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300 | as compared to the individuals without amyloid pathology a faster deficit in brain glucose metabolism brain volume and cognitive performance was experienced by individuals with amyloid deposits at baseline | [24012374 23477989 27450471 26595683 28609533] | it has been revealed by postmortem analyses that healthy elderly individuals can possess extensive amyloid pathology Moreover brain imaging analyses showed that Aβ pathology was observed in up to 44 of cognitively healthy older people | [16801647] |
301 | the receptor for mar1 is thought to be lgr6 and rorα of a nuclear receptor 737475 figure 1 mar1 exerts a potent antiinflammatory effect and promotes the macrophage phagocytosis and efferocytosis of apoptotic cells | [31657786 32360520 30855276 19103881 22253477] | the following sections will focus on mar1 rvd1 and npd1 which are produced in the human brain and discuss the relationship among these spms and ad mar1 is produced from dha by 15-lox and 5-lox. | [26650044 28004822 29757195] |
302 | the development of an nfl assay in plasma follows a greater trend in the ad community focused on developing plasma biomarkers to measure βamyloid aβ and tau pathologies plasma biomarkers have the potential to transform the tracking of biological effects of drugs in clinical trials by significantly reducing common barriers for sample collection such as high measurement cost timeconsuming procedures eg mri or aversion to lumbar puncture | [29420472 32123385 32123386 32333900 30171200] | comparing progression biomarkers in clinical trials of early alzheimer’s disease neurofilament light nfl is a cytoskeletal protein which is released from injured neurons in several neurodegenerative diseases including in alzheimers disease ad nfl concentration measured in cerebrospinal fluid csf nfl has served as a biomarker for axonal injury and neurodegeneration in research and to some degree clinical practice for decades and recently a highly sensitive assay has been developed to reliably measure nfl in plasma pnfl recent work has shown that pnfl levels increase over time in mild cognitive impairment and ad and are associated with brain atrophy in adassociated brain regions | [] |
303 | the vgfderived peptide tlqp62 regulates neuronal activity neural progenitor proliferation memory formation and depressionlike behavior via mechanisms largely dependent on bdnftrkb signaling and was never previously shown to be causal to ad | [26180209 28594546 29158577 26180209 24747217 30022437] | the vgf vgf gene we identified and validated is ngf and bdnf inducible and expressed in neurons in many different brain regions encoding a 615aminoacid 617 in mouse precursor polypeptide that is processed into several bioactive peptides regulating neuronal activity and survival neurogenesis energy balance and lipolysis and behavior vgf is robustly regulated in the hippocampus by voluntary exercise and by bdnftrkb signaling and in our studies vgf overexpression rescued cognitive deficits and neurogenesis in 5xfad mice figs and | [26180209 24747217 15233376 25675362 30022437 18059283 7551568] |
304 | tyr682 phosphorylation regulates app binding to specific adaptors and thus controls app endocytosis and distribution in neurons | [26658856 11544248 11606195 11279131 21266574] | as bace1 is optimally active in acidic environments such as in the late endosome and lysosome it is reasonable that increased aβ peptide production might be due to a preferential app trafficking towards such organelles we and others previously reported that the tyrosine 682 tyr682 residue in the 682yenpty687 motif of app is crucial for app trafficking in neurons | [20687525 10531052 31039414 14736502 26658856 25287911 19602287] |
305 | the paradoxical disconnect of classic ad pathologic changes without clinical dementia and the converse progressive dementia without pathologic ad changes could be explained by the presence or absence of disruption to normal bbb and glymphatic clearance | [14656067 1961359 16801647 24585367 21516511] | this ultimately leads to development, accumulation, and spread of toxic misfolded proteins (aβ and hp tau) and neurodegeneration, all required for pathologic diagnosis. the latter occurrence leads to dysfunction and death of neurons and supporting glia with loss of cognitive function | [26848654 24005412 25492702 26635213] |
306 | in fact researchers have found evidence pointing to the presence of pathogens such as viruses bacteria and fungi in ad brains | [22899188 30250480 25932012 25182736 30338482] | the cytokines interleukin 1 and interleukin 6 are especially elevated one source of the neuroinflammation in ad patients could be the response to invading microorganisms and viruses. | [20182045] |
307 | furthermore a number of studies have shown that trem2 is related with microglial phenotype switching in neurological disorders including ad | [29621548 26802771 28930663 31379859 28602351] | furthermore knockdown of trem2 in microglia suppresses phagocytic activity and activates gene transcription of tnfα whereas overexpression of trem2 in microglia not only promotes phagocytosis but also diminishes proinflammatory responses particularly it was shown that upregulated trem2 expression in the 5xfad mice reduced aβ plaque and neurite dystrophy and improved cognitive function and promoted microglial phagocytosis | [15728241 29518357] |
308 | for example in one study genechip and microfluidic fluorescent arraybased andor lednorthern dot blot mirna analysis that interrogates the entire 2650 mirnas yet characterized in human brain tissues revealed a selective upregulation of mirna146a in 3636 short postmortem interval pmi human superior temporal lobe neocortical tissue specimens analyzed compared to 30 age gender and pmimatched controls all pmis 31 h mirna146a levels were found to range from 17 to 36fold greater in ad than in age gender and pmimatched controls in the same anatomical regions | [28838542 23217212 20937840 30083102 22138609 23217212 20937840 30083102] | this wellcharacterized subset of rapidly activateable mirnas defines a subfamily of mirna all containing onetoseveral nfkb p50p65 recognition features in the immediate 5 upstream sequence of their proximal promoter regulatory regions one of these mirnas is mirna146a normally only moderately abundant in the human brain neocortex and hippocampus but inducible to many times its basal level by pathogenic agents associated with stress proinflammatory glycolipids such as lps local levels of reactive oxygen species ros and the abundance of aβ42 peptides and prion amyloids whose accumulation are characteristic respectively of the human disorders alzheimers disease ad and prion disease prd | [30734227 23217212 22138609 23217212 20937840 28193766] |
309 | interleukin1β il1β is an important proinflammatory cytokine in the brain it is generated by the cytosolic nucleotidebinding domain leucinerichcontaining family pyrin domaincontaining3 nlrp3 inflammasomes where nucleotidebinding oligomerizationdomainlike receptors nlrs are engaged resulting in increased il1β release evidence is growing that il1β plays a central role in ad progression the nlrp3il1β is synthesized and released from activated microglia and astrocytes | [ 3487617 1784142 25625584 2529544 2091832] | the pathophysiology of ad is characterized by abnormal extracellular accumulation of amyloidβ peptide aβ in amyloid plaques and abnormal intracellular accumulation of tau protein in neurofibrillary tangles nfts several theories are published regarding the ad pathogenesis the amyloid cascade theory proposes that the accumulation of aβ plaques in the brain is the primary pathogenic event the tau hypothesis proposes that tau hyperphosphorylation is the underlying etiology the cholinergic theory suggests ad is associated with a reduction in the choline acetyltransferase activity and acetylcholine levels in specific areas of the brain such as the cerebral cortex these proposed disease mechanisms result in a loss of synaptic function mitochondrial damage activation of microglia and neuronal death neuroinflammation is mediated primarily by microglia cells and neuroinflammation contributes to ad pathogenesis microglia activation has a dual effect on ad progression it leads to a a reduction of aβ accumulation by increasing phagocytosis clearance and degradation and b the release of proinflammatory cytokines and triggers the inflammatory cascade that contributes to neuronal damage and death | [27547756 7997077 2424016 2423512 3083509 2424015 66473 26207229
2874657 3670729 3263583 26207229] |
310 | in the second phase of their study daniels and colleagues showed that the fenamate drug class also prevented aβinduced memory deficits in rats and it decreased adrelated neuroinflammation in three adtransgenic tg mice that expressed the presenilin mutation ps1m146v the mutant amyloid precursor protein appswe and a transgene of the human mutant p301 tau gene taup301l transgene these animals develop a progressive neuropathological phenotype with increasing age that includes aβ plaques and neurofibrillary tangles fenamate treatment was associated with decreased il1β expression and microglial activation in ad mice equivalent to levels in wildtype mice | [27509875 8878479 11520987 15509565 28601278 27509875] | in 2016 daniels and colleagues also detected a protective effect of the fenamate class of nsaids against ad and they hypothesized that it was due to inhibition of il1β release from the nlrp3 inflammasome in immortalized mouse bonemarrowderived macrophages in the initial in vitro phase of their study the fenamates flufenamic acid mefenamic acid and meclofenamic acid were more effective at inhibiting il1β release than celecoxib or ibuprofen which had no effect on il1β release in contrast diclofenac was associated with a modest but significant reduction in il1β release | [27509875 27509875] |
311 | for example familial ad fad mutations have been identified in app and presenilin ps the catalytic subunit of gs | [ 1671712 7638622 7596406 10801983 21115843] | aβ aggregates are thought to trigger a cascade of reactions involving neurofibrillary tangle (nft) formation, neuronal death, neuroinflammation and, ultimately, cognitive decline. this hypothesis has significant genetic support. | [] |
312 | a review of the literature indicates that measures of neuroticism and conscientiousness show the largest and most reliable change before and after the onset of dementia in sporadic ad these same factors typically also show large differences between cognitively healthy older adults and those with either mild or very mild dementia furthermore evidence suggests that high levels of neuroticism andor low levels of conscientiousness confer the greatest risk for developing dementia in healthy older adults given the predictive power of personality recent guidelines have even suggested incorporating these measures into clinical diagnoses of dementia | [22552913 23364170 20973606 19153372 21514250] | personality traits refer to enduring characteristics including attitudes, values, social behaviors, and habits that manifest predictably across situations. it is generally agreed upon that personality can be adequately captured by five major factors collectively known as the big five neuroticism extraversion openness agreeableness and conscientiousness some common adjectives that describe each of these traits are anxious and worrying neuroticism energetic and outgoing extraversion curious and insightful openness generous and forgiving agreeableness and efficient and organized conscientiousness these traits have been shown to change with age and are related to a variety of life outcomes including physical health depressive symptoms and even mortality importantly personality traits also change with the onset of clinical symptoms of ad | [16435954 26014798 23911610] |
313 | t1weighted magnetic resonance imaging mri was performed to define regions of interest rois and to perform pvc using the mullergartner approach pet scans were performed on the highresolution research tomograph 207 slices resolution 3 mm full with at half maximum fwhm with eventbyevent motion correction dynamic 11cpib scans were acquired for 90 minutes following administration of a bolus of up to 555 mbq of tracer dynamic 11cucbj scans were acquired for 60 minutes after administration of a bolus of up to 740 mbq dynamic pet images were motion corrected fslflirt registered to the participants mri | [30014145 17301468 24089924 29111487 28792356] | all participants received a pet scan with 11cpittsburgh compound b 11cpib to determine the presence of brain amyloid β aβ accumulation as described previously 11cpib pet scans were required to be negative for cn participants and positive for mcidementia due to ad participants supplementary methods all participants provided written informed consent as approved by the yale university human investigation committee prior to participating in the study. | [30014145] |
314 | cyclooxygenase2 cox2 a major factor in inflammatory reactions catalyzes the conversion of its substrates such as arachidonic acid aa eicosapentaenoic acid epa and docosahexaenoic acid dha to proinflammatory lipid mediators including prostaglandins pgs 11hydroxyeicosatetraenoic acid hete 11hydroxyeicosapentaenoic acid or 15hydroxyeicosapentaenoic acid hepe and 13hydroxydocosahexaenoic acid hdha | [24684963 23786234 11034610 12391014 20194532] | n-as-triggered spms are direct regulators of microglia in a model of alzheimer’s disease | [] |
315 | the catecholamines norepinephrine and dopamine are synthesized by neurons in brainstem that project to forebrain with dense projections to subcortical structures such as the thalamus and striatum respectively and a more delicate projection to the cortex including the pfc methylphenidate blocks dopamine transporters and increases extracellular dopamine concentrations in the striatum and in the medial pfc a comprehensive examination of catecholamine changes made the surprising discovery that methylphenidate produces an even greater increase in norepinephrine than dopamine in rat medial pfc the low clinically relevant doses used had greater effects on pfc than those seen subcortically in nucleus accumbens or septum thus methylphenidate effects on pfc catecholamine actions may be particularly important to understanding the clinical benefits of this compound as described below | [ 1709528 3950077 9109529 28154152 16806100 16806100] | researchers have wondered whether they could lessen symptoms of apathy by administering methylphenidate a treatment for attention deficit hyperactivity disorder adhd that is known to improve motivation in nonad patients methylphenidate is thought to have many of its beneficial catecholamine actions in adhd by strengthening pfc function and it may boost remaining pfc circuits in ad patients as well methylphenidate may also enhance motivation by enhancing dopamine actions in striatum, a region more resilient in ad. | [23164814 23164814] |
316 | the amygdala volume has been strongly implicated in ad but studies concerning the rate of decline relative to the hippocampus have been inconsistent with the amygdala showing lower levels of atrophy equal levels of atrophy and greater levels of atrophy as shown in this study | [21920712 16367898 11706109 17030660 16524704] | these findings are supported by the braak model which suggests that mature neocortical neurons are not affected by pathology until later in the disease process interestingly, we report that the amygdala declined 11.6% faster than the hippocampus (95%ci 9.9, 13.0%) in ad patients in this study. | [16906426] |
317 | although no diseasemodifying therapy has been approved yet promising signals have been observed in a number of antiamyloid clinical trials in which small to modest reductions in brain amyloid levels were achieved in treatment groups albeit not accompanied by effects on cognitive decline these trials have maintained hope in the search for a successful therapy but also identified challenges in trial design | [27176461 29365294 24450891 29719179 27582220] | currently ad dementia is conceptualized as the endpoint of a cascade of events leading to cognitive impairment with the accumulation of amyloid beta aβ plaques being considered the first detectable change in the braina process that continues for decades prior to the onset of cognitive decline although no causal link between aβ plaque deposition and subsequent dementia has been established it remains a pathological hallmark in the pathway toward ad dementia as such, its measurement has been part of many observational studies in aging and dementia, and it has also been used in clinical trials both as inclusion criteria and as part of the outcome measures in the case of anti‐amyloid interventions. | [23332364] |
318 | tnfα exerts a key role in this early proinflammatory process observed in preclinical ad as emerges from preclinical studies in animal models of ad as well as from human longitudinal studies | [22096345 29516540 24567119 27697064 26996175] | cumulative evidence suggests that microglial inflammation-induced oxidative stress in ad is amplified. in contrast microglialmediated clearance mechanisms are not functional | [28862638 30593839] |
319 | several studies reference in curcumin analogues that have been labeled with fluorine18 4 and gallium68 113114 for future application in pet imaging and proton3 112 and iodine125 for future application in spect and in mri imaging respectively | [31858697 27608011 24766626 27461789 28841047] | furthermore, bmaoi14 is specifically bound to aβ plaques. Further research is in progress to optimizethe BMAOI 14(Table 3). | [] |
320 | their attitudes to influence learning and cognition in animal models of disease and also in humans have been exhibited by dietary supplementation experiments involving flavonoidrich food or plant extracts | [11976192 15236762 16547523 23810791 30914316] | as a whole when compared to nondemented older adults tau is at least 3to 4times more hyperphosphorylated in the brain of ad patients growing evidence confirms that flavonoids display promising neuroprotective potential due to their ability to lessen the progression of agerelated neurodegenerative disorders or avert the onset of neurodegeneration | [ 8226987 30733944] |
321 | the previous structural mri fmri and 18ffdg pet studies have reported reduced volume disrupted intrinsic activity and hypometabolism of hippocampus and hippocampal subregions in both ad and mci patients | [30420801 28653793 29629524 29592955 16473024] | in addition to fmri the fluorine 18 18f fluorodeoxyglucose 18ffdg pet showed that the glucose metabolism of the left hippocampal body ca23 and ca4dg subregions was significantly lower in the early ad group than in the control group in mci patients we found that the left hippocampal ca2 functional connectivity measured by restingstate fmri was associated with decreased dorsal raphe nuclei binding potential measured by 11cdasb pet | [29629524 28379618] |
322 | the mri data were centrally processed at lund university using previously reported procedures in brief cortical reconstruction and volumetric segmentation were performed with the freesurfer software version 60 image analysis pipelines the magnetization preparedrapid gradient echo mprage images underwent correction for intensity homogeneity removal of nonbrain tissue and segmentation into gray matter and white matter with intensity gradient and connectivity among voxels cortical thickness was measured as the distance from the gray matterwhite matter boundary to the corresponding pial surface reconstructed data sets were visually inspected for accuracy and segmentation errors were corrected | [30326496 21514249 21514250 27323247 26962052] | the pet images were acquired using a biograph micro-ct pet/ct scanner (siemens medical solutions) in the memory disorder clinic of gangnam severance hospital, discovery 690 pet scanner (ge medical systems) in the biofinder study, and a biograph 6 truepoint pet/ct scanner (siemens medical solutions) for ucsf patients. the pet data were locally reconstructed into 4 5minute frames for the 80 to 100minute interval after injection the mris were acquired on a 30t discovery mr750 scanner ge medical systems in the memory disorder clinic of gangnam severance hospital 30t tim trio or skyra scanner siemens medical solutions in the biofinder study and a 30t tim trio or prisma scanner siemens medical solutions at ucsf | [29050382 27323247 26962052] |
323 | noninvasive highresolution retinal imaging technologies such as fundus imaging optical coherence tomography oct as well as recently developed oct angiography 42 62 72 retinal amyloid imaging 4648 and retinal hyperspectral imaging incentivize the use of feasible and inexpensive retinal imaging in the clinical setting to improve ad screening and monitoring | [23918361 30352114 27830174 31530809 27333181] | among key findings were severe optic nerve and retinal ganglion cell rgc degeneration thinning of the retinal nerve fiber layer rnfl glial stress altered electroretinography responses and vascular abnormalities notably the pathological hallmarks of adaβ plaques and tauopathywere further identified in the retina of ad patients including earlystage cases | [29312125 23443359 27645291 28814675 2774510 30593285 20550967 28814675
26505992] |
324 | some of their postsynaptic counterparts influence formation of functional dendritic protrusions sept6 62 sept7 63 64 and sept11 41 and sept7 is reported to effectively suppress the lateral movement of membrane proteins by forming a barrier at the base of the dendritic spine | [21544625 17935993 17935997 19380581 25494357] | septins are fundamentally engaged in substantial synaptic functions. presynaptic septins tightly regulate synaptic vesicle trafficking and exocytosis moreover neurite growth and maintenance reviewed in | [25888325] |
325 | erk regulates adam9 10 and 17 at multiple levels and regulates transcription factor sox9 | [22002568 17704059 20087163 10655493 21512138] | however rivastigmine nanoformulation can produce significant inhibition in mrna levels of bace1 rivastigmine stimulates the activation of both erk and akt | [] |
326 | furthermore the current understanding
of crf in persons with ad is limited to a few studies that have investigated
vo
2peak
obtained via cpet using treadmill protocols in patients with
relatively mild ad only with ranges of
194216 mlkgmin most commonly reported | [22133248 21574893 18625967 22020383 23559521] | likewise there is
an increasing interest in exercise and fitness in alzheimers disease ad
given the accumulating evidence supporting the potential therapeutic effects of
aerobic exercise and fitness and the maintenance of cognitive health however, little data exist on the objective
measurement of crf in older adults with ad. | [] |
327 | for example the top 20 clonotypes account for 60 of all γδ t cells in the pb of adults γδ t cells are also found in peripheral and barrier tissues where they mediate antiviral and antimicrobial defense support wound healing and promote immune tolerance γδ t cells can also be involved in pathological processes such as oncogenesis autoimmunity and even stroke | [28218745 28920588 29963061 29203226 27019327] | upon somatic v(d)j recombination starting at γ- and δ- chains and then progressing to α- and β-chains, t cells are generated to express unique γδ- or αβ-tcr pairs on the cell membrane, respectively termed γδ and αβ t cells. unlike αβ t cells γδ t lymphocytes represent a less abundant population of peripheral blood pb cells and have on the one hand diverse tcr repertoire but on the other hand it is considered to be oligoclonal | [23085947 29720665] |
328 | finally other mechanisms that lead to secondary toxicity include inflammation oxidative stress glial activation among others molecular targets in this respect besides the aβ peptide include bace tau protein markers of inflammation and even the 5ht2a receptor | [21176189 30501965 31334330 27955995 30134967] | in cytoskeletal degeneration, i.e., tau pathology, nfts would be the primary target. however, upstream alterations responsible for nft formation would be better targets at earlier stages. | [] |
329 | in addition to aβ and nft neuroinflammation is exhibited in the brains of ad patients | [29107864 23930978 25792098 27179961 28185874] | to date, a considerable gap regarding the onset and progression of ad neuropathology and clinical symptoms still exists. over the last few decades, a third core neuropathological feature of ad has emerged. | [] |
330 | interestingly recent studies have reported that hsamir1013p is differentially expressed in ad serum and precursor as well as mature forms of mir101 regulate the expression of amyloidβ precursor protein in human hela cells and rat hippocampal neurons mir101 is also associated with the innate immune response in macrophages and hepatocellular carcinoma | [25349172 20395292 21172309 21068409 28559963] | as braak nft stage progressed, the expression of hsa-mir-101-3p was increased specifically in the ec. furthermore, overexpression of hsa-mir-101-3p in the human neuronal cell line sh-sy5y caused rac1 downregulation. | [] |
331 | while reports of increased activity in early stages of ad have mainly implicated the hippocampus this phenomenon has been documented in the prefrontal cortex as well for instance ad patients who had higher activity in prefrontal areas were better able to perform tasks of semantic and episodic memory nevertheless while previous studies have identified hyperactivation of adrelated regions under fmri the high temporal resolution of our eeg data suggests two processes to be involved one is a decrease in orientationrelated activity along the ad continuum while the other is a parallel increase of a distinct activity | [16315273 12574428 12574428 16087905 21194156 10944562 16315273] | nonetheless these results are in congruence with a growing body of evidence reporting a paradoxical increase in activity relative to baseline in patients at high risk for ad rather than a loss of activity for example mci patients performing an associative memory encoding task under fmri showed greater hippocampal activation compared to control similarly asymptomatic genetically atrisk individuals such as carriers of familial earlyonset ad fad and apoeε4 carriers demonstrated greater mean entorhinal or hippocampal taskrelated activation compared to noncarriers patients who had progressed to the ad stage exhibited decreased taskrelated hippocampal activity bilaterally correlating with deteriorating memory performance notably increased activity was found not only on the neurocognitive level but also in the molecular and cellular level it remains unclear whether these increased activations play a compensatory role to maintain performance in the early stages of ad or a causal role acting as a harbinger of imminent neuronal failure | [16087905 18206188 29986165 16087905 21194156 10944562 16087905 21194156
10944562 16315273 20463288 29986165] |
332 | this concept has evolved over time with various taxonomies nomenclatures and definitions which are summarised in and described in an historical context below
table 1various definitions of cognitive impairment that is not dementiatermbsfcdrqdaamiaacdcindpetersen mciwinblad mciniaaamncdcognitive complaintself or carer complaint about memoryself or carer complaint about cognitionselfcomplaint about memoryself or carer complaint about cognitionself or carer complaint about cognitionself or carer complaint about cognitionpsychometric impairment1 sd below healthy young adults1 sd below agematched samplebattery of neuropsychological tests15 sd below age and edu matched sampleno cutoff specifiedtypically 115 sd below age and edumatched samplemodest impairment typically 12 sd below age and edu matched sampleadlslight or mild changenormalminimal impairment in complex instrumental adlmild change but still independently functioningindependent but possibly with greater effort or strategiesdementianonononononononononotesmild dementia may have cdr 05at least 6 months durationdoes not exclude nondementia causesaka mayo criteriaaka revised mayo criteria or revised petersen criteriabiomarker criteria not presented hereaacd agingassociated cognitive decline aami agingassociated memory impairment adl activities of daily living aka also known as bsf benign senescent forgetfulness cdr clinical dementia rating scale cind cognitive impairment not dementia edu education mci mild cognitive impairment mncd mild neurocognitive disorder niaaa national institute on aging and the alzheimers association qd questionable dementia | [ 7104545 9269213 10190820 15324367 21514249] | alzheimers disease is a progressive neurodegenerative condition that is the most common cause of dementia accounting for approximately 5070 of cases its clinical hallmark is impairment of memory and new learning with rapid forgetting of newly learned information diagnostic criteria emphasise impairment of memory with insidious onset and gradual progression as well as impairment of at least one other cognitive domain which are severe enough to impair functional abilities significantly the most recent iteration of the dsm has adopted the term major neurocognitive disorder due to alzheimers disease while retaining the essential diagnostic criteria mci is an intermediate state between cognitively intact persons and those with dementia. | [17975326 10854354 21514250 21514250 9343469] |
333 | in particular while the overexpression of mutant app and apppsen1 yields amyloidosis neuroinflammation and degeneration of monoaminergic and cholinergic neurons it is generally not considered sufficient to cause aggregation of endogenous murine tau into neurofibrillary structures | [25774009 25680265 19091971 17662610 19560104] | transgenic mouse models that reproduce the amyloid aggregation and glial activation due to aβ overexpression have been generated based on mutations in the amyloid precursor protein app and presenilin 1 psen1 and 2 psen2 genes which are known to cause familial ad despite playing important roles in evaluating app processing aβ toxicity and amyloidtargeting therapeutic strategies transgenic mice are not being regarded as models that can replicate the full spectrum of ad histopathology | [28304309 28768718] |
334 | by contrast nfts in ad first develop in the brainstem and entorhinal cortex braak stage iii then in the medial temporal lobe braak stage iiiiv and finally in the neocortex braak stage vvi where nfts are evenly distributed in layers iii and v | [23208308 11484824 1759558 1285493 22002422] | histologically nft is one of the most common pathological findings in cte and has been observed focally and perivascularly in the cerebral cortex with a predilection for deep sulci in the superficial neocortical layers layers ii and iii in the later stages of cte, nfts typically spread irregularly to the neocortex, medial temporal lobe, diencephalon, basal ganglia, and brainstem. | [20720505 21358359 8866777 25943889] |
335 | previous studies also showed an association of osa and adrelated biomarkers including brain amyloid β load and cerebrospinal fluid levels of tau | [28550245 27129429 24439479 30794315 28329084] | in comparison the association between lateonset ad load and genetic variants is much more complex with at least 56 loadassociated genes reported in the literature these genes may involve lipid metabolism and regulate the production and clearance of amyloid β thereby inducing ad | [24336208 21460840 17324514 26611832 29181857 23296339 26828303 20460622
24162737 24022074 21460841 19734902 19734903 20413852 22829467 27097852
23666170 20971101 7968373 22261503 23150934 11455132 21840299 16608404
20420935] |
336 | consistently tnfrelated apoptosis inducing ligand tnfsf10 a potent proapoptotic member of the tnf superfamily also produced by injured neurons 13 and activated glia 14 is known to modulate cellmediated immune response 15 for example by inducing an increase of the treg cell subset of t lymphocytes 16 and it is in fact regarded as a critical regulator of autoimmune t cells | [12655302 17067687 19476510 20921531 11994437] | on the other hand in the past two decades laboratory research has shed more light on various adrelated candidate pathogenetic factors including superoxides 6 7 excitotoxicity 8 9 as well as inflammation in this line peripheral immune cells have more recently been indicated as factors disrupting the immune equilibrium of the brain potentially contributing to neurodegeneration | [18826565 20394761 8649576 23668663 26284939] |
337 | the clinical effects of azd0530 treatment were assessed by the alzheimers disease assessment scalecognitive subscale adascog11 score range 070 with the highest score indicating worst mmse adcsactivities of daily living scale adcsadl score range 078 with the highest score indicating best clinical dementia ratingsum of boxes cdrsb score range 018 with the highest score indicating worst and neuropsychiatric inventory npi score range 0144 with the highest score indicating worst the adascog11 was administered at baseline and weeks 13 26 39 and 52 and the mmse was administered at screening and weeks 13 26 39 and 52 | [9236948 6496779 9236950 7991117 9153155] | a 30-minute dynamic emission scan consisting of six 5-minute frames, either preceded by a ct scan (for pet/ct scanners) or followed by a transmission scan (for pet-only scanners), was acquired starting 30 minutes after intravenous injection of 18f-fdg (5 mci) as the patient lay quietly in a dimly lit room. data were corrected for radiation attenuation and scatter using transmission scans or x-ray ct and reconstructed using standardized algorithms. | [] |
338 | examination of soluble aβ species in ad brain extracts by several investigators has indicated that the neurotoxic activity resides primarily in the low molecular weight lmw fraction of aβo dimers trimers tetramers dodecamers while high molecular weight hmw aggregates are largely inert though they reportedly can dissociate into lmw species | [15608634 18568035 21421841 28053038 26051935] | the selectivity of hupmn310 for soluble toxic oligomers with no binding to plaque or aβ monomers is a therapeutic advantage as it is expected to prevent the loss of antibody to unproductive interactions and, more importantly, avert triggering dose-limiting induction of aria-e and aria-h. it is recognized that synthetic aβo, while a useful tool, do not exactly replicate the structural plasticity, conformational heterogeneity, co-aggregation species and polydispersion of native aβo found in ad brains. | [] |
339 | further ad is a multifactorial disease where the toxic context could be the result of different insults to the body and quercetin has been shown to have beneficial effects in many diseases such as hypertension diabetes and atherosclerosis as well as against oxidative stress and inflammation | [18827577 20637779 21606866 27713250 21856292] | therefore, studies controlling those variables, specifying doses per type of comorbidity, and clinical trials including middle cognitive impairment patients should be developed. nevertheless, with our present study, we are close to discovering a preventive intervention that could be successful in decreasing the probability of βa or tau accumulation in the brain, and in this way, prevent the toxic environment that initiates the neurodegeneration cascade. | [] |
340 | there is also evidence that blood lps levels in ad patients are 3 times those in controls 14 37 suggesting an association between lps with ad e coli bacteria that bear lps can trigger host inflammatory responses and induce the formation of extracellular amyloid plaques 14 38 39 that are very similar to the aβ aggregates in the brains of ad patients | [29403371 19013651 29403371 25653617 22197327 29403371 14597556] | cows milk fermented with lactobacillus has attenuated lpsinduced memory deficit by increasing antioxidant enzymes sod gsh and gpx and by decreasing mda ache and proinflammatory cytokines in mice 35 lactobacillus helveticus could improve behavioral and cognitive impairments and decreases in populations of these bacteria are correlated with ad pathology lps have also been found in large amounts in brain lysates from the hippocampus and superior temporal lobe neocortex of ad brains | [29154736 26408987 29302204] |
341 | cooccurring lrp may relate to visual hallucinations 63 extrapyramidal symptoms 51 53 72 and a shorter more aggressive disease course | [15068176 2153271 8453435 19752301 9710002] | these results were later confirmed in a larger cohort of autopsyconfirmed ad cases upon closer examination it indeed has turned out that a substantial proportion of ad patients examined at autopsy exhibited lrp in the neocortex 52 57 limbic system 2224 6163 65 and to a lesser extent in the substantia nigra | [ 8546207 8229084 8782917 15751230 10885656 15751230] |
342 | recently several studies that used oct found that the thickness of the retinal nerve fiber layer rnfl and also the ganglion cell layer was reduced in patients with ad when compared with healthy subjects | [27394689 21454010 26888864 23920375 25428254] | during 19861987 hinton and sadun provided evidence that visual dysfunction and opticnerve degeneration occurred during the early stage of ad spectral domain optical coherence tomography (sd-oct) is a newly developed sophisticated imaging technique that can be used to rapidly obtain objective and reliable measurements of the retinal layers with an axial resolution of ≤5 μm. | [3736630 3618708] |
343 | in ad lipid biochemistry is dysregulated causing profound effects on signaling and aβ plaque accumulation | [19303044 17986152 23306153 22835784 30207230] | memory impairment is more pronounced in ad than dlb whereas spect and pet scans have demonstrated hypometabolism and hypoperfusion in the primary visual cortex in dlb but not in ad lipids are involved in critical neurobiological functions such as membrane formation cellular binding and recognition transport energy and signaling | [19585950 17882252 28887769] |
344 | recent technological advances have improved assay sensitivity delivering ultrasensitive assays capable of measuring specific amyloid markers in plasma | [29458036 29758941 26480202 27241045 29420472] | these methods are not suitable either for high-volume screening of presymptomatic individuals, required to identify early disease, or frequent monitoring required in assessing response to interventions. biomarkers informative in csf are currently difficult to measure in plasma in the routine context | [26480202] |
345 | in particular smri and the study of brain networks can reveal the underlying pathology and its spread thus possibly helping to understand the emergence of these subtypes through different brain networks | [22951070 27239533 29070667 29136123 23531697] | however, the underlying biological mechanisms that determine this differential nft expression are still completely unknown. the finding of misfolded tau proteins first developing intraneuronally and then spreading from neuron to neuron through brain networks opens a promising door | [20029438 22445347] |
346 | among these delivery systems systems involving cellbased drugdelivery into the brain received considerable attention due to the ability of the cells to locally release efficacious doses of the protein of interest 561213 andor their ability to replace damaged neural cells and modulate inflammation | [20531393 29615705 29649621 18579298 29649621 27924726] | the development and optimization of platforms for targeted drug delivery to and within the central nerve system cns is one of the key challenges in the treatment of neurodegenerative disorders primarily due to the need to cross the bloodbrain barrier during the past decades several strategies for protein delivery to the cns were developed using cells 13 4 5 6 viral vectors 78 nanoparticles 9 liposomes 10 and specific transporters that facilitate the entry of proteins into the brain | [21348773 15036633 24601738 20531393 29615705 16299771 29535375 22100125
27212923 29600349] |
347 | however the plausibility of the glymphatic hypothesis has been questioned on theoretical grounds 2 21 24 and from the fact that clearance of βamyloid aggregates occurs primarily via the periarterial and not the perivenular spaces | [27929105 28847942 27836940 29754206 18208483] | one explanation has been offered a glymphatic hypothesis proposing that mislocalization of aqp4 causes failure of a transendfoot convective fluid flow which impairs clearance of toxic protein aggregates from the brain parenchyma into the perivenular spaces during sleep in support of this hypothesis an increase in βamyloid deposition has been observed in appps1 mice that lack aqp4 55 and human aqp4 polymorphisms have been reported as a genetic risk factor for ad | [22896675 24136970 26526066 29067342 29479071] |
348 | this is comparable to the spreading we and others have described after seeding with brain extracts of tau transgenic mice or tauopathy patients | [24531916 25534024 23690619 19503072 26150341] | inoculation of csf collected from ad and mci patients resulted in a significant increase of markers of tau pathology in the hippocampus of p301s tau host mice. advanced tau pathology was also notable in the contralateral hippocampus, and in anterior and posterior directions. | [] |
349 | furthermore those measuring baseline hdlc levels at middle age all found significant associations with alzheimers disease risk 677172 whereas those with baseline measures in subjects at least 70 years old did not | [24685634 27113638 17298957 18559637 11890840] | baseline age and followup length may explain these inconsistencies indeed the above studies with followup times greater than 10 years found significant associations between hdlc levels and alzheimers disease risk 7274 whereas others with less than 10 years of followup did not | [17298957 16217057 16217057 11890840] |
350 | some studies report significant crosssectional associations of blood lead with minimental status examination scores or word recall and perception comparison tests whereas other crosssectional analyses using blood lead did not show an association of blood lead with cognitive function tests in another analysis of nhanes data van wijngaarden et al found that blood lead was positively associated with a lower score on the digit symbol substitution test but that association was not statistically significant | [14569188 9511166 15583371 16971698 21093481] | however, there is an extensive literature evaluating the relation of environmental lead exposure with cognition, a key symptom of ad, discussed more below. results from cross-sectional analyses of lead and cognition are not consistent. | [] |
351 | moreover other studies also pointed out various pharmacological properties of semisynthetic derivatives of some amaryllidaceae alkaloids such as those related to haemanthamine 26 lycorine 2728 narciclasine and others figure 1 | [22910226 20627737 26443922 26263960 27542176] | notably some species of amaryllidaceae produce the alkaloid galanthamine which was isolated for the first time from galanthus woronowii in the 1950s and at the beginning of this century was approved for the treatment of mild to moderate stages of ad being a competitive ache inhibitor with modulatory properties towards nicotinic ach receptors other alkaloids isolated from amaryllidaceae plants like narciclasine haemanthamine pancratistatine and lycorine figure 1 have demonstrated interesting antitumor andor apoptotic effects | [11172080 28756149 26263960] |
352 | the observed pattern of retinal thinning in ad whereby thinning was greatest for the inner layers of the retina followed by the outer layers may likely be attributed to aβ deposition and consequent neurotoxicity as suggested by previous studies notably however the ipl was less severely thinned relative to the inl and onl | [26505992 20550967 28814675 27598262 27377656] | intriguingly, the magnitude of thickness reduction for the inl and onl was notably less than that of the rnfl and rgcl. these thickness findings may be explained by the distribution of the retinal aβ deposits which were more concentrated in the rgcl and to a lesser extent in the inl and onl similarly koronyohamaoui et al observed neuronal reduction in the inl and onl accompanied by retinal aβ pathology | [26505992 20550967] |
353 | this kind of crossdataset research approach was frequently used in the radiomic studies to avoid the overfitting problem as well as to test the generalization ability of the whole research framework | [26579733 24892406 26441442 27347764 27064691] | this study utilized statistical analysis and svm to investigate whether a radiomic method based on 18f-fdg pet images could be used for ad and mci computer-aided diagnosis. to prove the stability and generalization of the proposed radiomic method, we selected different samples by different pet scanners with different imaging properties, including samples from the adni database and huashan hospital. | [] |
354 | aβ oligomers can induce neuronal and synaptic damage through different mechanisms such as inhibition of hippocampal longterm potentiation inhibition of exocytosis by impairing snare complex formation deregulation of nmdamediated calcium influx triggering synaptic collapse or the formation of membrane pores causing permeabilization and inducing neuronal death | [11932745 26279571 28327181 22837695 27621459] | several in vitro and in vivo studies have shown that under certain conditions aβ peptides are able to form small soluble oligomers that grow into protofibrils and finally into dense insoluble structures that accumulate in the brain in form of extracellular βamyloid plaques there is growing evidence that soluble aβ species are more toxic than fibrillar aβ in causing neuronal loss and synaptic dysfunction | [17286590 25604547 17251419 27211547] |
355 | it is known that oligomeric aβ accumulation induces neuronal cell loss astrocytic dysfunction and synaptic toxicity and it is possible that higher levels of nonfibrillar aβ are a characteristic of adad and may be the reflection of abnormal app processing | [21487307 28607171 27258414 22637583 23224319] | however, we were able to detect non-fibrillar aβ structures 2 times smaller using at-sted in human tissue. in addition, we show preliminary evidence that non-fibrillar aβ structures were increased in an adad case compared to a sad case in human brain tissue. | [] |
356 | it is of interest to note that the receptormediated effects of apoe4 are associated with increased internalization and subsequent degradation of numerous receptors including nmda insulin and vegf receptors 33 69 147 as well as the amyloid precursor protein and apoer2 | [20547867 27372644 28957663 24251389 17428983] | the binding of apoe to these receptors is affected by the degree of lipidation of apoe such that nonlipidated apoe binds preferentially to lrp1 and vldlr whereas lipidated apoe binds more effectively to ldlr in addition lrp1 and apoer2 are differentially affected by apoe4 and apoe3 | [24559670 19339974 15863833 28292942 25015123] |
357 | the search included 13 articles from the temporal cortex 6476 6 from the hippocampus 65 7781 8 from the frontal cortex 77 78 8287 1 from the entorhinal region 81 and 1 the parietal lobe | [18801740 24014289 18525125 20507594 20126538] | this highlights the need for detailed standardised procedures. twenty-seven articles were found looking at deregulated mirna in the brain, corresponding to 250 mirnas. | [] |
358 | shank3 postsynaptic scaffolding proteins thereby play essential roles in synapse formation and organization synaptic cell adhesion dendritic spine maturation and synaptic vesicle release | [29739861 29939863 30292394 25309321 28469556] | shank proteins are essential to post-synaptic structure and function in connecting, linking, networking and anchoring neurotransmitter receptors, ion channels, and other integral membrane proteins to the actin cytoskeleton and in the normal “homeostatic” operation of g-protein-coupled signaling pathways. research evidence indicates that the massive shank3 protein at 185 kda forms an extensive postsynaptic cytoskeletal scaffolding network involving the linkage of multiple shank3 proteins at the psd to which the smaller psd95 at 95kda protein is tethered usually via the sapap protein 100 kda interestingly both shank3 and psd95 proteins highly interactive components of the psd complex are reduced in abundance in the temporal lobe of adaffected brain | [30292394 25264360 29321508] |
359 | in fact the spatial reorientation task requires translating between egocentric viewer dependent information about the landmarks and allocentric maplike representations of space | [24741034 28910623 17500630 8180489 29170377] | the task used here requires the mouse to use features of the environment to determine the new starting location, which would be a critical feature of navigating, particularly if an individual was navigating new environments. interestingly most human and animal studies have focused on allocentric maplike aspects of spatial navigation however a recent report showed that a distinguishing feature of human ad is the presence of both egocentric viewerdependent and allocentric navigational impairments | [28697554] |
360 | reversal of calcium dysregulation and related ad pathology with ryr negative allosteric modulators has been demonstrated in two ps1app lines appsweps1m146v 59 c57bl6sjlf1appc57bl6d2f1ps1 113 tg2576 114 and ps1m146vki mice 17 and the restoration of normal ca2 signaling results in reduced amyloid and tau pathology normalized synaptic transmission and plasticity and improved cognitive function | [16687509 2564640 23029404 27814403 25100603] | the pathogenic er ca2 dyshomeostasis component of ad has been consistently demonstrated over many years across numerous ad mouse models including the ps1m146vki 17 111 ps1app appsweps1m146v 112 ps1app c57bl6sjlf1appc57bl6d2f1ps1 113 and tg2576 114 among others Furthermore human cells obtained from AD patients demonstrate similar Ca2 signaling abnormalities 20 and RyR dyshomeostasis is identified in nonhuman primates with ADlike pathology | [16687509 24902695 17901262] |
361 | lipid rafts are cholesteroland sphingolipidenriched microdomains of the plasma membrane described as signaling platforms 129 130 rafts are strongly associated with aβ production and both βand γsecretases are enriched in these structures 129 131 132 lipid rafts also seem to influence aβ aggregation | [20590841 29632069 20590841 21660213 23723072 27295499] | the role of ceramide/s1p was analyzed in the context of these damage pathways as well as the process of amyloidogenesis. structural roles of sphingolipids in cellular membranes including lipid rafts constitute an important aspect of their engagement in aβppaβ metabolism | [28566300] |
362 | our agitation prevalence estimates fall within the 18 to 87 range described by a recent systematic review of previous studies on nps in dementia point prevalence rates for agitationwandering and mechanicalmotor abnormalities have previously been reported in the range of 18 to 57 and 10 to 61 respectively the variation in reported rates may be attributable to methodological differences due to earlier studies defining nps using the neuropsychiatric inventory npi an assessment tool commonly used in clinical studies to screen for behavioral symptoms among patients with dementia first while we identified agitation on the basis of ehr notes from direct physician encounters and available diagnosis codes the npi is conducted via an interview with the patients primary caregiver whose assessment of agitation may differ from that of a physician | [27491532 22323347 12834515 22323347 22323347 27623026 24059840] | in this large‐scale analysis, the prevalence of agitation during the 2‐year observation period was substantial: 44.6% in the full study sample and 61.3% in a subset of patients with staged ad/dementia severity. this constitutes not only a considerable strain on patient and caregiver health but also a considerable economic burden as agitation has been shown to engender high additional costs compared with cognitive impairment alone in a recent uk study the presence of agitation was associated with significantly increased health care costs among homedwelling patients with ad accounting for mean excess costs of 2 billion per year | [] |
363 | confounds arising from toxicity prevent calibration and absolute quantitation in living organisms however evaluating relative changes of in vivo nadh fluorescence intensity still provides a useful indication of pathologyinduced variations of mitochondrial function and intracellular oxygen requirements the in vivo measurement techniques utility was greatly extended by coupling nadh fluorescence with 2photon microscopy 2pm a powerful tool for investigating multiple facets of brain function with high spatial and temporal resolution using deeper penetrating nearinfrared excitation while fluorescence intensity imaging of nadh offers a nondestructive labelfree and simple method to evaluate mitochondrial function fluorescence lifetime imaging microscopy flim shares these benefits and is also insensitive to fluorophore concentration or excitation and emission intensity | [19703658 15232110 16388306 16772166 18270513] | for several decades, measurements of reduced nicotinamide adenine dinucleotide (nadh) have been utilized as a nondestructive tool to characterize mitochondrial respiratory chain activities. nadh is an electron carrier molecule residing in almost all eukaryotic cells both in cytosol and mitochondria and it performs vital roles in both anaerobic glycolysis and aerobic oxidative metabolism extensive studies have utilized single photon uv excitation of nadh fluorescence in isolated mitochondria or cell suspensions as a sensitive quantitative measure of oxygendependent mitochondrial respiratory chain activity under these in vitro conditions oxygen levels can be adjusted and metabolic substrates can be added such that the samples nadh can reversibly be adjusted between its fully oxidized and fully reduced states therefore providing calibration for the minimal and maximal detectable nadh fluorescence signal | [] |
364 | control apoe4 mice and showed increases in amyloid beta aβ42 and tau staining and a decrease in vglut levels compared to apoe3 mice 16 apoe4 ki mice have decreased spine densities and synaptic integrity at several ages compared to apoe3 ki mice | [23684315 19955384 20951774 28542068 20079752] | these studies place an emphasis on the increased risk of ad experienced by apoe4 carriers, with women being more affected than men. studies of apoe knock-in (ki) mice have complemented the studies in humans. | [] |
365 | consequently these interventions improve hippocampaldependent learning 159 160 and pattern separation ability in mice 32 and humans alike | [22138509 23110171 20133882 28698596 27997992] | moreover ee and physical exercise have an impact on diverse hippocampal neurotransmission systems 36 61 91 141 142 including the expression and properties of glutamate receptor subunits 143147 synaptic adaptor proteins 148151 and other molecules related to plasticity thus through a shift in the environment in which newborn neurons are born physical exercise and ee positively modulate the neurogenic permissiveness of the subgranular zone sgz and facilitate the incorporation of highly plastic newly generated maturing granule neurons into the trisynaptic circuit | [22798066 27789840 28883658 20393057 14960340 27267685 26545456 16648603] |
366 | this annotation project recognised that ageing go0007568 is a normal physiological process and consequently teased out data that described the association of dementia with ageing and the involvement of amyloidbeta in ad pathology | [11140684 11140685 11880515 23640054 19660551] | when annotating gene products relevant to a specific disease, this presents a major challenge, as it is necessary to determine what is ‘normal’. For the annotation of AD-relevant gene products, this was a significant hurdle, particularly when capturing the roles of amyloid-beta species, including monomers, dimers, and oligomers (Table S2). | [] |
367 | in addition scientific findings have demonstrated that the effects of amyloidbeta are agerelated ageing go0007568 is a normal physiological process involving the loss of functions such as resistance to disease homeostasis and fertility as well as wear and tear ie aspects that are directly translatable to impairments in cellular processes underlying dementia | [11140684 11140685 11880515 23640054 19660551] | a literature search revealed that in normal physiological conditions amyloidbeta levels are regulated by neuronal activity 99100101 and that amyloidbeta in turn modulates synaptic plasticity in neural circuits amyloidbeta has also been shown to positively affect neuronal growth | [12670422 16364896 23064434 19118188 22910355 15190117 2218531] |
368 | smi precipitates worry about ad 37 38 depressive symptoms 39 40 and withdrawal from cognitively protective activities eg physical or social activities | [28804427 18389396 18074258 22354117 26321944] | however, no research to date has: 1) elucidated mediators underlying linkages among smi and memory decline; 2) characterized smi subgroups at highest risk by identifying moderators of these mediational relationships; or 3) compared the differential predictive effects of specific smi assessment items. this study addresses each of these critical knowledge gaps through the testing of our conceptual model using multilevel modeling in constructlevel replication analyses across four longitudinal datasets | [19485624 19485626] |
369 | the elevated level of 8oxo2dg was observed in nuclear dna from frontal temporal and parietal lobes and cerebellum of ad patients 91 as well as in peripheral tissues | [ 9798928 17691219 27538622 21845541 19630534] | the gsh content decreases in severe dementia and the compensatory mechanisms associated with oxidative stress become disturbed. it seems that reduction of gsh in ad may be associated with increased oxidative stress and may promote accumulation of dna oxidation adducts such as 8oxo2dg | [28566155] |
370 | studies in cellular or mouse models of ad report changes in specific astrocyte functions including metabolic support 2 72 neurotransmitter recycling 51 antioxidant defense 2 83 and synaptic transmission | [20203192 25099753 8957017 20203192 26200696 25533482] | but astrocyte reactivity involves significant transcriptional changes that go well beyond these two morphological alterations and the functional consequences of reactivity are unclear in alzheimers disease ad the most frequent neurodegenerative disease nd characterized by amyloid and tau deposition in the brain as well as memory loss and synaptic alterations the role of reactive astrocytes is still debated | [26283915 24462092 28636962 26671410 29225140 26797041] |
371 | moreover other publications provide a broader review of the whole dementia spectrum and not only ad | [25093211 23900731 21778116 23432716 27430350] | however, none of these have treated exclusively the specific topic of eeg-based ad diagnosis. for instance some reviews do not study eeg as the main technique for diagnosis 9 47 6974 while others are exclusively focused on the synchronization of eeg signals | [27506128 21629749 25941486 25660305] |
372 | five papers using source localization methods used mediumto highdensity electrode montages ranging from 64 to 214 electrodes the 12 remaining used 19 electrodes | [22736322 24240722 22902196 23786792 27255822] | fifteen of these articles utilized the lowresolution electromagnetic tomography loreta method or its derivatives eloreta and sloreta the remaining two articles used the local autoregressive average laura source localization method | [24214287 21396882 22736322 24240722 26941594 27668356 26444753 28184183
23786792 26603651 24577480 26940242 26541308 26960946 28454845 22902196
27255822] |
373 | probable ad was diagnosed based on the criteria of the national institute on aging and alzheimers association and classified as mild according to final score one on the clinical dementia rating cdr the diagnosis of mci was defined using the criteria of petersen the control group comprised elderly without cognitive complaints recruited from the community that scored2 on the functional activities questionnaire faq and greater than the educationadjusted median on the mmse illiterate20 points 14 years of education25 points 58 years26 points 911 years28 points 11 years29 points and 7 on the memory recall of the brief cognitive screening battery bcsb only participants aged 60 years were eligible for inclusion | [21514250 15324362 7069156 14595482 7611936] | the mini-addenbrooke’s cognitive examination (m-ace) as a brief cognitive screening instrument in mild cognitive impairment and mild alzheimer’s disease twenty-three subjects with ad and 36 with mci were recruited from the neurology clinic and from the referral center for cognitive disorders of university (ceredic) of são paulo. | [] |
374 | using a similar approach the aβ4240 ratio has successfully been shown to increase diagnostic accuracy 22 34 56 and have diagnostic value in clinical settings 21 as well as circumventing the issue of highand lowproducers | [17374949 25079805 20043812 26034513 17254013] | the elisa presented here most likely quantifies both full-length and peptide ng, and the separation between the groups is not as good compared to peptide-to-total full-length ng ratio. in theory, it might be possible to develop two assays that quantify peptide and full-length ng, respectively. | [] |
375 | the majority of research demonstrated a higher plasma complement c3 level correlated with more brain amyloid burden 26 27 and less hippocampal volume 28 in sporadic ad 29 and mutation carriers of autosomal dominant form of ad | [20930274 23028511 20603455 2452738 27381087] | complement c3b adherence is a key step in the removal from the bloodstream of pathogens and proteins recognized as foreign. previous studies have shown inconsistent associations between plasma complement c3 and ad. | [] |
376 | the impact of sex differences on ad risk between women and men however has been variably interpreted | [ 8450993 9921852 17975326 11445258 20442496] | sex and age interact to determine clinicopathologic differences in alzheimer’s disease the strongest risk factor for alzheimers disease ad is increasing age | [] |
377 | first animal experiments demonstrated that exercise can promote neural plasticity and induce increases in neurogenesis in the hippocampus and aerobic fitness promotes blood flow glucose utilization and oxygen extraction and improves functional and structural brain reserves second exercise can promote the secretion of brainderived neurotrophic factor bdnf which is related to learning and memory | [21460835 12654355 12086747 21569847 15858047] | in order to achieve this positive result, it is necessary to start the exercise intervention in the early stage and to persevere in the long run as a daily habit. there are three mechanisms for exercise to improve cognition. | [] |
378 | studies from our group and others have described that the protective factors for better cognitive response to chei were lower cognitive status 14 17 male sex 17 18 older age 17 19 and absence of the apolipoprotein e apoe ε4 allele | [16906631 21774798 21774798 9777427 21774798 1775604 21774798 8618881] | in randomized clinical trials cheis have exhibited shortterm response in both cognitive abilities and activities of daily living adl 13 however the response differed between the ad patients after 6 months of therapy 4963 of the individuals had improved or were unchanged as measured by cognitive scales 15 while the corresponding percentages were 49 for instrumental adl and 74 for basic adl | [16437532 16906631 25213579 23126532] |
379 | the battery includes the selective reminding test the benton visual retention test recognition and matching trials the rosen drawing test the boston naming test the controlled oral word association test the category fluency test the color trails test the similarities subtest from the wechsler adult intelligence scale and the orientation items from the minimental state examination | [23571587 20460622 26101835 27016693 21911656] | in brief, efiga participants have been recruited since january 1998 from clinics in the dominican republic and puerto rico, as well as the alzheimer disease research center memory disorders clinic at columbia university in new york city. participants are followed up every 18 months at each visit participants completed a standardized assessment that included ascertainment of medical history physical and neurological examination and an extensive neuropsychological battery for evaluation of cognitive impairment which measures cognitive function in key domains affected by aging and dementia including memory visuospatial ability psychomotor speed and executive function | [1580806] |
380 | many studies have shown that patients with mci who subsequently declined to ad were first impaired in delayed recall memory in the early phase of mci executive functions were preserved as a compensation for hippocampal dysfunction however with the progression of the disease the frontal executive networks were also involved and caused encoding memory deficit that did not improve with cueing the memory index score of mocabc mocabcmis was calculated by adding the number of words remembered in free delayed recall categorycued recall and multiple choicecued recall multiplied by 3 2 and 1 respectively with a score ranging from 0 to 15 | [26620850 23236445 29019061 26027810 22193353 26027810 26027810] | however, no relevant research has been conducted concerning moca-bc in staging dementia severity. the present study aimed to find out whether moca-bc or its subtests could be applied as a preliminary screening method to distinguish among outpatients with mci, mild and moderate ad as a substitute for mmse. | [] |
381 | based on these protocols several mri volumetric studies have shown consistent pattern of hippocampus and cholinergic basal forebrain atrophy in ad dementia and prodromal atrisk stages of ad dementia such as amnestic mild cognitive impairment mci or individuals with amyloid positive mci | [16014654 20672311 19889714 19375072 24176625] | the hippocampus represents a key input area of cholinergic projections from the basal forebrain in recent years mri based protocols for an automated measurement of cholinergic basal forebrain volumes have been established that make use of stereotactic information derived from combined post mortem mri and histology | [23852922 16014654 24503619] |
382 | recent studies have shown that micrornas mirnas are involved in the pathogenesis of ad 6 and that mirnas might play important roles in neurogenesis neuronal maturation and brain development 78 and might regulate several neurodegenerative diseases including ad | [27524239 20380818 17711588 27264337 21728971] | currently, there are no diagnostic biomarkers for the early detection of ad, and there are no effective drug treatments that delay or prevent the progression of ad. therefore, further studies are required to identify ad-related genes and to develop screening methods for these genes to improve the diagnosis and the therapy for ad. | [] |
383 | most of these risk genes are either expressed by microglia or associated with their reactivity including cd33 bin1 cr1 trem2 and clu | [23623698 24316888 23454195 23150934 10918055] | the sustained activation of microglia results in a chronic neuroinflammatory response and increased production of proinflammatory cytokines such as tnfα and il1β of relevance, recent genome-wide association studies have uncovered several risk-associated genes in the development of sporadic ad. | [23254930] |
384 | butterbur petasites japonicus siebold zucc maxim has been known for various biological activities including antiallergic antiinflammatory and antioxidant effects 91011 p japonicus leaf pl extract and petaslignolide a an active compound of pl have been reported to have neuroprotective effects on oxidative stress induced by kainic acid in mice | [20828319 23711828 26674157 16248548 16117608] | accumulating evidence suggests that increased ros by aβ is one of the most important mechanisms involved in the neuronal degeneration synaptic loss and memory impairment of ad thus, inhibition of aβ-induced neurotoxicity may provide neuroprotective benefits in ad. | [25511446] |
385 | ppar agonists remain attractive because these small molecules cross the bloodbrain barrier are effective for remediating neurodegeneration in ngml concentrations 2836 and they modulate gene expression by targeting nuclear receptors bypassing abnormalities at the cell surface | [16988486 27802237 10548883 8695669 8725145] | however as ad progresses the fundamental abnormality that could eventually limit therapeutic efficacy of trophic factor administration is progressive brain insulin and igf resistance or reduced ability to respond to trophic factor stimulation one potential strategy shown to circumvent this barrier in experimental animals 2836 and to some extent in humans is to use insulin sensitizer drugs such as ppar agonists | [16340083 16988486 27802237 20930300 18645613] |
386 | the cause of microglial priming is unclear and likely results from multiple factors including but not limited to 1 a loss of inhibitory ligandreceptor communication with aging neurons 2 interactions with agerelated misfolded proteins such as aβ which promote proinflammatory cytokine production 3 agerelated exposure to increasing transforming growth factorβ which could compromise microglial transitioning from a pro to antiinflammatory phenotype 4 agerelated alterations in production of il4 and ccl11 in the choroid plexus and 5 unique microenvironment effects in white and gray matter | [24638131 17378753 25385836 21886162 23597431] | while the agerelated proinflammatory response to immune challenge is decreased in macrophages aged microglia displayed an exaggerated proinflammatory response referred to as microglial priming first described in a model of prion disease a primed microglia profile includes 1 increased basal expression of inflammatory markers and mediators 2 decreased activation threshold to express and release proinflammatory molecules and 3 exaggerated inflammatory response to immune challenge | [24157572 16207887 25445485] |
387 | liraglutide lowers phosphorylated tau levels in cultured neurons and in mice and reduces hippocampal neuronal loss in transgenic ad mice | [27131827 25869785 23948890 28382596 28337257] | for example, the glp‐1 receptor agonists exendin‐4 and liraglutide, a long‐lasting glp‐1r agonist, exert many protective effects in ad pathology. exendin4 or liraglutide reduces cortical and hippocampal plaque load and alleviates brain insulin resistance and glial activation in transgenic ad mice | [22476196 22938097 21525299 23973293 12749025] |
388 | hippocampal volume atrophy has long been associated with disease progression in ad 24 25 and it has been suggested that hippocampal atrophy could be used as a surrogate marker for efficacy in an ad ct 22 26whole brain atrophy has also been strongly associated with cognitive decline with rates of atrophy typically being higher the further down the ad disease trajectory a patient lies | [10953178 10227624 18302232 12552040 18574133] | as such, adni database contains several mri measurements including hippocampal and whole brain volume that are thought to be useful for the classification of cognitively impaired individuals into an ad or mci subset. for details of how the mri volumes are calculated see | [18302232 26194310] |
389 | thus many studies suggest that the progression and the severity of the disease directly correlates with neuronal loss 33 34 and synaptic dysfunction especially the decrease in the presynaptic marker synaptophysin and with the increase in the number of nft in the hippocampus entorhinal cortex and association cortices | [ 9005861 12743238 2360787 1789684 15037694] | the hippocampus is the major area that undergoes severe neuronal loss with atrophy reaching up to 10% per year. more than 50% of the neurons in the hippocampus are lost and the loss increases with the severity of the disease. | [] |
390 | alzheimers disease ad is a complex disorder in which genomic epigenomic cerebrovascular metabolic and environmental factors are potentially involved | [12943467 17957277 19732004 15265264 27324946] | pharmacogenetics of vascular risk factors in alzheimer’s disease | [] |
391 | recent literature suggests that ageing may induce posttranslational modifications in particular spontaneous aβ amino acid modifications defined as agerelated modifications which enhance its pathogenic properties 9 21 27 44 leading to the protein ageing hypothesis of ad | [24283798 20298218 10834947 27318146 27272258 10834947] | ageing is considered the main risk factor for ad, but the pathway through which ageing contributes to aβ misfolding remains unclear. in particular, we still do not know whether ageing induces molecular changes in aβ, driving its accumulation in the brain. | [] |
392 | all three promoters are active in the embryonic brain and in the adult may be expressed in multiple neuronal subtypes | [12112467 1986868 9539132 16366735 11086982] | several common promoter constructs have been used over the years including prion protein prnp ie tg2576 tgcrnd8 appps1 line 85 jnpl3 and ps19 plateletderived growth factor b chain pdgfb ie pdapp and j20 and thymus cell surface antigen 1 thy1 ie app23 5xfad and 3xtgad while these three promoters induce strong and persistent transgene expression in neurons pdgfb and prnp are also active to a lesser extent in nonneuronal cells of the cns and all three promoters elicit expression in multiple organs outside of the nervous system including heart and liver | [ 8810256 11279122 14645205 10932182 17270732 7845465 10818140 9371838
17021169 12895417 11709540 12112467 1986868] |
393 | all trials reported a positive safety profile and treatment was well tolerated in combination with alzheimers disease medications an analysis of these trials indicated that fortasyn connect can achieve clinically detectable effects in patients with mild alzheimers disease dementia but did not slow cognitive decline in mildtomoderate alzheimers disease dementia given the hypothesis that earlier intervention might be more beneficial the lipididiet trial was designed to investigate the effects of fortasyn connect on cognition and related measures in prodromal alzheimers disease | [20129316 22766770 25322923 24280255 27767993 24280255] | the aim was to provide neuroprotection by targeting disease processes in early alzheimers diseaseie by supplying ratelimiting compounds for brain phospholipid synthesis and addressing multiple alzheimers diseaserelated pathological processes in vivo results from animal studies showed that this multinutrient combination improved neuronal membrane composition increased the formation of synapses cholinergic neurotransmission and cerebral blood flow and perfusion preserved neuronal integrity restored hippocampal neurogenesis reduced βamyloid pathology and improved cognition concentrations of these nutrients in plasma and csf or the brain were also found to be lower in patients with alzheimers disease for clinical use fortasyn connect was adapted to address nutritional requirements in the presence of alzheimers disease pathology two previous randomised clinical trials in patients with mild alzheimers disease dementia reported that daily intake of fortasyn connect for 3 or 6 months improved memory performance increased neurophysiological measures of synaptic activity and enhanced functional connectivity in the brain a third randomised controlled trial in patients with mildtomoderate alzheimers disease dementia did not report benefits therefore heterogeneity in the benefits of fortasyn connect exists in previous trials | [14519522 16631143 21811020 22146060 22914588 24445040 24210253 22914588
24445040 24210253 18606862 24086523 25146455 26502816 20129316 22766770
22766770 24475144 24280255] |
394 | synthetic aβoligomers impaired longterm memory after icv injection into mice 4041424344 aβ peptides after icv injections reach brain cells by csf cerebrospinal fluid influx via the perivascular and glymphatic pathways | [20133875 19464276 17192927 21703413 26195256] | other less expensive, pharmacological animal models have also been introduced during the last 20 years. ad is considered to be a synaptic failure 37 and aβ oligomers induce synaptic dysfunction thus aβ peptides have been used in model experiments | [12399581 18359102 19930651] |
395 | mwm is one of the most commonly used experimental models for rodents to measure spatial learning and memory | [23073928 6471907 2869411 17406317 28052060] | biological effectiveness of these different aggregates was further studied in consecutive biological experiments. the morris water maze (mwm) task was used to assess spatial learning and memory. | [] |
396 | memory deficits are characteristic of typical ad but similar deficits of immediate and delayed episodic memory and autobiographical memory have been reported in frontotemporal dementia ftd | [23457466 23670951 21239854 21658396 25396740] | meanwhile the diagnostic utility of structural neuroimaging in early ad is controversial as atrophy may be subtle or nonspecific before the development of amyloid biomarkers efforts to improve ad diagnosis emphasized improving neuropsychological tests of memory | [16328732 20711906] |
397 | this method was previously shown to be successful in the differential diagnosis of parkinsonian disorders in predicting disease onset in prodromal individuals with parkinsons disease and in evaluating disease progression and treatment effects | [20061183 26449840 24453082 20089913 17470495] | for quantification, normalized scans are projected onto a previously identified disease pattern to calculate a subject score. the subject score reflects the degree to which the pattern is present in a subject’s scan. | [] |
398 | among them p38 mapk has been suggested to phosphorylate tau at specific amino acid residues figure 4 | [11578769 15632108 16987243 25131590 21215781] | numerous kinases including more than 20 serinethreonine kinases were suggested to phosphorylate of tau several kinases that are candidates for diseaserelated tau phosphorylation include glycogen synthase kinase3 cyclindependent kinase5 and the mapk family all of which have been known to be implicated in ad pathogenesis | [16712493 23798682 19903024 19903024] |
399 | another gene identified through this study ctnna1 encodes a catenin expressed at elevated levels in the nervous system 50 galr3 is a receptor for the neuropeptide galanin which has been shown to modulate a variety of processes including cognition and memory functions disrupted in ad 5152 mief1 was nominally associated with lateonset ad in a metaanalysis of two family datasets from the adgc thereby suggesting that it may play a wider role in ad that extends beyond a single multiplex ad family mief1 may play a role in dysfunctional mitochondria and their potential to damage neurons | [21708131 9832121 11259657 19491039 23840916] | neuroinflammation has been shown to occur in ad patients possibly through misregulation of microglia and triggered by amyloid beta plaques additionally established ad risk genes such as abca7 cd33 and trem2 have also been linked to the immune system | [26509334 8346443] |
Subsets and Splits