VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome

Abstract Background There is an urgent need for objective markers of Alzheimer’s disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment. Methods We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aβ42:40 ratio, CSF Aβ1-42, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing. Results In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aβ42:40 (adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002). Conclusion These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.

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VAMP-2 Is a Surrogate Cerebrospinal Fluid Marker of Alzheimer-related Cognitive Impairment in Adults With Down Syndrome

10.21203/rs.3.rs-340117/v1 ◽

2021 ◽

Author(s):

Alberto Lleó ◽

Maria Carmona-Iragui ◽

Laura Videla ◽

Susana Fernández ◽

Bessy Benejam ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Down Syndrome ◽

Cognitive Impairment ◽

Episodic Memory ◽

Cued Recall ◽

Synaptic Proteins ◽

Selected Reaction Monitoring ◽

Synaptic Protein ◽

Csf Levels ◽

Syntaxin 1B

Abstract Background. There is an urgent need for objective markers of Alzheimer’s disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression and assess response to disease-modifying therapies. Previously, GluA4 and Neuronal Pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment. Methods. We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF AD biomarkers, CSF Aβ42:40 ratio, CSF Aβ1-42 and CSF p-tau. P-values were adjusted for multiple testing. Results. In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p=.04) and age (adj.p=.0008) and was the best correlate of CSF Aβ42:40 (adj.p=.0001) and CSF p-tau (adj.p<.0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p=.02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4 and Syntaxin-1B all strongly correlated with NPTX2 (p<.0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p<.002). Conclusion. CSF VAMP-2 represents a promising objective surrogate marker of cognitive failure in DS. VAMP-2 also has potential for use in AD clinical trials as a measure of synapse engagement and therapeutic response that does not directly measure the drug target (typically Aβ and tau).

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Ante Mortem Cerebrospinal Fluid Levels of Calsyntenin-1 and Neurexin-2a Reflect Post-Mortem TDP-43 Pathology in a Pathological Cohort of Frontotemporal Lobar Degeneration

10.21203/rs.3.rs-885718/v1 ◽

2021 ◽

Author(s):

Alba Cervantes-González ◽

David J Irwin ◽

Daniel Alcolea ◽

Corey T McMillan ◽

Alice Chen-Plotkin ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Frontotemporal Lobar Degeneration ◽

Neurofibrillary Tangle ◽

Surrogate Marker ◽

Quantitative Measure ◽

Synaptic Proteins ◽

Analysis Of Covariance ◽

Early Event ◽

Post Mortem ◽

Csf Levels

Abstract Background. Frontotemporal dementia (FTD) clinical diagnosis is challenged by the variable correspondence between the clinical syndrome and underlying neuropathological changes, the phenotypic overlap with Alzheimer's disease (AD) and the lack of pathophysiologic diagnostic biomarkers. As synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD), a surrogate marker of synapse loss could be used to monitor early pathologic changes. The aim of this study was to evaluate the relationship of antemortem cerebrospinal fluid (CSF) levels of 9 synaptic proteins with postmortem global tau and TDP-43 burden in a neuropathological FTLD cohort. Methods. We included patients with a neuropathological confirmation of FTLD-Tau (n=24, mean age-at-CSF 67 years+/-11), FTLD-TDP (n=25, 66 years+/-9) or AD (n=25, 73 years+/-6) as well as cognitively normal controls (n=35, 69 years+/-7) from the Penn FTD Center and ADRC. A subset of 39 FTLD patients presented without AD comorbidity (neurofibrillary tangle score of B0/B1 according to the NIA-AA classification) and 18 AD patients presented without TDP-43 comorbidity. We quantified the synaptic panel in antemortem CSF by targeted mass spectrometry using isotopically-labeled peptides as internal standards. We used a semi-quantitative measure of tau and TDP-43 inclusions to quantify pathological burden across 16 brain regions. Statistical methods included Spearman rank correlations, one-way analysis of covariance (controlling for sex and age-at-CSF), linear regression (controlling for age-at-death) and receiver-operating characteristic curves. Result. CSF calsyntenin-1 and neurexin-2a were correlated in all patient groups (rs=.55 to .88). In FTLD-TDP, we observed low antemortem CSF levels of calsyntenin-1 and neurexin-2a compared to AD (.72-fold, p=.001, .77-fold, p=.04, respectively) and controls (.80-fold, p=.02, .78-fold, p=.02, respectively), which were inversely associated with post-mortem global TDP-43 burden (regression r2=.36, p=.04 and r2=.35, p=.04, respectively). Neurexin-2a showed 75.0% (95% CI 60-88) accuracy to discriminate FTLD-TDP from controls. Calsyntenin-1 showed 75.1% (95% CI 62-87) accuracy to discriminate FTLD-TDP from AD. None of the synaptic proteins were altered in FTLD-Tau compared to controls (0.79 to 1.12-fold, p>.12) or associated with post-mortem global tau burden (r2=.12, p=.36). Comorbidity had a limited effect on these findings. Conclusion. CSF calsyntenin-1 and neurexin-2a have potential as objective measures of TDP-43-mediated degeneration in FTLD.

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Increased Cerebrospinal Fluid Concentration of ZnT3 Is Associated with Cognitive Impairment in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-200498 ◽

2020 ◽

Vol 77 (3) ◽

pp. 1143-1155

Author(s):

Daniela Enache ◽

Joana B. Pereira ◽

Vesna Jelic ◽

Bengt Winblad ◽

Per Nilsson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Depressive Symptoms ◽

Cognitive Decline ◽

Lewy Bodies ◽

Lewy Body Dementia ◽

Synaptic Proteins ◽

Subjective Cognitive Decline

Background: Cognitive deficits arising in the course of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Parkinson’s disease with dementia (PDD) are directly linked to synaptic loss. Postmortem studies suggest that zinc transporter protein 3 (ZnT3), AMPA glutamate receptor 3 (GluA3), and Dynamin1 are associated with cognitive decline in AD and Lewy body dementia patients. Objective: We aimed to evaluate the diagnostic value of ZnT3, GluA3, and Dynamin 1 in the cerebrospinal fluid (CSF) of patients with dementia due to AD, DLB, and PDD compared to cognitively normal subjective cognitive decline (SCD) patients in a retrospective study. In addition, we assessed the relationship between synaptic markers and age, sex, cognitive impairment, and depressive symptoms as well as CSF amyloid, phosphorylated tau (p-tau), and total tau (T-tau). Methods: Commercially available ELISA immunoassay was used to measure the levels of proteins in a total of 97 CSF samples from AD (N = 24), PDD (N = 18), DLB (N = 27), and SCD (N = 28) patients. Cognitive impairment was assessed using the Mini-Mental State Examination (MMSE). Results: We found a significant increase in the concentrations of ZnT3, GluA3, and Dynamin1 in AD (p = 0.002) and of ZnT3 and Dynamin 1 in DLB (p = 0.001, p = 0.002) when compared to SCD patients. Changes in ZnT3 concentrations correlated with MMSE scores in AD (p = 0.011), and with depressive symptoms in SCD (p = 0.041). Conclusion: We found alteration of CSF levels of synaptic proteins in AD, PDD, and DLB. Our results reveal distinct changes in CSF concentrations of ZnT3 that could reflect cognitive impairment in AD with implications for future prognostic and diagnostic marker development.

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Potential Fluid Biomarkers for the Diagnosis of Mild Cognitive Impairment

International Journal of Molecular Sciences ◽

10.3390/ijms20174149 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4149 ◽

Cited By ~ 11

Author(s):

Vo Van Giau ◽

Eva Bagyinszky ◽

Seong Soo A. An

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Phosphorylated Tau ◽

Transitional State ◽

Total Tau ◽

Current State ◽

Risk Of Progression ◽

Csf Levels ◽

Potential Fluid

Mild cognitive impairment (MCI) is characterized by a level of cognitive impairment that is lower than normal for a person’s age, but a higher function than that that observed in a demented person. MCI represents a transitional state between normal aging and dementia disorders, especially Alzheimer’s disease (AD). Much effort has been made towards determining the prognosis of a person with MCI who will convert to AD. It is now clear that cerebrospinal fluid (CSF) levels of Aβ40, Aβ42, total tau and phosphorylated tau are useful for predicting the risk of progression from MCI to AD. This review highlights the advantages of the current blood-based biomarkers in MCI, and discusses some of these challenges, with an emphasis on recent studies to provide an overview of the current state of MCI.

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Influence of APOE Genotype on Alzheimer’s Disease CSF Biomarkers in a Spanish Population

BioMed Research International ◽

10.1155/2016/1390620 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

J. A. Monge-Argilés ◽

R. Gasparini-Berenguer ◽

M. Gutierrez-Agulló ◽

C. Muñoz-Ruiz ◽

J. Sánchez-Payá ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Apoe Genotype ◽

Amnestic Mild Cognitive Impairment ◽

Spanish Population ◽

Csf Biomarkers ◽

Csf Levels

Objectives. To evaluate the association between apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) levels of Alzheimer’s disease (AD) biomarkers and to study the influence of APOE genotype on the development of AD in a Spanish population.Material and Methods. The study comprised 29 amnestic mild cognitive impairment (MCI) patients and 27 control subjects. Using ELISA methodology, CSF biomarkers and tau/Aβratios were obtained. ANOVA and adjusted odds ratios were calculated.Results. We observed the effect of APOE genotype and age on CSF AD variables. The progression to AD was more clearly influenced by CSF AD variables than by age or APOE status.Conclusions. APOE status influences CSF AD variables. However, the presence of APOEε4 does not appear to be a deterministic factor for the development of AD, because CSF variables have a greater influence on progression to the disease. These results confirm previous observations and, to our knowledge, are the first published in a Spanish population.

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CSF synaptic protein concentrations are raised in those with atypical Alzheimer’s disease but not frontotemporal dementia

Alzheimer s Research & Therapy ◽

10.1186/s13195-019-0564-2 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 8

Author(s):

Mica T. M. Clarke ◽

Ann Brinkmalm ◽

Martha S. Foiani ◽

Ione O. C. Woollacott ◽

Carolin Heller ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontotemporal Dementia ◽

Subgroup Analysis ◽

Synaptic Proteins ◽

Synaptic Protein ◽

Atypical Form ◽

Synaptic Markers ◽

Synaptotagmin 1 ◽

Csf Levels

Abstract Background Increased CSF levels of a number of synaptic markers have been reported in Alzheimer’s disease (AD), but little is known about their concentrations in frontotemporal dementia (FTD). We investigated this in three synaptic proteins, neurogranin, SNAP-25, and synaptotagmin-1. Methods CSF samples were analysed from 66 patients with a disorder in the FTD spectrum and 19 healthy controls. Patients were stratified by their tau to Aβ42 ratio: those with a ratio of > 1 considered as having likely AD pathology, i.e. an atypical form of AD (‘AD biomarker’ group [n = 18]), and < 1 as likely FTD pathology (‘FTD biomarker’ group [n = 48]). A subgroup analysis compared those in the FTD group with likely tau (n = 7) and TDP-43 (n = 18) pathology. Concentrations of neurogranin were measured using two different ELISAs (Ng22 and Ng36), and concentrations of two SNAP-25 fragments (SNAP-25tot and SNAP-25aa40) and synaptotagmin-1 were measured via mass spectrometry. Results The AD biomarker group had significantly higher concentrations of all synaptic proteins compared to controls except for synaptotagmin-1 where there was only a trend to increased levels—Ng22, AD mean 232.2 (standard deviation 138.9) pg/ml, controls 137.6 (95.9); Ng36, 225.5 (148.8) pg/ml, 130.0 (80.9); SNAP-25tot, 71.4 (27.9) pM, 53.5 (11.7); SNAP-25aa40, 14.0 (6.3), 7.9 (2.3) pM; and synaptotagmin-1, 287.7 (156.0) pM, 238.3 (71.4). All synaptic measures were significantly higher in the atypical AD group than the FTD biomarker group except for Ng36 where there was only a trend to increased levels—Ng22, 114.0 (117.5); Ng36, 171.1 (75.2); SNAP-25tot, 49.2 (16.7); SNAP-25aa40, 8.2 (3.4); and synaptotagmin-1, 197.1 (78.9). No markers were higher in the FTD biomarker group than controls. No significant differences were seen in the subgroup analysis, but there was a trend to increased levels in those with likely tau pathology. Conclusions No CSF synaptic proteins have been shown to be abnormal in those with likely FTD pathologically. Higher CSF synaptic protein concentrations of neurogranin, SNAP-25, and synaptotagmin-1 appear to be related to AD pathology.

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Joint effects of gray matter atrophy and altered functional connectivity on cognitive deficits in amnestic mild cognitive impairment patients

Psychological Medicine ◽

10.1017/s0033291714002876 ◽

2014 ◽

Vol 45 (9) ◽

pp. 1799-1810 ◽

Cited By ~ 14

Author(s):

C. Xie ◽

F. Bai ◽

B. Yuan ◽

H. Yu ◽

Y. Shi ◽

...

Keyword(s):

Regression Analysis ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Functional Connectivity ◽

Episodic Memory ◽

Cognitive Performance ◽

Gray Matter ◽

Cognitive Deficits ◽

Amnestic Mild Cognitive Impairment ◽

Multivariate Linear Regression Analysis

BackgroundGray matter (GM) atrophy and disrupted intrinsic functional connectivity (IFC) are often present in patients with amnestic mild cognitive impairment (aMCI), which shows high risk of developing into Alzheimer's disease. Little is known, however, about the relationship between GM atrophy and altered IFC, and whether they are related to cognitive decline.MethodA total of 30 aMCI and 26 cognitively normal (CN) subjects were recruited for this study. Optimized voxel-based morphometric and resting-state functional connectivity magnetic resonance imaging approaches were performed to measure the GM volumes (GMVs) and atrophy-related IFC, respectively. Multivariate linear regression analysis was used to examine the effects of GM atrophy and IFC on cognitive performance across subjects, after controlling for the effects of age, education, gender and group.ResultsCompared with CN subjects, aMCI subjects showed significantly reduced GMVs and decreased IFC in the frontal-parietal and medial temporal lobe systems. Multivariate regression analysis further demonstrated that the GMVs and decreased IFC simultaneously affected the cognitive function. Specifically, GMVs were positively correlated with cognitive performances, including global cognition and episodic memory, and showed a strong trend in correlation between GMVs and non-episodic memory, whilst IFC was positively correlated with the above three cognitive measures, across all subjects. In addition, significant correlation was found between GMVs and altered IFC strength across all subjects.ConclusionsOur findings demonstrated that GMVs and IFC jointly contribute to cognitive performance, and combining quantitative information about GMVs and the strength of functional connectivity may serve as an indicator of cognitive deficits in non-demented elderly.

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Association of the LRP1 gene and cognitive performance with amnestic mild cognitive impairment in elderly Chinese

International Psychogeriatrics ◽

10.1017/s104161020999072x ◽

2009 ◽

Vol 21 (6) ◽

pp. 1072-1080 ◽

Cited By ~ 5

Author(s):

Yong M. Shi ◽

Hong Zhou ◽

Zhi J. Zhang ◽

Hui Yu ◽

Feng Bai ◽

...

Keyword(s):

Genetic Variation ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Episodic Memory ◽

Cognitive Performance ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Poor Performance ◽

Amnestic Mild Cognitive Impairment ◽

Healthy Controls

ABSTRACTBackground: The genetic region coding for low-density lipoprotein receptor-related protein1 (LRP1) is considered an intriguing susceptibility locus for Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) is characterized by episodic memory impairment and represents the prodromal stage of AD. Our aim in this study is to investigate the relationship between LRP1 genetic variation and aMCI, and the influence of LRP1 on cognitive performance.Methods: We performed a case-control association study analyzing five polymorphisms in LRP1 gene by TaqMan Assays-on-Demand SNP Genotyping. All samples were derived from Chinese subjects (109 cases, 104 healthy controls) and assessed using multi-dimension neuropsychological instruments.Results: We identified haplotypes within the region containing the LRP1 gene. Of these, haplotype TAA (T: rs1800194; A: rs11837145; A: rs10876967) was significantly associated with aMCI, being over-represented in aMCI versus healthy controls. Haplotype TAA was associated with poor performance on episodic memory in all subjects.Conclusions: This study confirms the association between genetic variants in LRP1 and aMCI. Moreover, we have identified a relationship between LRP1 genetic variation and specific aspects of neurocognitive function. Our convergent results suggest that LRP1 plays an important role in cognitive function and possibly in the pathogenesis of aMCI.

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Association of Cigarette Smoking With Male Cognitive Impairment and Metal Ions in Cerebrospinal Fluid

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.738358 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hui Li ◽

Qingshuang Mu ◽

Yimin Kang ◽

Xiaoyu Yang ◽

Ligang Shan ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Cigarette Smoking ◽

Metal Ions ◽

Cruciate Ligament ◽

History Of ◽

Copper Zinc ◽

Csf Levels ◽

Young Smokers ◽

Anterior Cruciate

Objective: Cigarette smoking might accelerate cognitive impairment; however, this has never been investigated using human cerebrospinal fluid (CSF). We conducted this study to investigate the association between cigarette smoking and cognitive impairment through metal ions in CSF.Methods: We obtained 5-ml CSF samples from routine lumbar puncture procedures in patients undergoing anterior cruciate ligament reconstruction before surgery in China. A total of 180 Chinese males were recruited (80 active smokers and 100 non-smokers). We measured specific cigarette-related neurotoxic metal ions in CSF, including iron, copper, zinc, lead, aluminum, and manganese. Sociodemographic data and history of smoking were obtained. The Montreal Cognitive Assessment (MoCA) was applied.Results: Active smokers had fewer years of education (11.83 ± 3.13 vs. 13.17 ± 2.60, p = 0.01), and higher age (33.70 ± 10.20 vs. 29.76 ± 9.58, p = 0.01) and body mass index (25.84 ± 3.52 vs. 24.98 ± 4.06, p =0.03) than non-smokers. Compared to non-smokers, active smokers had significantly higher CSF levels of iron, zinc, lead, and aluminum and lower MoCA scores (all p < 0.05). Average daily numbers of cigarettes smoked negatively correlated with the MoCA scores (r = −0.244, p = 0.048). In young smokers, CSF manganese levels negatively correlated with MoCA scores (r = −0.373, p = 0.009).Conclusions and Relevance: Cigarette smoking might be associated with male cognitive impairment, as shown by lower MoCA scores and higher levels of CSF iron, zinc, lead, and aluminum in active smokers. This might be early evidence of cigarette smoking accelerating male cognitive impairment.

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Mini Review: Correlations of Cognitive Domains With Cerebrospinal Fluid α-Synuclein Levels in Patients With Parkinson's Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.616357 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hidetomo Murakami ◽

Kenjiro Ono ◽

Tomotaka Shiraishi ◽

Tadashi Umehara ◽

Shusaku Omoto ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Performance ◽

Lewy Bodies ◽

Executive Dysfunction ◽

Cognitive Outcome ◽

The Other ◽

Cognitive Domains ◽

Csf Levels

The level of α-synuclein, a component of Lewy bodies, in cerebrospinal fluid (CSF) in Parkinson's disease (PD) has attracted recent attention. Most meta-analyses conclude that CSF levels of α-synuclein are decreased in PD. Patients with PD present with cognitive impairment, including frontal/executive dysfunction in the early phase and later emergence of visuospatial and mnemonic deficits. To examine whether CSF α-synuclein levels reflect the activities of various cognitive domains, we reviewed reports examining the association of these levels with cognitive performance in each domain in PD. Among 13 cross-sectional studies, five showed that a lower CSF α-synuclein level was associated with worse cognitive function. In four of these five reports, frontal/executive function showed this association, suggesting a link of the pathophysiology with Lewy bodies. In three other reports, a higher CSF α-synuclein level was associated with temporal-parieto-occipital cognitive deterioration such as memory. In the other five reports, the CSF α-synuclein level did not correlate with cognitive performance for any domain. In four longitudinal studies, a higher baseline CSF α-synuclein level was associated with a worse cognitive outcome, including cognitive processing speed, visuospatial function and memory in two, but not with any cognitive outcome in the other two. The different associations may reflect the heterogeneous pathophysiology in PD, including different pathogenic proteins, neurotransmitters. Thus, more studies of the association between cognitive domains and CSF levels of pathogenic proteins are warranted.

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