Investigation of the genetic aetiology of Lewy body diseases with and without dementia.

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be key to understanding disease pathways and ultimately therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7,804 patients of European ancestry from Tracking Parkinson's (PRoBaND), The Oxford Discovery Cohort, and AMP-PD. We conducted a discrete phenotype genome-wide association studies comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk alleles rs429358 tagging APOEe4 and rs7668531 near the MMRN1 and SNCA-AS1 genes, increase the odds of developing dementia and that an intronic variant rs17442721 tagging LRRK2 G2019S, on chromosome 12 is protective against dementia. These results should be validated in autopsy confirmed cases in future studies.

Identification of a possible proteomic biomarker in Parkinson's disease: discovery and replication in blood, brain and cerebrospinal fluid.

Biomarkers to aid diagnosis and delineate the progression of Parkinson's disease are vital for targeting treatment in the early phases of the disease. Here, we aim to discover a multi-protein panel representative of Parkinson's and make mechanistic inferences from protein expression profiles within the broader objective of finding novel biomarkers. We used aptamer-based technology (SomaLogic®) to measure proteins in 1599 serum samples, 85 cerebrospinal fluid samples and 37 brain tissue samples collected from two observational longitudinal cohorts (the Oxford Parkinson's Disease Centre and Tracking Parkinson's) and the Parkinson's Disease Brain Bank, respectively. Random forest machine learning was performed to discover new proteins related to disease status and generate multi-protein expression signatures with potential novel biomarkers. Differential regulation analysis and pathway analysis were performed to identify functional and mechanistic disease associations. The most consistent diagnostic classifier signature was tested across modalities [cerebrospinal fluid (area under curve) = 0.74, P = 0.0009; brain area under curve = 0.75, P = 0.006; serum area under curve = 0.66, P = 0.0002]. Focusing on serum samples and using only those with severe disease compared with controls increased the area under curve to 0.72 (P = 1.0 × 10-4). In the validation data set, we showed that the same classifiers were significantly related to disease status (P < 0.001). Differential expression analysis and weighted gene correlation network analysis highlighted key proteins and pathways with known relationships to Parkinson's. Proteins from the complement and coagulation cascades suggest a disease relationship to immune response. The combined analytical approaches in a relatively large number of samples, across tissue types, with replication and validation, provide mechanistic insights into the disease as well as nominate a protein signature classifier that deserves further biomarker evaluation.

Association between the LRP1B and APOE loci and the development of Parkinson's disease dementia.

Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson's disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson's disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson's disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson's disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson's disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson's disease dementia [hazard ratio = 2.41 (1.94-3.00), P = 2.32 × 10-15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17-4.81), P = 7.07 × 10-09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21-3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson's disease dementia, with significantly reduced levels of amyloid ß42 (P = 0.0012) in Parkinson's disease dementia compared to Parkinson's disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson's disease dementia.

Genome-Wide Association Studies of Cognitive and Motor Progression in Parkinson's Disease.

BACKGROUND: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression. METHODS: We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression in genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis. RESULTS: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ε4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However, in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (P = 5.3 × 10-6 ). CONCLUSIONS: We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE ε4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genetic analysis of Mendelian mutations in a large UK population-based Parkinson's disease study.

Our objective was to define the prevalence and clinical features of genetic Parkinson's disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson's Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson's study, 424 had young-onset Parkinson's disease (age at onset ≤ 50) and 1799 had late onset Parkinson's disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 'Kompetitive' allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson's disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson's disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.

Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study.

OBJECTIVES: To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson's disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function. METHODS: We prospectively recruited patients with PD in the Tracking Parkinson's study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia. RESULTS: We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher's disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage. CONCLUSIONS: Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA-PD. CLINICAL TRIAL REGISTRATION: NCT02881099; Results.

Tracking Parkinson's: Study Design and Baseline Patient Data.

BACKGROUND: There is wide variation in the phenotypic expression of Parkinson's disease (PD), which is driven by both genetic and epidemiological influences. OBJECTIVES: To define and explain variation in the clinical phenotype of PD, in relation to genotypic variation. METHODS: Tracking Parkinson's is a multicentre prospective longitudinal epidemiologic and biomarker study of PD. Patients attending specialist clinics in the United Kingdom with recent onset (<3.5 years) and young onset (diagnosed <50 years of age) PD were enrolled. Motor, non-motor and quality of life assessments were performed using validated scales. Cases are followed up 6 monthly up to 4.5 years for recent onset PD, and up to 1 year for young onset PD. We present here baseline clinical data from this large and demographically representative cohort. RESULTS: 2247 PD cases were recruited (1987 recent onset, 260 young onset). Recent onset cases had a mean (standard deviation, SD) age of 67.6 years (9.3) at study entry, 65.7% males, with disease duration 1.3 years (0.9), MDS-UPDRS 3 scores 22.9 (12.3), LEDD 295 mg/day (211) and PDQ-8 score 5.9 (4.8). Young onset cases were 53.5 years old (7.8) at study entry, 66.9% male, with disease duration 10.2 years (6.7), MDS-UPDRS 3 scores 27.4 (15.3), LEDD 926 mg/day (567) and PDQ-8 score 11.6 (6.1). CONCLUSIONS: We have established a large clinical PD cohort, consisting of young onset and recent onset cases, which is designed to evaluate variation in clinical expression, in relation to genetic influences, and which offers a platform for future imaging and biomarker research.