text:
Parkinson's Disease
Volume 2011 (2011), Article ID 941268, 8 pages
Idiopathic REM Sleep Behavior Disorder: Implications for the Pathogenesis of Lewy Body Diseases
Department of Neurology, Center of Sleep Medicine, School of Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan
Received 11 October 2010; Accepted 15 February 2011
Academic Editor: Irena Rektorova
Copyright © 2011 Tomoyuki Miyamoto et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objectives. Both results of the odor identification and cardiac 123I-metaiodobenzylguanidine accumulation have been investigated for their potential to enhance the detection of pathogenesis resembling that of Lewy body-related α-synucleinopathies in patients clinically diagnosed as having idiopathic REM sleep behavior disorder. Methods. We performed both the Odor Stick Identification Test for Japanese and 123I-metaiodobenzylguanidine scintigraphy in 30 patients with idiopathic REM sleep behavior disorder, 38 patients with Parkinson's disease, and 20 control subjects. Results. In idiopathic REM sleep behavior disorder, reduced odor identification score and an early or delayed heart to mediastinum ratio on 123I-metaiodobenzylguanidine were almost as severe as in Parkinson's disease patients. Delayed cardiac 123I-metaiodobenzylguanidine uptake was even more severe in the idiopathic REM sleep behavior disorder group than in the Parkinson's disease group. Conclusions. Reduced cardiac 123I-metaiodobenzylguanidine uptake, which is independent of parkinsonism, may be more closely associated with idiopathic REM sleep behavior disorder than olfactory impairment.
1. Introduction
REM sleep behavior disorder (RBD) is characterized by dream-enacting behaviors and unpleasant dreams and presents a risk for self-injury and harm to others due to abnormal REM sleep during which control of muscle tonus is lacking (REM sleep without atonia) [1, 2]. RBD is a heterogeneous disease entity consisting of a variety of manifestations [1]. Idiopathic RBD (iRBD), which develops in middle age or later and progresses chronically, in particular is a common clinical manifestation of Lewy body-related syndrome and is regarded as a clinical entity from the pathological aspect. For example, it has been elucidated that iRBD is often accompanied by soft motor signs, olfactory and color identification deficits, decreased cardiovascular and respiratory changes between REM and NREM sleep, reduced cardiac 123I-metaiodobenzylguanidine (123I-MIBG) uptake, impairment of visual memory and visuospatial construction on neuropsychological testing, EEG slowing during wakefulness or sleep, and decreased strial dopaminergic innervations, and reduced presynaptic strial dopamine transporter binding on SPECT or positron emission topography (PET) scans, which are considered as nonmotor symptoms of Parkinson's disease (PD) [3–5]. Furthermore, despite the limited number of pathological reports on iRBD, the characteristics of iRBD have been supported to have a close relationship with Lewy body pathology [6]. Therefore, additional clinical features that could distinguish iRBD with Lewy body-related α-synucleinopathies from iRBD from other causes would be helpful in clinical practice. Recently, an association between loss of olfactory function and loss of cardiac noradrenergic innervation in PD has been noted [7]. Moreover, both loss of sense of smell and cardiac sympathetic denervation can precede the onset of motor symptoms, suggesting that the combination might provide a biomarker for the risk of Lewy body disease [8].
In this study, by the combination of tests to detect odor identification [9] and to determine cardiac 123I-MIBG cardiac uptake [4, 5] that were selected from among various tests to examine nonmotor symptoms of PD, we investigated if there was an association between olfaction and cardiac 123I-MIBG uptake in patients with iRBD and PD to evaluate the correlation between results of these two tests and to determine which would more enhance the detection of pathogenesis resembling that of Lewy body-related α-synucleinopathies in patients clinically diagnosed as having iRBD.
2. Methods
2.1. Patient Selection
This study was performed in accordance with the Declaration of Helsinki. Procedures were approved by the Ethics Review Committee of Dokkyo Medical University, and informed consent was obtained from each subject. Subjects were 82 patients matched according to age group: 30 had iRBD (iRBD group; years; 25 males, 5 females), 38 had PD (PD group; years; 24 males, 14 females), and 20 had obstructive sleep apnea (OSA) without RBD (control group; years; 18 males, 2 females; pretreatment events/h) (Table 1). RBD and OSAS were defined according to the International Classification of Sleep Disorders, second edition [2]. Exclusion criteria were an abnormal neurologic examination in subjects with iRBD and OSAS. PD patients fulfilled the United Kingdom Parkinson's Disease Society Brain Bank criteria for idiopathic PD [10]. Parkinsonism was assessed and classified according to the Hoehn and Yahr stage [11] and the motor subset of Unified Parkinson's Disease Rating Scale (UPDRS-III), which was administered to the PD and iRBD groups [12]. The mean UPDRS-III score was points for PD patients and points for the iRBD subjects. There were two phenotypes of PD among the PD group: tremor-dominant and postural instability gait difficulty-(PIGD-) dominant based on UPDRS components. The mean PIGD score was defined as the sum of an individual's baseline falling, freezing, walking, gait, and postural stability scores divided by 5. Patients were categorized as having tremor-dominant PD if the ratio of the mean tremor score to the mean PIGD score was 1.5 or higher and as having PIGD-dominant PD if that ratio was 1.00 or lower [13]. According to that categorization, 13 patients in the PD group were placed in the tremor-dominant subgroup and 21 in PIGD-dominant subgroup. For this particular study, all patients with Mini-Mental State Examination (MMSE) scores <24 were excluded [14].
2.2. Polysomnographic Evaluation and Definition of iRBD
Polysomnographic (PSG) monitoring included electroencephalography (C3, C4, O1, and O2), electrooculography, chin muscle electromyography (EMG), electrocardiography, detection of airflow by thermistor, plethysmography for ribcage and abdominal wall motion, oximetry for measurement of arterial oxyhemoglobin saturation, detection of changes in sleeping position, and bilateral EMG of the tibialis anterior muscles. PSG monitoring was performed for at least 8 h. Sleep stages were manually scored according to criteria of Rechtschaffen and Kales [15]. Apnea was defined as the absence of breathing for more than 10 s. Hypopnea was defined as a reduction of more than 50% in breathing; when the reduction in breathing was less than 50%, more than 3% oxygen desaturation or arousal for more than 10 s was defined as hypopnea. The apnea-hypopnea index was calculated as the average of the total number of apnea and hypopnea episodes experienced per hour of sleep. For the iRBD group, the presence of REM sleep without atonia was based on EMG findings of excessive sustained or intermittent elevation of submental EMG tone or excessive phasic submental or lower limb EMG twitching according to the ICSD-2ed [2].
2.3. Cardiac 123I-MIBG Scintigraphy
123I-MIBG planar images of the chest were obtained using a triple-headed gamma camera (GCA-9300A-HG, Toshiba Co, Tokyo, Japan). 123I-MIBG (Fujifilm RI Pharma Co., Tokyo, Japan) accumulations were recorded at the early (15 min) and delayed phases (4 h). The heart-to-mediastum (H/M) ratio was calculated by dividing the count density of the left ventricular region of interest (ROI) by that of the mediastinal ROI [16–18]. None of the subjects took medications that could influence the 123I-MIBG examination, and none had a history of cardiac disease.
2.4. Odor Stick Identification Test for Japanese (OSIT-J)
The Odor Stick Identification Test for Japanese (OSIT-J) (Daiichi Yakuhin, Co., Ltd., Tokyo, Japan) is composed of 12 different odorants familiar to the Japanese population [9]. All subjects were free from other conditions that can affect olfactory function such as usage of certain medications, chronic nasal infection, chronic sinonasal disease, head trauma, and abuse of drugs or alcohol by medical history. Subjects with an infection of the upper airways at the time of the investigation were also not allowed to participate. OSIT-J was performed as previously described. In this study, functional hyposmia was defined by an OSIT-J score ≤8 [9].
2.5. Statistical Analysis
Values are expressed as mean ± SD. Age, MMSE, OSIT-J scores and degrees of accumulation based on the H/M ratio (early and delayed phase) in cardiac muscle obtained were compared among the three groups by the one-way analysis of variance (ANOVA) followed by post-hoc Bonferroni correction. The Mann-Whitney U-test was applied for statistical comparisons of disease duration and scores of the motor subsets of the UPDRS between the iRBD and PD groups. Group comparisons of the frequency of genders and smokers were performed by the Chi-square test for categorical variables. The correlations of OSIT-J and early or delayed 123I-MIBG uptake were assessed by the Spearman correlation coefficient for iRBD and PD. To explore the most influential factor on the OSIT-J score, we included age, sex, disease duration, MMSE, Hoehn and Yahr stage, UPDRS motor subsets, motor phenotypes, levodopa-equivalent unit (LEU), smoking status, and delayed 123I-MIBG uptake in a multiple regression analysis for PD. Receiver operating characteristic (ROC) curves were analyzed. The significance level was set at . Statistical analyses were performed with the Statistical Package for Social Science Software (Graphpad Prism, San Diego, CA and SPSS II Windows Ver 11.0, Japan).
3. Results
A total of 30 iRBD patients (mean symptom duration: ), 38 PD patients, and 20 control subjects with a similar age distribution were evaluated. Demographic information is presented in Table 1. Interval between 123I-MIBG examinations and OSIT-J was a mean of 72 days.
Cardiac 123I-MIBG accumulation based on H/M (early phase, delayed phase) was significantly decreased in the iRBD group (, ) and the PD group (, ) compared with the control group (, ) (). OSIT-J scores were significantly lower in the iRBD group () and the PD group () than in the control group (Table 1). As shown in Table 2, results of multiple regression analysis of OSIT-J-related parameters in patients with PD, which included age, sex, disease duration, MMSE, Hoehn and Yahr stage, UPDRS motor subset, motor phenotype, LEU, smoking status, and delayed H/M ratio, showed that age, sex, and delayed H/M ratio were the significant factors in the model for the OSIT-J score. There was a significant positive correlation between the OSIT-J score and delayed H/M ratio (, , Spearman's correlation). On the other hand, results of multiple regression analysis of OSIT-J-related parameters in patients with iRBD, which included age, sex, disease duration, MMSE, UPDRS motor subset, smoking status, and delayed H/M ratio, showed that there were no significant factors in the model for the OSIT-J score. Among the iRBD group, there was no significant correlation between the OSIT-J score and delayed H/M ratio (, , Spearman's correlation) or the duration of RBD (, , Spearman's correlation).
ROC analysis of the early or delayed H/M ratio and odor identification showed an area under the curve of 0.96 (95%, ), 0.99 (95%, ) and 0.96 (95%, ) for iRBD (Figure 1(a)) and of 0.84 (95%, ), 0.88 (95%, ) and 0.98 (95%, ) for PD (Figure 1(b)).
For differentiating the iRBD patients from control subjects, the sensitivity and specificity of the OSIT-J score with a cut-off value at 8.5 were 90.0% and 83.3%, respectively; those of the early H/M ratio with a cut-off value at 2.30 were 95.0% and 86.7%, respectively, and those of a delayed H/M ratio with a cut-off value at 2.03 were 95.0% and 96.7%, respectively (Table 3). For differentiating PD patients from control subjects, the sensitivity and specificity of the OSIT-J score with a cut-off value at 8.5 were 90.0% and 92.1%, respectively; those of the early H/M ratio with a cut-off value at 2.30 were 95.0% and 71.1%, respectively; and those of the delayed H/M ratio with a cut-off value at 2.03 were 95.0% and 71.1%, respectively (Table 3). With optimal cut-off values set at 2.03 for the delayed H/M ratio and at 8.5 for OSIT-J score for iRBD patients (Table 3, Figure 2), identification of iRBD was confirmed in 23 (76.7%) patients in the iRBD group through abnormal results of both of these tests. Optimal cut-off values were set at 2.03 for delayed H/M ratio and at 8.5 for OSIT-J score for PD patients (Table 3, Figure 2); as a result, 25 (65.8%) were confirmed through abnormal results of both of these tests to have PD. However, results of both of these tests were normal in the control group.
4. Discussion
In this study, the olfactory dysfunction and reduced cardiac 123I-MIBG uptake that were found in most iRBD patients share similarities with those described in PD. Moreover, delayed cardiac 123I-MIBG uptake was more severe in the iRBD group than in the PD group (Figure 1(a)) while reduced odor identification was more severe in those with PD than with iRBD (Figure1(b)). Also, the degree of olfactory identification impairment correlated significantly with the degree of delayed cardiac 123I-MIBG uptake only in the PD group. Age, sex, and delayed cardiac 123I-MIBG uptake were significant factors with regard to PD patients in the model using the OSIT-J score. The degree of reduction of MIBG uptake does not match the degree of reduction in odor identification in iRBD patients but does match in PD patients. Results of a recent study indicated that the cardiac sympathetic nervous system might degenerate in parallel with the olfactory system in patients with early PD and that these two systems might degenerate at different rates of speed in advanced PD [16].
4.1. Cardiac Sympathetic Denervation Is Related to Lewy Body Pathology
There is evidence that 123I-MIBG cardiac uptake is markedly reduced in patients with Lewy body diseases such as PD, dementia with Lewy bodies (DLB), and pure autonomic failure (PAF) [17–19]. In was reported that cardiac 123I-MIBG imaging could distinguish between clinically diagnosed DLB and Alzheimer's disease (AD) with high levels of sensitivity and specificity [19]. Interestingly, pathological findings occur even in patients with DLB who have no parkinsonism. Since PAF patients do not have parkinsonism or decreased striatal dopaminergic innervation and since cardiac noradrenergic denervation occurs in both diseases, the pathogenetic mechanisms of cardiac noradrenergic denervation in Lewy body diseases differ from those producing parkinsonism and nigrostriatal dopaminergic denervation [8]. As pathological evidence [20–22], it has been proven that the Lewy body is present in cardiac sympathetic nerve postganglionic fibers and it has been suggested that Lewy body-related pathology potentially causes severe denervation and reduced 123I-MIBG uptake in the cardiac postganglionic sympathetic nerve. The reduction in 123I-MIBG uptake in sympathetic terminals was observed in cases with early-phase PD and incidental Lewy body disease (ILBD) irrespective of the presence or absence of remarkable autonomic nerve injury [17].
4.2. Olfactory Dysfunction Is Related to Lewy Body Pathology
Olfactory disturbance is present in most PD or PAF cases [8, 23, 24]. The deficit in olfaction in PD contrasts with previous reports of preserved or only mildly reduced olfaction in patients with atypical parkinsonism such as a tauopathy or multiple system atrophy [25, 26]. In dementia patients, neuropathologic studies reported neuronal alterations in several subcortical structures such as the olfactory tract/bulb, anterior olfactory nucleus, orbito-frontal cortex, hippocampus, and amygdala in the olfactory system [27]. Olfactory abnormalities have been reported in AD, but anosmia appears to be common in DLB but not in pure AD [28]. Interestingly, a Lewy body variant of AD had an increased frequency of anosmia compared with "pure" AD [29]. Furthermore, olfactory impairment is more marked in patients with mild dementia with Lewy bodies than in those with mild AD [30]. In addition to reduced odor identification prior to the onset of PD, olfactory dysfunction also has been frequently recognized in patients with ILBD [31]. Also, neuropathological olfactory bulb alpha-synclein has high specificity and sensitivity for Lewy body formation in confirmed cases of PD and DLB [32]. On the basis of pathological studies of a large number of autopsy cases, Braak et al. proposed a hypothesis as to the onset and advancement pattern of PD in that the disease developed from the medulla and olfactory bulb and extended to the pons and substantia nigra (SN) [33]. In the Honolulu-Asia Aging Study on Japanese Americans, 2,267 males without PD and dementia at the time of olfaction testing were followed up and significantly more subjects who developed olfactory dysfunction in the first 4-year follow-up period also developed PD [34]. Haehner's study was to clinically follow up patients with idiopathic hyposmia to determine the percentage of patients who developed idiopathic PD after a 4-year interval [35]. In Ponsen's prospective study involving first-degree relatives of PD patients, a low score on three olfactory processing tasks was associated with an increased risk of developing PD within 5 years [36]. The point of view that reduced odor identification is manifested at the very beginning of the development of PD has been supported. These reports indicate that the rhinencephalon may be an area of selective vulnerability for α-synuclein accumulation [37] and iRBD that develops in middle age or older progresses mostly to Lewy body diseases among synucleinopathies such as PD and DLB, which have some pathological features in common.
4.3. RBD and Relevance to Lewy Body Pathology
Men over the age of 50 years who have iRBD are at very high risk for future PD or DLB several years after the onset of RBD [38, 39]. Neuropathologic studies at autopsy of cases that had been diagnosed with RBD while alive showed that every case had Lewy bodies [6]. For example, cognitive abnormalities appeared 15 years after the onset of RBD and probable DLB was diagnosed, and eventually the presence of Lewy bodies was confirmed pathologically [40]. In PD, approximately 60% of the nigrostriatal neurons of the substantia nigra are degenerated before patients fulfill the clinical criteria of PD [41]. In some cases of PD, the patient appears to develop cortical disease before the motor sign of "stage 3" disease, whereas, iRBD patients with ILBD could be diagnosed after long-standing disease with no evidence of motor or cognitive abnormalities [3, 4]. If progression of syncleinopathies is not universal, it is essential to understand the reason. Since a variety of symptoms of PD and disorders resembling PD have been elucidated, Langston [42] proposed a "Parkinson's complex" because parkinsonism would represent only the tip of the iceberg as typically viewed by both clinicians and researchers. However, when the disease process is measured by neuronal degeneration, the presence of Lewy bodies and neuritic pathology are widespread in the central and peripheral nervous systems. From this point of view, iRBD can be positioned as an earlier preclinical stage of PD or DLB, or a variant of Lewy body-related α-synucleinopathies. To gain such an understanding, it is necessary to extract a group with abnormalities in a combination of markers from among iRBD patients and provide follow up, considering the possibility that some patients in that group may develop neurodegenerative disease. These steps may help elucidate the possibility that iRBD is the spectrum of manifestations or a subtype of Lewy body-related α-synucleinopathies.
In conclusion, reduced cardiac 123I-MIBG uptake may be more closely associated with iRBD than olfactory impairment. Moreover, odor identification impairment or cardiac sympathetic function assessed by cardiac 123I-MIBG uptake and the nigrostriatal dopaminergic function would occur and progress independently in iRBD patients or PD patients.
Limitations of this study include the small number of OSAS patients that comprise the control group. Untreated sleep apnea syndrome may be associated with physical movements during sleep [1], and, therefore, it is important to first differentiate between those with iRBD and OSAS with abnormal sleep behavior. A second limitation is that more than 80% of patients presenting at sleep centers with iRBD are men [1, 3, 39] so that the male-to-female ratio was not matched in the iRBD, PD, and control groups.
Conflict of Interests
The authors report no financial conflict of interest. This work is not an industry supported study.
The authors are indebted to their colleagues with whom they work on the RBD, namely, Y. Inoue (Japan Somnology Center, Neuropsychiatry Research Institute and Department of Somnology, Tokyo Medical University). The authors thank T. Hashimoto (Department of Radiology, Dokkyo Medical University School of Medicine) for his helpful comments.
- C. H. Schenck and M. W. Mahowald, "REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in sleep," Sleep, vol. 25, no. 2, pp. 120–138, 2002. View at Google Scholar · View at Scopus
- American Academy of Sleep Medicine, "Internal classification of sleep disorders," in Diagnosis and Cording Manual, pp. 148–152, American Academy of Sleep Medicine, Westchester, Ill, USA, 2nd edition, 2005. View at Google Scholar
- J. F. Gagnon, R. B. Postuma, S. Mazza, J. Doyon, and J. Montplaisir, "Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases," Lancet Neurology, vol. 5, no. 5, pp. 424–432, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- T. Miyamoto, M. Miyamoto, Y. Inoue, Y. Usui, K. Suzuki, and K. Hirata, "Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder," Neurology, vol. 67, no. 12, pp. 2236–2238, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- T. Miyamoto, M. Miyamoto, K. Suzuki, M. Nishibayashi, M. Iwanami, and K. Hirata, "I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder," Sleep, vol. 31, no. 5, pp. 717–723, 2008. View at Google Scholar · View at Scopus
- B. F. Boeve, M. H. Silber, C. B. Saper et al., "Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease," Brain, vol. 130, no. 11, pp. 2770–2788, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- P. H. Lee, S. H. Yeo, H. J. Kim, and H. Y. Youm, "Correlation between cardiac 123I-MIBG and odor identification in patients with Parkinson's disease and multiple system atrophy," Movement Disorders, vol. 21, no. 11, pp. 1975–1977, 2006. View at Publisher · View at Google Scholar · View at PubMed
- D. S. Goldstein and L. Sewell, "Olfactory dysfunction in pure autonomic failure: implications for the pathogenesis of Lewy body diseases," Parkinsonism and Related Disorders, vol. 15, no. 7, pp. 516–520, 2009. View at Publisher · View at Google Scholar · View at Scopus
- T. Miyamoto, M. Miyamoto, M. Iwanami, K. Suzuki, Y. Inoue, and K. Hirata, "Odor identification test as an indicator of idiopathic REM sleep behavior disorder," Movement Disorders, vol. 24, no. 2, pp. 268–273, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- A. J. Hughes, S. E. Daniel, L. Kilford, and A. J. Lees, "Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases," Journal of Neurology Neurosurgery and Psychiatry, vol. 55, no. 3, pp. 181–184, 1992. View at Google Scholar · View at Scopus
- M. M. Hoehn and M. D. Yahr, "Parkinsonism: onset, progression and mortality," Neurology, vol. 17, no. 5, pp. 427–442, 1967. View at Google Scholar · View at Scopus
- S. Fahn and R. L. Elton, "Unified Parkinson's disease rating scale," in Recent Developments in Parkinson's Disease, S. Fahn, M. Goldstein, D. Marsden, and D. B. Calne, Eds., vol. 2, pp. 153–163, Macmillan, New Jersy, NJ, USA, 1987. View at Google Scholar
- J. Jankovic and A. S. Kapadia, "Functional decline in Parkinson disease," Archives of Neurology, vol. 58, no. 10, pp. 1611–1615, 2001. View at Google Scholar · View at Scopus
- M. L. Bleecker, K. Bolla-Wilson, C. Kawas, and J. Agnew, "Age-specific norms for the Mini-Mental State Exam," Neurology, vol. 38, no. 10, pp. 1565–1568, 1988. View at Google Scholar · View at Scopus
- A. Rechtschaffen and A. Kales, A Manual of Standardized Terminology, Techniques and Scoring Systems for Sleep Stages of Human Subjects, Brain Information Service / Brain Research Institute, UCLA, Los Angeles, Calif, USA, 1968.
- M. Iijima, M. Osawa, M. Momose et al., "Cardiac sympathetic degeneration correlates with olfactory function in Parkinson's disease," Movement Disorders, vol. 25, no. 9, pp. 1143–1149, 2010. View at Publisher · View at Google Scholar
- F. Courbon, C. Brefel-Courbon, C. Thalamas et al., "Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson's disease," Movement Disorders, vol. 18, no. 8, pp. 890–897, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- K. Kashihara, M. Ohno, S. Kawada, and Y. Okumura, "Reduced cardiac uptake and enhanced washout of 123I-MIBG in pure autonomic failure occurs conjointly with Parkinson's disease and dementia with Lewy bodies," Journal of Nuclear Medicine, vol. 47, no. 7, pp. 1099–1101, 2006. View at Google Scholar · View at Scopus
- M. Yoshita, J. Taki, K. Yokoyama et al., "Value of 123I-MIBG radioactivity in the differential diagnosis of DLB from AD," Neurology, vol. 66, no. 12, pp. 1850–1854, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- S. Orimo, A. Takahashi, T. Uchihara et al., "Degeneration of cardiac sympathetic nerve begins in the early disease process of Parkinson's disease," Brain Pathology, vol. 17, no. 1, pp. 24–30, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- S. Orimo, T. Uchihara, A. Nakamura et al., "Axonal α-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson's disease," Brain, vol. 131, no. 3, pp. 642–650, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- H. Fujishiro, R. Frigerio, M. Burnett et al., "Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson's disease," Movement Disorders, vol. 23, no. 8, pp. 1085–1092, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- R. L. Doty, S. M. Bromley, and M. B. Stern, "Olfactory testing as an aid in the diagnosis of Parkinson's disease: development of optimal discrimination criteria," Neurodegeneration, vol. 4, no. 1, pp. 93–97, 1995. View at Publisher · View at Google Scholar · View at Scopus
- L. Silveira-Moriyama, C. Mathias, L. Mason, C. Best, N. P. Quinn, and A. J. Lees, "Hyposmia in pure autonomic failure," Neurology, vol. 72, no. 19, pp. 1677–1681, 2009. View at Publisher · View at Google Scholar · View at Scopus
- R. L. Doty, L. I. Golbe, D. A. McKeown, M. B. Stern, C. M. Lehrach, and D. Crawford, "Olfactory testing differentiates between progressive supranuclear palsy and idiopathic Parkinson's disease," Neurology, vol. 43, no. 5, pp. 962–965, 1993. View at Google Scholar · View at Scopus
- G. K. Wenning, B. Shephard, C. Hawkes, A. Petruckevitch, A. Lees, and N. Quinn, "Olfactory function in atypical parkinsonian syndromes," Acta Neurologica Scandinavica, vol. 91, no. 4, pp. 247–250, 1995. View at Google Scholar · View at Scopus
- P. S. Hubbard, M. M. Esiri, M. Reading, R. McShane, and Z. Nagy, "Alpha-synuclein pathology in the olfactory pathways of dementia patients," Journal of Anatomy, vol. 211, no. 1, pp. 117–124, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- R. H. McShane, Z. Nagy, M. M. Esiri et al., "Anosmia in dementia is associated with Lewy bodies rather than Alzheimer's pathology," Journal of Neurology Neurosurgery and Psychiatry, vol. 70, no. 6, pp. 739–743, 2001. View at Publisher · View at Google Scholar · View at Scopus
- J. M. Olichney, C. Murphy, C. R. Hofstetter et al., "Anosmia is very common in the Lewy body variant of Alzheimer's disease," Journal of Neurology, Neurosurgery and Psychiatry, vol. 76, no. 10, pp. 1342–1347, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- S. S. Williams, J. Williams, M. Combrinck, S. Christie, A. D. Smith, and R. McShane, "Olfactory impairment is more marked in patients with mild dementia with Lewy bodies than those with mild Alzheimer disease," Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 6, pp. 667–670, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- G. W. Ross, R. D. Abbott, H. Petrovitch et al., "Association of olfactory dysfunction with incidental Lewy bodies," Movement Disorders, vol. 21, no. 12, pp. 2062–2067, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- T. G. Beach, C. L. White, C. L. Hladik et al., "Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders," Acta Neuropathologica, vol. 117, no. 2, pp. 169–174, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- H. Braak, K. Del Tredici, U. Rüb, R. A. I. De Vos, E. N. H. Jansen Steur, and E. Braak, "Staging of brain pathology related to sporadic Parkinson's disease," Neurobiology of Aging, vol. 24, no. 2, pp. 197–211, 2003. View at Publisher · View at Google Scholar · View at Scopus
- G. W. Ross, H. Petrovitch, R. D. Abbott et al., "Association of olfactory dysfunction with risk for future Parkinson's disease," Annals of Neurology, vol. 63, no. 2, pp. 167–173, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- A. Haehner, T. Hummel, C. Hummel, U. Sommer, S. Junghanns, and H. Reichmann, "Olfactory loss may be a first sign of idiopathic Parkinson's disease," Movement Disorders, vol. 22, no. 6, pp. 839–842, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- M. M. Ponsen, D. Stoffers, J. W. R. Twisk, E. CH. Wolters, and H. W. Berendse, "Hyposmia and executive dysfunction as predictors of future Parkinson's disease: a prospective study," Movement Disorders, vol. 24, no. 7, pp. 1060–1065, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- R. Sengoku, Y. Saito, M. Ikemura et al., "Incidence and extent of lewy body-related α-synucleinopathy in aging human olfactory bulb," Journal of Neuropathology and Experimental Neurology, vol. 67, no. 11, pp. 1072–1083, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- C. H. Schenck, S. R. Bundlie, and M. W. Mahowald, "Delayed emergence of a parkinsonian disorder in 38% of 29 older, men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder," Neurology, vol. 46, no. 2, pp. 388–393, 1996. View at Google Scholar · View at Scopus
- R. B. Postuma, J. F. Gagnon, M. Vendette, M. L. Fantini, J. Massicotte-Marquez, and J. Montplaisir, "Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder," Neurology, vol. 72, no. 15, pp. 1296–1300, 2009. View at Publisher · View at Google Scholar · View at Scopus
- R. S. Turner, C. J. D'Amato, R. D. Chervin, and M. Blaivas, "The pathology of REM sleep behavior disorder with comorbid Lewy body dementia," Neurology, vol. 55, no. 11, pp. 1730–1732, 2000. View at Google Scholar · View at Scopus
- J. M. Fearnley and A. J. Lees, "Ageing and Parkinson's disease: substantia nigra regional selectivity," Brain, vol. 114, no. 5, pp. 2283–2301, 1991. View at Google Scholar · View at Scopus
- J. W. Langston, "The Parkinson's complex: parkinsonism is just the tip of the Iceberg," Annals of Neurology, vol. 59, no. 4, pp. 591–596, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus


text:
Stock market experts often provide the same words of wisdom over and over: Invest for the long haul. Diversify your portfolio. You can 't beat the market. And while this is great advice for the average investor looking to secure their retirement, these rules aren 't as hard and fast as the experts may want you to think. History has shown us there are plenty of individuals who beat the market and beat it consistently. Consider Warren Buffet or James Simons—examples of investors who executed the right combination of steady investment methods and calculated risk over decades to build truly impressive fortunes.
A basic introduction to self directed stock investing, basic technical indicators and charting, long term vs short term trading, mutual funds vs ETFs and index tracking stocks…everything you need to know to advance to the next level (options and more advanced technical analysis, swing and trend trading, index options and spreads, etc).
Serving Professional Traders Since 2008
This book collection is perfect for anyone either wanting to begin learning about trading and investing, or add a lot of quality books to their collection quickly on varied subjects and well known authors.

subset: commoncrawl


text:
The CRISPR technology could be the most im-portant new genetic engineering technique since the beginning of the biotechnology age in the 1970s. It was shown that its possible to use CRISPR to rid mice of muscular dystrophy, cure them of a rare liver disease, make human cells immune to HIV, and genetically modify monkeys. In addition there is interest in using CRISPR to gen-erate monkey models of diseases like autism, schizophrenia, Alzheimers disease, and bipolar disorder.
Further information: PDF
DKFZ (German Cancer Research Center, Deutsches Krebsforschungszentrum)
Phone: +49-6221-42 2955
Dr. Ruth Herzog
As Germany's association of technology- and patenttransfer agencies TechnologieAllianz e.V. is offering businesses access to the entire range of innovative research results of almost all German universities and numerous non-university research institutions. More than 2000 technology offers of 14 branches are beeing made accessable to businesses in order to assure your advance on the market. At www.technologieallianz.de a free, fast and non-bureaucratic access to all further offers of the German research landscape is offered to our members aiming to sucessfully transfer technologies.
email@example.com | TechnologieAllianz e.V.
Further information:
New Lithium Salts of Pentafluorophenylamide Anions as Electrolytes in Lithium Ionic Batteries
18.04.2017 | TechnologieAllianz e.V.
Gratings on glass surfaces
28.03.2017 | TechnologieAllianz e.V.
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel's Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...
"Lasers in Composites Symposium" in Aachen – from Science to Application
19.09.2017 | Event News
12.09.2017 | Event News
EMBO at Basel Life, a new conference on current and emerging life science research
06.09.2017 | Event News
Comet or asteroid? Hubble discovers that a unique object is a binary
21.09.2017 | Physics and Astronomy
Cnidarians remotely control bacteria
21.09.2017 | Life Sciences
Monitoring the heart's mitochondria to predict cardiac arrest?
21.09.2017 | Health and Medicine


text:
Our favorite patchwork scarf-maker, Margo Petitti, is back this fall, with scarves that are bigger, badder, softer, and finer than ever. Plenty of patchwork scarves, like last year, but also a number of other designs that are a little more conservative for those that find the patchwork to be too awesome.
Each scarf is made in the USA, and each is a one-of-a-kind.
At left, Margo Petitti Benito Cashmere/Silk Scarf $190.


text:
You may remember how the Tesla Motors Inc (NASDAQ:TSLA) Model S received the top U.S. crash rating by the National Highway Traffic Safety Administration (NHTSA). Rhett Allain, an associate professor of physics at Southeastern Louisiana University, was determined to find out how the Model S was so safe.
There is a lot of math involved in Allain's article, but the conclusion is that the car's ability to crumple easier makes the vehicle safer without smashing "up the human."
Allain wrote "the Tesla Model S does have an advantage ? it?s new. Most cars have some type of legacy structure that they are built on. If you want to use a 2008 engine in your traditional car, you have to have a 2008-like frame in which to put this engine. The Model S is a pure electric car. It doesn?t have these legacy issues."
Most other cars have some type of legacy structure that they are built on. Since the Model S is a pure electric car, it does not have legacy issues.
Below is a demo video of the Tesla Model S frontal crash test. You will notice how much of the car crumples and absorbs the impact before the dummy hits the air bag:


text:
February 18, 2009 - Theo Chocolate, Inc. is voluntarily recalling Peanut Butter Big Daddy and Peanut Confections because they have the potential to be contaminated with Salmonella.
The products being recalled are:
Theo Brand PEANUT BUTTER BIG DADDY
contains 3 pieces in a brown cardboard package with a red and white sleeve. This product has a 90-day shelf life with a "BEST BY" sticker located on the underneath of the package.
BEST BY dates: 8/15/2008 to 2/28/2009
Theo Brand 12 PIECE COLLECTION BOX 4.5 oz
contains peanut confections with peanut sprinkles, or individual, loose peanut confections purchased from the Theo Retail Store or website in 2, 4, 6, 12, 18 or 32 piece brown cardboard box packaging and no UPC codes. These products had a two-week shelf life.
BEST BY dates: 8/15/2008 to 12/15/2008
No known illnesses have been reported to date in connection with this product. This recall was initiated after it was determined that that the peanut product (organic peanut splits) received from Theo Chocolate's supplier, GloryBee Foods, may have been manufactured by Peanut Corporation of America (PCA) at their Texas facility. Theo Chocolate has informed FDA of its actions and is fully cooperating with the Agency.
For more information please contact Theo Chocolate at (206) 632-5100 or consult the FDA website.


text: Onion Keeper (Colors May Vary) Flag this deal What's the matter? Choose a reason Dead deal Duplicate Bad link Spam Inaccurate No value Alive again Edit deal NatassiaC Mar 22, 2012 I bought one of these a while ago and I don't know what I ever did before it. I love this thing! Reply newjerseychickxo Mar 22, 2012 I know,I feel the same way. Reply MrBklynW Mar 18, 2012 This seems like a very useful item, never know what to do with them when i only use part of it. i wrap it plastic wrap but it just looks ugly in the fridge. Reply jasoned Mar 18, 2012 With a small family we often use only part of an onion, this is a great idea for us. Reply kumslee Mar 17, 2012 ha ha... it's a cool product. I'd buy one if shipping is free. Reply sra0263 Mar 17, 2012 cool Reply Hisgelt Mar 17, 2012 I love these things!! Reply iowahawkeyes Mar 17, 2012 Sweet idea! never seen these. I'm down to buy one at this price Reply 1 like hutbay Mar 17, 2012 if you have prime shipping with amazon, other sellers sells it for about $4.50 with prime shipping Reply 1 like cdealswme Mar 17, 2012 Love the idea! If I order 1, how many keepers do I get? 1 for 1??? Reply newjerseychickxo Mar 17, 2012 just the one Reply poe601 Mar 17, 2012 I have this and it works great, highly recommended! Nice find Reply 1 like catchersmom Mar 17, 2012 I have never seen this before and for this price I can try it Reply 1 like FibroMom Mar 17, 2012 Cool Idea - I always have potions of leftover onions that I put in the fridge and forget about - this will remind me. Thanks! :) Reply 1 like newjerseychickxo Mar 17, 2012 yw:) Reply dvinegrace83 Mar 16, 2012 very cute and super affordable! i usually pass these up cuz they're pricey for what they are and i can just use a reg container, but for THAT price, i might "splurge" just cuz of the cuteness points! haha Reply 1 like newjerseychickxo Mar 17, 2012 :) Reply blackfoot Mar 16, 2012 Great price even with shipping included. Might have to pick up one. Reply 1 like Dexterous Mar 16, 2012 These are really cute, and they dropped the price. Shipping is still good. Reply 1 like newjerseychickxo Mar 16, 2012 ty Reply glwrks Mar 16, 2012 I put onion in a lot of things, and plastic wrap the unused part. These little packages always seem to get lost in the fridge. This is great being reusable + easy to spot in the fridge. Thanks Reply 1 like newjerseychickxo Mar 16, 2012 yvw:)I also have this and others.They are a life saver. Reply 1 like Christine Mar 16, 2012 how cutee!! simple, yet great idea =) Reply 1 like newjerseychickxo Mar 16, 2012 ty Reply Load More Comments


text: ThinkStock [ Man Arrested for Stabbing Co-worker near Greeley By Susan Moore January 31, 2014 Uriah James Anthony Lopez was immediately transported by ambulance to NCMC. Read More Category: Greeley News Tags: Man Stabs Co-worker Near Greeley, Stabbing at Gas and Oil Well in Weld County Send to a friend! Share on Facebook Share on Twitter Pin it! Reddit This! Share on Tumblr!


text:
News Articles
Welcome to our news section!
Bi Visibility Day 2016
Date Published: 22/09/2016
In support of Bi Visibility Day 2016, Women's Programme volunteer Sarah Harris tells us why this day is important..read more
Bi Visibility Day 2016 - Jen's Story
Date Published: 22/09/2016
In support of Bi Visibility Day 2016, Jen tells us her story about being bi and why Bi Visibility Day is important.read more
Bi Visibility Day 2016 - Sarah's Story
Date Published: 22/09/2016
In celebration of Bi Visibility Day 2016, Sarah tells us about her experiences of identifying as a bi woman and why Bi Visibility Day is important.read more
Meet our Volunteer: Yvy DeLuca
Date Published: 31/08/2016
Our amazing volunteer Yvy, who some of you may have seen working her magic across Pride, is here to tell you a bit about herself and why she got involved with the Women's programmeread more
Our Stories: Lizzie's story of experiencing abuse
Date Published: 15/08/2016
As part of our campaign: 'Lesbian and Bisexual Women & Abuse', Lizzie* tells us about her experiences of abuse.read more
Date Published: 28/07/2016
LGBT Foundation Drug & Alcohol Service in partnership with Patrick Cash and Dragonflies Theatre are hosting a free event for gay, bisexual and other men who have sex with men to enable open conversation on the subject of chemsex in Manchester.read more
ALL NEW IMPROVED: Pride in Practice!
Date Published: 25/07/2016
For the last four years our GP quality assurance service has been supporting clinicians, practice managers and staff to effectively meet the needs of lesbian, gay and bisexual people. Now the service is to be improved by becoming fully trans inclusive and by extending the project's reach to include support for dentists, optometrists and pharmacies across Greater Manchester. However, none of this is possible without the direct input of LGBT people like you …read more
Lesbian and Bisexual Women & Abuse: Coercive Control
Date Published: 21/07/2016
In support of the Women's Programme's campaign for lesbian and bisexual women on abuse, Amber Edmondson, a legal and rights-focussed writer, talks from her personal professional experience about coercive control.read more
LGBT Foundation response:UK Government Trans Equality Enquir…
Date Published: 08/07/2016
Legal processes for registering a change of gender are to be overhauled and being transgender will no longer be deemed a mental illness by any public body.However there is much more still to do as a result of the government's review of the 2004 Gender Recognition Act.read more
Statement from LGBT Sector Leaders on EU Referendum
Date Published: 30/06/2016
The Lesbian, Gay, Bisexual and Trans sectors are strong, resilient and passionately believe in equality for all. It is important this is the first message we send—one of positivity, one of strength and one of solidarity not only with our own communities but with all diverse communities—at a time when hard fought freedoms could be at threat.read more
Women's Programme Campaign Launch: Lesbian and Bisexual Wome…
Date Published: 30/06/2016
The Women's Programme's 2016 campaign 'Lesbian and Bisexual Women & Abuse' is launching on July 1st.read more
Meet our Volunteer: Samantha Steele
Date Published: 30/06/2016
As part of the Women's Programme Volunteer Corner, Samantha Steele tells us about her experience of working with lesbian and bisexual women who are seeking asylum..read more
Lesbian and Bisexual Women & Abuse: Power, norms and dom…
Date Published: 29/06/2016
To launch our campaign for lesbian and bisexual women on abuse, Women's Programme volunteer Anna Nikoghosyan talks about power, norms and domestic abuse in relationships between women.read more
Manchester to stand united in face of Orlando hate crime
Date Published: 13/06/2016read more
OPINION: PrEP needed today, not tomorrow
Date Published: 06/06/2016
Rob Cookson, Deputy Chief Executive of LGBT Foundation shares his personal views on the recent decision by NHS England not to commission PrEP - the drug that could halt the spread of HIV.read more
Missed opportunity for HIV prevention
Date Published: 31/05/2016read more
Meet our Volunteer: Rachel Cruz
Date Published: 27/05/2016
Welcome to the Women's Programme Volunteer Corner and welcome to Rachel Cruz!
Rachel has recently become a volunteer for the Women's Programme and is going to tell you a bit about her life, her identity as a trans lesbian woman and what she's been up to recently.read more
LGBT people could finally be acknowledged in the 2021 Census…
Date Published: 25/05/2016
In a positive development for LGBT communities, the next national census could be the first to ask people about their sexuality and gender identity.read more
Charity of the Year Award win at the British LGBT Awards
Date Published: 16/05/2016
We're very excited to announce that we have won the Charity of the Year Award at the RBS British LGBT Awards for our work with lesbian, gay, bisexual and trans (LGBT) communities.read more
Stand with us against Homophobia, Biphobia and Transphobia
Date Published: 16/05/2016
LGBT Foundation are taking a stand against homophobia, biphobia and transphobia by hosting a free community vigil on 17 May to commemorate International Day Against Homophobia, Biphobia and Transphobia (IDAHOBIT).read more