Combining biomarkers for prognostic modelling of Parkinson's disease.

BACKGROUND: Patients with Parkinson's disease (PD) have variable rates of progression. More accurate prediction of progression could improve selection for clinical trials. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be further improved by blood biomarkers. OBJECTIVE: To determine if blood biomarkers (serum neurofilament light (NfL) and genetic status (glucocerebrosidase, GBA and apolipoprotein E (APOE))) are useful in addition to clinical measures for prognostic modelling in PD. METHODS: We evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients' genetic (GBA and APOE) status. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model, and explored how blood biomarkers compared with clinical variables in distinguishing prognostic phenotypes . RESULTS: 291 patients were assessed in this study. Baseline serum NfL was associated with baseline cognitive status. Nfl predicted a shorter time to dementia, postural instability and death (dementia-HR 2.64; postural instability-HR 1.32; mortality-HR 1.89) whereas APOEe4 status was associated with progression to dementia (dementia-HR 3.12, 95% CI 1.63 to 6.00). NfL levels and genetic variables predicted unfavourable progression to a similar extent as clinical predictors. The combination of clinical, NfL and genetic data produced a stronger prediction of unfavourable outcomes compared with age and gender (area under the curve: 0.74-age/gender vs 0.84-ALL p=0.0103). CONCLUSIONS: Clinical trials of disease-modifying therapies might usefully stratify patients using clinical, genetic and NfL status at the time of recruitment.

Genetics of validated Parkinson's disease subtypes in the Oxford Discovery and Tracking Parkinson's cohorts.

OBJECTIVES: To explore the genetics of four Parkinson's disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables. METHODS: We looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 against our subtypes. Then we calculated Genetic Risk Scores (GRS) for PD, multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, and Alzheimer's disease. These GRSs were regressed against the probability of belonging to a subtype in the two independent cohorts and we calculated q-values as an adjustment for multiple testing across four subtypes. We also carried out a Genome-Wide Association Study (GWAS) of belonging to a subtype. RESULTS: A severe disease subtype had the highest rates of patients carrying GBA mutations while the mild disease subtype had the lowest rates (p=0.009). Using the GRS, we found a severe disease subtype had a reduced genetic risk of PD (p=0.004 and q=0.015). In our GWAS no individual variants met genome wide significance (<5×10e-8) although four variants require further follow-up, meeting a threshold of <1×10e-6. CONCLUSIONS: We have found that four previously defined PD subtypes have different genetic determinants which will help to inform future studies looking at underlying disease mechanisms and pathogenesis in these different subtypes of disease.

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.

Cognitive impairment in Parkinson's disease is multifactorial: A neuropsychological study.

BACKGROUND: In Parkinson's disease, mild cognitive impairment and dementia are associated with α-synuclein deposition and spread. However, coexistent Alzheimer's disease and cerebrovascular disease are common at autopsy, and may affect cognition. Our objective was to map cognitive impairment in Parkinson's disease to these different causes using clinical assessment. METHODS: Neuropsychological testing was performed in a cross-sectional sample of cognitively impaired patients with Parkinson's disease. The pattern of deficits in varying cognitive domains was mapped to the presentations that typify different diseases. Data were analysed by an expert multidisciplinary panel, referencing diagnostic criteria, to reach a consensus diagnosis for the cognitive dysfunction. RESULTS: There were 45 participants with Parkinson's disease and cognitive impairment, 73.3% male, mean age 69.1 years (SD 8.3). Twenty-seven (60.0%) had mild cognitive impairment, and 18 had dementia (40.0%). Cognitive impairment was primarily attributable to Lewy body disease alone in 19 of 45 patients (42.2%), to Lewy body disease plus Alzheimer's in 14 of 45 (31.1%), to Lewy body plus cerebrovascular disease in 6 of 45 (13.3%), and to Lewy body plus Alzheimer's and cerebrovascular disease in 1 of 45 (2.2%). The cognitive decline was not primarily Lewy-related in 5 of 45 patients (11.1%); in 4 of 45 (8.9%), it was primarily attributable to Alzheimer's disease, and 1 of 45 (2.2%) had behavioural-variant frontotemporal dementia. CONCLUSION: Neuropsychological testing identifies distinct patterns of cognitive impairment in Parkinson's disease that provide clear pointers to comorbid disease processes, the most common being Alzheimer's disease. This approach may prove useful in clinical practice and has implications for clinical trials that target α-synuclein.

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.

Factor structure of the Montreal Cognitive Assessment in Parkinson disease.

OBJECTIVES: The Montreal Cognitive Assessment (MoCA) is a common tool for screening mild cognitive impairment (MCI) and dementia. Studies in multiple clinical groups provide evidence for various factor structures mapping to different cognitive domains. We tested the factor structure of the MoCA in a large cohort of early Parkinson disease (PD). MATERIALS AND METHODS: Complete MoCA data were available from an observational cohort study for 1738 patients with recent-onset PD (64.6% male, mean age 67.6, SD 9.2). Confirmatory factor analysis (CFA) was applied to test previously defined two-factor, six-factor, and three-factor models in the full sample and in a subgroup with possible cognitive impairment (MoCA < 26). Secondary analysis used exploratory factor analysis (EFA; principal factors with oblique rotation). RESULTS: The mean MoCA score was 25.3 (SD 3.4, range 10-30). Fit statistics in the six-factor model (χ2 /df 17.77, root mean square error of approximation [RMSEA] 0.10, comparative fit index [CFI] 0.74, Tucker-Lewis index [TLI] 0.69, standardised root mean square residual [SRMR] 0.07) indicated poorer fit than did previous studies. Findings were similar in the two-factor and three-factor models. EFA suggested an alternative six-factor solution (short-term recall, visuospatial-executive, attention/working memory, verbal-executive, orientation, and expressive language), although CFA did not support the validity of the new model. CONCLUSIONS: The factor structure of the MoCA in early PD was not consistent with that of previous research. This may reflect higher cognitive performance and differing demographics in our sample. The results do not support a clear, clinically relevant factor structure in an early PD group, suggesting that the MoCA should be followed with detailed assessment to obtain domain-specific cognitive profiles.

Neuropathology of dementia in patients with Parkinson's disease: a systematic review of autopsy studies.

BACKGROUND: Dementia is a common, debilitating feature of late Parkinson's disease (PD). PD dementia (PDD) is associated with α-synuclein propagation, but coexistent Alzheimer's disease (AD) pathology may coexist. Other pathologies (cerebrovascular, transactive response DNA-binding protein 43 (TDP-43)) may also influence cognition. We aimed to describe the neuropathology underlying dementia in PD. METHODS: Systematic review of autopsy studies published in English involving PD cases with dementia. Comparison groups included PD without dementia, AD, dementia with Lewy bodies (DLB) and healthy controls. RESULTS: 44 reports involving 2002 cases, 57.2% with dementia, met inclusion criteria. While limbic and neocortical α-synuclein pathology had the strongest association with dementia, between a fifth and a third of all PD cases in the largest studies had comorbid AD. In PD cases with dementia, tau pathology was moderate or severe in around a third, and amyloid-ß pathology was moderate or severe in over half. Amyloid-ß was associated with a more rapid cognitive decline and earlier mortality, and in the striatum, distinguished PDD from DLB. Positive correlations between multiple measures of α-synuclein, tau and amyloid-ß were found. Cerebrovascular and TDP-43 pathologies did not generally contribute to dementia in PD. TDP-43 and amyloid angiopathy correlated with coexistent Alzheimer pathology. CONCLUSIONS: While significant α-synuclein pathology is the main substrate of dementia in PD, coexistent pathologies are common. In particular, tau and amyloid-ß pathologies independently contribute to the development and pattern of cognitive decline in PD. Their presence should be assessed in future clinical trials where dementia is a key outcome measure. TRIAL REGISTRATION NUMBER: CRD42018088691.

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.

Developing and validating Parkinson's disease subtypes and their motor and cognitive progression.

OBJECTIVES: To use a data-driven approach to determine the existence and natural history of subtypes of Parkinson's disease (PD) using two large independent cohorts of patients newly diagnosed with this condition. METHODS: 1601 and 944 patients with idiopathic PD, from Tracking Parkinson's and Discovery cohorts, respectively, were evaluated in motor, cognitive and non-motor domains at the baseline assessment. Patients were recently diagnosed at entry (within 3.5 years of diagnosis) and were followed up every 18 months. We used a factor analysis followed by a k-means cluster analysis, while prognosis was measured using random slope and intercept models. RESULTS: We identified four clusters: (1)  fast motor progression with symmetrical motor disease, poor olfaction, cognition and postural hypotension; (2) mild motor and non-motor disease with intermediate motor progression; (3) severe motor disease, poor psychological well-being and  poor sleep with an intermediate motor progression; (4) slow motor progression with tremor-dominant, unilateral disease. Clusters were moderately to substantially stable across the two cohorts (kappa 0.58). Cluster 1 had the fastest motor progression in Tracking Parkinson's at 3.2 (95% CI 2.8 to 3.6) UPDRS III points per year while cluster 4 had the slowest at 0.6 (0.1-1.1). In Tracking Parkinson's, cluster 2 had the largest response to levodopa 36.3% and cluster 4 the lowest 28.8%. CONCLUSIONS: We have found four novel clusters that replicated well across two independent early PD cohorts and were associated with levodopa response and motor progression rates. This has potential implications for better understanding disease pathophysiology and the relevance of patient stratification in future clinical trials.

Statin usage, vascular diagnosis and vascular risk factors in Parkinson's disease.

Background and aims Vascular disease is a common comorbidity in Parkinson's disease patients. Statins are potentially neuroprotective for Parkinson's disease through non-vascular mechanisms. We investigated prevailing statin use in a Parkinson's disease cohort. Methods and results Data on diagnostic indication for statins, anti-Parkinson therapy, vascular risk factors, and statin prescription, were obtained from electronic medical record review for consecutive Parkinson's disease patients. The ASsessing cardiac risk using Scottish Intercollegiate Guidelines Network system was used to calculate future cardiovascular risk and identify those warranting statin use. Of 441 patients included, 59.9% were male, with a mean age of 68.9 years (standard deviation 10.3). One hundred and seventy-four (39.5%) patients had at least one diagnostic indication for statin use, of whom 136 (78.2%) were prescribed a statin. In the 267 (60.5%) cases without a diagnostic indication, 54 (20.2%) were excluded owing to age limitations defined in ASsessing cardiac risk using Scottish Intercollegiate Guidelines Network. Of the remaining 213, 62 (29.1%) had an ASsessing cardiac risk using Scottish Intercollegiate Guidelines Network score in the recommended range for statin therapy, of whom 15 (24.1%) were prescribed statins. Conclusion There is suboptimal implementation of statin therapy in Parkinson's disease patients. Given the possible neuroprotective effects of statins in Parkinson's disease in addition to reducing cardiovascular risk, reasons for suboptimal implementation warrant further investigation.

Statins are underused in recent-onset Parkinson's disease with increased vascular risk: findings from the UK Tracking Parkinson's and Oxford Parkinson's Disease Centre (OPDC) discovery cohorts.

BACKGROUND: Cardiovascular disease (CVD) influences phenotypic variation in Parkinson's disease (PD), and is usually an indication for statin therapy. It is less clear whether cardiovascular risk factors influence PD phenotype, and if statins are prescribed appropriately. OBJECTIVES: To quantify vascular risk and statin use in recent-onset PD, and examine the relationship between vascular risk, PD severity and phenotype. METHODS: Cardiovascular risk was quantified using the QRISK2 calculator (high ≥20%, medium ≥10 and <20%, low risk <10%). Motor severity and phenotype were assessed using the Movement Disorder Society Unified PD Rating Scale (UPDRS) and cognition by the Montreal cognitive assessment. RESULTS: In 2909 individuals with recent-onset PD, the mean age was 67.5 years (SD 9.3), 63.5% were men and the mean disease duration was 1.3 years (SD 0.9). 33.8% of cases had high vascular risk, 28.7% medium risk, and 22.3% low risk, while 15.2% of cases had established CVD. Increasing vascular risk and CVD were associated with older age (p<0.001), worse motor score (p<0.001), more cognitive impairment (p<0.001) and worse motor phenotype (p=0.021). Statins were prescribed in 37.2% with high vascular risk, 15.1% with medium vascular risk and 6.5% with low vascular risk, which compared with statin usage in 75.3% of those with CVD. CONCLUSIONS: Over 60% of recent-onset PD patients have high or medium cardiovascular risk (meriting statin usage), which is associated with a worse motor and cognitive phenotype. Statins are underused in these patients, compared with those with vascular disease, which is a missed opportunity for preventive treatment. TRIAL REGISTRATION NUMBER: GN11NE062, NCT02881099.

Vascular disease and vascular risk factors in relation to motor features and cognition in early Parkinson's disease.

OBJECTIVE: The purpose of this study was to examine the relationship between vascular disease (and vascular risk factors), cognition and motor phenotype in Parkinson's disease (PD). METHODS: Recently diagnosed PD cases were enrolled in a multicenter prospective observational longitudinal cohort study. Montreal cognitive assessment (normal >23, mild cognitive impairment 22 to 23 or lower but without functional impairment, and dementia 21 or less with functional impairment) and Movement Disorder Society Unified PD Rating Scale part 3 (UPDRS 3) scores were analyzed in relation to a history of vascular events and risk factors. RESULTS: In 1759 PD cases, mean age 67.5 (standard deviation 9.3) years, mean disease duration 1.3 (standard deviation 0.9) years, 65.2% were men, 4.7% had a history of prior stroke or transient ischemic attack, and 12.5% had cardiac disease (angina, myocardial infarction, heart failure). In cases without a history of vascular disease, hypertension was recorded in 30.4%, high cholesterol 27.3%, obesity 20.7%, diabetes 7.2%, and cigarette smoking in 4.6%. Patients with prior stroke or transient ischemic attack were more likely to have cognitive impairment (42% vs 25%) and postural instability gait difficulty (53.5% vs 39.5%), but these findings were not significant after adjustment for age, sex, and disease duration (P = .075). The presence of more than 2 vascular risks was associated with worse UPDRS 3 motor scores (beta coefficient 4.05, 95% confidence interval 1.48, 6.61, p = .002) and with cognitive impairment (ordinal odds ratio 2.24, 95% confidence interval 1.34, 3.74, p = .002). In 842 patients (47.8%) with structural brain imaging, white matter leukoaraiosis, but not lacunar or territorial infarction, was associated with impaired cognition (p = .006) and postural instability gait difficulty (p = .010). CONCLUSION: Vascular comorbidity is significantly associated with cognitive and gait impairment in patients with early PD, which may have prognostic and treatment implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Dopa Responsiveness in Parkinson's Disease.

BACKGROUND: Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time. OBJECTIVES: To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these. METHODS: We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥24.5% defined as a definite response). Growth-mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters. RESULTS: 1525 dopaminergic challenge tests were performed in 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer disease duration (51.1-74.3%). We identified 3 response groups: "Striking" (n = 29, 8.7%); "Excellent" (n = 110; 32.7%) and "Modest" (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01). CONCLUSION: Three distinct patterns of the dopaminergic response were observed. As the proportion of PD cases with definite dopa responsiveness increased over time, the initial treatment response may be an unreliable diagnostic aid.

Motor Complications in Parkinson's Disease: Results from 3343 Patients Followed for up to 12 Years.

BACKGROUND: Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. OBJECTIVES: To quantify the presence, severity, impact and associated factors for motor complications in PD. METHODS: Analysis of three large prospective cohort studies of recent-onset PD patients followed for up to 12 years. The MDS-UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms. RESULTS: 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4-6 years and 59.0% (55.6, 62.3) at 8-10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4-6 years and 42.1% (38.7, 45.5) at 8-10 years. Dystonia affected 13.4% (12.1, 14.9) at 4-6 years and 22.8% (20.1, 25.9) at 8-10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2-4 years post-diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years). CONCLUSIONS: Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications.

Genome-wide determinants of mortality and motor progression in Parkinson's disease.

There are 90 independent genome-wide significant genetic risk variants for Parkinson's disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

Striatal Dopamine Loss in Early Parkinson's Disease: Systematic Review and Novel Analysis of Dopamine Transporter Imaging.

Background: Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50-80%. Functional neuroimaging can be applied in larger numbers during life, which allows analysis of the extent of dopamine loss more directly. Objective: To quantify dopamine transporter (DaT) activity by neuroimaging in early PD. Methods: Systematic review and novel analysis of DaT imaging studies in early PD. Results: In our systematic review, in 423 unique cases from 27 studies with disease duration of less than 6 years, mean age 58.0 (SD 11.5) years, and mean disease duration 1.8 (SD 1.2) years, striatal loss was 43.5% (95% CI 41.6, 45.4) contralaterally, and 36.0% (95% CI 33.6, 38.3) ipsilaterally. For unilateral PD, in 436 unique cases, mean age 57.5 (SD 10.2) years, and mean disease duration 1.8 (SD 1.4) years, striatal loss was 40.6% (95% CI 38.8, 42.4) contralaterally, and 31.6% (95% CI 29.4, 33.8) ipsilaterally. In our novel analysis of the Parkinson's Progressive Marker Initiative study, 413 cases had 1436 scans performed. For a disease duration of less than 1 year, age was 61.8 (SD 9.8) years, and striatal loss was 51.2% (95% CI 49.1, 53.3) contralaterally and 39.5% (36.9, 42.1) ipsilaterally, giving an overall striatal loss of 45.3% (43.0, 47.6). Conclusions: Loss of striatal DaT activity in early PD is less at 35-45%, rather than the 50-80% striatal dopamine loss estimated to be present at the time of symptom onset, based on backwards extrapolation from autopsy studies.

Comparison between four published definitions of hyposmia in Parkinson's disease.

OBJECTIVES: Hyposmia is a common feature of Parkinson's disease (PD), yet there is no standard method to define it. A comparison of four published methods was performed to explore and highlight differences. MATERIALS AND METHODS: Olfactory testing was performed in 2097 cases of early PD in two prospective studies. Olfaction was assessed using various cut-offs, usually corrected by age and/or gender. Control data were simulated based on the age and gender structure of the PD cases and published normal ranges. Association with age, gender, and disease duration was explored by method and study cohort. Prevalence of hyposmia was compared with the age and gender-matched simulated controls. Between method agreement was measured using Cohen's kappa and Gwet's AC1. RESULTS: Hyposmia was present in between 69.1% and 97.9% of cases in Tracking Parkinson's cases, and between 62.2% and 90.8% of cases in the Parkinson's Progression Marker Initiative, depending on the method. Between-method agreement varied (kappa 0.09-0.80, AC1 0.55-0.86). The absolute difference between PD cases and simulated controls was similar for men and women across methods. Age and male gender were positively associated with hyposmia (p < .001, all methods). Odds of having hyposmia increased with advancing age (OR:1.06, 95% CI:1.03, 1.10, p < .001). Longer disease duration had a negative impact on overall olfactory performance. CONCLUSIONS: Different definitions of hyposmia give different results using the same dataset. A standardized definition of hyposmia in PD is required, adjusting for age and gender, to account for the background decline in olfactory performance with ageing, especially in men.

The Levodopa Response Varies in Pathologically Confirmed Parkinson's Disease: A Systematic Review.

BACKGROUND: A good response to levodopa is a key feature of Parkinson's disease (PD), and a poor response suggests an alternative diagnosis, but the extent of variation in the levodopa response in definite PD is not well defined. LITERATURE REVIEW: A systematic review of articles reporting pathologically confirmed PD and levodopa responsiveness from 1971 to 2018 was performed using the medical subheadings "postmortem," "Parkinson's disease," "levodopa," and "l-dopa" in PubMed, Embase, and Latin American and Caribbean Health Sciences Literature (LILACS) databases. CASES: A total of 12 articles described 445 PD cases: 61.7% male, age at disease onset 64.0 years (SD 9.6), age at death 77.1 years (SD 7.2). Levodopa responsiveness was reported in 399 cases (89.7%) either as a graded or a binary response. In the 280 cases (70.2%) describing a graded response, it was excellent in 37.5%, good in 45.7%, moderate in 12.1%, and poor in 4.6%. In the 119 cases describing a binary response (29.8%), 73.1% were levodopa responsive, and 26.9% were nonresponsive. Comorbid brain pathology was present in 137 of 235 cases assessed, being cerebrovascular in 46.0% and Alzheimer's disease in 37.2% of these, but its contribution to levodopa responsiveness was unclear. CONCLUSIONS: The levodopa motor response varies in definite PD. Explanations other than diagnostic inaccuracy should be explored.

Geographical difference in Parkinson's disease prevalence within West Scotland.

The wide range in reported prevalence of Parkinson's disease (PD) in the United Kingdom (between 108 and 164 per 100,000) is usually attributed to differences in study methodology. We report prevalence of PD in four geographic areas within West Scotland, which was calculated using the same methodology, from prescription database searches within primary care, combined with full case record review. Crude prevalence was 119.2 per 100,000 (95% CI 109.7-128.6) and age-adjusted prevalence was 129.5 (95% CI 119.6-139.4) in 92 General Practices covering a population of 511,927. Prevalence was significantly lower in South Glasgow (men 98.3, CI 78.7-117.9; women 83.9, CI 65.6-102.2) than South Lanarkshire (men 202.7, CI 175.0-230.4; women 151.1, CI 127.7-174.5), age-adjusted rates, both P < 0.001. Factors associated with higher prevalence of PD, such as lower cigarette smoking rates, higher education level, and rural living, were higher in South Lanarkshire than South Glasgow, but the magnitude of the difference was greater than expected considering studies describing relative risk for these factors. Access to services, and specialist clinic attendance were both higher for South Glasgow, which may influence diagnostic accuracy, time to diagnosis, and time to initiating antiparkinson therapy. Exploration of these factors is justified to explain further such wide variation in PD prevalence.