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Background: Observational studies in Parkinson’s disease (PD) have focused on relatively small numbers of research participants who are studied extensively. The Molecular Integration in Neurological Diagnosis Initiative at the University of Pennsylvania aims to characterize molecular and clinical features of PD in every patient in a large academic center. Objective: To determine the feasibility and interest in a global-capture biomarker research protocol. Additionally, to describe the clinical characteristics and GBA and LRRK2 variant carrier status among participants. Methods: All patients at UPenn with a clinical diagnosis of PD were eligible. Informed consent included options for access to the medical record, future recontact, and use of biosamples for additional studies. A blood sample and a completed questionnaire were obtained from participants. Targeted genotyping for four GBA and eight LRRK2 variants was performed, with plasma and DNA banked for future research. Results: Between September 2018 and December 2019, 704 PD patients were approached for enrollment; 652 (92.6%) enrolled, 28 (3.97%) declined, and 24 (3.41%) did not meet eligibility criteria. Median age was 69 (IQR 63_75) years, disease duration was 5.41 (IQR 2.49_9.95) years, and 11.10%of the cohort was non-white. Disease risk-associated variants in GBA were identified in 39 participants (5.98%) and in LRRK2 in 16 participants (2.45%). Conclusions: We report the clinical and genetic characteristics of PD patients in an all-comers, global capture protocol from an academic center. Patient interest in participation and yield for identification of GBA and LRRK2 mutation carriers is high, demonstrating feasibility of PD clinic-wide molecular characterization.

ObjectiveTo determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)–type copathology are more impaired on confrontation naming than those without likely AD-type copathology.MethodsWe selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid1-42 (Aβ42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aβ42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD − AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD − AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes.ResultsPatients with LBD + AD performed worse on BNT than patients with LBD − AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = −0.28, p < 0.05) and p-tau (ρ = −0.26, p = 0.05) but not Aβ42 (p > 0.1).ConclusionMarkers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

ObjectivesTo investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD).MethodsWe studied 72 LBD patients (Parkinson disease (PD)=2, PD-MCI=25, PD with dementia=10, dementia with Lewy bodies=35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aβ1-42 >0.3) (LBD+AD, N=19), and those without AD co-pathology (LBD-AD, N=53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD-AD=14, LBD+AD=7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Aβ, and alpha-synuclein using digital histopathology in five representative neocortical regions.ResultsThe LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P&nbsp

Objective The objective of this study was to determine the frequency and impact of subjective cognitive complaint (SCC) in Parkinson's disease (PD) patients with normal cognition. Methods Patients with PD with expert consensus-determined normal cognition at baseline were asked a single question regarding the presence of SCC. Baseline (N = 153) and longitudinal (up to 4 follow-up visits during a 5-year period; N = 121) between-group differences in patients with PD with (+SCC) and without (-SCC) cognitive complaint were examined, including cognitive test performance and self-rated and informant-rated functional abilities. Results A total of 81 (53%) participants reported a cognitive complaint. There were no between-group differences in global cognition at baseline. Longitudinally, the +SCC group declined more than the -SCC group on global cognition (Mattis Dementia Rating Scale-2 total score, F1,431 = 5.71, P = 0.02), processing speed (Symbol Digit Modalities Test, F1,425 = 7.52, P = 0.006), and executive function (Trail Making Test Part B, F1,419 = 4.48, P = 0.04), although the results were not significant after correction for multiple testing. In addition, the +SCC group was more likely to progress to a diagnosis of cognitive impairment over time (hazard ratio = 2.61, P = 0.02). The +SCC group also demonstrated significantly lower self-reported and knowledgeable informant-reported cognition-related functional abilities at baseline, and declined more on an assessment of global functional abilities longitudinally. Conclusions Patients with PD with normal cognition, but with SCC, report poorer cognition-specific functional abilities, and are more likely to be diagnosed with cognitive impairment and experience global functional ability decline long term. These findings suggest that SCC and worse cognition-related functional abilities may be sensitive indicators of initial cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society.

Biomarkers to discriminate the main pathologies underlying frontotemporal lobar degeneration (FTLD-Tau, FTLD-TDP) are lacking. Our previous FTLD cerebrospinal fluid (CSF) proteomestudy revealed that sex hormone-binding globulin (SHBG) was specifically increased in FTLD-Taupatients. Here we investigated the potential of CSF SHBG as a novel biomarker discriminating themain FTLD pathological subtypes. SHBG was measured in CSF samples from patients with FTLDTau (n = 23), FTLD-TDP (n = 29) and controls (n = 33) using an automated electro-chemiluminescentimmunoassay. Differences in CSF SHBG levels across groups, as well as its association with CSFYKL40, pTau181/total-Tau ratio and cognitive function were analyzed. CSF SHBG did not differacross groups, though a trend towards elevated levels in FTLD-Tau cases compared to FTLD-TDPand controls was observed. CSF SHBG levels were not associated with either CSF YKL40 or thep/tTau ratio. They, however, inversely correlated with the MMSE score (r = −0.307, p = 0.011), anassociation likely driven by the FTLD-Tau group (r FTLD-Tau = −0.38; r FTLD-TDP = −0.02). CSFSHBG is not a suitable biomarker to discriminate FTLD-Tau from FTLD-TDP

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.

BACKGROUND: Neurofilament light chain protein (NfL) is a promising biomarker of neurodegeneration. OBJECTIVES: To determine whether plasma and CSF NfL (1) associate with motor or cognitive status in Parkinson’s disease (PD) and (2) predict future motor or cognitive decline in PD. METHODS: Six hundred and fifteen participants with neurodegenerative diseases, including 152 PD and 200 healthy control participants, provided a plasma and/or cerebrospinal fluid (CSF) NfL sample. Diagnostic groups were compared using the KruskalWallis rank test. Within PD, cross-sectional associations between NfL and Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) and Mattis Dementia Rating Scale (DRS-2) scores were assessed by linear regression; longitudinal analyses were performed using linear mixed-effects models and Cox regression. RESULTS: Plasma and CSF NfL levels correlated substantially (Spearman r = 0.64, P < 0.001); NfL was highest in neurocognitive disorders. PD participants with high plasma NfL were more likely to develop incident cognitive impairment (HR 5.34, P = 0.005). CONCLUSIONS: Plasma NfL is a useful prognostic biomarker for PD, predicting clinical conversion to mild cognitive impairment or dementia. © 2021 International Parkinson and Movement Disorder Society

Concomitant neuropathological hallmarks of Alzheimer’s Disease (AD) are common in the brains of people with Parkinson’s disease (PD). Furthermore, AD biomarkers are associated with cognitive decline and dementia in PD patients during life. Here, we highlight the considerable overlap between AD and PD, emphasizing neuropathological, biomarker, and mechanistic studies. We suggest that precision medicine approaches may successfully identify PD patients most likely to develop concomitant AD. The ability to identify PD patients at high risk for future concomitant AD in turn provides an ideal cohort for trials of AD-directed therapies in PD patients, aimed at delaying or preventing cognitive symptoms.

C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglia promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities.

Concomitant neuropathological hallmarks of Alzheimer’s Disease (AD) are common in the brains of people with Parkinson’s disease (PD). Furthermore, AD biomarkers are associated with cognitive decline and dementia in PD patients during life. Here, we highlight the considerable overlap between AD and PD, emphasizing neuropathological, biomarker, and mechanistic studies. We suggest that precision medicine approaches may successfully identify PD patients most likely to develop concomitant AD. The ability to identify PD patients at high risk for future concomitant AD in turn provides an ideal cohort for trials of AD-directed therapies in PD patients, aimed at delaying or preventing cognitive symptoms.

The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well-understood. Here, we investigated the influence of genotypes at TMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions in C9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)- allele homozygotes at the TMEM106B locus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions. C9orf72 expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting for C9orf72 expansion status did not affect the relationship between TMEM106B genotype and TDP-43 pathology. In order to elucidate the direction of causality for this association, we directly manipulated TMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown of TMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.

ObjectiveAccurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few CSF markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL) would be associated with longitudinal cognitive decline in patients with known FTLD-TAR DNA binding protein ~43kD (TDP) pathology.MethodsThis case-control study evaluated CSF NfL, total tau, phosphorylated tau, and β-amyloid1-42 in patients with known FTLD-tau or FTLD-TDP pathology (n = 50) and healthy controls (n = 65) and an extended cohort of clinically diagnosed patients with likely FTLD-tau or FTLD-TDP (n = 148). Regression analyses related CSF analytes to longitudinal cognitive decline (follow-up ∼1 year), controlling for demographic variables and core AD CSF analytes.ResultsIn FTLD-TDP with known pathology, CSF NfL is significantly elevated compared with controls and significantly associated with longitudinal decline on specific executive and language measures, after controlling for age, disease duration, and core AD CSF analytes. Similar findings are found in the extended cohort, also including clinically identified likely FTLD-TDP. Although CSF NfL is elevated in FTLD-tau compared with controls, the association between NfL and longitudinal cognitive decline is limited to executive measures.ConclusionCSF NfL is associated with longitudinal clinical decline in relevant cognitive domains in patients with FTLD-TDP after controlling for demographic factors and core AD CSF analytes and may also be related to longitudinal decline in executive functioning in FTLD-tau.

Background: A composite measure that assesses both cognitive and functional abilities in Parkinson’s disease (PD) would be useful for diagnosing mild cognitive impairment (MCI) and PD dementia (PDD) and as an outcome measure in randomized controlled trials. The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) was designed to assess both cognition and basic-instrumental activities of daily living in Alzheimer’s disease but has not yet been validated in PD. Objective: To validate the CDR-SOB as a composite cognitive-functional measure for PD patients, as well as to assess its sensitivity to change. Methods: The CDR-SOB and a comprehensive cognitive and functional battery was administered to 101 PD patients at baseline (39 normal cognition [NC], 41 MCI and 21 PDD by expert consensus panel), and re-administered to 64 patients after 1-2 years follow-up (32 NC and 32 cognitive impairment [CI] at baseline). Results: Cross-sectionally, CDR-SOB and domain scores were correlated with corresponding neuropsychological or functional measures and were significantly different between cognitive subgroups both at baseline and at follow-up. In addition, CDR-SOB ROC curves distinguished between normal cognition and dementia with high sensitivity, but did not distinguish well between NC and MCI. Longitudinal changes in the CDR-SOB and domain scores were not significant and were inconsistent in predicting change in commonly-used cognitive and functional tests. Conclusion: The CDR-SOB detects dementia-level cognitive impairment in PD but may not be appropriate for predicting longitudinal combined cognitive-functional changes in patients without significant cognitive impairment at baseline.

Frontotemporal lobar degeneration (FTLD) is a leading cause of early-onset dementia, but the pathological mechanisms underlying this disorder are not well understood. Common variants in the gene encoding Transmembrane Protein 106B (TMEM106B) increase genetic risk for FTLD with TAR DNA-binding Protein 43 (TDP-43) inclusions (FTLD-TDP-43), and variants associated with increased TMEM106B expression confer greater disease risk. Here, we demonstrate that TMEM106B expression increases the formation of enlarged autolysosomes and elucidate the molecular mechanism underlying this phenotype. By immunoprecipitating TMEM106B and identifying co-immunoprecipitated proteins by mass spectrometry (IP-MS), we found that TMEM106B interacts with the Vesicle-associated membrane protein 8 (VAMP8), a SNARE protein known to mediate lysosome-autophagosome fusion. TMEM106B and VAMP8 co-localize in lysosomes, and their interaction is dependent on lysosomal pH. Knockdown of VAMP8, or its partner in lysosome-autophagosome fusion Syntaxin-17 (Stx17), rescues the TMEM106B-induced vacuolar phenotype of enlarged autolysosomes. Moreover, deacidification of lysosomes in HeLa cells and iPSC-neurons abrogates co-localization of TMEM106B and VAMP8, with redistribution of VAMP8 to the cell periphery. Taken together, our data suggest that TMEM106B modulates VAMP8-Stx17-mediated lysosome-autophagosome fusion, in a lysosomal pH-dependent manner.

BACKGROUND: The genetic basis of variation in the progression of primary tauopathies has not been determined. Here, we used a genome-wide association study (GWAS) to identify genetic determinants of survival in progressive supranuclear palsy (PSP). METHODS: Data were collected and analysed between 1(st) August 2016 and 1(st) February 2020. In stage one, we collected pathological and clinical-criteria diagnosed PSP cases from two separate cohorts (2011 PSP GWAS cohort cases from the Mayo Clinic and Munich brain banks; UCL PSP cohort cases from UK brain banks and the PROSPECT study). Cases were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death) and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data from these cases were used to conduct a survival GWAS using a Cox-proportional hazards model. In stage two, replication data from additional Mayo Clinic brain bank cases, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the eQTL profile of variants which passed genome-wide significance in our GWAS using the FUMA platform, and conducted colocalisation analyses using the eQTLGen and PsychENCODE datasets. FINDINGS: Data were available for 1,001 PSP cases of white European ancestry in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead SNP: rs2242367 – p=7.5x10(-10); hazard ratio (95% confidence interval)=1.42 (1.22-1.67)). In stage two, the addition of 238 cases resulted in significant pooled association statistics for rs2242367 (n=1,239; p=1.3x10(-10); hazard ratio (95% confidence interval)=1.37 (1.25-1.51). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and long intergenic non-coding (lnc) RNAs, LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 (PP4) of 0.77, suggesting colocalisation due to a single shared causal variant. INTERPRETATION: Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association may be through a lncRNA-regulated effect on LRRK2 expression as LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson’s disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies. FUNDING: PSP Association, CBD Solutions, Medical Research Council.

Growing evidence suggests overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD) pathophysiology in a subset of patients. Indeed, 50–80% of autopsy cases with a primary clinicopathological diagnosis of Lewy body disease (LBD) – most commonly manifesting during life as PD – have concomitant amyloid-beta and tau pathology, the defining pathologies of AD. Here we evaluated common genetic variants in genome-wide association with AD as predictors of concomitant AD pathology in the brains of people with a primary clinicopathological diagnosis of PD or Dementia with Lewy Bodies (DLB), diseases both characterized by neuronal Lewy bodies. In the first stage of our study, 127 consecutive autopsy-confirmed cases of PD or DLB from a single center were assessed for AD neuropathological change (ADNC), and these same cases were genotyped at 20 single nucleotide polymorphisms (SNPs) found by genome-wide association study to associate with risk for AD. In these 127 Training set individuals, we developed a logistic regression model predicting the presence of ADNC, using backward stepwise regression for model selection and 10-fold cross-validation to estimate performance. The best-fit model generated a risk score for ADNC (ADNC-RS) based on age at disease onset and genotype at three SNPs (APOE, BIN1, and SORL1 loci), with an area under the receiver operating curve (AUC) of 0.751 in our Training set. In the replication stage of our study, we assessed model performance in a separate Test set of the next 81 individuals genotyped in our center. In the Test set, the AUC was 0.781, and individuals with ADNC-RS in the top quintile had four-fold increased likelihood of having AD pathology at autopsy compared with those in each of the lowest two quintiles. Finally, in the validation stage of our study, we applied our ADNC-RS model to 70 LBD individuals from 20 Alzheimer’s Disease Research Centers (ADRC) whose autopsy and genetic data were available in the National Alzheimer’s Coordinating Center (NACC) database. In this Validation set, the AUC was 0.754. Thus, in patients with autopsy-confirmed PD or DLB, a simple model incorporating three AD-risk SNPs and age at disease onset substantially enriches for concomitant AD pathology at autopsy, with implications for identifying LBD patients in which targeting amyloid-beta or tau is a therapeutic strategy.

Clinical definitions of Parkinson's disease (PD) are over 200 years old, while neuropathological definitions- which are still the basis of how we define the disease now- are over 100 years old. We argue that for both clinical care and therapeutic development, these definitions need updating for the molecular age in which we live. We highlight specific instances in which genetic or biochemical biomarkers are increasingly used for clinical trial enrollment in the neurodegenerative diseases, suggesting that molecular definition(s) of PD are already emerging. We review candidate biomarkers for PD-related pathologies and highlight the need for further validation.

Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p

ObjectiveTo test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD).MethodsPatients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN − AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine181, and Aβ1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN − AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves.ResultsSYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aβ1-42 (mean difference −84.0 ± 22.9 g/mL) compared to SYN − AD (p < 0.01, both). Increasing global cerebral tau and plaque scores were associated with higher CSF t-tau (R2 = 0.15–0.16, p < 0.05, both) and lower Aβ1-42 (R2 = 0.43–0.49, p < 0.001, both), while increasing cerebral SYN scores were associated with lower CSF Aβ1-42 (R2 = 0.31, p < 0.001) and higher CSF t-tau/Aβ1-42 ratio (R2 = 0.27, p = 0.01). CSF t-tau/Aβ1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aβ1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage.ConclusionsHigher antemortem CSF t-tau/Aβ1-42 and lower Aβ1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies.

PURPOSE OF REVIEW: To review the evidence for genetic modifier effects in the neurodegenerative diseases Huntington’s Disease (HD), Frontotemporal Lobar Degeneration (FTLD), Alzheimer’s Disease (AD), and Parkinson’s Disease (PD). RECENT FINDINGS: Increasingly, we understand human disease genetics less through the lens of single-locus/single-trait effects, and more through that of polygenic contributions to disease risk. In addition, specific examples of genetic modifier effects of the chromosome 7 gene TMEM106B on various target genes including those causal for Mendelian classes of FTLD – GRN and c9orf72 – have emerged from both genetic cohort studies and mechanistic examinations of biological pathways. SUMMARY: Here, we summarize the literature reporting genetic modifier effects in HD, FTLD, AD, and PD. We further contextualize reported genetic modifier effects in these diseases in terms of insight they may lend to the concept of a polygenic landscape for the major neurodegenerative diseases.

BACKGROUND People with PD are at high risk of developing cognitive impairment and dementia. Cross-sectional studies have identified candidate biomarkers associated with cognitive decline. However, longitudinal studies on this topic are rarer, and few have investigated the use of biomarker panels encompassing multiple modalities. The objective of this study was to find baseline predictors of cognitive decline in longitudinally followed, nondemented Parkinson's disease patients. METHODS We performed a prospective cohort study of 100 PD patients with a median disease duration of 6.4 years. All participants were nondemented at baseline. We examined 16 baseline biomarkers from clinical, genetic, biochemical, and MRI-based imaging modalities for their association with longitudinal cognitive decline for up to 8 years. We investigated biomarkers individually, as well as in a multivariate linear mixed-effects model encompassing multimodal biomarkers, with change in the Mattis Dementia Rating Scale-2 over time as the primary outcome. Annual consensus process-derived cognitive diagnosis was used for Cox proportional hazards modeling of risk for cognitive decline. RESULTS In multivariate analysis, the presence of the APOE E4 allele, thought disorder, and an Alzheimer's disease pattern of brain atrophy (spatial pattern of abnormality for recognition of early Alzheimer's disease index) best predicted cognitive decline, with APOE E4 genotype exerting the greatest effect. The presence of the APOE E4 allele was associated with a 3.5 times higher risk of worsening cognitive diagnosis over time (HR, 3.53; 95% CI, 1.52-8.24; P

Background The relationship between statins and cognition in Parkinson's disease (PD) is poorly understood. Objectives Analyses were performed to determine associations between statin use and cross-sectional and longitudinal cognitive performance in PD. Methods Neuropsychological tests, medication logs, and ratings of functional abilities were collected from 313 PD participants longitudinally. Results At baseline, statin users (SU; N = 129) were older, more likely male, and had shorter PD duration than non-statin users (NSU; N = 184). In Cross-sectional analysis, SU performed better on global cognition, Trails B, semantic fluency, and phonemic fluency tasks. Rate of long-term global cognitive (Dementia Rating Scale-2 and MoCA) decline was significantly less in SU.

Background Lower vitamin D levels have been associated with manifest Parkinson's disease, prompting the hypothesis that vitamin D insufficiency or deficiency may increase risk for PD. Objectives To evaluate vitamin D levels in a population at risk for developing PD. Methods Plasma vitamin D levels were measured in the Parkinson Associated Risk Syndrome Study, a cohort of asymptomatic individuals, some of whom are at high risk for PD. Vitamin D levels were compared between subjects at high risk for PD (hyposmia and dopamine transporter scan deficit) versus all others and examined for correlations with dopaminergic system integrity. Results Mean vitamin D levels did not differ between groups, with a level of 27.8 ng/mL (standard deviation = 12.0) in the high-risk group versus 24.7 ng/mL (standard deviation = 9.0) in all others (P = 0.09). Vitamin D levels did not associate with putaminal dopamine transporter uptake. Conclusions Our data from the asymptomatic Parkinson Associated Risk Syndrome cohort do not support the hypothesis that chronic vitamin D insufficiency threatens dopaminergic system integrity, contributing to PD pathogenesis. © 2017 International Parkinson and Movement Disorder Society

Background Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting about 5 million people worldwide with no disease-modifying therapies. We sought blood-based biomarkers in order to provide molecular characterization of individuals with PD for diagnostic confirmation and prediction of progression. Methods and findings In 141 plasma samples (96 PD, 45 neurologically normal control [NC] individuals; 45.4% female, mean age 70.0 years) from a longitudinally followed Discovery Cohort based at the University of Pennsylvania (UPenn), we measured levels of 1,129 proteins using an aptamer-based platform. We modeled protein plasma concentration (log10 of relative fluorescence units [RFUs]) as the effect of treatment group (PD versus NC), age at plasma collection, sex, and the levodopa equivalent daily dose (LEDD), deriving first-pass candidate protein biomarkers based on p-value for PD versus NC. These candidate proteins were then ranked by Stability Selection. We confirmed findings from our Discovery Cohort in a Replication Cohort of 317 individuals (215 PD, 102 NC; 47.9% female, mean age 66.7 years) from the multisite, longitudinally followed National Institute of Neurological Disorders and Stroke Parkinson’s Disease Biomarker Program (PDBP) Cohort. Analytical approach in the Replication Cohort mirrored the approach in the Discovery Cohort: each protein plasma concentration (log10 of RFU) was modeled as the effect of group (PD versus NC), age at plasma collection, sex, clinical site, and batch. Of the top 10 proteins from the Discovery Cohort ranked by Stability Selection, four associations were replicated in the Replication Cohort. These blood-based biomarkers were bone sialoprotein (BSP, Discovery false discovery rate [FDR]-corrected p = 2.82 × 10−2, Replication FDR-corrected p = 1.03 × 10−4), osteomodulin (OMD, Discovery FDR-corrected p = 2.14 × 10−2, Replication FDR-corrected p = 9.14 × 10−5), aminoacylase-1 (ACY1, Discovery FDR-corrected p = 1.86 × 10−3, Replication FDR-corrected p = 2.18 × 10−2), and growth hormone receptor (GHR, Discovery FDR-corrected p = 3.49 × 10−4, Replication FDR-corrected p = 2.97 × 10−3). Measures of these proteins were not significantly affected by differences in sample handling, and they did not change comparing plasma samples from 10 PD participants sampled both on versus off dopaminergic medication. Plasma measures of OMD, ACY1, and GHR differed in PD versus NC but did not differ between individuals with amyotrophic lateral sclerosis (ALS, n = 59) versus NC. In the Discovery Cohort, individuals with baseline levels of GHR and ACY1 in the lowest tertile were more likely to progress to mild cognitive impairment (MCI) or dementia in Cox proportional hazards analyses adjusting for age, sex, and disease duration (hazard ratio [HR] 2.27 [95% CI 1.04–5.0, p = 0.04] for GHR, and HR 3.0 [95% CI 1.24–7.0, p = 0.014] for ACY1). GHR’s association with cognitive decline was confirmed in the Replication Cohort (HR 3.6 [95% CI 1.20–11.1, p = 0.02]). The main limitations of this study were its reliance on the aptamer-based platform for protein measurement and limited follow-up time available for some cohorts. Conclusions In this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD., Alice Chen-Plotkin and colleagues investigate possible biomarkers for diagnosis and progression of Parkinson’s disease., Author summary Why was this study done? No blood tests currently exist that distinguish people with Parkinson’s disease (PD) from neurologically normal individuals or that predict the rate of disease progression in people who have already been diagnosed with PD. Blood tests that distinguish people with PD would be helpful for confirmation of diagnosis (diagnostic biomarkers), whereas blood tests that predict the rate of disease progression (prognostic biomarkers) would be helpful for clinical trials and clinical care. What did the researchers do and find? We screened more than 1,000 blood-based proteins from 527 people with PD, amyotrophic lateral sclerosis (ALS), or neither neurological disease in order to discover new diagnostic and prognostic biomarkers. We used one group of participants to identify potential biomarkers and then used a separate group of participants to confirm these biomarkers. We found that blood levels of four proteins—bone sialoprotein (BSP), osteomodulin (OMD), aminoacylase-1 (ACY1), and growth hormone receptor (GHR)—consistently differed in people with PD compared to people without PD. We found that lower GHR levels at baseline predicted a faster rate of cognitive decline in people with PD. What do these findings mean? Levels of some blood proteins consistently differ between people with versus without PD, and some of these proteins also predict which PD individuals may have faster progression of disease. It may be possible to develop blood-based tests to help confirm PD diagnosis and predict disease progression.

The past 15 years have seen a boom in the use and integration of 'omic' approaches (limited here to genomic, transcriptomic, and epigenomic techniques) to study neurodegenerative disease in an unprecedented way. We first highlight advances in and the limitations of using such approaches in the neurodegenerative disease literature, with a focus on Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). We next discuss how these studies can advance human health in the form of generating leads for downstream mechanistic investigation or yielding polygenic risk scores (PRSs) for prognostication. However, we argue that these approaches constitute a new form of molecular description, analogous to clinical or pathological description, that alone does not hold the key to solving these complex diseases.

Objective Common variants near TMEM106B associate with risk of developing frontotemporal dementia (FTD). Emerging evidence suggests a role for TMEM106B in neurodegenerative processes beyond FTD. We evaluate the effect of TMEM106B genotype on cognitive decline across multiple neurogenerative diseases. Methods We longitudinally followed 870 subjects with diagnoses of Parkinson disease (PD; n = 179), FTD (n = 179), Alzheimer disease (AD; n = 300), memory-predominant mild cognitive impairment (MCI; n = 75), or neurologically normal control subjects (NC; n = 137) at the University of Pennsylvania (UPenn). All participants had annual Mini-Mental State Examination (MMSE; median follow-up duration = 3.0 years) and were genotyped at TMEM106B index single nucleotide polymorphism rs1990622. Genotype effects on cognition were confirmed by extending analyses to additional cognitive instruments (Mattis Dementia Rating Scale-2 [DRS-2] and Montreal Cognitive Assessment [MoCA]) and to an international validation cohort (Parkinson's Progression Markers Initiative [PPMI], N = 371). Results The TMEM106B rs1990622T allele, linked to increased risk of FTD, associated with greater MMSE decline over time in PD subjects but not in AD or MCI subjects. For FTD subjects, rs1990622T associated with more rapid decrease in MMSE only under the minor-allele, rs1990622C , dominant model. Among PD patients, rs1990622T carriers from the UPenn cohort demonstrated more rapid longitudinal decline in DRS-2 scores. Finally, in the PPMI cohort, TMEM106B risk allele carriers demonstrated more rapid longitudinal decline in MoCA scores. Interpretation Irrespective of cognitive instrument or cohort assessed, TMEM106B acts as a genetic modifier for cognitive trajectory in PD. Our results implicate lysosomal dysfunction in the pathogenesis of cognitive decline in 2 different proteinopathies. ANN NEUROL 2019;85:801-811.

Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single-mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller, but well-defined, subsets of PD amenable to successful neuroprotection. Fil: Espay, Alberto J.. University of Cincinnati; Estados Unidos Fil: Schwarzschild, Michael A.. Massachusetts General Hospital; Estados Unidos Fil: Tanner, Caroline M.. University of California; Estados Unidos Fil: Fernandez, Hubert H.. Cleveland Clinic; Estados Unidos Fil: Simon, David K.. Harvard Medical School; Estados Unidos Fil: Leverenz, James B.. Cleveland Clinic; Estados Unidos Fil: Merola, Aristide. University of Cincinnati; Estados Unidos Fil: Chen Plotkin, Alice. University of Pennsylvania; Estados Unidos Fil: Brundin, Patrik. Van Andel Research Institute. Center for Neurodegenerative Science; Estados Unidos Fil: Kauffman, Marcelo Andres. Universidad Austral; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina Fil: Erro, Roberto. Universita di Verona; Italia. University College London; Reino Unido Fil: Kieburtz, Karl. University of Rochester Medical Center; Estados Unidos Fil: Woo, Daniel. University of Cincinnati; Estados Unidos Fil: Macklin, Eric A.. Massachusetts General Hospital; Estados Unidos Fil: Standaert, David G.. University of Alabama at Birmingahm; Estados Unidos Fil: Lang, Anthony E.. University of Toronto; Canadá

Adeno-associated virus-mediated gene replacement is emerging as a safe and effective means of correcting single-gene mutations affecting the CNS. AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRN-deficient frontotemporal dementia and neuronal ceroid lipofuscinosis, and recent studies using intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse models. Here, we used AAV9 to deliver GRN to the lateral ventricle to achieve widespread expression in the Grn null mouse brain. We found that, despite a global increase in progranulin, overexpression resulted in dramatic and selective hippocampal toxicity and degeneration affecting neurons and glia. Hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing. GRN delivery with an ependymal-targeting AAV for selective secretion of progranulin into the cerebrospinal fluid similarly resulted in T cell infiltration, as well as ependymal hypertrophy. Interestingly, overexpression of GRN in wild-type animals also provoked T cell infiltration. These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression prior to progressing to the clinic.

TDP-43 is the major disease protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Here we identify the transcriptional elongation factor Ell—a shared component of little elongation complex (LEC) and super elongation complex (SEC)—as a strong modifier of TDP-43-mediated neurodegeneration. Our data indicate select targets of LEC and SEC become upregulated in the fly ALS/FTLD-TDP model. Among them, U12 snRNA and a stress-induced long non-coding RNA Hsrω, functionally contribute to TDP-43-mediated degeneration. We extend the findings of Hsrω, which we identify as a chromosomal target of TDP-43, to show that the human orthologue Sat III is elevated in a human cellular disease model and FTLD-TDP patient tissue. We further demonstrate an interaction between TDP-43 and human ELL2 by co-immunoprecipitation from human cells. These findings reveal important roles of Ell-complexes LEC and SEC in TDP-43-associated toxicity, providing potential therapeutic insight for TDP-43-associated neurodegeneration., TDP-43 is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTD-TDP). Here, the authors identify the transcriptional elongation factor Ell as a strong modifier of TDP-43-mediated neurodegeneration through the Ell transcriptional elongation complexes LEC and SEC.

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43.

Adeno-associated virus (AAV)-mediated gene replacement is emerging as a safe and effective means of correcting single-gene mutations, and use of AAV vectors for treatment of diseases of the CNS is increasing. AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRN-deficient frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis (NCL), and two recent studies using focal intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse FTD models. Here, we used AAV9 to deliver GRN to the lateral ventricle to achieve widespread expression in the Grn null mouse brain. We found that despite a global increase in progranulin throughout many brain regions, overexpression of GRN resulted in dramatic and selective hippocampal toxicity and degeneration affecting both neurons and glia. Histologically, hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing, suggesting an inflammatory component to the ensuing neuronal loss. GRN delivery with an ependymal-targeting AAV for selective secretion of progranulin into the cerebrospinal fluid (CSF) similarly resulted in T cell infiltration as well as ependymal hypertrophy. Interestingly, overexpression of GRN in wild-type animals also provoked T cell infiltration. These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response following GRN gene delivery. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression in relevant animal models prior to progressing to the clinic.Significance StatementGene therapies using adeno-associated viral (AAV) vectors show great promise for many human diseases, including diseases that affect the central nervous system (CNS). Frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis (NCL) are neurodegenerative diseases resulting from loss of one or both copies of the gene encoding progranulin (GRN), and gene replacement has been proposed for these currently untreatable disorders. Here, we used two different AAV vectors to induce widespread brain GRN expression in mice lacking the gene, as well as in wild-type mice. Unexpectedly, GRN overexpression resulted in T cell infiltration, followed by marked hippocampal neurodegeneration. Our results call into question the safety of GRN overexpression in the CNS, with wider implications for development of CNS gene therapies.

Background Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials. Methods Using a novel consortium design, the Parkinson's Disease Biomarker Program is focused on the development of clinical and laboratory-based biomarkers for PD diagnosis, progression, and prognosis. Standardized operating procedures and pooled reference samples were created to allow cross-project comparisons and assessment of batch effects. A web-based Data Management Resource facilitates rapid sharing of data and biosamples across the research community for additional biomarker projects. Results Eleven consortium projects are ongoing, seven of which recruit participants and obtain biosamples. As of October 2014, 1,082 participants have enrolled (620 PD, 101 with other causes of parkinsonism, 23 essential tremor, and 338 controls), 1,040 of whom have at least one biosample. Six thousand eight hundred ninety-eight total biosamples are available from baseline, 6-, 12-, and 18-month visits: 1,006 DNA, 1,661 RNA, 1,419 whole blood, 1,382 plasma, 1,200 serum, and 230 cerebrospinal fluid (CSF). Quality control analysis of plasma, serum, and CSF samples indicates that almost all samples are high quality (24 of 2,812 samples exceed acceptable hemoglobin levels). Conclusions By making samples and data widely available, using stringent operating procedures based on existing standards, hypothesis testing for biomarker discovery, and providing a resource that complements existing programs, the Parkinson's Disease Biomarker Program will accelerate the pace of PD biomarker research. © 2015 International Parkinson and Movement Disorder Society

Background Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. Methods We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test–Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections. Results Mutation carriers (n = 60; 4.4%) and E326K carriers (n = 65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio = 5.1; P = 9.7 × 10−6; E326K, odds ratio = 6.4; P = 5.7 × 10−7) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc] = 9.0 × 10−4; E326K, Pc = 0.036), Trail Making B-A (mutations, Pc = 0.018; E326K, Pc = 0.018), and Benton Judgment of Line Orientation (mutations, Pc = 0.0045; E326K, Pc = 0.0013). Conclusions Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits. © 2015 International Parkinson and Movement Disorder Society

Introduction Apathy is a common, troublesome symptom in Parkinson's disease (PD). However, little is known about its relationship with long-term cognition. We sought to determine if a caregiver-reported apathy measure predicts the development of PD dementia. Methods Non-demented PD patients were recruited as part of a longitudinal study of cognition. Demographics, medications, Dementia Rating Scale-2, Unified Parkinson's Disease Rating Scale, Geriatric Depression Scale and the Neuropsychiatric Inventory-Questionnaire (NPI-Q) ratings were obtained. Apathy was defined as an NPI-Q apathy score ≥1. Participants were evaluated annually with cognitive and functional assessments until the end of the study period or a physician consensus diagnosis of dementia was assigned. Cox proportional hazard models were used to assess the effects of baseline apathy on dementia development while controlling for other clinical and demographic factors. Results Of 132 PD patients 12.1% (N = 16) scored in the apathetic range at baseline. A total of 19.6% (N = 26) individuals developed dementia over the course of the study, 8 of whom (30.8% of future dementia patients) had baseline apathy. In bivariate analyses baseline apathy, older age, and worse cognitive, motor, and depressive symptom scores predicted the development of dementia. In a multivariate analysis the predictive effects of baseline apathy were still significant (HR = 3.56; 95% CI = 1.09–11.62; p = 0.04). Conclusions A simple, caregiver-reported measure of apathy is an independent predictor of progression to dementia in PD. This highlights the importance of apathy as a clinical characteristic of PD and could prove useful for the prediction of future dementia.

Background: Development of robust plasma-based biomarkers in Parkinson's disease (PD) could lead to new approaches for identifying those at risk for PD and developing novel therapies. Here, we validate plasma apolipoprotein A1 (ApoA1) as a correlate of age at onset and motor severity in PD. Methods: Plasma ApoA1 and high-density lipoprotein at baseline, 6 months, and 12 months were measured in 254 research volunteers (154 patients with PD and 100 normal controls) enrolled in the Parkinson's Progression Markers Initiative (PPMI) study. Results: Lower baseline plasma ApoA1 levels associate with an earlier age at PD onset in early-stage, drug-naive PPMI PD patients (P = 0.023). Moreover, lower baseline ApoA1 levels trend toward association with worse motor severity in PPMI PD patients (p = 0.080). Over 12 months of follow-up, plasma ApoA1 levels do not predict motor decline in the PPMI PD cohort. Finally, a meta-analysis of five PD cohorts encompassing >1,000 patients confirms significant association of lower plasma ApoA1 with earlier age at PD onset (P

INTRODUCTION: The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid β peptide 1-42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g., CSF α-synuclein [α-syn] for Lewy body pathology) may be needed to further improve the differential diagnosis.METHODS: CSF total α-syn, phosphorylated α-syn at Ser129, and AD CSF biomarkers were evaluated with Luminex immunoassays in 367 participants, followed by validation in 74 different neuropathologically confirmed cases.RESULTS: CSF total α-syn, when combined with amyloid β peptide 1-42 and either total tau or phosphorylated tau, improved the differential diagnosis of AD versus frontotemporal dementia, Lewy body disorders, or other neurological disorders. The diagnostic accuracy of the combined models attained clinical relevance (area under curve ∼0.9) and was largely validated in neuropathologically confirmed cases.DISCUSSION: Combining CSF biomarkers representing AD and Lewy body pathologies may have clinical value in the differential diagnosis of AD.

Background Minimally invasive specific biomarkers of neurodegenerative diseases (NDs) would facilitate patient selection and disease progression monitoring. We describe the assessment of circulating brain-enriched microRNAs as potential biomarkers for Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Methods In this case-control study, the plasma samples were collected from 250 research participants with a clinical diagnosis of AD, FTD, PD, and ALS, as well as from age- and sex-matched control subjects (n = 50 for each group), recruited from 2003 to 2015 at the University of Pennsylvania Health System, including the Alzheimer’s Disease Center, the Parkinson’s Disease and Movement Disorders Center, the Frontotemporal Degeneration Center, and the Amyotrophic Lateral Sclerosis Clinic. Each group was randomly divided into training and confirmation sets of equal size. To evaluate the potential of circulating microRNAs enriched in specific brain regions affected by NDs and present in synapses as biomarkers of NDs, the levels of 37 brain-enriched and inflammation-associated microRNAs in the plasma of all participants were measured using individual qRT-PCR. A “microRNA pair” approach was used for data normalization. Results MicroRNA pairs and their combinations (classifiers) capable of differentiating NDs from control and from each other were defined using independently and jointly analyzed training and confirmation datasets. AD, PD, FTD, and ALS are differentiated from control with accuracy of 0.89, 0.90, 0.88, and 0.83 (AUCs, 0.96, 0.96, 0.94, and 0.93), respectively; NDs are differentiated from each other with accuracy ranging from 0.77 (AUC, 0.87) for AD vs. FTD to 0.93 (AUC, 0.98) for AD vs. ALS. The data further indicate sex dependence of some microRNA markers. The average increase in accuracy in distinguishing ND from control for all and male/female groups is 0.06; the largest increase is for ALS, from 0.83 for all participants to 0.92/0.98 for male/female participants. Conclusions The work presented here suggests the possibility of developing microRNA-based diagnostics for detection and differentiation of NDs. Larger multicenter clinical studies are needed to further evaluate circulating brain-enriched microRNAs as biomarkers for NDs and to investigate their association with other ND biomarkers in clinical trial settings. Electronic supplementary material The online version of this article (doi:10.1186/s13195-017-0316-0) contains supplementary material, which is available to authorized users.

Neurodegenerative diseases pose an extraordinary threat to the world's aging population, yet no disease-modifying therapies are available. Although genome-wide association studies (GWASs) have identified hundreds of risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Here, we investigated the association between common genetic variants at the 7p21 locus and risk of the neurodegenerative disease frontotemporal lobar degeneration. We showed that variants associated with disease risk correlate with increased expression of the 7p21 gene TMEM106B and no other genes; co-localization analyses implicated a common causal variant underlying both association with disease and association with TMEM106B expression in lymphoblastoid cell lines and human brain. Furthermore, increases in the amount of TMEM106B resulted in increases in abnormal lysosomal phenotypes and cell toxicity in both immortalized cell lines and neurons. We then combined fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, that differentially recruits CTCF in lymphoblastoid cell lines and human brain to influence CTCF-mediated long-range chromatin-looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWASs to frontotemporal lobar degeneration, nominating a causal variant and causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk of neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in CTCF-binding sites found in brain-relevant tissues, implicating CTCF-mediated gene regulation in risk of neurodegeneration more generally.

Summary Background Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical–genetic score to predict global cognitive impairment in patients with the disease. Methods In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population. Findings 3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6–4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase ( GBA ) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1–7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82–0·90) and replication (95% CI 0·78–0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4–36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79–0·94) and a negative predictive value of 0·92 (95% 0·88–0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets. Interpretation Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis. Funding National Institutes of Health, US Department of Defense.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset.

Cognitive impairment is one of the earliest, most common, and most disabling non-motor symptoms in Parkinson's disease (PD). Thus, routine screening of global cognitive abilities is important for the optimal management of PD patients. Few global cognitive screening instruments have been developed for or validated in PD patients. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Dementia Rating Scale-2 (DRS-2) have been used extensively for cognitive screening in both clinical and research settings. Determining how to convert the scores between instruments would facilitate the longitudinal assessment of cognition in clinical settings and the comparison and synthesis of cognitive data in multicenter and longitudinal cohort studies. The primary aim of this study was to apply a simple and reliable algorithm for the conversion of MoCA to MMSE scores in PD patients. A secondary aim was to apply this algorithm for the conversion of DRS-2 to both MMSE and MoCA scores. The cognitive performance of a convenience sample of 360 patients with idiopathic PD was assessed by at least two of these cognitive screening instruments. We then developed conversion scores between the MMSE, MoCA, and DRS-2 using equipercentile equating and log-linear smoothing. The conversion score tables reported here enable direct and easy comparison of three routinely used cognitive screening assessments in PD patients.

Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia have several important features in common. They are progressive, they affect a relatively inaccessible organ, and we have no disease-modifying therapies for them. For these brain-based diseases, current diagnosis and evaluation of disease severity rely almost entirely on clinical examination, which may only be a rough approximation of disease state. Thus, the development of biomarkers – objective, relatively easily measured and precise indicators of pathogenic processes – could improve patient care and accelerate therapeutic discovery. Yet existing, rigorously tested neurodegenerative disease biomarkers are few, and even fewer biomarkers have translated into clinical use. To find new biomarkers for these diseases, an unbiased, high-throughput screening approach may be needed. In this review, I will describe the potential utility of such an approach to biomarker discovery, using Parkinson’s disease as a case example.

The discovery of novel plasma-based biomarkers could lead to new approaches in the treatment of Parkinson's disease (PD). Here, we explore the role of plasma apolipoprotein A1 (ApoA1) as a risk marker for PD and evaluate the influence of APOA1 promoter variation on plasma ApoA1 levels. Plasma ApoA1 and the single-nucleotide polymorphism, rs670, were assayed in a discovery cohort (cohort 1) of 301 PD patients, 80 normal controls (NCs), and 165 subjects with other neurodegenerative diseases, as well as a cohort (cohort 2) of 158 PD patients from a second clinical site. Additionally, rs670 was genotyped in a third cohort of 1,494 PD and 925 NC subjects from both clinical sites. Compared to both normal and disease controls, PD patients have lower plasma ApoA1 (P

Cognitive decline is common in Parkinson's disease (PD), even in the early motor stage, and this non-motor feature impacts quality of life and prognosis tremendously. In this article, we discuss marker candidates for cognitive decline in PD from different angles, including functional and structural imaging techniques, biological fluid markers in cerebrospinal fluid, and blood genetic predictors, as well as gait as a surrogate marker of cognitive decline. Specifically, imaging-based markers of cognitive impairment in PD include cortical atrophy, reduced cortical metabolism, loss of cortical cholinergic and frontal dopaminergic function, as well as an increased cortical amyloid load. Reduced β-amyloid(1-42) in cerebrospinal fluid and lower plasma levels of epidermal growth factor are predictors for cognitive decline in PD. In addition, genetic variation in the apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), microtubule-associated protein tau (MAPT), and glucocerebrosidase (GBA) genes may confer risk for cognitive impairment in PD; and gait disturbance may also indicate an increased risk for dementia. Other marker candidates have been proposed and are discussed. All of the current studies are hampered by gaps in our knowledge about the molecular causes of cognitive decline, which will have to be considered in future biomarker studies.

BACKGROUND Methods to detect early cognitive decline and account for heterogeneity of deficits in Parkinson's disease (PD) are needed. Quantitative methods such as latent class analysis (LCA) offer an objective approach to delineate discrete phenotypes of impairment. OBJECTIVE To identify discrete neurocognitive phenotypes in PD patients without dementia. METHODS LCA was applied to a battery of 8 neuropsychological measures to identify cognitive subtypes in a cohort of 199 non-demented PD patients. Two measures were analyzed from each of four domains: executive functioning, memory, visuospatial abilities, and language. Additional analyses compared groups on clinical characteristics and cognitive diagnosis. RESULTS LCA identified 3 distinct groups of PD patients: an intact cognition group (54.8%), an amnestic group (32.2%), and a mixed impairment group with dysexecutive, visuospatial and lexical retrieval deficits (13.1%). The two impairment groups had significantly lower instrumental activities of daily living ratings and greater motor symptoms than the intact group. Of those diagnosed as cognitively normal according to MDS criteria, LCA classified 23.2% patients as amnestic and 9.9% as mixed cognitive impairment. CONCLUSIONS Non-demented PD patients exhibit distinct neuropsychological profiles. One-third of patients with LCA-determined impairment were diagnosed as cognitively intact by expert consensus, indicating that classification using a statistical algorithm may improve detection of initial and subtle cognitive decline. This study also demonstrates that memory impairment is common in non-demented PD even when cognitive impairment is not clinically apparent. This study has implications for predicting eventual emergence of significant cognitive decline, and treatment trials for cognitive dysfunction in PD.

Author(s): Cooper, Christine A; Jain, Nimansha; Gallagher, Michael D; Weintraub, Daniel; Xie, Sharon X; Berlyand, Yosef; Espay, Alberto J; Quinn, Joseph; Edwards, Karen L; Montine, Thomas; Van Deerlin, Vivianna M; Trojanowski, John; Zabetian, Cyrus P; Chen-Plotkin, Alice S | Abstract: ObjectiveParkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression.MethodsWe screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database.ResultsGenotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005).InterpretationOur study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.

Importance Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. Objective To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. Design, Setting, and Participants The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. Main Outcomes and Measures Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society–sponsored version of the Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. Results Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β = 4.65; 95% CI, 1.72-7.58; P = .002), E326K (β = 3.42; 95% CI, 0.66-6.17; P = .02), and GBA variants combined as a single group (β = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10 −4 ) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β = 0.38; 95% CI, 0.23-0.53; P = .01) and E326K (β = 0.64; 95% CI, 0.43-0.86; P = .002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progressed to mild cognitive impairment or dementia. Conclusions and Relevance GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

Objectives: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer’s Disease Neuroimaging Initiative (ADNI). Methods: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n 566). Regression analysis showed CSF A42 levels and t-tau/A42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. Conclusion: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study. Neurology ® 2012;79:897–905