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Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and affects 1% of the population above 60 years old. Although Parkinson's disease commonly manifests with motor symptoms, a majority of patients with Parkinson's disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson's disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer's disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson's disease may be associated with appearance of pathological amyloid-β and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer's disease. Given the known association of microglial activation with advancing Parkinson's disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson's disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson's disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-β and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson's disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson's disease subgroups with a positive CSF amyloid-β biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson's disease., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Neurodegenerative diseases require characterization based on underlying biology using biochemical biomarkers. Mixed pathology complicates discovery of biomarkers and characterization of cohorts, but inclusion of greater numbers of patients with different, related diseases with frequently co-occurring pathology could allow better accuracy. Combining cohorts collected from different studies would be a more efficient use of resources than recruiting subjects from each population of interest for each study., Objective: To explore the possibility of combining existing datasets by controlling pre-analytic variables in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Parkinson's Progression Markers Initiative (PPMI) studies., Methods: Cerebrospinal fluid (CSF) was collected and processed from 30 subjects according to both the ADNI and PPMI protocols. Relationships between reported levels of Alzheimer's disease (AD) and Parkinson's disease (PD) biomarkers in the same subject under each protocol were examined., Results: Protocol-related differences were observed for Aβ, but not t-tau or α-syn, and trended different for p-tau and pS129. Values of α-syn differed by platform. Conversion of α-syn values between ADNI and PPMI platforms did not completely eliminate differences in distribution., Discussion: Factors not captured in the pre-analytical sample handling influence reported biomarker values. Assay standardization and better harmonized characterization of cohorts should be included in future studies of CSF biomarkers.

Frontotemporal lobar degeneration is a neuropathological disorder that causes a variety of clinical syndromes including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal syndrome (CBS). FTD associated with parkinsonism occurs frequently as a result of mutations in the C9orf72 gene and also in the genes coding for the protein associated with microtubule tau (MAPT) and progranulin (GRN) on chromosome 17 (FTDP-17). Herein, we report an Argentinean family, of Basque ancestry, with an extensive family history of behavioral variant of FTD. Twenty-one members over 6 generations composed the pedigree. An extensive neurologic and neurocognitive examination was performed on 2 symptomatic individuals and 3 nonsymptomatic individuals. Two different phenotypes were identified among affected members, CBS in the proband and FTD in his brother. DNA was extracted from blood for these 5 individuals and whole-exome sequencing was performed on 3 of them followed by Sanger sequencing of candidate genes on the other 2. In both affected individuals, a missense mutation (p.P301L; rs63751273) in exon 10 of the MAPT gene (chr17q21.3) was identified. Among MAPT mutations, p.P301L is the most frequently associated to different phenotypes: (1) aggressive, symmetrical, and early-onset Parkinsonism; (2) late parkinsonism associated with FTD; and (3) progressive supranuclear palsy but only exceptionally it is reported associated to CBS. This is the first report of the occurrence of the p.P301L-MAPT mutation in South America and supports the marked phenotypic heterogeneity among members of the same family as previously reported., (Published by Elsevier Inc.)

Introduction: Alzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood., Methods: Tau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects., Results: The efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau., Conclusions: Tau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD., Competing Interests: Nothing to report., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Importance: Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature., Objective: To determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD., Design, Setting, and Participants: We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene., Main Outcomes and Measures: Nine variables derived from 7 psychometric tests., Results: The APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10(-6); corrected P [Pc] = 6.0 × 10(-5)), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10(-5); Pc = 9 × 10(-5)); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests., Conclusions and Relevance: Our data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

Objective: The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid β (Aβ) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aβ and tau as markers of early or presymptomatic PD., Methods: CSF Aβ42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with 18F-6-fluoro-l-dopa (FD), 11C-(±)-α-dihydrotetrabenazine (DTBZ), and 11C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement., Results: Reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in our cohort, significant correlations were also observed for tau., Conclusions: The disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.

Our aim was to examine disease-related and genetic correlates of the development of psychotic symptoms in a large population of patients with Parkinson's disease. We studied 500 patients with Parkinson's disease from the NeuroGenetics Research Consortium using logistic regression models. Predictors were demographic, clinical (motor/nonmotor features), and genetic, measured as continuous or dichotomous variables. Continuous measures were divided into population-based tertiles. Results are given as odds ratios (95% confidence intervals) for dichotomous variables and by ascending tertile for continuous variables. Psychotic symptoms were associated with increasing age: 4.86 (1.62-14.30) and 6.25 (2.09-18.74) (test for trend: P = 0.01); and duration of disease: 3.81 (1.23-11.76) and 5.33 (1.68-16.89) (test for trend: P = 0.03). For nonmotor features, we demonstrated positive trends with depression: 1.31 (0.47-3.61) and 5.01 (2.04-12.33) (test for trend: P < 0.0001); cognitive dysfunction: 0.69 (0.26-1.84) and 2.51 (1.00-6.29) (test for trend: P = 0.03); and an excess for those with sleep disorders: 2.00 (1.03-3.89) (P = 0.04). Psychotic symptoms were not associated with tremor or postural instability scores, but there was an association with freezing of gait: 3.83 (1.67-8.75) (P < 0.002). Psychotic symptoms were not associated with the presence of any examined polymorphisms in the apolipoprotein, alpha-synuclein, or microtubule associated protein tau genes. This is the largest study to examine correlates of psychotic symptoms in Parkinson's disease. We discovered a novel association with freezing of gait. We demonstrated an association with depression and duration of disease, both of which were inconsistently related in previous studies, and confirmed the association with age, cognitive dysfunction, and sleep disorders., (Copyright © 2011 Movement Disorder Society.)

Recent genome-wide association studies of Parkinson's disease have nominated 3 new susceptibility loci (PARK16-18) and confirmed 2 known risk genes (MAPT and SNCA) in populations of European ancestry. We sought to replicate these findings. We genotyped single-nucleotide polymorphisms in each of these genes/loci in 1445 Parkinson's disease patients and 1161 controls from northern Spain. Logistic regression was used to test for association between genotype and Parkinson's disease under an additive model, adjusting for sex, age, and site. We also performed analyses stratified by age at onset. Single-nucleotide polymorphisms in MAPT (rs1800547; P = 3.1 × 10(-4) ) and SNCA (rs356219; P = 5.5 × 10(-4) ) were significantly associated with Parkinson's disease. However, none of the markers in PARK16-18 associated with Parkinson's disease in the overall sample, or in any age stratum, with P values ranging from .09 to .88. Although our data further validate MAPT and SNCA as Parkinson's disease susceptibility genes, we failed to replicate PARK16, PARK17, and PARK18. Potential reasons for the discordance between our study and previous genome-wide association studies include effects of population structure, power, and population-specific environmental interactions. Our findings suggest that additional studies of PARK16-18 are necessary to establish the role of these loci in modifying risk for Parkinson's disease in European-derived populations. © 2011 Movement Disorder Society., (Copyright © 2011 Movement Disorder Society.)

Objective: There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of Parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ-1 and/or α-synuclein in the cerebrospinal fluid (CSF) is a potential index for Parkinson disease diagnosis, but not for PD severity., Methods: Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (Aβ(1-42)), Flt3 ligand, and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these 5 markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ-1 and α-synuclein. The major results were further validated in an independent cohort of cross-sectional PD patients as well as in PD cases with CSF samples collected longitudinally., Results: The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease (AD) and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/Aβ(1-42) that positively correlated with PD severity in cross-sectional samples as well as with PD progression in longitudinal samples., Interpretation: We have demonstrated that this panel of 7 CSF proteins could aid in Parkinson disease diagnosis, differential diagnosis, and correlation with disease severity and progression., (Copyright © 2011 American Neurological Association.)

We tested the hypothesis that the CSF biomarker signature associated with Alzheimer's disease (AD) is present in a subset of individuals with Parkinson's disease and Dementia (PD-D) or with PD and Cognitive Impairment, Not Dementia (PD-CIND). We quantified CSF Aβ(42), total tau (T-tau), and phospho-tau (P181-tau) using commercially available kits. Samples were from 345 individuals in seven groups (n): Controls ≤50 years (35), Controls >50 years (115), amnestic Mild Cognitive Impairment (aMCI) (24), AD (49), PD (49), PD-CIND (62), and PD-D (11). We observed expected changes in AD or aMCI compared with age-matched or younger controls. CSF Aβ(42) was reduced in PD-CIND (P < 0.05) and PD-D (P < 0.01), whereas average CSF T-tau and P181-tau were unchanged or decreased. One-third of PD-CIND and one-half of PD-D patients had the biomarker signature of AD. Abnormal metabolism of Aβ(42) may be a common feature of PD-CIND and PD-D., (© 2010 Movement Disorder Society.)

The objective of this study was to explore combined effects of four candidate susceptibility genes and two exposures on Parkinson's disease (PD) risk; namely, alpha-synuclein (SNCA) promoter polymorphism REP1, microtubule-associated protein tau (MAPT) H1/H2 haplotypes, apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 polymorphism, ubiquitin carboxy-terminal esterase L1 (UCHL1) S18Y variant, cigarette smoking and caffeinated coffee consumption. 932 PD patients and 664 control subjects from the NeuroGenetics Research Consortium, with complete data on all six factors, were studied. Uniform protocols were used for diagnosis, recruitment, data collection and genotyping. A logistic regression model which included gene-exposure interactions was applied. Likelihood ratio tests (LRTs) were used for significance testing and Bayesian inference was used to estimate odds ratios (ORs). MAPT (P = 0.007), SNCA REP1 (P = 0.012), smoking (P = 0.001), and coffee (P = 0.011) were associated with PD risk. Two novel interactions were detected: APOE with coffee (P = 0.005), and REP1 with smoking (P = 0.021). While the individual main effects were modest, each yielding OR < 1.6, the effects were cumulative, with some combinations reaching OR = 12.6 (95% CI: 5.9-26.8). This study provides evidence for the long-held notion that PD risk is modulated by cumulative and interactive effects of genes and exposures. Furthermore, the study demonstrates that while interaction studies are useful for exploring risk relationships that might otherwise go undetected, results should be interpreted with caution because of the inherent loss of power due to multiple testing. The novel findings of this study that warrant replication are the evidence for interaction of coffee with APOE, and of smoking with REP1 on PD risk.

Objective: An inversion polymorphism of approximately 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene defines two haplotype clades, H1 and H2. Several small case-control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinson's disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings., Methods: We genotyped 1,762 PD patients and 2,010 control subjects for a single nucleotide polymorphism (SNP) that differentiates the H1 and H2 clades. We also analyzed four SNPs that define subhaplotypes within H1 previously reported to associate with PD or other neurodegenerative disorders., Results: After adjusting for age, sex, and site, we observed a robust association between the H1/H1 diplotype and PD risk (odds ratio for H1/H1 vs H1/H2 and H2/H2, 1.46; 95% confidence interval, 1.25-1.69; p = 8 x 10(-7)). The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. Within H1/H1 individuals, there was no significant difference between cases and control subjects in the overall frequency distribution of H1 subhaplotypes., Interpretation: Our data provide strong evidence that the H1 clade, which contains MAPT and several other genes, is a risk factor for PD. However, attributing this finding to variants within a specific region of MAPT is premature. Thorough fine-mapping of the H1 clade in large numbers of individuals is now needed to identify the underlying functional variant(s) that alter susceptibility for PD.