined as intraocular pressure (IOP) >21 mmHg, normal optic nerve head appearance and normal retinal nerve fiber layer thickness. IOP was corrected for its dependence on central corneal thickness (CCT) and corneal curvature radius. Estimated CSFP was calculated as CSFP [mmHg]?=?0.44�Body Mass Index [kg/m2]+0.16�Diastolic Blood Pressure [mmHg]?0.18�Age [Years]?1.91. Estimated trans-lamina cribrosa pressure difference (estTLCPD) was IOP�estCSFP. Results EstCSFP (10.5�3.6 mmHg versus 9.0�3.7 mmHg; P?=?0.003) and estTLCPD (12.0�4.4 mmHg versus 5.4�3.8 mmHg; P<0.001) were higher in the ocular hypertensive group than in the normotensive group. In binary regression analysis, ocular hypertension was associated with increased estCSFP (P?=?0.03; odds ratio (OR): 1.08; 95% confidence interval (CI): 1.01, 1.17) after adjusting for prevalence of arterial hypertension (P?=?0.07; OR: 1.79; 95%CI: 0.96, 3.34), retinal nerve fiber layer thickness (P?=?0.03; OR: 0.97; 95%CI: 0.95, 0.997) and blood glucose concentration (P?=?0.006; OR: 1.17; 95%CI: 1.04, 1.30). Conclusions Ocular hypertensive subjects (with IOP correction for CCT and corneal curvature) as compared to ocular normotensive subjects had a significantly higher estCSFP in univariate analysis and in multivariate analysis. Despite of a higher estCSFP, estTLCPD was still markedly higher in ocular hypertensive eyes than in ocular normotensive eyes. PMID:24988292
You, Qi Sheng; Yang, Diya; Xu, Liang
Changes in oxidative damage, inflammation and [NAD(H)] with age in cerebrospinal fluid.
An extensive body of evidence indicates that oxidative stress and inflammation play a central role in the degenerative changes of systemic tissues in aging. However a comparatively limited amount of data is available to verify whether these processes also contribute to normal aging within the brain. High levels of oxidative damage results in key cellular changes including a reduction in available nicotinamide adenine dinucleotide (NAD(+)), an essential molecule required for a number of vital cellular processes including DNA repair, immune signaling and epigenetic processing. In this study we quantified changes in [NAD(H)] and markers of inflammation and oxidative damage (F2-isoprostanes, 8-OHdG, total antioxidant capacity) in the cerebrospinal fluid (CSF) of healthy humans across a wide age range (24-91 years). CSF was collected from consenting patients who required a spinal tap for the administration of anesthetic. CSF of participants aged >45 years was found to contain increased levels of lipid peroxidation (F2-isoprostanes) (p?=?0.04) and inflammation (IL-6) (p?=?0.00) and decreased levels of both total antioxidant capacity (p?=?0.00) and NAD(H) (p?=?0.05), compared to their younger counterparts. A positive association was also observed between plasma [NAD(H)] and CSF NAD(H) levels (p?=?0.03). Further analysis of the data identified a relationship between alcohol intake and CSF [NAD(H)] and markers of inflammation. The CSF of participants who consumed >1 standard drink of alcohol per day contained lower levels of NAD(H) compared to those who consumed no alcohol (p<0.05). An increase in CSF IL-6 was observed in participants who reported drinking >0-1 (p<0.05) and >1 (p<0.05) standard alcoholic drinks per day compared to those who did not drink alcohol. Taken together these data suggest a progressive age associated increase in oxidative damage, inflammation and reduced [NAD(H)] in the brain which may be exacerbated by alcohol intake. PMID:24454842
Guest, Jade; Grant, Ross; Mori, Trevor A; Croft, Kevin D
Cyclic adenosine 3', 5'-monophosphate in cerebrospinal fluid during thermoregulation and fever.
1. Samples of cerebrospinal fluid (c.s.f.) have been taken from the cisterna magna of unanaesthetized cats, whilst rectal temperature was recorded, during exposure of the animals to various ambient temperatures and during fever induced by pyrogen. The concentration of adenosine 3', 5'-monophosphate (cyclic AMP) in samples of c.s.f. has been assayed. 2. Cats exposed to low ambient temperatures (-2 to +2 degrees C) for 3 h maintained body temperature by both behavioural and autonomic heat gain activity. Exposure of cats to high ambient temperatures (44 - 45 degrees C) for 3.5 h caused a rise in body temperatures of about 2.5 degrees C, despite behavioural and autonomic heat loss activity. Neither cold nor heat stress had a significant effect on c.s.f. cyclic AMP. 3. Fever induced by intravenous Shigella dysenteriae (2 and 20 mug/kg) was associated with a dose-related increase in the concentration of cyclic AMP in c.s.f. Paracetamol (75 mg/kg) injected I.P. before the onset of fever, suppressed the increase in both temperature and c.s.f. cyclic AMP in response to pyrogen. Paracetamol (50 and 100 mg/kg), injected after the onset of fever, caused a fall in temperature, which was not associated with a decrease in the concentration of cyclic AMP in c.s.f. 4. Fever induced in cats by intravenous Shigella dysenteriae (20 mug/kg) was associated with an increase in the concentration of cyclic AMP in plasma as well as in c.s.f. 5. The sodium salt of cyclic AMP (0.1-10 mg/kg) injected I.V. into unanaesthetized cats caused a dose-related hypothermia, which was associated with autonomic heat loss activity and a dose-related increase in the concentration of cyclic AMP in cisternal c.s.f., which was not mimicked by adenosine. 6. It is concluded that the raised concentrations of cyclic AMP in c.s.f., in response to pyrogen I.V., do not mediate fever in the cat and that the concentration of cyclic AMP in cisternal c.s.f. may be affected by changes in the plasma concentration of the nucleotide. PMID:190383
Dascombe, M J; Milton, A S
The cerebrospinal fluid proteome in HIV infection: change associated with disease severity
Background Central nervous system (CNS) infection is a nearly universal feature of untreated systemic HIV infection with a clinical spectrum that ranges from chronic asymptomatic infection to severe cognitive and motor dysfunction. Analysis of cerebrospinal fluid (CSF) has played an important part in defining the character of this evolving infection and response to treatment. To further characterize CNS HIV infection and its effects, we applied advanced high-throughput proteomic methods to CSF to identify novel proteins and their changes with disease progression and treatment. Results After establishing an accurate mass and time (AMT) tag database containing 23,141 AMT tags for CSF peptides, we analyzed 91 CSF samples by LC-MS from 12 HIV-uninfected and 14 HIV-infected subjects studied in the context of initiation of antiretroviral therapy and correlated abundances of identified proteins a) within and between subjects, b) with all other proteins across the entire sample set, and c) with "external" CSF biomarkers of infection (HIV RNA), immune activation (neopterin) and neural injury (neurofilament light chain protein, NFL). We identified a mean of 2,333 +/- 328 (SD) peptides covering 307 +/-16 proteins in the 91 CSF sample set. Protein abundances differed both between and within subjects sampled at different time points and readily separated those with and without HIV infection. Proteins also showed inter-correlations across the sample set that were associated with biologically relevant dynamic processes. One-hundred and fifty proteins showed correlations with the external biomarkers. For example, using a threshold of cross correlation coefficient (Pearson's) ? -0.3 and ?0.3 for potentially meaningful relationships, a total of 99 proteins correlated with CSF neopterin (43 negative and 56 positive correlations) and related principally to neuronal plasticity and survival and to innate immunity. Pathway analysis defined several networks connecting the identified proteins, including one with amyloid precursor protein as a central node. Conclusions Advanced CSF proteomic analysis enabled the identification of an array of novel protein changes across the spectrum of CNS HIV infection and disease. This initial analysis clearly demonstrated the value of contemporary state-of-the-art proteomic CSF analysis as a discovery tool in HIV infection with likely similar application to other neurological inflammatory and degenerative diseases. PMID:22433316
Cerebrospinal Fluid Biomarker and Brain Biopsy Findings in Idiopathic Normal Pressure Hydrocephalus
Background The significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown. Objective To investigate the role of soluble APP (sAPP) and amyloid beta (A?) isoforms, proinflammatory cytokines, and biomarkers of neuronal damage in the cerebrospinal fluid (CSF) in relation to brain biopsy A? and hyperphosphorylated tau (HP?) findings. Methods The study population comprised 102 patients with possible NPH with cortical brain biopsies, ventricular and lumbar CSF samples, and DNA available. The final clinical diagnoses were: 53 iNPH (91% shunt-responders), 26 AD (10 mixed iNPH+AD), and 23 others. Biopsy samples were immunostained against A? and HP?. CSF levels of AD-related biomarkers (A?42, p-tau, total tau), non-AD-related A? isoforms (A?38, A?40), sAPP isoforms (sAPP?, sAPP?), proinflammatory cytokines (several interleukins (IL), interferon-gamma, monocyte chemoattractant protein-1, tumor necrosis factor-alpha) and biomarkers of neuronal damage (neurofilament light and myelin basic protein) were measured. All patients were genotyped for APOE. Results Lumbar CSF levels of sAPP? were lower (p<0.05) in patients with shunt-responsive iNPH compared to non-iNPH patients. sAPP? showed a similar trend (p?=?0.06). CSF sAPP isoform levels showed no association to A? or HP? in the brain biopsy. Quantified A? load in the brain biopsy showed a negative correlation with CSF levels of A?42 in ventricular (r?=??0.295, p?=?0.003) and lumbar (r?=??0.356, p?=?0.01) samples, while the levels of A?38 and A?40 showed no correlation. CSF levels of proinflammatory cytokines and biomarkers of neuronal damage did not associate to the brain biopsy findings, diagnosis, or shunt response. Higher lumbar/ventricular CSF IL-8 ratios (p<0.001) were seen in lumbar samples collected after ventriculostomy compared to the samples collected before the procedure. Conclusions The role of sAPP isoforms in iNPH seems to be independent from the amyloid cascade. No neuroinflammatory background was observed in iNPH or AD. PMID:24638077
Pyykko, Okko T.; Lumela, Miikka; Rummukainen, Jaana; Nerg, Ossi; Seppala, Toni T.; Herukka, Sanna-Kaisa; Koivisto, Anne M.; Alafuzoff, Irina; Puli, Lakshman; Savolainen, Sakari; Soininen, Hilkka; Jaaskelainen, Juha E.; Hiltunen, Mikko; Zetterberg, Henrik; Leinonen, Ville
Diet Intervention and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment
Objective To compare the effects of a 4-week high�saturated fat/high�glycemic index (HIGH) diet with a low�saturated fat/low�glycemic index (LOW) diet on insulin and lipid metabolism, cerebrospinal fluid (CSF) markers of Alzheimer disease, and cognition for healthy adults and adults with amnestic mild cognitive impairment (aMCI). Design Randomized controlled trial. Setting Veterans Affairs Medical Center clinical research unit. Participants Forty-nine older adults (20 healthy adults with a mean [SD] age of 69.3 [7.4] years and 29 adults with aMCI with a mean [SD] age of 67.6 [6.8] years). Intervention Participants received the HIGH diet (fat, 45% [saturated fat, >25%]; carbohydrates, 35%�40% [glycemic index, >70]; and protein, 15%�20%) or the LOW diet (fat, 25%; [saturated fat, <7%]; carbohydrates, 55%�60% [glycemic index, <5]; and protein, 15%�20%) for 4 weeks. Cognitive tests, an oral glucose tolerance test, and lumbar puncture were conducted at baseline and during the fourth week of the diet. Main Outcome Measures The CSF concentrations of ?-amyloid (A?42 and A?40), tau protein, insulin, F2-isoprostanes, and apolipoprotein E, plasma lipids and insulin, and measures of cognition. Results For the aMCI group, the LOW diet increased CSF A?42 concentrations, contrary to the pathologic pattern of lowered CSF A?42 typically observed in Alzheimer disease. The LOW diet had the opposite effect for healthy adults, ie, decreasing CSF A?42, whereas the HIGH diet increased CSF A?42. The CSF apolipoprotein E concentration was increased by the LOW diet and decreased by the HIGH diet for both groups. For the aMCI group, the CSF insulin concentration increased with the LOW diet, but the HIGH diet lowered the CSF insulin concentration for healthy adults. The HIGH diet increased and the LOW diet decreased plasma lipids, insulin, and CSF F2-isoprostane concentrations. Delayed visual memory improved for both groups after completion of 4 weeks of the LOW diet. Conclusion Our results suggest that diet may be a powerful environmental factor that modulates Alzheimer disease risk through its effects on central nervous system concentrations of A?42, lipoproteins, oxidative stress, and insulin. PMID:21670398
Bayer-Carter, Jennifer L.; Green, Pattie S.; Montine, Thomas J.; VanFossen, Brian; Baker, Laura D.; Watson, G. Stennis; Bonner, Laura M.; Callaghan, Maureen; Leverenz, James B.; Walter, Brooke K.; Tsai, Elaine; Plymate, Stephen R.; Postupna, Nadia; Wilkinson, Charles W.; Zhang, Jing; Lampe, Johanna; Kahn, Steven E.; Craft, Suzanne
The cerebrospinal fluid proteome in HIV infection: change associated with disease severity.
Central nervous system (CNS) infection is a constant feature of systemic HIV infection with a clinical spectrum that ranges from chronic asymptomatic infection to severe cognitive and motor dysfunction. Analysis of cerebrospinal fluid (CSF) has played an important part in defining the character of this evolving infection and response to treatment. To further characterize CNS HIV infection and its effects, we applied advanced high-throughput proteomic methods to CSF to identify novel proteins and their changes with disease progression and treatment. After establishing an accurate mass and time (AMT) tag database containing 23,141 AMT tags for CSF peptides, we analyzed 91 CSF samples by LC-MS from 12 HIV-uninfected and 14 HIV-infected subjects studied in the context of initiation of antiretroviral and correlated abundances of identified proteins (a) within and between subjects, (b) with all other proteins across the entire sample set, and (c) with 'external' CSF biomarkers of infection (HIV RNA), immune activation (neopterin) and neural injury (neurofilament light chain protein, NFL). We identified a mean of 2,333 +/- 328 (SD) peptides covering 307 +/-16 proteins in the 91 CSF sample set. Protein abundances differed both between and within subjects sampled at different time points and readily separated those with and without HIV infection. Proteins also showed inter-correlations across the sample set that were associated with biologically relevant dynamic processes. One-hundred and fifty proteins showed correlations with the external biomarkers. For example, using a threshold of cross correlation coefficient (Pearson's) {le}0.3 and {ge}0.3 for potentially meaningful relationships, a total of 99 proteins correlated with CSF neopterin (43 negative and 56 positive correlations) and related principally to neuronal plasticity and survival and to innate immunity. Pathway analysis defined several networks connecting the identified proteins, including one with amyloid precursor protein as a central node. Advanced CSF proteomic analysis enabled the identification of an array of novel protein changes across the spectrum of CNS HIV infection and disease. This initial analysis clearly demonstrated the value of contemporary state-of-the-art proteomic CSF analysis as a discovery tool in HIV infection with likely similar application to other neurological inflammatory and degenerative diseases.
Angel, Thomas E.; Jacobs, Jon M.; Spudich, Serena S.; Gritsenko, Marina A.; Fuchs, Dietmar; Liegler, Teri; Zetterberg, Henrik; Camp, David G.; Price, Richard W.; Smith, Richard D.
With the increase of human lifespan and refinement of diagnostic techniques dementia, and Alzheimer's disease (AD) in particular, have become a multi-decade process with a complex pathogenesis. The prognosis of AD patients, especially in late stages, may be strongly influenced by factors that go far beyond the well-recognized cascades (tau deposition, amyloid plaques). In this context, AD and Frailty, a multidimensional process of the elderly, inevitably overlap. Not surprisingly, the routine biomarkers collectable in the cerebrospinal fluid, while highly relevant in allowing specific diagnoses, becoming limiting when used to define severity and rate of progression of cognitive impairment. In reviewing merits and pitfalls of routine cerebrospinal fluid profile for AD, this manuscript will examine the state-of-the-art related to a parallel field, the extrapyramidal disorders. For synucleinopathies, we will discuss the possibility to detect factors directly involved in earliest disease pathology (alpha-synuclein, tau-proteins) together with indexes of disease progression (i.e. dopamine-metabolite ratio and loss of blood-brain barrier integrity). This approach might guarantee the capability of monitoring putative disease-modifying strategies. However, we will show the likelihood that nonconventional approaches already proposed for Frail subjects (such as exercise-mediated neuro-protection) might prove to be a useful aid for an ageing brain already impaired by AD alterations. A crucial test for these hypotheses would be to apply this sort of interventional, and not merely pharmacological, therapy to homogeneous patient cohorts. PMID:23574170
Stefani, Alessandro; Olivola, Enrica; Stampanoni Bassi, Mario; Pisani, Valerio; Imbriani, Paola; Pisani, Antonio; Pierantozzi, Mariangela
The present investigation was undertaken to find out whether whole-body hyperthermia (WBH) alters blood-cerebrospinal fluid barrier (BCSFB) permeability to exogenously-administered tracers and whether choroid plexus and ependymal cells exhibit morphological alterations in hyperthermia. Rats subjected to 4 hours of heat stress at 38 degrees C in a biological oxygen demand (BOD) incubator exhibited a profound increase in the BCSFB to Evans blue and radioiodine. Blue staining of the dorsal surface of the hippocampus and caudate nucleus and a significant increase in Evans blue and [131]Iodine in cisternal cerebrospinal fluid were seen following 4-hour heat stress compared to control. Degeneration of choroidal epithelial cells and underlying ependyma, a dilated ventricular space, and degenerative changes in the underlying neuropil were frequent. Hippocampus, caudate nucleus, thalamus, and hypothalamus exhibited profound increases in water content after 4 hours of heat stress. These observations suggest that hyperthermia induced by WBH is capable of breaking down the BCSFB and contributing to cell and tissue injury in the central nervous system. PMID:16671499
Sharma, H S; Duncan, J A; Johanson, C E
To determine the effects of sepsis on cerebral energy metabolism, the cerebrospinal fluid adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, hypoxanthine, xanthine, and urate concentrations were determined by high-performance liquid chromatography and the neuron-specific enolase levels by means of an enzyme immunoassay method in 32 children with sepsis, without meningitis, aged between 2 months and 13 years, and in 160 age-matched controls. The septic group had significantly higher cerebrospinal fluid concentrations of inosine, adenosine, xanthine, and urate than controls. These results suggest that sepsis could provoke some degree of neuronal hypoxia and significant alterations of cerebral energy metabolism homeostasis. PMID:11575617
Rodr�guez-N��ez, A; Cid, E; Rodr�guez-Garc�a, J; Cami�a, F; Rodr�guez-Segade, S; Castro-Gago, M
Oropouche fever is the second most frequent arboviral infection in Brazil, surpassed only by dengue. Oropouche virus (OROV) causes large and explosive outbreaks of acute febrile illness in cities and villages in the Amazon and Central-Plateau regions. Cerebrospinal fluid (CSF) samples from 110 meningoencephalitis patients were analyzed. The RNA extracted from fluid was submitted to reverse transcription-polymerase chain reaction and sequencing to identify OROV. Three CSF samples showed the presence of OROV causing infection in the central nervous system (CNS). These patients are adults. Two of the patients had other diseases affecting CNS and immune systems: neurocysticercosis and acquired immunodeficiency syndrome, respectively. Nucleotide sequence analysis showed that the OROV from the CSF of these patients belonged to genotype I. We show here that severe Oropouche disease is occurring during outbreaks of this virus in Brazil PMID:22492162
Bastos, Michele de Souza; Figueiredo, Luiz Tadeu Moraes; Naveca, Felipe Gomes; Monte, Rossicleia Lins; Lessa, Natalia; Pinto de Figueiredo, Regina Maria; Gimaque, Joao Bosco de Lima; Pivoto Joao, Guilherme; Ramasawmy, Rajendranath; Mourao, Maria Paula Gomes
Chemerin is a chemoattractant involved in immunity that may also function as an adipokine. Chemerin circulates as an inactive precursor (chem163S), and its activation requires proteolytic cleavages at its C terminus, involving proteases involved in coagulation, fibrinolysis, and inflammation. However, the key proteolytic steps in prochemerin activation in vivo remain to be established. Previously, we have shown that C-terminal cleavage of chem163S by plasmin to chem158K, followed by a carboxypeptidase cleavage, leads to the most active isoform, chem157S. To identify and quantify the in vivo chemerin isoforms in biological specimens, we developed specific ELISAs for chem163S, chem158K, and chem157S, using antibodies raised against peptides from the C terminus of the different chemerin isoforms. We found that the mean plasma concentrations of chem163S, chem158K, and chem157S were 40 � 7.9, 8.1 � 2.9, and 0.7 � 0.8 ng/ml, respectively. The total level of cleaved and noncleaved chemerins in cerebrospinal fluids was ?10% of plasma levels whereas it was elevated ?2-fold in synovial fluids from patients with arthritis. On the other hand, the fraction of cleaved chemerins was much higher in synovial fluid and cerebrospinal fluid samples than in plasma (?75%, 50%, and 18% respectively). Chem158K was the dominant chemerin isoform, and it was not generated by ex vivo processing, indicating that cleavage of prochemerin at position Lys-158, whether by plasmin or another serine protease, represents a major step in prochemerin activation in vivo. Our study provides the first direct evidence that chemerin undergoes extensive proteolytic processing in vivo, underlining the importance of measuring individual isoforms. PMID:21930706
Zhao, Lei; Yamaguchi, Yasuto; Sharif, Shadi; Du, Xiao-Yan; Song, Jason J.; Lee, David M.; Recht, Lawrence D.; Robinson, William H.; Morser, John; Leung, Lawrence L. K.
Background It has been shown that distal cerebrospinal fluid-contacting neurons (dCSF-CNs) exist near the ventral midline of the midbrain aqueduct and also in the grey matter of the inferior third ventricle and the fourth ventricle floor in the superior segment of the pons. The dCSF-CNs communicate between the cerebrospinal fluid (CSF) and the brain parenchyma and may participate in the transduction and regulation of pain signals. The cold sensation receptor channel, TRPM8 is involved in analgesia for neuropathic pain, but whether the TRPM8 receptor exists on dCSF-CNs remains unknown. However, there is preliminary evidence that TRPM8 is expressed in dCSF-CNs and may participate in the transmission and regulation of sensory information between brain parenchyma and cerebrospinal fluid (CSF) in rats. Methods Retrograde tracing of the cholera toxin subunit B labeled with horseradish peroxidase (CB-HRP) injected into the lateral ventricle was used to identify dCSF-CNs. A double-labeled immunofluorescent technique and laser scanning confocal microscopy were used to identify the expression of TRPM8 in dCSF-CNs. Software Image-Pro Plus was used to count the number of neurons in three sections where CB-HRP positive neurons were located in the mesencephalon of six rats. Results The cell bodies of CB-HRP-positive dCSF-CNs were found in the brain parenchyma near the midline of the ventral Aq, also in the grey of the 3V, and the 4V floor in the superior segment of the pons. In the mesencephalon their processes extended into the CSF. TRPM8 labeled neurons were also found in the same area as were CB-HRP/TRPM8 double-labeled neurons. CB-HRP/TRPM8 double-labeled neurons were found in 42.9 � 2.3% of neurons labeled by TRPM8, and all CB-HRP-labeled neurons were also labeled with TPRM8. Conclusion This study has demonstrated that the cold sensation receptor channel, TRPM8, is localised within the dCSF-CNs of the mesencephalon. TRPM8 acts as receptor of dCSF-CNs for sensation transmission and pain regulation. PMID:19292918
Du, Jing; Yang, Xinwei; Zhang, Licai; Zeng, Yin-ming
Borrelia burgdorferi antibodies preferentially present in cerebrospinal fluid (CSF) were examined by differ- entially probing a B. burgdorferi expression library with CSF and sera from patients with neurologic Lyme disease. Several phage clones selectively reacted with CSF, and these genes were then expressed in recombinant form and used to detect specific antibody in an enzyme-linked immunosorbent assay. Decorin-binding protein B
Erol Fikrig; Patricia K. Coyle; Steven E. Schutzer; Manchuan Chen; Zhidian Deng; Richard A. Flavell
Cerebrospinal fluid (CSF) is routinely used for diagnosing and monitoring neurological diseases. The CSF proteins used so far for diagnostic purposes (except for those associ- ated with whole cells) are soluble. Here, we show that human CSF contains specific membrane particles that carry promi- nin-1\\/CD133, a neural stem cell marker implicated in brain tumors, notably glioblastoma. Differential and equilibrium centrifugation
Hagen B. Huttner; Peggy Janich; Martin K�hrmann; J�zsef J�szai; Florian Siebzehnrubl; Ingmar Bl�mcke; Meinolf Suttorp; Manfred Gahr; Daniela Kuhnt; Christopher Nimsky; Dietmar Krex; Gabriele Schackert; Kai L�wenbr�ck; Heinz Reichmann; Eric J�ttler; Werner Hacke; Peter D. Schellinger; Stefan Schwab; Michaela Wilsch-Br�uninger; Anne-Marie Marzesco; Denis Corbeil
Cerebrospinal fluid (CSF) biomarkers play an important role in the differential diagnosis of neurodegenerative diseases such as Alzheimer�s disease (AD) and its postulated precursor stage mild cognitive impairment (MCI). While CSF tau protein, phospho-tau protein and ?-amyloid have become part of the diagnostic process in clinical routine, the importance of several other biomarkers remains quite unclear. Among these, amino acids
Elmar Kaiser; Peter Schoenknecht; Stefan Kassner; Wulf Hildebrandt; Ralf Kinscherf; Johannes Schroeder
Leptomeningeal metastasis (LM) is a devastating complication that occurs in 5% of patients with breast cancer. Early diagnosis and initiation of treatment are essential to prevent neurological deterioration. However, early diagnosis of LM remains challenging because 25% of cerebrospinal fluid (CSF) samples produce false-negative results at first cytological examination. We developed a new, MS-based method to investigate the protein expression
Lennard J. Dekker; Willem Boogerd; Guenther Stockhammer; Johannes C. Dalebout; Ivar Siccama; Pingpin Zheng; Johannes M. Bonfrer; Jan J. Verschuuren; Guido Jenster; Marcel M. Verbeek; Theo M. Luider; Peter A. Sillevis Smitt
A new, rapid, and simple method for the isolation of either RNA or DNA from cerebrospinal fluid samples for subsequent amplification by specific polymerase chain reaction (PCR) assays is described. The technique involves a single extraction with a guanidinium thiocyanate acid (GuSCN) buffer, and does not require the use of organic solvents. Applied to the recovery of enteroviral RNA, herpes
I. Casas; L. Powell; P. E. Klapper; G. M. Cleator
Probenecid was administered to 17 depressed, 19 manic and 15 control patients and further to 11 healthy volunteers. Before and after the administration the levels of 5-hydroxyindoleacetic acid (5-HIAA) were determined in cerebrospinal fluid (CSF). In six of the depressed, seven of the manic and seven of the patients from the group of controls and volunteers also homovanillic acid (HVA)
B. E. Roos; R. Sj�str�m
Introduction Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by degeneration of motoneuron cells in anterior spinal horns. There is a need for early and accurate diagnosis with this condition. In this case report we used two complementary methods: scanning electron microscopy and fluorescence-activated cell sorting. This is the first report to our knowledge of microparticles in the cerebrospinal fluid of a patient with amyotrophic lateral sclerosis. Case presentation An 80-year-old Swedish man of Caucasian ethnicity presented to our facility with symptoms of amyotrophic lateral sclerosis starting a year before his first hospital examination, such as muscle weakness and twitching in his right hand progressing to arms, body and leg muscles. Electromyography showed classical neurophysiological findings of amyotrophic lateral sclerosis. Routine blood sample results were normal. A lumbar puncture was performed as a routine investigation and his cerebrospinal fluid was normal with regard to cell count and protein levels, and there were no signs of inflammation. However, scanning electron microscopy and fluorescence-activated cell sorting showed pronounced abnormalities compared to healthy controls. Flow cytometry analysis of two fractions of cerebrospinal fluid from our patient with amyotrophic lateral sclerosis was used to measure the specific binding of antibodies to CD42a, CD144 and CD45, and of phosphatidylserine to lactadherin. Our patient displayed over 100 times more phosphatidylserine-positive microparticles and over 400 times more cell-derived microparticles of leukocyte origin in his cerebrospinal fluid compared to healthy control subjects. The first cerebrospinal fluid fraction contained about 50% more microparticles than the second fraction. The scanning electron microscopy filters used with cerebrospinal fluid from our patient were filled with compact aggregates of spherical particles of lipid appearance, sticking together in a viscous batter. The quantitative increase in scanning electron microscopy findings corresponded to the flow cytometry result of an increase in leukocyte-derived microparticles. Conclusions Microparticles represent subcellular arrangements that can influence the pathogenesis of amyotrophic lateral sclerosis and may serve as biomarkers for underlying cellular disturbances. The increased number of leukocyte-derived microparticles with normal cell counts in cerebrospinal fluid may contribute to the amyotrophic lateral sclerosis inflammatory process by formation of immune complexes of prion-like propagation, possibly due to misfolded proteins. The two complementary methods used in this report may be additional tools for revealing the etiology of amyotrophic lateral sclerosis, for early diagnostic purposes and for evaluation of clinical trials, long-term follow-up studies and elucidating the pathophysiology in amyotrophic lateral sclerosis. PMID:22943439
A simple, accurate and rapid method for simultaneous analysis of vancomycin and ceftazidime in cerebrospinal fluid (CSF), utilizing high-performance liquid chromatography (HPLC), has been developed and thoroughly validated to satisfy strict FDA guidelines for bioanalytical methods. Protein precipitation was used as the sample pretreatment method. In order to increase the accuracy, tinidazole was chosen as the internal standard. Separation was achieved on a Diamonsil C18 column (200 mm x 4.6mm I.D., 5 microm) using a mobile phase composed of acetonitrile and acetate buffer (pH 3.5) (8:92, v/v) at room temperature (25 degrees C), and the detection wavelength was 240 nm. All the validation data, such as accuracy, precision, and inter-day repeatability, were within the required limits. The method was applied to determine vancomycin and ceftazidime concentrations in CSF in five craniotomy patients. PMID:18657374
Ye, Guangming; Cai, Xuejian; Wang, Biao; Zhou, Zhongxian; Yu, Xiaohua; Wang, Weibin; Zhang, Jiandong; Wang, Yuhai; Dong, Jierong; Jiang, Yunyun
We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV-1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system. PMID:24338353
Dahl, Viktor; Gisslen, Magnus; Hagberg, Lars; Peterson, Julia; Shao, Wei; Spudich, Serena; Price, Richard W; Palmer, Sarah
A total of 525 cerebrospinal fluid (CSF) samples submitted during the 2007 and 2008 enteroviral seasons were included in a study to determine the prevalence of and potential risk factors for invalid Cepheid GeneXpert enterovirus assay (GXEA) results, as well as possible solutions for the problem. The invalid GXEA results were reported for 43 (8.2%) specimens and correlated with increased visibility of red blood cells (P < 0.0001) but not with CSF xanthochromia and clotting. Invalid GXEA result rates were markedly diminished by 82.1% and 96.0% and test sensitivities were minimally decreased by 1.7% and 3.6% when these specimens were tested at a 1:5 dilution and after a freeze-thaw cycle, respectively. PMID:19605580
Sefers, Susan E.; Raymer, Anna K.; Kilby, Jessica T.; Persing, David H.; Tang, Yi-Wei
We report a patient who developed delayed cerebrospinal fluid (CSF) rhinorrhea 11 years after gamma knife radiosurgery for a growth hormone (GH)-secreting adenoma. The treatment dose was 18 Gy for the tumor margin (50% isodose). One year later, an MRI of the head revealed that the tumor size had decreased. Eleven years later, the patient developed CSF rhinorrhea from the left nostril. Subsequent MRI examination revealed complete remission of the tumor in the sella turcica and the empty sella. The patient was admitted for direct endoscopic surgical repair of the skull base. We suggest that the cause of the CSF rhinorrhea is secondary empty sella. The other potential causes may be the original invasiveness of the tumor or delayed radiation damage to the mucous membranes of the skull. Long-term follow-up is required to monitor recurrence of CSF rhinorrhea. PMID:22349430
Hongmei, Yan; Zhe, Wang; Jing, Wang; Daokui, Wang; Peicheng, Cao; Yongjie, Li
Abnormal cerebrospinal fluid (CSF) flow is suspected to be a contributor to the pathogenesis of neurodegenerative diseases such as Alzheimer's through the accumulation of toxic metabolites, and to the malfunction of intracranial pressure regulation, possibly through disruption of neuroendocrine communication. For the understanding of transport processes involved in either, knowledge of in vivo CSF dynamics is important. We present a three-dimensional, transient, subject-specific computational analysis of CSF flow in the human cranial subarachnoid space (SAS) based on in vivo magnetic resonance imaging. We observed large variations in the spatial distribution of flow velocities with a temporal peak of 5 cm s(-1) in the anterior SAS and less than 4 mm s(-1) in the superior part. This could reflect dissimilar flushing requirements of brain areas that may show differences in susceptibility to pathological CSF flow. Our methods can be used to compare the transport of metabolites and neuroendocrine substances in healthy and diseased brains. PMID:20236960
Gupta, Sumeet; Soellinger, Michaela; Grzybowski, Deborah M; Boesiger, Peter; Biddiscombe, John; Poulikakos, Dimos; Kurtcuoglu, Vartan
The objectives of this study were to establish a reference interval for canine cerebrospinal fluid lactate (CSFL) and to compare CSFL and plasma lactate (PL) concentrations in anesthetized dogs with and without intracranial disease. Using a prospective study, canine blood and cerebrospinal fluid were collected for lactate analysis in 11 dogs with intracranial disease after undergoing magnetic resonance imaging (MRI) (Group ID-MRI), in 10 healthy dogs post-MRI (Group H-MRI), and in 39 healthy dogs after induction of anesthesia (Group H-Sx). Dogs were anesthetized for the procedures using different anesthetic protocols. Neurological scores (NS) and sedation scores (SS) were assessed pre-anesthesia in ID-MRI dogs. The CSFL reference interval [90% confidence interval (CI) for lower and upper limits] was 1.1 (1.0 to 1.2) to 2.0 (2.0 to 2.1) mmol/L. Mean � SD CSFL concentrations were: ID-MRI, 2.1 � 0.8; H-MRI, 1.6 � 0.4; and H-Sx, 1.6 � 0.2 mmol/L. There was a tendency for higher CSFL in dogs in the ID-MRI group than in those in the H-MRI or H-Sx groups (P = 0.12). There was agreement between CSFL and PL in ID-MRI dogs (P = 0.007), but not in dogs in H-MRI (P = 0.5) or H-Sx (P = 0.2). Of the ID-MRI dogs, those with worse NS had higher CSFL (r2 = 0.44). The correlation between CSFL and PL in dogs with intracranial disease and between worse NS and higher CSFL warrants further investigation into the use of CSFL and PL for diagnostic and prognostic purposes. PMID:24124273
Caines, Deanne; Sinclair, Melissa; Wood, Darren; Valverde, Alexander; Dyson, Doris; Gaitero, Luis; Nykamp, Stephanie
Background The consumption of foods rich in carotenoids that possess significant antioxidant and inflammatory modulating properties has been linked to reduced risk of neuropathology. The objective of this study was to evaluate the relationship between plasma carotenoid concentrations and plasma and cerebrospinal fluid (CSF) markers of inflammation, oxidative stress and nicotinamide adenine dinucleotide (NAD+) in an essentially healthy human cohort. Methods Thirty-eight matched CSF and plasma samples were collected from consenting participants who required a spinal tap for the administration of anaesthetic. Plasma concentrations of carotenoids and both plasma and cerebrospinal fluid (CSF) levels of NAD(H) and markers of inflammation (IL-6, TNF-?) and oxidative stress (F2-isoprostanes, 8-OHdG and total antioxidant capacity) were quantified. Results The average age of participants was 53�years (SD?=?20, interquartile range?=?38). Both ?-carotene (P?=?0.01) and ?-carotene (P?0.001) correlated positively with plasma total antioxidant capacity. A positive correlation was observed between ?-carotene and CSF TNF-? levels (P?=?0.02). ?-cryptoxanthin (P?=?0.04) and lycopene (P?=?0.02) inversely correlated with CSF and plasma IL-6 respectively. A positive correlation was also observed between lycopene and both plasma (P?0.001) and CSF (P?0.01) [NAD(H)]. Surprisingly no statistically significant associations were found between the most abundant carotenoids, lutein and zeaxanthin and either plasma or CSF markers of oxidative stress. Conclusion Together these findings suggest that consumption of carotenoids may modulate inflammation and enhance antioxidant defences within both the central nervous system (CNS) and systemic circulation. Increased levels of lycopene also appear to moderate decline in the essential pyridine nucleotide [NAD(H)] in both the plasma and the CSF. PMID:24985027
Intracranial hypertension is a severe therapeutic problem, as there is insufficient knowledge about the physiology of cerebrospinal fluid (CSF) pressure. In this paper a new CSF pressure regulation hypothesis is proposed. According to this hypothesis, the CSF pressure depends on the laws of fluid mechanics and on the anatomical characteristics inside the cranial and spinal space, and not, as is today generally believed, on CSF secretion, circulation and absorption. The volume and pressure changes in the newly developed CSF model, which by its anatomical dimensions and basic biophysical features imitates the craniospinal system in cats, are compared to those obtained on cats with and without the blockade of craniospinal communication in different body positions. During verticalization, a long-lasting occurrence of negative CSF pressure inside the cranium in animals with normal cranio-spinal communication was observed. CSF pressure gradients change depending on the body position, but those gradients do not enable unidirectional CSF circulation from the hypothetical site of secretion to the site of absorption in any of them. Thus, our results indicate the existence of new physiological/pathophysiological correlations between intracranial fluids, which opens up the possibility of new therapeutic approaches to intracranial hypertension. PMID:24748150
Klarica, Marijan; Rado�, Milan; Erceg, Gorislav; Peto�i?, Antonio; Jurjevi?, Ivana; Ore�kovi?, Darko
Intracranial hypertension is a severe therapeutic problem, as there is insufficient knowledge about the physiology of cerebrospinal fluid (CSF) pressure. In this paper a new CSF pressure regulation hypothesis is proposed. According to this hypothesis, the CSF pressure depends on the laws of fluid mechanics and on the anatomical characteristics inside the cranial and spinal space, and not, as is today generally believed, on CSF secretion, circulation and absorption. The volume and pressure changes in the newly developed CSF model, which by its anatomical dimensions and basic biophysical features imitates the craniospinal system in cats, are compared to those obtained on cats with and without the blockade of craniospinal communication in different body positions. During verticalization, a long-lasting occurrence of negative CSF pressure inside the cranium in animals with normal cranio-spinal communication was observed. CSF pressure gradients change depending on the body position, but those gradients do not enable unidirectional CSF circulation from the hypothetical site of secretion to the site of absorption in any of them. Thus, our results indicate the existence of new physiological/pathophysiological correlations between intracranial fluids, which opens up the possibility of new therapeutic approaches to intracranial hypertension. PMID:24748150
Rados, Milan; Erceg, Gorislav; Petosic, Antonio; Jurjevic, Ivana
Alzheimer�s disease is characterised by the inappropriate death of brain cells and accumulation of the A? peptide in the brain. Thus, it is possible that there are fundamental differences between Alzheimer�s disease patients and healthy individuals in their abilities to clear A? from brain fluid and to protect neurons from A? toxicity. In the present study, we examined (1) the cytotoxicity of Alzheimer�s disease cerebrospinal fluid (CSF) compared to control CSF, (2) the ability of Alzheimer�s disease and control CSF to protect cells from A? toxicity and to promote cell-mediated clearance of A? and lastly (3) the effects of extracellular chaperones, normally found in CSF, on these processes. We show that the Alzheimer�s disease CSF samples tested were more toxic to cultured neuroblastoma cells than normal CSF. In addition, the Alzheimer�s disease CSF samples tested were less able to protect cells from A?-induced toxicity and less efficient at promoting macrophage-like cell uptake when compared to normal CSF. The addition of physiologically relevant concentrations of the extracellular chaperones, clusterin, haptoglobin and ?2-macroglobulin into CSF protected neuroblastoma cells from ??1-42 toxicity and promoted ??1-42 uptake in macrophage-like cells. These results suggest that extracellular chaperones are an important element of a system of extracellular protein folding quality control that protects against A? toxicity and accumulation. PMID:19472074
Wilson, Mark R.
Brain development requires precise orchestration of cellular events through the coordinate exchange of information between distally located cells. One mechanism by which intercellular communication is achieved is through the transfer of extracellular vesicles (EVs). Exosomes are EVs that carry lipids, nucleic acids, and proteins and are detectable in most biological fluids including cerebrospinal fluid (CSF). Here we report that CSF EV concentrations undergo age dependent fluctuations. We characterized EV RNA content by next generation small RNA sequencing and miRNA microarray analysis and identified a temporal shift in CSF EV content. CSF EVs encapsulated miRNAs that contain a conserved hnRNPA2/B1 recognition sequence. We found that hnRNPA2/B1-containing EVs were produced by choroid plexus epithelial cells and that hnRNPA2/B1 containing EVs decreased with age. These results provide insight into EV exchange of miRNAs within the central nervous system and a framework to understand how changes in EVs may have an important impact on brain development. PMID:25420022
Tietje, Ashlee; Maron, Kourtney N.; Wei, Yanzhang; Feliciano, David M.
In this study, the human cerebrospinal fluid (CSF) proteome was mapped using three different strategies prior to Orbitrap LC-MS/MS analysis: SDS-PAGE and mixed mode reversed phase-anion exchange for mapping the global CSF proteome, and hydrazide-based glycopeptide capture for mapping glycopeptides. A maximal protein set of 3081 proteins (28,811 peptide sequences) was identified, of which 520 were identified as glycoproteins from the glycopeptide enrichment strategy, including 1121 glycopeptides and their glycosylation sites. To our knowledge, this is the largest number of identified proteins and glycopeptides reported for CSF, including 417 glycosylation sites not previously reported. From parallel plasma samples, we identified 1050 proteins (9739 peptide sequences). An overlap of 877 proteins was found between the two body fluids, whereas 2204 proteins were identified only in CSF and 173 only in plasma. All mapping results are freely available via the new CSF Proteome Resource (http://probe.uib.no/csf-pr), which can be used to navigate the CSF proteome and help guide the selection of signature peptides in targeted quantitative proteomics. PMID:25038066
Guldbrandsen, Astrid; Vethe, Heidrun; Farag, Yehia; Oveland, Eystein; Garberg, Hilde; Berle, Magnus; Myhr, Kjell-Morten; Opsahl, Jill A; Barsnes, Harald; Berven, Frode S
In this study, the human cerebrospinal fluid (CSF) proteome was mapped using three different strategies prior to Orbitrap LC-MS/MS analysis: SDS-PAGE and mixed mode reversed phase-anion exchange for mapping the global CSF proteome, and hydrazide-based glycopeptide capture for mapping glycopeptides. A maximal protein set of 3081 proteins (28,811 peptide sequences) was identified, of which 520 were identified as glycoproteins from the glycopeptide enrichment strategy, including 1121 glycopeptides and their glycosylation sites. To our knowledge, this is the largest number of identified proteins and glycopeptides reported for CSF, including 417 glycosylation sites not previously reported. From parallel plasma samples, we identified 1050 proteins (9739 peptide sequences). An overlap of 877 proteins was found between the two body fluids, whereas 2204 proteins were identified only in CSF and 173 only in plasma. All mapping results are freely available via the new CSF Proteome Resource (http://probe.uib.no/csf-pr), which can be used to navigate the CSF proteome and help guide the selection of signature peptides in targeted quantitative proteomics. PMID:25038066
Guldbrandsen, Astrid; Vethe, Heidrun; Farag, Yehia; Oveland, Eystein; Garberg, Hilde; Berle, Magnus; Myhr, Kjell-Morten; Opsahl, Jill A.; Barsnes, Harald; Berven, Frode S.
A method for analysis of indinavir in serum, cerebrospinal fluid, and urine was developed. The method is based on liquid-liquid extraction followed by high performance liquid chromatography with UV detection. The method has a shorter analysis time than previously published methods, and it is sensitive enough to measure levels in all three fluids under routine clinical conditions. The method is linear up to 32 micromol/L, the limit of detection is 0.01 micromol/L, and recovery of the method is 86%. The interassay coefficient of variation at 2.0 micromol/L was 2.8%, and no internal standard is needed. Over 700 clinical samples have been analyzed by this method, and concomitant antiviral drugs do not interfere with the assay. Paroxetin and dipyridamol are the only two compounds encountered to elute with retention times similar to that of indinavir. Examples of chromatograms and a pharmacokinetic curve are given. The method is well suited for routine therapeutic drug monitoring as well as for pharmacokinetic studies for research purposes. PMID:11034271
Svensson, J O; S�nnerborg, A; St�hle, L
Age-Dependent Changes in the Cerebrospinal Fluid Proteome by Slow Off-Rate Modified Aptamer Array
An important precondition for the successful development of diagnostic assays of cerebrospinal fluid (CSF) biomarkers of age-related neurodegenerative diseases is an understanding of the dynamic nature of the CSF proteome during the normal aging process. In this study, a novel proteomic technology was used to quantify hundreds of proteins simultaneously in the CSF from 90 cognitively normal adults 21 to 85 years of age. SomaLogic's highly multiplexed proteomic platform can measure more than 800 proteins simultaneously from small volumes of biological fluids using novel slow off-rate modified aptamer (SOMAmer) protein affinity reagents with sensitivity, specificity, and dynamic ranges that meet or exceed those of enzyme-linked immunosorbent assays. In the first application of this technology to CSF, we detected 248 proteins that possessed signals greater than twofold over background. Several novel correlations between detected protein concentrations and age were discovered that indicate that both inflammation and response to injury in the central nervous system may increase with age. Applying this powerful proteomic approach to CSF provides potential new insight into the aging of the human central nervous system that may have utility in discovering new disease-related changes in the CSF proteome. PMID:22122984
Baird, Geoffrey S.; Nelson, Sally K.; Keeney, Tracy R.; Stewart, Alex; Williams, Stephen; Kraemer, Stephan; Peskind, Elaine R.; Montine, Thomas J.
Background Whether low-intensity radiofrequency radiation damages the blood-brain barrier has long been debated, but little or no consideration has been given to the blood-cerebrospinal fluid barrier. In this cross-sectional study we tested whether long-term and/or short-term use of wireless telephones was associated with changes in the serum transthyretin level, indicating altered transthyretin concentration in the cerebrospinal fluid, possibly reflecting an effect of radiation. Methods One thousand subjects, 500 of each sex aged 18�65 years, were randomly recruited using the population registry. Data on wireless telephone use were assessed by a postal questionnaire and blood samples were analyzed for serum transthyretin concentrations determined by standard immunonephelometric techniques on a BN Prospec� instrument. Results The response rate was 31.4%. Logistic regression of dichotomized TTR serum levels with a cut-point of 0.31 g/l on wireless telephone use yielded increased odds ratios that were statistically not significant. Linear regression of time since first use overall and on the day that blood was withdrawn gave different results for males and females: for men significantly higher serum concentrations of TTR were seen the longer an analogue telephone or a mobile and cordless desktop telephone combined had been used, and in contrast, significantly lower serum levels were seen the longer an UMTS telephone had been used. Adjustment for fractions of use of the different telephone types did not modify the effect for cumulative use or years since first use for mobile telephone and DECT, combined. For women, linear regression gave a significant association for short-term use of mobile and cordless telephones combined, indicating that the sooner blood was withdrawn after the most recent telephone call, the higher the expected transthyretin concentration. Conclusion In this hypothesis-generating descriptive study time since first use of mobile telephones and DECT combined was significantly associated with higher TTR levels regardless of how much each telephone type had been used. Regarding short-term use, significantly higher TTR concentrations were seen in women the sooner blood was withdrawn after the most recent telephone call on that day. PMID:19383125
We studied gray-white matter and cerebrospinal fluid (CSF) alterations that may be critical for language, through an optimized voxel-based morphometry evaluation in children with Specific Language Impairment (SLI), compared to Typical Language Development (TLD). Ten children with SLI (8;5-10;9) and 14 children with TLD (8;2-11;8) participated. They received a comprehensive language and reading test battery. We also analyzed a subgroup of six children with SLI+RD (Reading Disability). Brain images from 3-Tesla MRIs were analyzed with intelligence, age, gender, and total intracranial volume as covariates. Children with SLI or SLI+RD exhibited a significant lower overall gray matter volume than children with TLD. Particularly, children with SLI showed a significantly lower volume of gray matter compared to children with TLD in the right postcentral parietal gyrus (BA4), and left and right medial occipital gyri (BA19). The group with SLI also exhibited a significantly greater volume of gray matter in the right superior occipital gyrus (BA19), which may reflect a brain reorganization to compensate for their lower volumes at medial occipital gyri. Children with SLI+RD, compared to children with TLD, showed a significantly lower volume of: (a) gray matter in the right postcentral parietal gyrus; and (b) white matter in the right inferior longitudinal fasciculus (RILF), which interconnects the temporal and occipital lobes. Children with TLD exhibited a significantly lower CSF volume than children with SLI and children with SLI+RD respectively, who had somewhat smaller volumes of gray matter allowing for more CSF volume. The significant lower gray matter volume at the right postcentral parietal gyrus and greater cerebrospinal fluid volume may prove to be unique markers for SLI. We discuss the association of poor knowledge/visual representations and language input to brain development. Our comorbid study showed that a significant lower volume of white matter in the right inferior longitudinal fasciculus may be unique to children with SLI and Reading Disability. It was significantly associated to reading comprehension of sentences and receptive language composite z-score, especially receptive vocabulary and oral comprehension of stories. PMID:24418156
Girbau-Massana, Dolors; Garcia-Marti, Gracian; Marti-Bonmati, Luis; Schwartz, Richard G
The subcommissural organ (SCO) is a brain gland secreting glycoproteins into the cerebrospinal fluid (CSF), where they aggregate\\u000a forming the Reissner�s fiber (RF). By the continuous addition of newly released glycoproteins, RF grows along the cerebral\\u000a aqueduct, fourth ventricle, and central canal of the spinal cord. At the filum, RF-glycoproteins escape from the central canal\\u000a and reach the local blood
Sara Rodr�guez; Karin Vio; Carolina Wagner; Miguel Barr�a; Edison H. Navarrete; Victor D. Ram�rez; Jos� M. P�rez-F�gares; Esteban M. Rodr�guez
In human cerebrospinal fluid substances were detected that are capable of reversibly displacing the hallucinogen d-lysergic acid diethylamide (LSD) from its high-affinity binding sites in neuronal membranes. The binding sites may represent a specific type of LSD-serotonin receptor protein. The LSD-displacing factors (LDF) occur physiologically in concentrations high enough to interact with the putative LSD-serotonin receptors. The LDF can be
E. Mehl; E. R�ther; J. Redemann
The blood-brain barrier and a blood-cerebrospinal-fluid (CSF) barrier function together to isolate the brain from circulating drugs, toxins, and xenobiotics. The blood-CSF drug-permeability barrier is localized to the epithelium of the choroid plexus (CP). However, the molecular mechanisms regulating drug permeability across the CP epithelium are defined poorly. Herein, we describe a drug-permeability barrier in human and rodent CP mediated
Vallabhaneni V. Rao; Julie L. Dahlheimer; Mark E. Bardgett; Abraham Z. Snyder; Rick A. Finch; Alan C. Sartorelli; David Piwnica-Worms
Changes in cerebrospinal fluid (CSF) and anatomical and histopathological central nervous system (CNS) lesions were evaluated,\\u000a and the presence of Trypanosoma vivax in CNS tissues was investigated through PCR. Twelve adult male goats were divided into three groups (G): G1, infected with\\u000a T. vivax and evaluated during the acute phase; G2, infected goats evaluated during the chronic phase; and G3,
Jael S Batista; Carla MF Rodrigues; Herakles A Garc�a; Francisco SB Bezerra; Rob�rio G Olinda; Marta MG Teixeira; Benito Soto-Blanco
To better understand the development of hydrocephalus of different origins, we evaluated cytokine and growth factor concentration\\u000a in cerebrospinal fluid from patients with hydrocephalus. CSF was collected from patients developing hydrocephalus following\\u000a hemorrhage (n�=�15), patients with normal pressure hydrocephalus (n�=�10), and following the embolization of unruptured intracranial aneurysms (n�=�9). Myelography patients (n�=�15) served as controls. Quantification of 11 molecules relating
Monika Killer; Adam Arthur; Abdul Rahman Al-Schameri; John Barr; Donald Elbert; Gunther Ladurner; Julie Shum; Gregory Cruise
The discovery and reliable detection of markers for neurodegenerative diseases have been complicated by the inaccessibility of the diseased tissue- such as the inability to biopsy or test tissue from the central nervous system directly. RNAs originating from hard to access tissues, such as neurons within the brain and spinal cord, have the potential to get to the periphery where they can be detected non-invasively. The formation and extracellular release of microvesicles and RNA binding proteins have been found to carry RNA from cells of the central nervous system to the periphery and protect the RNA from degradation. Extracellular miRNAs detectable in peripheral circulation can provide information about cellular changes associated with human health and disease. In order to associate miRNA signals present in cell-free peripheral biofluids with neurodegenerative disease status of patients with Alzheimer's and Parkinson's diseases, we assessed the miRNA content in cerebrospinal fluid and serum from postmortem subjects with full neuropathology evaluations. We profiled the miRNA content from 69 patients with Alzheimer's disease, 67 with Parkinson's disease and 78 neurologically normal controls using next generation small RNA sequencing (NGS). We report the average abundance of each detected miRNA in cerebrospinal fluid and in serum and describe 13 novel miRNAs that were identified. We correlated changes in miRNA expression with aspects of disease severity such as Braak stage, dementia status, plaque and tangle densities, and the presence and severity of Lewy body pathology. Many of the differentially expressed miRNAs detected in peripheral cell-free cerebrospinal fluid and serum were previously reported in the literature to be deregulated in brain tissue from patients with neurodegenerative disease. These data indicate that extracellular miRNAs detectable in the cerebrospinal fluid and serum are reflective of cell-based changes in pathology and can be used to assess disease progression and therapeutic efficacy. PMID:24797360
Metpally, Raghu; Courtright, Amanda; Rakela, Benjamin; Beach, Thomas; Shill, Holly; Adler, Charles; Sabbagh, Marwan; Villa, Stephen; Tembe, Waibhav; Craig, David; Van Keuren-Jensen, Kendall
Chronic fatigue syndrome (CFS) is a controversial diagnosis because of the lack of biomarkers for the illness and its symptom overlap with neuropsychiatric, infectious, and rheumatological disorders. We compared lateral ventricular volumes derived from tissue-segmented T1-weighted volumetric MRI data and cerebrospinal fluid (CSF) lactate concentrations measured by proton MRS imaging (1H MRSI) in 16 subjects with CFS (modified US Centers
Sanjay J. Mathew; Xiangling Mao; Kathryn A. Keegan; Susan M. Levine; Eric L. P. Smith; Linda A. Heier; Viktor Otcheretkoa; Jeremy D. Copland; Dikoma C. Shungu
Previous studies have shown that postmortem serum levels of adrenocorticotropic hormone (ACTH) were significantly lower in cases of asphyxia and poisoning than in other groups, whereas ACTH levels in cerebrospinal fluid (CSF) were significantly lower for hypothermia and hyperthermia. This study comparatively analyzed growth hormone (GH) levels in serum and CSF in relation to cause of death in routine forensic work. Autopsy cases (n�=�116), including cases of blunt injury, sharp instrument injury, fire fatality, asphyxia, drowning, hypothermia, and acute myocardial infarction/ischemia (AMI), were examined. GH concentrations were measured using an immunoradiometric assay technique. GH levels in serum were significantly higher in cases of blunt injury, sharp instrument injury, hypothermia, and AMI than in the other groups. GH levels in CSF were significantly higher in fire fatality cases with a high COHb level than in the other groups. In a previous study ACTH immunopositivity in the adenohypophysis was significantly higher in cases of blunt injury, fire fatality, and AMI whereas GH immunopositivity was not significantly different among the groups, although positivity was higher in cases of fire fatality with a low COHb level. These observations suggest that postmortem serum/CSF GH and ACTH levels in acute deaths change differently, depending on the cause of death, because of varied stress reactions of the hypothalamic-pituitary-adrenal (HPA) axis. PMID:21547353
Ishikawa, Takaki; Michiue, Tomomi; Maeda, Hitoshi
Background Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis. Methods We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder. Results There were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p =?0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls. Conclusions The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis. PMID:25073638
Background Post-dural puncture headache (PDPH) due to excessive cerebrospinal fluid (CSF) leakage is a well-known complication of lumbar puncture. Although various factors, especially the type of spinal needle, have been demonstrated to be associated with PDPH, the clinical implications of CSF leakage detected on magnetic resonance myelography (MRM) images remain unclear. The objective of this case�control study was to evaluate the association between radiologically visualized CSF leakage and PDPH. Methods Clinical data including patients� age and gender, types of spinal needle, duration of bed rest, interval between lumbar puncture procedures and MRM studies, and incidence of PDPH were compared between patients who were radiologically-positive and -negative for CSF leakage. Results Of the 22 patients with definite CSF leakage on MRM images, most were asymptomatic (86%, 19/22). The remaining three patients, who were suffering from PDPH, only complained of headaches and were treated conservatively. In a review of patients� clinical data, there were no significant differences in any parameter including the incidence of PDPH between the 22 patients who were radiologically-positive for CSF leakage and the 31 radiologically-negative patients. Conclusion The significance of radiologically visualized CSF leakage should not be overestimated, as most such incidents are not associated with PDPH and do not require any treatment. PMID:24160550
Background Oculorrhea, or cerebrospinal fluid leakage developing from a cranio-orbital fistula, is a rare development following traumatic injury. Case Report A 22-year-old man involved in a motor vehicle accident developed a blowout fracture of the left orbital roof penetrating the frontal lobe, inducing oculorrhea. He underwent a supraorbital craniotomy for removal of the bony fragment and skull base reconstruction using a pericranial flap. Methods A systematic review of the database was performed to identify all prior cases of traumatic oculorrhea. Results Twenty-two reported cases met inclusion criteria for subsequent analysis. Oculorrhea developed due to blunt and penetrating head injury in 14 (64%) and 8 patients (36%), respectively. The most common mechanisms were car accidents, stab wounds, falls, and gunshot wounds. Ocular signs and symptoms-including visual loss, ophthalmoplegia, and pupillary dysfunction-were commonly associated findings. Initial conservative management was successful in four patients. Thirteen patients underwent initial surgical intervention, and three additional patients required operative intervention following failed conservative treatment. Conclusion Although oculorrhea rarely develops following severe orbital trauma, suspicion should nevertheless be maintained to facilitate more prompt diagnosis and management. The decision for conservative versus surgical management often depends on the severity of the fracture and dural injury. PMID:23943723
Pease, Matthew; Marquez, Yvette; Tuchman, Alex; Markarian, Alex; Zada, Gabriel
Background Oculorrhea, or cerebrospinal fluid leakage developing from a cranio-orbital fistula, is a rare development following traumatic injury. Case Report A 22-year-old man involved in a motor vehicle accident developed a blowout fracture of the left orbital roof penetrating the frontal lobe, inducing oculorrhea. He underwent a supraorbital craniotomy for removal of the bony fragment and skull base reconstruction using a pericranial flap. Methods A systematic review of the database was performed to identify all prior cases of traumatic oculorrhea. Results Twenty-two reported cases met inclusion criteria for subsequent analysis. Oculorrhea developed due to blunt and penetrating head injury in 14 (64%) and 8 patients (36%), respectively. The most common mechanisms were car accidents, stab wounds, falls, and gunshot wounds. Ocular signs and symptoms�including visual loss, ophthalmoplegia, and pupillary dysfunction�were commonly associated findings. Initial conservative management was successful in four patients. Thirteen patients underwent initial surgical intervention, and three additional patients required operative intervention following failed conservative treatment. Conclusion Although oculorrhea rarely develops following severe orbital trauma, suspicion should nevertheless be maintained to facilitate more prompt diagnosis and management. The decision for conservative versus surgical management often depends on the severity of the fracture and dural injury. PMID:23943723
Pease, Matthew; Marquez, Yvette; Tuchman, Alex; Markarian, Alex; Zada, Gabriel
Previous mass spectrometry analysis of cerebrospinal fluid (CSF) has allowed the identification of a panel of molecular markers that are associated with Alzheimer�s disease (AD). The panel comprises Amyloid beta, Apolipoprotein E, Fibrinogen alpha chain precursor, Keratin type I cytoskeletal 9, Serum albumin precursor, SPARC-like 1 protein and Tetranectin. Here we report the development and implementation of immunoassays to measure the abundance and diagnostic capacity of these putative biomarkers in matched lumbar CSF and blood plasma samples taken in life from individuals confirmed at post-mortem as suffering from AD (n = 10) and from screened �cognitively healthy� subjects (n = 18). The inflammatory components of Alzheimer�s disease were also investigated. Employment of supervised learning techniques permitted examination of the interrelated expression patterns of the putative biomarkers and identified inflammatory components, resulting in biomarker panels with a diagnostic accuracy of 87.5% and 86.7% for the plasma and CSF datasets respectively. This is extremely important as it offers an ideal high-throughput and relatively inexpensive population screening approach. It appears possible to determine the presence or absence of AD based on our biomarker panel and it seems likely that a cheap and rapid blood test for AD is feasible. PMID:24959311
Richens, Joanna L; Vere, Kelly-Ann; Light, Roger A; Soria, Daniele; Garibaldi, Jonathan; Smith, A David; Warden, Donald; Wilcock, Gordon; Bajaj, Nin; Morgan, Kevin; O'Shea, Paul
Circulating cells, proteins, microparticles, and DNA in cerebrospinal fluid (CSF) are excellent biomarkers of many diseases, including cancer and infections. However, the sensitivity of existing methods is limited in their ability to detect rare CSF biomarkers at the treatable, early-stage of diseases. Here, we introduce novel CSF tests based on in vivo multicolor photoacoustic flow cytometry (PAFC) and ex vivo photothermal scanning cytometry. In the CSF of tumor-bearing mice, we molecularly detected in vivo circulating tumor cells (CTCs) before the development of breast cancer brain metastasis with 20-times higher sensitivity than with current assays. For the first time, we demonstrated assessing three pathways (i.e., blood, lymphatic, and CSF) of CTC dissemination, tracking nanoparticles in CSF in vivo and their imaging ex vivo. In label-free CSF samples, we counted leukocytes, erythrocytes, melanoma cells, and bacteria and imaged intracellular cytochromes, hemoglobin, melanin, and carotenoids, respectively. Taking into account the safety of PAFC, its translation for use in humans is expected to improve disease diagnosis beyond conventional detection limits. PMID:23681943
Nedosekin, Dmitry A.; Juratli, Mazen A.; Sarimollaoglu, Mustafa; Moore, Christopher L.; Rusch, Nancy J.; Smeltzer, Mark S.; Zharov, Vladimir P.; Galanzha, Ekaterina I.
Pro-inflammatory cytokines and neurotrophins in the central nervous system (CNS) have been recognized as mediators of both neurodegenerative and neuroprotective mechanisms in a number of CNS pathologies. A rapid, sustained elevation of these molecules was recently reported after traumatic and ischemic brain injury. Inflammatory mechanisms and immune activation have been hypothesized to play a role in the pathogenesis of cerebral ischemia. Stroke is the third largest cause of death next to heart disease and cancer in the world, and it is an important cause of death and disability in developed countries. Role of excitatory amino acids receptors activation, calcium overload, nitric oxide and oxidative stress in the pathogenesis of ischemic brain damage is well established. Stroke may modulate peripheral neurotrophic factors levels. In experimental animal models, neurotrophin-3 (NT-3) has been shown to be produced by glial cells as an adaptability response to hypoxia. In spite of substantial research and significant number of neuroprotective drugs that have been developed to limit ischemic brain damage and to improve the outcome for stroke patients, no specific therapy for stroke is available. The neurotrophins have been proposed as therapeutic agents for the treatment of neurodegenerative disorders and ischemic injury. In the present work, we investigated the possible correlation of NT-3 with tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the serum and cerebrospinal fluid (CSF) from patients with ischemic stroke (IS). PMID:17405311
Pasarica, Daniela; Gheorghiu, Mihaela; Top�rceanu, Florica; Bleotu, Coralia; Ichim, Loretta; Trandafir, T
The D-amino acid oxidase activator (DAOA) protein regulates the function of D-amino oxidase (DAO), an enzyme that catalyzes the oxidative deamination of D-3,4-dihydroxyphenylalanine (D-DOPA) and D-serine. D-DOPA is converted to L-3,4-DOPA, a precursor of dopamine, whereas D-serine participates in glutamatergic transmission. We hypothesized that DAOA polymorphisms are associated with dopamine, serotonin and noradrenaline turnover in the human brain. Four single-nucleotide polymorphisms, previously reported to be associated with schizophrenia, were genotyped. Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture, and the concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured. Two of the investigated polymorphisms, rs3918342 and rs1421292, were significantly associated with CSF HVA concentrations. Rs3918342 was found to be nominally associated with CSF 5-HIAA concentrations. None of the polymorphisms were significantly associated with MHPG concentrations. Our results indicate that DAOA gene variation affects dopamine turnover in healthy individuals, suggesting that disturbed dopamine turnover is a possible mechanism behind the observed associations between genetic variation in DAOA and behavioral phenotypes in humans. PMID:22454242
Andreou, Dimitrios; Saetre, Peter; Werge, Thomas; Andreassen, Ole A; Agartz, Ingrid; Sedvall, G�ran C; Hall, H�kan; Terenius, Lars; J�nsson, Erik G
Background Neural stem cells (NSCs) are a promising source for cell replacement therapies for neurological diseases. Growing evidence suggests an important role of cerebrospinal fluid (CSF) not only on neuroectodermal cells during brain development but also on the survival, proliferation and fate specification of NSCs in the adult brain. Existing in vitro studies focused on embryonic cell lines and embryonic CSF. We therefore studied the effects of adult human leptomeningeal CSF on the behaviour of adult human NSCs (ahNSCs). Results Adult CSF increased the survival rate of adult human NSCs compared to standard serum free culture media during both stem cell maintenance and differentiation. The presence of CSF promoted differentiation of NSCs leading to a faster loss of their self-renewal capacity as it is measured by the proliferation markers Ki67 and BrdU and stronger cell extension outgrowth with longer and more cell extensions per cell. After differentiation in CSF, we found a larger number of GFAP+ astroglial cells compared to differentiation in standard culture media and a lower number of ?-tubulin III+ neuronal cells. Conclusions Our data demonstrate that adult human leptomeningeal CSF creates a beneficial environment for the survival and differentiation of adult human NSCs. Adult CSF is in vitro a strong glial differentiation stimulus and leads to a rapid loss of stem cell potential. PMID:20377845
Cerebrospinal fluid (CSF) provides an invaluable analytical window to the central nervous system (CNS) because it reflects the dynamically changing complement of CNS constituents. We describe an improved method for sampling CSF in rats that is easy to perform. It has a 96% success rate of CSF collection and consistently yields large volumes (150-200 ?l) of CSF. The blood contamination rate is also low (6%) as determined by both visual inspection and the lack of molecular detection of apolipoprotein B, a plasma-derived protein, which is absent in the CNS. This improved method of CSF sampling can have broad applicability in physiological and pharmacological evaluation for diverse CNS targets. We used this technique to provide proof of principle by examining the effect of intraperitoneal insulin on the level of apolipoprotein E (apoE) in the CSF. Insulin (0.5 and 1 U/kg) led to a significant increase of insulin in both plasma and CSF at 2 h after intraperitoneal administration and decreased blood glucose for at least 2h. ApoE concentrations in CSF, but not in plasma, were also significantly increased, and its time-course was inversely correlated with the alterations in blood glucose over 2 h. These results provide a pharmacological validation of the novel CSF sampling and validation procedure for sampling rat CSF. PMID:22691999
Liu, Min; Shen, Ling; Begg, Denovan P; D'alessio, David A; Woods, Stephen C
The blood-brain barrier supplies brain tissues with nutrients and filters certain compounds from the brain back to the bloodstream. In several neurodegenerative diseases, including Parkinson's disease (PD), there are disruptions of the blood-brain barrier. Cerebrospinal fluid (CSF) has been widely investigated in PD and in other parkinsonian syndromes with the aim of establishing useful biomarkers for an accurate differential diagnosis among these syndromes. This review article summarizes the studies reported on CSF levels of many potential biomarkers of PD. The most consistent findings are: (a) the possible role of CSF urate on the progression of the disease; (b) the possible relations of CSF total tau and phosphotau protein with the progression of PD and with the preservation of cognitive function in PD patients; (c) the possible value of CSF beta-amyloid 1-42 as a useful marker of further cognitive decline in PD patients, and (d) the potential usefulness of CSF neurofilament (NFL) protein levels in the differential diagnosis between PD and other parkinsonian syndromes. Future multicentric, longitudinal, prospective studies with long-term follow-up and neuropathological confirmation would be useful in establishing appropriate biomarkers for PD.
Jim�nez-Jim�nez, F�lix J.; Alonso-Navarro, Hortensia; Garc�a-Mart�n, Elena; Ag�ndez, Jos� A. G.
The number of circulating tumor cells (CTCs) in the peripheral blood of metastatic breast cancer patients is now an established prognostic marker. While the central nervous system (CNS) is a common site of metastasis in breast cancer, the standard marker for disease progression in this setting is cerebrospinal fluid (CSF) cytology. However, the significance of CSF cytology is unclear, requires large sample size, is insensitive and subjective, and sometimes yields equivocal results. Here, we report the detection of breast cancer cells in CSF using molecular markers by adapting the CellSearch system (Veridex). We used this platform to isolate and enumerate breast cancer cells in CSF of breast cancer patients with central nervous system metastases. The number of CSF tumor cells correlated with tumor response to chemotherapy and were dynamically associated with disease burden. This CSF tumor cell detection method provides a semi-automated molecular analysis that vastly improves the sensitivity, reliability, objectivity, and accuracy of detecting CSF tumor cells compared to CSF cytology. CSF tumor cells may serve as a marker of disease progression and early-stage brain metastasis in breast cancer and potentiate further molecular analysis to elucidate the biology and significance of tumor cells in the CSF. PMID:21987585
Dicker, David T.; Peters, Kristi L.; Sheehan, Jonas M.; Glantz, Michael J.; El-Deiry, Wafik S.
Ketamine and norketamine are being transported across the blood brain barrier and are also entering from blood into cerebrospinal fluid (CSF). Enantioselective distributions of these compounds in brain and CSF have never been determined. The enantioselective CE based assay previously developed for equine plasma was adapted to the analysis of these compounds in equine brain via use of an acidic pre-extraction of interferences prior to liquid/liquid extraction at alkaline pH. CSF can be treated as plasma. With 100 mg of brain tissue and 0.5 mL of CSF or plasma, assay conditions for up to 30 nmol/g and 6 ?M, respectively, of each enantiomer with LOQs of 0.5 nmol/g and 0.1 ?M, respectively, were established and the assays were applied to equine samples. CSF and plasma samples analyzed stemmed from anesthetized patient horses and brain, CSF and plasma were obtained from anesthetized horses that were euthanized with an overdose of pentobarbital. Data obtained indicate that ketamine and norketamine enantiomers are penetrating into brain and CSF with those of ketamine being more favorably transported than norketamine, whereas metabolites of norketamine are hindered. More work is required to properly investigate possible stereoselectivities of the ketamine metabolism and transport of metabolites from blood into brain tissue and CSF. PMID:24789372
Theurillat, Regula; Larenza, M Paula; Feige, Karsten; Bettschart-Wolfensberger, Regula; Thormann, Wolfgang
Activity of strictly intracellular enzymes in the cerebrospinal fluid (CSF) may indicate leakage from dysfunctional brain cells. Increased activity of adenylate kinase (AK) in the CSF is indicative of brain cell injury arising from several sources, among them orthognathic surgery. The mechanism in the latter case is obscure, but the use of an oscillating saw which generates vibrations, and the site of surgery close to the brain may be contributing factors. Anaesthesia may also play a role. In the present study, CSF-AK activity was measured after hysterectomy and was compared with activity after orthognathic surgery in two other studies. Four of 19 patients (21%) in the present study expressed pathological activity, compared with 34 of 47 (72%) orthognathic patients in the two other studies. No firm conclusion may be drawn from historical comparisons, and the difference in activity seen between the two types of surgery might not necessarily be the result of surgical factors. Until this is investigated further, however, we conclude that there may be a difference in postoperative CSF-AK activity between orthognathic and lower abdominal surgery. PMID:9100164
Enlund, M; Mentell, O; Edmark, L; Ronquist, G
Background/Aims The goal of this study was to monitor tuberculosis (TB)-specific T-cell responses in cerebrospinal fluid-mononuclear cells (CSF-MCs) and peripheral blood mononuclear cells (PBMCs) in patients with tuberculous meningitis (TBM) over the course of anti-TB therapy. Methods Adult patients (? 16 years) with TBM admitted to Asan Medical Center, Seoul, South Korea, were prospectively enrolled between April 2008 and April 2011. Serial blood or CSF samples were collected over the course of the anti-TB therapy, and analyzed using an enzyme-linked immunosorbent spot (ELISPOT) assay. Results Serial ELISPOT assays were performed on PBMCs from 17 patients (seven definite, four probable, and six possible TBM) and CSF-MC from nine patients (all definite TBM). The median number of interferon-gamma (IFN-?)-producing T-cells steadily increased during the first 6 months after commencement of anti-TB therapy in PBMCs. Serial CSF-MC ELISPOT assays revealed significant variability in immune responses during the first 6 weeks of anti-TB therapy, though early increases in CSF-MC ELISPOT results were associated with treatment failure or paradoxical response. Conclusions Serial analysis of PBMCs by ELISPOT during the course of treatment was ineffective for predicting clinical response. However, increases in TB-specific IFN-?-producing T-cells in CSF-MC during the early phase of anti-TB therapy may be predictive of clinical failure. PMID:25378978
Park, Ki-Ho; Lee, Mi Suk; Lee, Sang-Oh; Choi, Sang-Ho; Kim, Yang Soo; Woo, Jun Hee; Kang, Joong Koo; Lee, Sang-Ahm
Purpose To develop a population pharmacokinetic model to quantitate the distribution kinetics of glycylsarcosine (GlySar), a substrate of peptide transporter 2 (PEPT2), in blood, CSF and kidney in wild-type and PEPT2 knockout mice. Methods A stepwise compartment modeling approach was performed to describe the concentration profiles of GlySar in blood, CSF, and kidney simultaneously using nonlinear mixed effects modeling (NONMEM). The final model was selected based on the likelihood ratio test and graphical goodness-of-fit. Results The profiles of GlySar in blood, CSF, and kidney were best described by a four-compartment model. The estimated systemic elimination clearance, volume of distribution in the central and peripheral compartments were 0.236 vs 0.449 ml/min, 3.79 vs 4.75 ml, and 5.75 vs 9.18 ml for wild-type versus knockout mice. Total CSF efflux clearance was 4.3 fold higher for wild-type compared to knockout mice. NONMEM parameter estimates indicated that 77% of CSF efflux clearance was mediated by PEPT2 and the remaining 23% was mediated by the diffusional and bulk clearances. Conclusions Due to the availability of PEPT2 knockout mice, we were able to quantitatively determine the significance of PEPT2 in the efflux kinetics of GlySar at the blood-cerebrospinal fluid barrier. PMID:23371515
Huh, Yeamin; Hynes, Scott M.; Smith, David E.
1. A method was devised to sample cerebrospinal fluid (c.s.f.) from the third ventricle of conscious rabbits. 2. Levels of PGE were measured in c.s.f. withdrawn from the third ventricle of rabbits exposed to a variety of manipulations of both brain and body core temperatures which mimicked various facets of fever in these animals. These results were compared to the levels of PGE in the c.s.f. of the same rabbits made febrile by I.V. injections of endogenous pyrogen. 3. Levels of PGE in ventricular c.s.f. remained unaltered at 2-3 ng/ml. during exposure to cold, hyperthermia due to heat exposure, hypothalamic cooling or hypothalamic heating, whereas during fever produced by endogenous pyrogen, they rose to an average of 11-12 ng/ml. Furthermore, a significant positive correlation was established between the level of PGE measured in the c.s.f. and the subsequent height of the fever produced by the pyrogen. 4. Since production of PGE within the brain is not caused by changes in the brain or body temperatures which are comparable to those observed during fever, and yet greater than fivefold increases in the PGE levels in c.s.f. are produced by I.V. injections of endogenous pyrogen, it is concluded that PGE production in the brain is involved in the pathogenesis of fever. PMID:7411449
Bernheim, H. A.; Gilbert, T. M.; Stitt, J. T.
An increasing body of evidence suggests that patients afflicted with multiple sclerosis (MS) show alterations in immunologic markers including increases in proinflammatory cytokine activity and inflammation. Secretory Phospholipase A2 (sPLA2) is one of the key molecules contributing to the production of inflammatory lipid mediators, mainly eicosanoids. They are considered proinflammatory enzymes and their inhibition has long been recognized as a desirable therapeutic target. The aim of this study was to measure the enzyme activity of sPLA2 both in serum and cerebrospinal fluid (CSF) of MS patients. Twenty MS patients accompanied with 20 age-sex matched controls were recruited. The results showed that the enzyme activity of serum sPLA2 was 0.007�0.021 (?mol/min/ml) in MS patients vs. 0.007�0.016 (?mol/min/ml) in patients with other neurological diseases as a control group (P=0.5). Our findings also indicated that there is no correlation (P=0.6) between CSF sPLA2 enzyme activity and MS disease when the results of two groups were compared (0.072�0.020 in cases vs. 0.071�0.01 in control group). The results suggest that the enzyme activity of sPLA2 is not altered during the disease course. PMID:23859159
Siroos, Bahaadin; Balood, Mohammad; Zahednasab, Hamid; Mesbah-Namin, Seyed Alireza; Pourgholy, Fatemeh; Harirchian, Mohammad Hossein
Para-aminosalicylic acid (PAS), an approved drug for treatment of tuberculosis, is a promising therapeutic agent for treatment of manganese (Mn)-induced parkinsonian syndromes. Lack of a quantifying method, however, has hindered the clinical evaluation of its efficacy and thereupon new drug development. This study was aimed at developing a simple and effective method to quantify PAS and its major metabolite, N-acetyl-para-aminosalicylic acid (AcPAS), in plasma, cerebrospinal fluid (CSF) and tissues. Biological samples underwent one-step protein precipitation. The supernatant was fractionated on a reversed-phase C18 column with a gradient mobile system, followed by on-line fluorescence detection. The lower limits of quantification for both PAS and AcPAS were 50 ng/ml of plasma and 17 ng/g of tissues. The intra-day and inter-day precision values did not exceed 5% and 8%, respectively, in all three matrices. The method was used to quantify PAS and AcPAS in rat plasma and brain following a single iv injection of PAS. Data showed a greater amount of PAS than AcPAS in plasma, while a greater amount of AcPAS than PAS was found in brain tissues. The method has been proven to be sensitive, reproducible, and practically useful for laboratory and clinical investigations of PAS in treatment of Mn Parkinsonism. PMID:21159459
Hong, Lan; Jiang, Wendy; Zheng, Wei; Zeng, Su
T cells with a CD4(+) CD8(+) double-positive (DP) phenotype are present in small numbers in the peripheral blood of healthy humans and may have anti-viral capacities. Here we investigate numbers and function of DP T cells in patients with relapsing-remitting multiple sclerosis (MS), either treatment-naive or under therapy with natalizumab. Flow cytometry analysis revealed that frequencies of circulating DP T cells in treatment-naive and natalizumab-treated MS patients are comparable to healthy controls. These cells have a memory phenotype with cytotoxic potential, express high levels of CD49d and are similarly functional in treatment-naive as well as natalizumab-treated MS patients. DP T cells were enriched in the cerebrospinal fluid, but do not invade acutely inflamed MS lesions. In conclusion, DP T cells are functional in MS and may play a role in the immune surveillance of the central nervous system, but do not display functional impairment under natalizumab therapy. PMID:24730443
Waschbisch, A; Sammet, L; Schr�der, S; Lee, D-H; Barrantes-Freer, A; Stadelmann, C; Linker, R A
This study was conducted to establish a reference value for cerebrospinal fluid (CSF) human chorionic gonadotropin (hCG) levels. We also evaluated the sensitivity of CSF hCG as a biomarker to detect intracranial ectopic germinomas that arise in rare sites other than the pineal and suprasellar regions. CSF hCG was measured in 201 male patients who had various types of neurological disease (not tumours of germ cell origin or other malignant tumours). A reference value of 1.009 U/L was established, and the CSF hCG level among different age groups was not significantly different. CSF and serum hCG were measured before and after radiotherapy in 14 consecutive patients with intracranial ectopic germinomas. The CSF hCG levels were all above 1.009 U/L before radiotherapy. In male patients, a CSF hCG value above 1.009 U/L suggests abnormal intrathecal hCG secretion. These results demonstrate that the CSF hCG assay is a sensitive method for diagnosing intracranial ectopic germinoma. PMID:21163658
Tian, Chenglin; Shi, Qiang; Pu, Chuanqiang; Huang, Xusheng; Yu, Shengyuan; Zhang, Jiatang; Huang, Dehui; Wang, Xiangqing; Liu, Ruozhuo
Based on quantitative and qualitative studies in a variety of mammalian species, it would appear that a significant portion of cerebrospinal fluid (CSF) drainage is associated with transport along cranial and spinal nerves with absorption taking place into lymphatic vessels external to the central nervous system. CSF appears to convect primarily through the cribriform plate into lymphatics associated with the submucosa of the olfactory and respiratory epithelium. However, the significance of this pathway for CSF absorption in primates has never been established unequivocally. In past studies, we infused Microfil into the subarachnoid compartment of numerous species to visualize CSF transport pathways. The success of this method encouraged us to use a similar approach in the non-human primate. Yellow Microfil was injected post mortem into the cisterna magna of 6 years old Barbados green monkeys (Cercopithecus aethiops sabeus, n = 6). Macroscopic and microscopic examination revealed that Microfil was (1) distributed throughout the subarachnoid compartment, (2) located in the perineurial spaces associated with the fila olfactoria, (3) present within the olfactory submucosa, and (4) situated within an extensive network of lymphatic vessels in the nasal submucosa, nasal septum and turbinate tissues. We conclude that the Microfil distribution patterns in the monkey were very similar to those observed in many other species suggesting that significant nasal lymphatic uptake of CSF occurs in the non-human primate. PMID:16281912
Johnston, M; Zakharov, A; Koh, L; Armstrong, D
Caspase-6 (Casp6) activation in the brain is implicated early in the pathogenesis of Alzheimer disease (AD). In view of the need for early AD diagnosis, brain Casp6 activity was investigated by measuring Tau cleaved by Casp6 (Tau?Casp6) protein in postmortem cerebrospinal fluid (CSF) of 7 non-cognitively impaired, 5 mild cognitively impaired and 12 mild, moderate and severe AD patients. Levels of Tau?Casp6 in CSF accurately reflected the levels of active Casp6 and Tau?Casp6 detected using immunohistochemistry in hippocampal sections from the same individuals. Levels of CSF Tau?Casp6 significantly correlated with AD severity, and with lower global cognitive scores, mini mental state exam, and episodic, semantic, and working memory scores. Regression analyses suggested that the CSF Tau?Casp6 levels combined with Tau?Casp6 brain pathology predict cognitive performance. These results indicate that CSF Tau?Casp6 levels holds promise as a novel early biomarker of AD. PMID:23965742
Ramcharitar, Jasmine; Albrecht, Steffen; Afonso, Veronica M.; Kaushal, Vikas; Bennett, David A.; LeBlanc, Andrea C.
Hydrocephalus is defined as an abnormal enlargement of the ventricles of the brain due to an excessive accumulation of cerebrospinal fluid (CSF) because of a disturbance of its flow, absorption and/or secretion. The usual method of CSF diversion is a ventriculo-peritoneal shunt. Complications of implanted shunt systems include mechanical failure, shunt pathway obstruction, infection, foreign body (allergic) reaction to implants and CSF leakage along the implanted shunt pathway. These problems are solved with the use of programmable ventricular-peritoneal CSF valves. In this case, we describe a radionuclidic method for the control of successful reprogramming of the CSF valve. Furthermore, we analyze some technical data of such a valve-type are essential for the application of the above technique by nuclear medicine physicians. Scintigraphic evaluation of the electronic V-P drainage valve regulation is a noninvasive, not expensive, rapid and safe method with no complications for the patient and provides a reliable proof of the patency of the V-P shunt. PMID:19936336
Zissimopoulos, Athanassios; Birbilis, Theodossios; Cassimos, Dimitrios; Deftereos, Savas; Karathanos, Evangelos; Chatzimichael, Athanassios; Prassopoulos, Panos
Background: Spontaneous cerebrospinal fluid (CSF) rhinorrhea is a rare entity. The accurate preoperative localization of the leak point is essential for planning surgical treatment, but is sometimes difficult. To localize the leak point, magnetic resonance cisternography (MRC) is the method of choice, but its effectiveness remains unclear. Case Description: A 34-year-old mildly obese female experienced spontaneous CSF rhinorrhea after an attack of bronchial asthma. High-resolution computed tomography (CT) failed to reveal the leak point, while MRC demonstrated an arachnoid herniation at the olfactory cleft. The patient underwent endoscopic endonasal repair of the CSF leak with success. There has been no recurrence of CSF rhinorrhea for 14 months after surgery followed by the administration of acetazolamide. Conclusion: We report a rare case of spontaneous CSF rhinorrhea associated with benign intracranial hypertension, in which the leak point was successfully detected by MRC. The CSF leak was completely repaired by minimally invasive endoscopic endonasal surgery. MRC may be a reliable method for detecting CSF leak points. PMID:24872916
Matsubara, Teppei; Akutsu, Hiroyoshi; Tanaka, Shuho; Yamamoto, Tetsuya; Ishikawa, Eiichi; Matsumura, Akira
The patterns of cerebrospinal fluid (CSF) flow within the human ventricular system are still not fully understood in all their complexity. Knowledge is based on either the interpretation of CSF flow curves or computational simulations. Both approaches only provide an incomplete insight into the spatial and temporal dynamics of CSF flow. Time-resolved three-dimensional magnetic resonance velocity mapping has previously been used to investigate normal and pathologic blood flow patterns in the human vascular system. Here we used this technique to study the spatial and temporal dynamics of CSF flow in the ventricular system of 40 normal volunteers. Classification of the patterns of CSF flow based on calculation of three-dimensional particle path lines over the cardiac cycle revealed one uniform flow pattern for the lateral ventricles, three categories for the third and two categories for the fourth ventricle. We found no significant aging effects on either the presence of a specific CSF flow pattern or on CSF flow velocities. Our results provide the first detailed demonstration of the patterns of CSF flow within the human ventricular system. PMID:20152907
Stadlbauer, Andreas; Salomonowitz, Erich; van der Riet, Wilma; Buchfelder, Michael; Ganslandt, Oliver
Histaminergic neurons of the hypothalamic tuberomammillary nucleus constitute a major wake-promoting system. In animals, cerebrospinal fluid (CSF) histamine levels are increased during wakefulness and after sleep deprivation and decreased during sleep. An involvement of the histamine system in human disorders has not, to our knowledge, been reported. We measured hypocretin-1 and histamine levels in the lumbar CSF of 28 patients with and without excessive daytime sleepiness (EDS) as assessed by the Epworth Sleepiness Scale (ESS). There were 10 patients with EDS (ESS > 10, mean ESS = 14). Diagnoses included narcolepsy (n = 4), idiopathic hypersomnia (n = 2), sleep apnoea (n = 2) and multiple sclerosis (n = 2). Three patients were treated with stimulants. Their mean CSF histamine was 258 � 159 PM. There were 18 patients without EDS (ESS < 9, mean ESS = 5). No patients were treated with stimulants. Their mean CSF histamine was significantly higher (624 � 481 PM, P = 0.007). There was a significant inverse correlation (r = -0.48, P = 0.02) between ESS and both CSF histamine and hypocretin-1 levels. These observations suggest that narcolepsy and EDS of other origin are associated in humans with lower CSF histamine levels and therefore with a reduced activity of the wake-promoting histaminergic neuronal system. PMID:20846244
Bassetti, Claudio L; Baumann, Christian R; Dauvilliers, Yves; Croyal, Michael; Robert, Philippe; Schwartz, Jean-Charles
Elevated or reduced velocity of cerebrospinal fluid (CSF) at the craniovertebral junction (CVJ) has been associated with type I Chiari malformation (CMI). Thus, quantification of hydrodynamic parameters that describe the CSF dynamics could help assess disease severity and surgical outcome. In this study, we describe the methodology to quantify CSF hydrodynamic parameters near the CVJ and upper cervical spine utilizing subject-specific computational fluid dynamics (CFD) simulations based on in vivo MRI measurements of flow and geometry. Hydrodynamic parameters were computed for a healthy subject and two CMI patients both pre- and post-decompression surgery to determine the differences between cases. For the first time, we present the methods to quantify longitudinal impedance (LI) to CSF motion, a subject-specific hydrodynamic parameter that may have value to help quantify the CSF flow blockage severity in CMI. In addition, the following hydrodynamic parameters were quantified for each case: maximum velocity in systole and diastole, Reynolds and Womersley number, and peak pressure drop during the CSF cardiac flow cycle. The following geometric parameters were quantified: cross-sectional area and hydraulic diameter of the spinal subarachnoid space (SAS). The mean values of the geometric parameters increased post-surgically for the CMI models, but remained smaller than the healthy volunteer. All hydrodynamic parameters, except pressure drop, decreased post-surgically for the CMI patients, but remained greater than in the healthy case. Peak pressure drop alterations were mixed. To our knowledge this study represents the first subject-specific CFD simulation of CMI decompression surgery and quantification of LI in the CSF space. Further study in a larger patient and control group is needed to determine if the presented geometric and/or hydrodynamic parameters are helpful for surgical planning. PMID:24130704
Martin, Bryn A.; Kalata, Wojciech; Shaffer, Nicholas; Fischer, Paul; Luciano, Mark; Loth, Francis
Cerebrospinal fluid (CSF) dynamics in the spinal subarachnoid space (SSS) have been thought to play an important pathophysiological role in syringomyelia, Chiari I malformation (CM), and a role in intrathecal drug delivery. Yet, the impact that fine anatomical structures, including nerve roots and denticulate ligaments (NRDL), have on SSS CSF dynamics is not clear. In the present study we assessed the impact of NRDL on CSF dynamics in the cervical SSS. The 3D geometry of the cervical SSS was reconstructed based on manual segmentation of MRI images of a healthy volunteer and a patient with CM. Idealized NRDL were designed and added to each of the geometries based on in vivo measurments in the literature and confirmation by a neuroanatomist. CFD simulations were performed for the healthy and patient case with and without NRDL included. Our results showed that the NRDL had an important impact on CSF dynamics in terms of velocity field and flow patterns. However, pressure distribution was not altered greatly although the NRDL cases required a larger pressure gradient to maintain the same flow. Also, the NRDL did not alter CSF dynamics to a great degree in the SSS from the foramen magnum to the C1 level for the healthy subject and CM patient with mild tonsillar herniation (?6 mm). Overall, the NRDL increased fluid mixing phenomena and resulted in a more complex flow field. Comparison of the streamlines of CSF flow revealed that the presence of NRDL lead to the formation of vortical structures and remarkably increased the local mixing of the CSF throughout the SSS. PMID:24710111
Heidari Pahlavian, Soroush; Yiallourou, Theresia; Tubbs, R. Shane; Bunck, Alexander C.; Loth, Francis; Goodin, Mark; Raisee, Mehrdad; Martin, Bryn A.
Cerebrospinal fluid (CSF) dynamics in the spinal subarachnoid space (SSS) have been thought to play an important pathophysiological role in syringomyelia, Chiari I malformation (CM), and a role in intrathecal drug delivery. Yet, the impact that fine anatomical structures, including nerve roots and denticulate ligaments (NRDL), have on SSS CSF dynamics is not clear. In the present study we assessed the impact of NRDL on CSF dynamics in the cervical SSS. The 3D geometry of the cervical SSS was reconstructed based on manual segmentation of MRI images of a healthy volunteer and a patient with CM. Idealized NRDL were designed and added to each of the geometries based on in vivo measurments in the literature and confirmation by a neuroanatomist. CFD simulations were performed for the healthy and patient case with and without NRDL included. Our results showed that the NRDL had an important impact on CSF dynamics in terms of velocity field and flow patterns. However, pressure distribution was not altered greatly although the NRDL cases required a larger pressure gradient to maintain the same flow. Also, the NRDL did not alter CSF dynamics to a great degree in the SSS from the foramen magnum to the C1 level for the healthy subject and CM patient with mild tonsillar herniation (? 6 mm). Overall, the NRDL increased fluid mixing phenomena and resulted in a more complex flow field. Comparison of the streamlines of CSF flow revealed that the presence of NRDL lead to the formation of vortical structures and remarkably increased the local mixing of the CSF throughout the SSS. PMID:24710111
Heidari Pahlavian, Soroush; Yiallourou, Theresia; Tubbs, R Shane; Bunck, Alexander C; Loth, Francis; Goodin, Mark; Raisee, Mehrdad; Martin, Bryn A
Elevated or reduced velocity of cerebrospinal fluid (CSF) at the craniovertebral junction (CVJ) has been associated with type I Chiari malformation (CMI). Thus, quantification of hydrodynamic parameters that describe the CSF dynamics could help assess disease severity and surgical outcome. In this study, we describe the methodology to quantify CSF hydrodynamic parameters near the CVJ and upper cervical spine utilizing subject-specific computational fluid dynamics (CFD) simulations based on in vivo MRI measurements of flow and geometry. Hydrodynamic parameters were computed for a healthy subject and two CMI patients both pre- and post-decompression surgery to determine the differences between cases. For the first time, we present the methods to quantify longitudinal impedance (LI) to CSF motion, a subject-specific hydrodynamic parameter that may have value to help quantify the CSF flow blockage severity in CMI. In addition, the following hydrodynamic parameters were quantified for each case: maximum velocity in systole and diastole, Reynolds and Womersley number, and peak pressure drop during the CSF cardiac flow cycle. The following geometric parameters were quantified: cross-sectional area and hydraulic diameter of the spinal subarachnoid space (SAS). The mean values of the geometric parameters increased post-surgically for the CMI models, but remained smaller than the healthy volunteer. All hydrodynamic parameters, except pressure drop, decreased post-surgically for the CMI patients, but remained greater than in the healthy case. Peak pressure drop alterations were mixed. To our knowledge this study represents the first subject-specific CFD simulation of CMI decompression surgery and quantification of LI in the CSF space. Further study in a larger patient and control group is needed to determine if the presented geometric and/or hydrodynamic parameters are helpful for surgical planning. PMID:24130704
Martin, Bryn A; Kalata, Wojciech; Shaffer, Nicholas; Fischer, Paul; Luciano, Mark; Loth, Francis
Purpose: A rare complication of carotid artery stenting (CAS), prolonged reversible neurological symptoms with delayed cerebrospinal fluid (CSF) space enhancement on fluid attenuated inversion recovery (FLAIR) images, is associated with blood-brain barrier (BBB) disruption. We prospectively identified patients who showed CSF space enhancement on FLAIR images. Methods: Nineteen patients-5 acute-phase and 14 scheduled-underwent 21 CAS procedures. Balloon catheters were navigated across stenoses, angioplasty was performed using a neuroprotective balloon, and stents were placed with after dilation under distal balloon protection. CSF space hyperintensity or obscuration on FLAIR after versus before CAS indicated CSF space enhancement. Correlations with clinical factors were examined. Results: CSF space was enhanced on FLAIR in 12 (57.1%) cases. Postprocedural CSF space enhancement was significantly related to age, stenosis rate, acute-stage procedure, and total occlusion time. All acute-stage CAS patients showed delayed enhancement. Only age was associated with delayed CSF space enhancement in scheduled CAS patients. Conclusions: Ischemic intolerance for severe carotid artery stenosis and temporary neuroprotective balloon occlusion, causing reperfusion injury, seem to be the main factors that underlie BBB disruption with delayed CSF space enhancement shortly after CAS, rather than sudden poststenting hemodynamic change. Our results suggest that factors related to hemodynamic instability or ischemic intolerance seem to be associated with post-CAS BBB vulnerability. Patients at risk for hemodynamic instability or with ischemic intolerance, which decrease BBB integrity, require careful management to prevent intracranial hemorrhagic and other post-CAS complications.
Ogami, Ryo, E-mail: email@example.com; Nakahara, Toshinori [Mazda Hospital, Department of Neurosurgery (Japan); Hamasaki, Osamu [Shimane Prefectural Central Hospital, Department of Neurosurgery (Japan); Araki, Hayato [Mazda Hospital, Department of Neurosurgery (Japan); Kurisu, Kaoru [Hiroshima University Graduate School of Biomedical Sciences, Department of Neurosurgery (Japan)
NASA Astrophysics Data System (ADS)
Trace elements play an important role in the human central nervous system. Significant variations of the concentration of trace elements in body fluids may occur in neurodegenerative diseases. In the present work an investigation of the elemental composition of the serum, and the cerebrospinal fluid in amyotrophic lateral sclerosis patients and a control group was performed. For the analysis of the body fluids Total reflection X-ray Fluorescence (TXRF) spectrometry was used. The samples were taken during routine diagnostic procedures. Na, Mg, Cl, K, Ca, Cu, Zn, and Br were determined in both fluids. In order to validate the results of analysis a serum standard reference material was measured. A t-test was applied to check if the mean concentrations of the elements are different for ALS and the control group. For the serum samples higher values for Br were found in the ALS group, for the cerebrospinal fluid lower values of Na, Mg and Zn as well as higher Ca values were found in the ALS group compared to the control group.
Ostachowicz, B.; Lankosz, M.; Tomik, B.; Adamek, D.; Wobrauschek, P.; Streli, C.; Kregsamer, P.
Efficient processing of information by the central nervous system (CNS) represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB), which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF) from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF) barrier (BCSFB), which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs) that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC) transport proteins at those two barriers and underlines differences in their expression between the two barriers. Also, many blood-borne molecules and xenobiotics can diffuse into brain ISF and then into neuronal membranes due to their physicochemical properties. Entry of these compounds could be detrimental for neural transmission and signalling. Thus, BBB and BCSFB express transport proteins that actively restrict entry of lipophilic and amphipathic substances from blood and/or remove those molecules from the brain extracellular fluids. The third part of this review concentrates on the molecular biology of ATP-binding cassette (ABC)-transporters and those SLC transporters that are involved in efflux transport of xenobiotics, their expression at the BBB and BCSFB and differences in expression in the two major blood-brain interfaces. In addition, transport and diffusion of ions by the BBB and CP epithelium are involved in the formation of fluid, the ISF and CSF, respectively, so the last part of this review discusses molecular biology of ion transporters/exchangers and ion channels in the brain endothelial and CP epithelial cells. PMID:21349151
Background The influence of coughing, on the biomechanical environment in the spinal subarachnoid space (SAS) in the presence of a cerebrospinal fluid flow stenosis, is thought to be an important etiological factor in craniospinal disorders, including syringomyelia (SM), Chiari I malformation, and hydrocephalus. The aim of this study was to investigate SAS and syrinx pressures during simulated coughing using in vitro models and to provide information for the understanding of the craniospinal fluid system dynamics to help develop better computational models. Methods Four in vitro models were constructed to be simplified representations of: 1) non-communicating SM with spinal SAS stenosis; 2) non-communicating SM due to spinal SAS stenosis with a distensible spinal column; 3) non-communicating SM post surgical removal of a spinal SAS stenosis; and 4) a spinal SAS stenosis due to spinal trauma. All of the models had a flexible spinal cord. To simulate coughing conditions, an abrupt CSF pressure pulse (~ 5 ms) was imposed at the caudal end of the spinal SAS by a computer-controlled pump. Pressure measurements were obtained at 4 cm intervals along the spinal SAS and syrinx using catheter tip transducers. Results Pressure measurements during a simulated cough, showed that removal of the stenosis was a key factor in reducing pressure gradients in the spinal SAS. The presence of a stenosis resulted in a caudocranial pressure drop in the SAS, whereas pressure within the syrinx cavity varied little caudocranially. A stenosis in the SAS caused the syrinx to balloon outward at the rostral end and be compressed at the caudal end. A >90% SAS stenosis did not result in a significant Venturi effect. Increasing compliance of the spinal column reduced forces acting on the spinal cord. The presence of a syrinx in the cord when there was a stenosis in the SAS, reduced pressure forces in the SAS. Longitudinal pressure dissociation acted to suck fluid and tissue caudocranially in the SAS with a stenosis. Conclusions Pressures in the spinal SAS during a simulated cough in vitro had similar peak, transmural, and longitudinal pressures to in vivo measurements reported in the literature. The pressure wave velocities and pressure gradients during coughing (longitudinal pressure dissociation and transmural pressure) were impacted by alterations in geometry, compliance, and the presence of a syrinx and/or stenosis. PMID:20043856
Implantable device for in-vivo intracranial and cerebrospinal fluid pressure monitoring
The present invention relates to a completely implantable intracranial pressure monitor, which can couple to existing fluid shunting systems as well as other internal monitoring probes. The implant sensor produces an analog data signal which is then converted electronically to a digital pulse by generation of a spreading code signal and then transmitted to a location outside the patient by a radio-frequency transmitter to an external receiver. The implanted device can receive power from an internal source as well as an inductive external source. Remote control of the implant is also provided by a control receiver which passes commands from an external source to the implant system logic. Alarm parameters can be programmed into the device which are capable of producing an audible or visual alarm signal. The utility of the monitor can be greatly expanded by using multiple pressure sensors simultaneously or by combining sensors of various physiological types.
Ericson, Milton N. (Knoxville, TN); McKnight, Timothy E. (Greenback, TN); Smith, Stephen F. (London, TN); Hylton, James O. (Clinton, TN)
Cerebrospinal fluid (CSF) dynamics in the cervical spinal subarachnoid space (SSS) have been thought to be important to help diagnose and assess craniospinal disorders such as Chiari I malformation (CM). In this study we obtained time-resolved three directional velocity encoded phase-contrast MRI (4D PC MRI) in three healthy volunteers and four CM patients and compared the 4D PC MRI measurements to subject-specific 3D computational fluid dynamics (CFD) simulations. The CFD simulations considered the geometry to be rigid-walled and did not include small anatomical structures such as nerve roots, denticulate ligaments and arachnoid trabeculae. Results were compared at nine axial planes along the cervical SSS in terms of peak CSF velocities in both the cranial and caudal direction and visual interpretation of thru-plane velocity profiles. 4D PC MRI peak CSF velocities were consistently greater than the CFD peak velocities and these differences were more pronounced in CM patients than in healthy subjects. In the upper cervical SSS of CM patients the 4D PC MRI quantified stronger fluid jets than the CFD. Visual interpretation of the 4D PC MRI thru-plane velocity profiles showed greater pulsatile movement of CSF in the anterior SSS in comparison to the posterior and reduction in local CSF velocities near nerve roots. CFD velocity profiles were relatively uniform around the spinal cord for all subjects. This study represents the first comparison of 4D PC MRI measurements to CFD of CSF flow in the cervical SSS. The results highlight the utility of 4D PC MRI for evaluation of complex CSF dynamics and the need for improvement of CFD methodology. Future studies are needed to investigate whether integration of fine anatomical structures and gross motion of the brain and/or spinal cord into the computational model will lead to a better agreement between the two techniques. PMID:23284970
Yiallourou, Theresia I; Kr�ger, Jan Robert; Stergiopulos, Nikolaos; Maintz, David; Martin, Bryn A; Bunck, Alexander C
The blood-cerebrospinal fluid (CSF) barrier (BCB) resides within the choroid plexus, with the apical side facing the CSF and the basolateral side towards the blood. Previous studies demonstrate that manganese (Mn) exposure in rats disrupts iron (Fe) homeostasis in the blood and CSF. The present study used a primary culture of rat choroidal epithelial cells grown in the two-chamber Transwell system to investigate the transepithelial transport of Fe across the BCB. Free, unbound Fe as [59Fe] was added to the donor chamber and the radioactivity in the acceptor chamber was quantified to determine the direction of Fe fluxes. Under the normal condition, the [59Fe] efflux (from the CSF to the blood) was 128% higher than that of the influx (P < 0.01). Mn exposure significantly increased the efflux rate of [59Fe] (P < 0.01) and the effect was inhibited when the cells were pre-incubated with the antibody against divalent metal transport 1 (DMT1). Moreover, when the siRNA knocked down the cellular DMT1 expression, the elevated Fe uptake caused by Mn exposure in the choroidal epithelial Z310 cells was completely abolished, indicating that Mn may facilitate Fe efflux via a DMT1-mediated transport mechanism. In vivo subchronic exposure to Mn in rats reduced Fe clearance from the CSF, as demonstrated by the ventriculo-cisternal brain perfusion, along with up-regulated mRNAs encoding DMT1 and transferrin receptor (TfR) in the same animals. Taken together, these data suggest that free Fe appears to be favorably transported from the CSF toward the blood by DMT1 and this process can be facilitated by Mn exposure. Enhanced TfR-mediated influx of Fe from the blood and ferroportin-mediated expelling Fe toward the CSF may compromise DMT1-mediated efflux, leading to an increased Fe concentration in the CSF as seen in Mn-exposed animals. PMID:18849539
Wang, Xueqian; Li, G. Jane; Zheng, Wei
Background Amyloid accumulation in the brain parenchyma is a hallmark of Alzheimer's disease (AD) and is seen in normal aging. Alterations in cerebrospinal fluid (CSF) dynamics are also associated with normal aging and AD. This study analyzed CSF volume, production and turnover rate in relation to amyloid-beta peptide (A?) accumulation in the aging rat brain. Methods Aging Fischer 344/Brown-Norway hybrid rats at 3, 12, 20, and 30 months were studied. CSF production was measured by ventriculo-cisternal perfusion with blue dextran in artificial CSF; CSF volume by MRI; and CSF turnover rate by dividing the CSF production rate by the volume of the CSF space. A?40 and A?42 concentrations in the cortex and hippocampus were measured by ELISA. Results There was a significant linear increase in total cranial CSF volume with age: 3-20 months (p < 0.01); 3-30 months (p < 0.001). CSF production rate increased from 3-12 months (p < 0.01) and decreased from 12-30 months (p < 0.05). CSF turnover showed an initial increase from 3 months (9.40 day-1) to 12 months (11.30 day-1) and then a decrease to 20 months (10.23 day-1) and 30 months (6.62 day-1). A?40 and A?42 concentrations in brain increased from 3-30 months (p < 0.001). Both A?42 and A?40 concentrations approached a steady state level by 30 months. Conclusions In young rats there is no correlation between CSF turnover and A? brain concentrations. After 12 months, CSF turnover decreases as brain A? continues to accumulate. This decrease in CSF turnover rate may be one of several clearance pathway alterations that influence age-related accumulation of brain amyloid. PMID:22269091
The goals of this study were to elucidate the temporal and quantitative relationships between caffeine and its major bioactive metabolites in blood and cerebrospinal fluid (CSF) and to characterize the pharmacokinetic-pharmacodynamic relationship for caffeine-induced changes in spontaneous locomotor activity in the horse. We hypothesized that caffeine and its metabolites distribute efficiently into the CSF to antagonize adenosine A1 and A2a receptors and that spontaneous locomotor activity correlates well with caffeine and/or metabolite concentrations in CSF and blood. A microdialysis system was developed to allow simultaneous monitoring of locomotor activity and collection of CSF and blood samples for pharmacokinetic analysis. CSF concentrations of caffeine and its metabolites were evaluated to determine the percentage of central adenosine receptor blockade by the established standard inhibition curves. Caffeine increased the spontaneous locomotor activity for up to 4 h in a dose-dependent manner. After 3 mg/kg caffeine administration, blood caffeine concentration as well as locomotor activity increased sharply to near peak level while CSF caffeine concentrations exhibited a slow rise to a steady-state 75 min later. High correlation coefficient was found between locomotor activity and caffeine concentrations in blood (R(2 )=0.95) and in CSF (R(2) = 0.93). At 3 mg/kg dosage, theophylline was the only detectable caffeine metabolite in the CSF. The concentrations reached in the CSF were sufficient to partially block central adenosine A1 (14% blockade) and A2a (11% blockade) receptors. There were no statistically significant differences between the pharmacokinetics of caffeine in the blood and CSF. This study provides novel evidence that locomotor stimulation in horses is closely correlated with caffeine concentrations in the blood and CSF and, furthermore, is consistent with blockade of central adenosine receptors. PMID:18307508
Vickroy, T W; Chang, S-K; Chou, C-C
Background: Fibrin sealants (FS)/glues (FG) are primarily utilized in spinal surgery to either strengthen repairs of elective (e.g., intradural tumors/pathology) or traumatic cerebrospinal fluid (CSF) fistulas. Here, additional roles/benefits of FS/FG in spine surgery are explored; these include increased hemostasis, reduction of scar, reduction of the risk of infection if impregnated with antibiotics, and its application to restrict diffusion and limit some of the major complications attributed to the controversial �off-label� use of bone morphogeneitc protein (rhBMP-2/INFUSE). Methods: We reviewed multiple studies, focusing not just on the utility of FS/FG in the treatment of CSF fistulas, but on its other applications. Results: FS/FG have been primarily used to supplement elective/traumatic dural closure in spinal surgery. However, FS/FG also contribute to; hemostasis, reducing intraoperative/postoperative bleeding/transfusion requirements, length of stay (LOS)/costs, reduced postoperative scar/radiculitis, and infection when impregnated with antibiotics. Nevertheless, one should seriously question whether FS/FG should be applied to prevent diffusion and limit major complications attributed to the �off-label� use of BMP/INFUSE (e.g., limit/prevent heterotopic ossification, dysphagia/respiratory decompensation, and new neurological deficits). Conclusions: FS/FG successfully supplement watertight dural closure following elective (e.g., intradural tumor) or traumatic CSF fistulas occurring during spinal surgery. Additional benefits include: intraoperative hemostasis with reduced postoperative drainage, reduced transfusion requirements, reduced LOS, cost, scar, and prophylaxis against infection (e.g., impregnated with antibiotics). However, one should seriously question whether FS/FG should be used to contain the diffusion of BMP/INFUSE and limit its complications when utilized �off-label�. PMID:25289150
Epstein, Nancy E.
Background Progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease caused by JC virus (JCV), occurs mainly in immunocompromised patients. While JCV DNA is detected in the cerebrospinal fluid (CSF) from a certain proportion of patients suspected of having PML, JCV-negative patients may also develop brain lesions due to other infectious agents. This study assessed the prevalence of six herpesviruses in the CSF from patients diagnosed with or suspected of PML. Methods Two hundred and ninety-nine CSF specimens and clinical data were collected from 255 patients, including 31 confirmed PML cases. Quantitative PCR assays were carried out to detect the genomic DNA of JCV, herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6). Results Herpesvirus DNAs were detected in the CSF specimens from 29 of 255 patients (11.4%). HSV-1 and CMV were detected in JCV-negative patients, whereas VZV and EBV were detected in both CSF JCV-positive and -negative individuals. The herpesvirus-positive patients had underlying disorders that caused immunosuppression, such as HIV infection, congenital immunodeficiencies, and hematologic malignancies, and presented with neurologic symptoms and MRI lesions, mainly in the cerebral white matter. The median values of CSF cell counts and protein levels in the herpesvirus-positive patients were slightly higher than those in the PML patients. Conclusions The results demonstrate that herpesviruses are occasionally detected in the CSF from PML patients and immunocompromised individuals suspected of having PML. Thus, this study provides a significant basis for the diagnosis and treatment of neurological disorders in immunocompromised patients. PMID:24330281
Background Little is known of vitamin D concentration in cerebrospinal fluid (CSF) in Alzheimer�s disease (AD) and its relation with CSF acetylcholinesterase (AChE) activity, a marker of cholinergic function. Methods A cross-sectional study of 52 consecutive patients under primary evaluation of cognitive impairment and 17 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 28), other dementias (n = 12), and stable MCI (SMCI, n = 12). We determined serum and CSF concentrations of calcium, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), and CSF activities of AChE and butyrylcholinesterase (BuChE). Findings CSF 25OHD level was reduced in AD patients (P < 0.05), and CSF AChE activity was decreased both in patients with AD (P < 0.05) and other dementias (P < 0.01) compared to healthy controls. None of the measured variables differed between BuChE K-variant genotypes whereas the participants that were homozygous in terms of the apolipoprotein E (APOE) ?4 allele had decreased CSF AChE activity compared to subjects lacking the APOE ?4 allele (P = 0.01). In AD patients (n=28), CSF AChE activity correlated positively with CSF levels of total tau (T-tau) (r = 0.44, P < 0.05) and phosphorylated tau protein (P-tau) (r = 0.50, P < 0.01), but CSF activities of AChE or BuChE did not correlate with serum or CSF levels of 25OHD. Conclusions In this pilot study, both CSF 25OHD level and CSF AChE activity were reduced in AD patients. However, the lack of correlations between 25OHD levels and CSF activities of AChE or BuChE might suggest different mechanisms of action, which could have implications for treatment trials. PMID:24312390
Johansson, Per; Almqvist, Erik G.; Johansson, Jan-Ove; Mattsson, Niklas; Andreasson, Ulf; Hansson, Oskar; Wallin, Anders; Blennow, Kaj; Zetterberg, Henrik; Svensson, Johan
Background A decreased concentration of beta amyloid (1�42) (A?42) has consistently been found in the cerebrospinal fluid (CSF) of patients with Alzheimer�s disease (AD) and is considered a diagnostic biomarker. However, it is not clear to which extent CSF A?42 levels are reflective of cerebral pathology in AD. The aim of the study was to determine the association between cerebral amyloid plaque load, as measured by means of the positron emission tomography (PET) tracer carbon-11-labeled Pittsburgh Compound B ([11C]PiB) and CSF A?42 in AD. Methods A group of 30 patients with probable AD, as defined by established clinical criteria and by an AD-typical pattern of tracer uptake in fluorine-18-labeled fluorodeoxyglucose ([18F]FDG) PET, were included. In all patients, [11C]PiB PET and CSF analysis were performed. The association between amyloid load and CSF A?42 levels was examined in three different ways: by linear regression analysis using an overall [11C]PiB value for the entire cerebrum, by correlation analyses using [11C]PiB measurements in anatomically defined regions of interest, and by voxel-based regression analyses. Results All patients showed a positive [11C]PiB scan demonstrating amyloid deposition. Linear regression analysis revealed a significant inverse correlation between the overall [11C]PiB uptake and CSF A?42 levels. Voxel-based regression and regional correlation analyses did not attain statistical significance after correction for multiple comparisons. Numerically, correlation coefficients were higher in brain regions adjacent to CSF spaces. Conclusions The study demonstrates a moderate linear negative association between cerebral amyloid plaque load and CSF A?42 levels in AD patients in vivo and suggests possible regional differences of the association. PMID:19268916
Grimmer, Timo; Riemenschneider, Matthias; F�rstl, Hans; Henriksen, Gjermund; Klunk, William E.; Mathis, Chester A.; Shiga, Tohru; Wester, Hans-J�rgen; Kurz, Alexander; Drzezga, Alexander
In a crossover study, 5 calves were made acidotic by intermittent intravenous infusion of isotonic hydrochloric acid (HCl) over approximately 24 h. This was followed by rapid (4 h) or slow (24 h) correction of blood pH with isotonic sodium bicarbonate (NaHCO3) to determine if rapid correction of acidemia produced paradoxical cerebrospinal fluid (CSF) acidosis. Infusion of HCl produced a marked metabolic acidosis with respiratory compensation. Venous blood pH (mean � Sx) was 7.362 � 0.021 and 7.116 � 0.032, partial pressure of carbon dioxide (Pco2, torr) 48.8 � 1.3 and 34.8 � 1.4, and bicarbonate (mmol/L), 27.2 � 1.27 and 11 � 0.96; CSF pH was 7.344 � 0.031 and 7.240 � 0.039, Pco2 42.8 � 2.9 and 34.5 � 1.4, and bicarbonate 23.5 � 0.91 and 14.2 � 1.09 for the period before the infusion of hydrochloric acid and immediately before the start of sodium bicarbonate correction, respectively. In calves treated with rapid infusion of sodium bicarbonate, correction of venous acidemia was significantly more rapid and increases in Pco2 and bicarbonate in CSF were also more rapid. However, there was no significant difference in CSF pH. After 4 h of correction, CSF pH was 7.238 � 0.040 and 7.256 � 0.050, Pco2 44.4 � 2.2 and 34.2 � 2.1, and bicarbonate 17.8 � 1.02 and 14.6 � 1.4 for rapid and slow correction, respectively. Under the conditions of this experiment, rapid correction of acidemia did not provoke paradoxical CSF acidosis. PMID:22754090
Abeysekara, Saman; Zello, Gordon A.; Lohmann, Katharina L.; Alcorn, Jane; Hamilton, Don L.; Naylor, Jonathan M.
The inflammatory response in bacterial meningitis is mediated by cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1), which are produced in the subarachnoid space by different cells, e.g., leukocytes, astrocytes, and microglia. The recruitment of leukocytes into the cerebrospinal fluid (CSF) has been shown to contribute to the neurological damage in this disease, a process which could be enhanced by treatment with antibiotics. In this study, we have used a rabbit meningitis model for two sets of experiments with intracisternal (i.c.) injections of Streptococcus pneumoniae. First, pneumococcal cell wall (PCW) components were injected i.c., inducing an inflammatory response with pleocytosis and increased levels of CSF TNF-alpha) and IL-1 at 6 and 12 h after PCW injection. Treatment with fucoidin, known to inhibit leukocyte rolling, abolished pleocytosis and inhibited the release of TNF-alpha and IL-1. In the second experiment, live pneumococcal bacteria were injected i.c. and treatment with one dose of ampicillin (40 mg/kg of body weight intravenously) was given 16 h after induction of meningitis, causing a sevenfold increase in CSF leukocytes over a 4-h period. CSF IL-1 levels at 16 h were high but did not increase further at 20 h. Also, CSF TNF-alpha levels were high at 16 h and tended to increase at 20 h. Fucoidin treatment prevented the antibiotic-induced increase of CSF leukocytes but had no effect on the TNF-alpha and IL-1 levels. Taken together, fucoidin reduced CSF TNF-alpha and IL-1 levels in acute bacterial meningitis induced by PCW fragments but had no effect later in the course of the disease, when live bacteria were used and an inflammatory increase was caused by a dose of antibiotics. PMID:10225856
Granert, C; Raud, J; Waage, A; Lindquist, L
Purpose In order to predict whether tumor markers assist in the histopathologic diagnosis of germ cell tumors (GCTs), we analyzed the correlation of beta human chorionic gonadotropin (bHCG) and alpha-fetoprotein (AFP) in serum and cerebrospinal fluid (CSF) samples at baseline and subsequent follow-up examinations. Method A retrospective study of patients diagnosed with intracranial GCTs between July 1985 and February 2011 at our institution was conducted to review clinical, surgical, radiological, laboratory and histopathologic data. Results Of 67 patients eligible for the study, 42 had germinomas and 25 non germinomatous GCTs. At baseline, serum and CSF AFP agreed in 97.9% of patients (Cohen�s Kappa 0.93). Baseline bHCG samples agreed in only 72.5% of patients (Cohen�s Kappa 0.46). In most cases, values were higher in serum for AFP and in CSF for bHCG. ROC curves estimated from logistic regression model indicated that CSF and serum samples had almost equal diagnostic utility, and the DeLong test showed that the difference in area under curves was not statistically significant. During follow-up (185 paired CSF and serum values from 43 patients), 90.3% of AFP values correlated between CSF and serum (Cohen�s Kappa 0.22, showing fair agreement). For bHCG, 96.2% of values agreed in serum and CSF (Cohen�s Kappa 0.61). Conclusions In some patients, intracranial GCTs can be diagnosed based solely upon positive serum AFP values. In addition, marker values from serum only may be sufficient to predict tumor relapse at interval follow-up examinations. PMID:22547227
Qaddoumi, Ibrahim; Sane, Miheer; Li, Shaoyu; Kocak, Mehmet; Pai-Panandiker, Atmaram; Harreld, Julie; Klimo, Paul; Wright, Karen; Broniscer, Alberto; Gajjar, Amar
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive dementia (RPD) that can be difficult to identify ante-mortem, with definitive diagnosis requiring tissue confirmation. We describe the clinical, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and electroencephalogram (EEG) measures of a small cohort of 30 patients evaluated for RPD. Clinical and diagnostic measures were cross-sectionally obtained from 17 sCJD patients (15 definite, 2 probable), 13 non-prion rapidly progressive dementia patients (npRPD), and 18 unimpaired controls. In a subset of patients (9 sCJD and 9 npRPD) diffusion tensor imaging (DTI) measures [fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)] were also obtained for the caudate, corpus callosum, posterior limb of the internal capsule, pulvinar, precuneus, and frontal lobe. Differences among groups were assessed by an analysis of variance. Compared to npRPD individuals, sCJD patients had cerebellar dysfunction, significantly higher CSF tau, �positive� CSF 14-3-3, and hyperintensities on diffusion weighted imaging (DWI) that met previously established imaging criteria for sCJD. EEG changes were similar for the two groups. In addition, sCJD patients had significant decreases in DTI measures (MD, AD, RD but not FA) within the caudate and pulvinar compared to either npRPD patients or unimpaired controls. Our results confirm that CSF abnormalities and MRI (especially DWI) can assist in distinguishing sCJD patients from npRPD patients. Future longitudinal studies using multiple measures (including CSF and MRI) are needed for evaluating pathological changes seen in sCJD patients. PMID:22968768
Wang, Leo H.; Bucelli, Robert C.; Patrick, Erica; Rajderkar, Dhanashree; Alvarez, Enrique; Lim, Miranda M.; DeBruin, Gabriela; Sharma, Victoria; Dahiya, Sonika; Schmidt, Robert E.; Benzinger, Tammie S.; Ward, Beth A.; Ances, Beau M.
Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 � 10(-7)) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman's rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders. PMID:24105442
Luykx, J J; Bakker, S C; van Geloven, N; Eijkemans, M J C; Horvath, S; Lentjes, E; Boks, M P M; Strengman, E; DeYoung, J; Buizer-Voskamp, J E; Cantor, R M; Lu, A; van Dongen, E P A; Borgdorff, P; Bruins, P; Kahn, R S; Ophoff, R A
Caffeine, the most widely consumed psychoactive drug and a weak adenosine receptor antagonist, can be neuroprotective or neurotoxic depending on the experimental model or neurologic disorder. However, its contribution to pathophysiology and outcome in traumatic brain injury (TBI) in humans is undefined. We assessed serial cerebrospinal fluid (CSF) concentrations of caffeine and its metabolites (theobromine, paraxanthine, and theophylline) by high-pressure liquid chromatography/ultraviolet in 97 ventricular CSF samples from an established bank, from 30 adults with severe TBI. We prospectively selected a threshold caffeine level of > or = 1 micromol/L (194 ng/mL) as clinically significant. Demographics, Glasgow Coma Scale (GCS) score, admission blood alcohol level, and 6-month dichotomized Glasgow Outcome Scale (GOS) score were assessed. Mean time from injury to initial CSF sampling was 10.77+/-3.13 h. On initial sampling, caffeine was detected in 24 of 30 patients, and the threshold was achieved in 9 patients. Favorable GOS was seen more often in patients with CSF caffeine concentration > or = versus < the threshold (55.6 versus 11.8%, P=0.028). Gender, age, admission CGS score, admission blood alcohol level, and admission systolic arterial blood pressure did not differ between patients with CSF caffeine concentration > or = versus < the threshold. Increases in CSF concentrations of the caffeine metabolites theobromine and paraxanthine were also associated with favorable outcome (P=0.018 and 0.056, respectively). Caffeine and its metabolites are commonly detected in CSF in patients with severe TBI and in an exploratory assessment are associated with favorable outcome. We speculate that caffeine may be neuroprotective by long-term upregulation of adenosine A1 receptors or acute inhibition of A2a receptors. PMID:17684518
Sachse, Kathleen T; Jackson, Edwin K; Wisniewski, Stephen R; Gillespie, Delbert G; Puccio, Ava M; Clark, Robert S B; Dixon, C Edward; Kochanek, Patrick M
There is growing interest in studying oxytocin biology in the context of social functioning in human and non-human primates. Studies of human subjects are typically restricted to peripheral oxytocin assessments because opportunities to collect cerebrospinal fluid (CSF) are rare. A few studies have exam