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BackgroundPatients 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.ObjectiveTo determine if blood biomarkers (serum neurofilament light (NfL) and genetic status (glucocerebrosidase,GBAand apolipoprotein E (APOE))) are useful in addition to clinical measures for prognostic modelling in PD.MethodsWe evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients’ genetic (GBAandAPOE) 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 .Results291 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).ConclusionsClinical trials of disease-modifying therapies might usefully stratify patients using clinical, genetic and NfL status at the time of recruitment.

Background Parkinson's disease (PD) is a highly age-related disorder, where common genetic risk variants affect both disease risk and age at onset. A statistical approach that integrates these effects across all common variants may be clinically useful for individual risk stratification. A polygenic hazard score methodology, leveraging a time-to-event framework, has recently been successfully applied in other age-related disorders. Objectives We aimed to develop and validate a polygenic hazard score model in sporadic PD. Methods Using a Cox regression framework, we modeled the polygenic hazard score in a training data set of 11,693 PD patients and 9841 controls. The score was then validated in an independent test data set of 5112 PD patients and 5372 controls and a small single-study sample of 360 patients and 160 controls. Results A polygenic hazard score predicts the onset of PD with a hazard ratio of 3.78 (95% confidence interval 3.49-4.10) when comparing the highest to the lowest risk decile. Combined with epidemiological data on incidence rate, we apply the score to estimate genetically stratified instantaneous PD risk across age groups. Conclusions We demonstrate the feasibility of a polygenic hazard approach in PD, integrating the genetic effects on disease risk and age at onset in a single model. In combination with other predictive biomarkers, the approach may hold promise for risk stratification in future clinical trials of disease-modifying therapies, which aim at postponing the onset of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

ImportanceThere is a pressing need to understand the biology of Parkinson’s disease (PD) progression and to identify biological pathways as possible therapeutic targets.ObjectiveTo identify genomic variation associated with PD motor presentation and early stage progression.DesignGWAS meta-analysis of early PD motor progression, from multiple longitudinal cohorts, using MDS-UPDRS III clinical assessments.SettingMulticentreParticipants3572 unrelated European ancestry individuals diagnosed with PD from 6 studies.Main Outcomes and MeasuresLinear mixed effect models under an additive model corrected for age at diagnosis, gender, and the first 5 genetic principal components (PCs), with axial, limb, and total MDS-UPDRS III as outcomes of the model.ResultsWe identified an association between the PD axial rate of progression and variation at theGJA5locus at 1q12 (Beta = -0.25, SE = 0.04,P= 3.4e-10). Exploration of the regulation of gene expression in the region (cis-eQTL analysis) showed that the lead variant was associated with expression ofACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTLs p-values in blood and brain RNA expression datasets: < 10−8in eQTLGen and 10−7in PsychEncode). In addition, we found a nominal association between axial motor presentation and theMAD1L1gene at 7q21.11 (Beta = 0.54, SE = 0.11,P= 1.6e-7), a gene previously associated with neuropsychiatric disease, and in the long non-coding RNALINC00511at 17q21.31 (Beta = -0.62, SE = 0.11,P= 6.3e-8). Further functional annotation allowed us to nominate the likely causal variants and determine that variants at 7q21.11 may be related to dysregulation ofMAD1L1expression. Variants atLINC00511may cause a disruption of a distal epigenetic regulation ofSOX9through an anchored chromatin loop.Conclusions and RelevanceOur large multicentre study sheds new light on the genetic architecture of PD progression, which is distinct from PD susceptibility. Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets to tackle disease progression.

ObjectivesTo 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.MethodsWe 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.ResultsA 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 (ConclusionsWe 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.

BackgroundThere are 90 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.MethodsWe studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to motor progression, defined by reaching Hoehn and Yahr stage 3 or greater, cognitive impairment as defined by serial cognitive examination, and death (mortality).FindingsThere was a robust effect of the APOE ε4 allele on mortality and cognitive impairment in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity or expression quantitative trait loci data. One locus within the TBXAS1 gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10-10). Another locus near the SYT10 gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31×10-8). A genomic variant associated with the expression of ADORA2A, encoding the A2A adenosine receptor, was associated with motor progression (HR=4.83 [95% CI 2.89 to 8.08], p-value=1.94×10-9). Only the non-Gaucher disease causing GBA PD risk variant E326K, of the known PD risk variants, was associated with progression in PD.InterpretationWe report three novel loci associated with PD progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release and the A2A adenosine receptor may represent new candidates for disease modification in PD.RESEARCH IN CONTEXTEvidence before this studyWe searched PubMed for articles on Parkinson’s disease (PD) with no language restrictions from database inception up to February 9, 2022. We used the search terms “Parkinson disease AND genetics” and “disease progression OR survival OR mortality OR prognosis OR longitudinal studies”. We also conducted this search with the addition of “genome-wide association study” (GWAS) to focus on these genome-wide analyses. There are now three published large-scale GWASs investigating PD progression, and many candidate variant studies. However, no genome-wide studies have reported on survival/mortality in PD.Added value of this studyTo our knowledge, this is the first GWAS of survival in PD. Our study highlights new loci influencing survival in PD, including TBXAS1 and SYT10. We also conducted GWASs of progression to other clinical milestones, Hoehn and Yahr stage 3 or greater, and cognitive impairment. We show that APOE influences both mortality and cognitive progression in PD, and report an additional locus influencing expression of ADORA2A which affects the rate of motor progression.Implications of all the available evidenceWith the exception of APOE, we report new loci which have not been previously associated with PD progression or for mortality and ageing in the general population. These loci could be investigated in functional studies as potential drug targets to stop or slow progression of PD. In addition, new genetic loci can help to improve our understanding of the biology of PD progression and prediction of progression. Further replication of these loci is also needed in independent, longitudinal PD cohorts.

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.

Introduction:\ud CVT-301 is an orally inhaled levodopa therapy approved for the intermittent treatment of OFF episodes in Parkinson's disease patients who are taking a standard oral levodopa regimen. This open-label, randomized, controlled study over 12 months characterizes the safety, including pulmonary safety, of CVT-301 84 mg (nominal respirable levodopa fine-particle dose, 50 mg).\ud \ud Methods:\ud Patients experiencing motor fluctuations were randomized 2:1 to CVT-301 or an observational cohort (OC) receiving oral standard of care. Pulmonary safety was assessed using spirometry and carbon monoxide diffusion capacity (DLCO). Exploratory efficacy endpoints, assessed only for CVT-301, included change in Unified Parkinson's Disease Rating Scale Part III (UPDRS-III), patients achieving ON within 60 min and remaining ON at 60 min, Patient Global Impression of Change (PGIC) scale, and total daily OFF time.\ud \ud Results:\ud Of 408 patients randomized, 310 completed the study (204 in CVT-301 and 106 in OC). Mean 12-month changes from baseline for CVT-301 were −0.105 L (FEV1) and −0.378 mL/min/mm Hg (DLCO), and for OC were −0.117 L and −0.722 mL/min/mm Hg, respectively. Between-group comparisons were not statistically significant. For FEV1/FVC the 12-month change was −0.3 and −1.6, respectively, which was a significant between-group difference. However, between-group differences were not significant at 3 and 9 months and all changes from baseline were small (75% reported improvement in PGIC. OFF time decreased by 1.32–1.42 h/day.\ud \ud Conclusion:\ud CVT-301 84 mg induced no clinically significant differences in pulmonary function compared with the OC. Improvements in motor scores, OFF time, and patient-reported outcomes support clinical efficacy for up to 12 months.

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.

Background: Clinical diagnosis and monitoring of Parkinson's disease (PD) remain challenging because of the lack of an established biomarker. Neuromelanin-magnetic resonance imaging (NM-MRI) is an emerging biomarker of nigral depigmentation indexing the loss of melanized neurons but has unknown prospective diagnostic and tracking performance in multicenter settings. Objectives: The aim was to investigate the diagnostic accuracy of NM-MRI in early PD in a multiprotocol setting and to determine and compare serial NM-MRI changes in PD and controls. Methods: In this longitudinal case–control 3 T MRI study, 148 patients and 97 controls were included from six UK clinical centers, of whom 140 underwent a second scan after 1.5 to 3 years. An automated template-based analysis was applied for subregional substantia nigra NM-MRI contrast and volume assessment. A point estimate of the period of prediagnostic depigmentation was computed. Results: All NM metrics performed well to discriminate patients from controls, with receiver operating characteristic showing 85% accuracy for ventral NM contrast and 83% for volume. Generalizability using a priori volume cutoff was good (79% accuracy). Serial MRI demonstrated accelerated NM loss in patients compared to controls. Ventral NM contrast loss was point estimated to start 5 to 6 years before clinical diagnosis. Ventral nigral depigmentation was greater in the most affected side, more severe cases, and nigral NM volume change correlated with change in motor severity. Conclusions: We demonstrate that NM-MRI provides clinically useful diagnostic information in early PD across protocols, platforms, and sites. It provides methods and estimated depigmentation rates that highlight the potential to detect preclinical PD and track progression for biomarker-enabled clinical trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundPatients with Parkinson’s disease (PD) have variable disease progression. More accurate prediction of progression could improve clinical trial design. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be improved by blood biomarkers.ObjectiveTo determine if serum neurofilament light (NfL) is a useful biomarker for prognostic modelling in PD.MethodsWe evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients’ genetic (GBA and APOE) status in a large clinical dataset. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model and explored whether serum NfL could distinguish prognostic phenotypes. We compared NfL with baseline candidate predictor variables and studied the combination of clinical, serum and genetic data.ResultsSerum NfL was associated with patients’ cognitive status at baseline. Baseline NfL was associated with the progression of motor and functional impairment and with increased mortality (Survival HR 1.85, CI: 1.03-3.33, p=0.04). Baseline NfL levels predicted unfavourable progression to a similar extent as previously validated clinical predictors (AUC: 0.74 vs 0.78, p=0.22). The combination of clinical, genetic and biomarker data produced a strong predication of unfavourable outcomes as compared to age and gender alone (AUC: 0.71-age/gender vs 0.83-ALL p = 0.0076)ConclusionsBaseline serum NfL provides an objective measure of neurodegeneration in PD patients. Clinical trials of disease-modifying therapies might usefully stratify patients according using clinical, genetic and NfL status at the time of recruitment.

ImportanceType 2 diabetes (T2DM) is an established risk factor for developing Parkinson’s disease (PD) but its effect on disease progression is not well understood.ObjectiveTo examine the effects of co-morbid T2DM on Parkinson’s disease progression and quality of life.DesignWe analysed data from the Tracking Parkinson’s study, a large multi-centre prospective study in the UK.ParticipantsThe study included 1930 adults with recent onset PD, recruited between February 2012 and May 2014, and followed up regularly thereafter.ExposureA diagnosis of pre-existing T2DM was based on self-report at baseline. After controlling for confounders, an evaluation of how T2DM affects PD was performed by comparing symptom severity scores; and analyses using multivariable mixed models was used to determine the effects of T2DM on Parkinson’s disease progression.Main Outcomes and MeasuresThe impact of T2DM on Parkinson’s disease severity was derived from scores collected using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Non-Motor Symptoms Scale (NMSS), Montreal Cognitive Assessment (MoCA), Questionnaire for impulsive-compulsive disorders in PD (QUIP), Leeds Anxiety and Depression Scale (LADS), and Schwab and England ADL scale.ResultsWe identified 167 (8.7%) patients with PD and T2DM (PD+T2DM) and 1763 (91.3%) with PD without T2DM (PD). Patients with T2DM had more severe motor symptoms, as assessed by MDS-UPDS III 25.8 (0.9) vs 22.5 (0.3) p=0.002, had significantly faster motor symptom progression over time (p=0.012), and T2DM was an independent predictor for the development of substantial gait impairment (HR 1.55, CI 1.07-2.23, p=0.020). Patients were more likely to have loss of independence (OR 2.08, CI 1.34-3.25, p=0.001); and depression (OR 1.62, CI 1.10-2.39, p=0.015), and developed worsening mood (p=0.041) over time compared to the PD group. T2DM was also an independent predictor for the development mild cognitive impairment (HR 1.7, CI 1.24-2.51, p=0.002) over timeConclusions and relevanceT2DM is associated with faster disease progression in PD, highlighting an interaction between these two diseases. As it is a potentially modifiable, metabolic state, with multiple peripheral and central targets for intervention, it may represent a target for ameliorating parkinsonian symptoms, and progression to disability and dementia.Key pointsQuestionWhat is the impact of Type 2 diabetes on Parkinson’s disease progression?FindingsIn this prospective study of 1930 patients with recent onset PD, T2DM is an independent risk factor for more severe motor features, non-motor symptoms, and poorer quality of life; and importantly is associated with faster motor and non-motor symptom progression, and increases the risk of developing cognitive impairment.MeaningT2DM is identified as a new factor that alters Parkinson’s disease progression. T2DM predicts both motor and non-motor symptom progression in PD and is associated with poorer quality of life, highlighting an interaction of two chronic disease states. This highlights a particular need for improved treatment in this subgroup of patients with Parkinson’s.

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As therapeutic trials target early stages of Parkinson's disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson's Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the Parkinson's Progression Markers Initiative (PPMI) study to estimate the degree of enrichment achieved and impact on future trials in subjects with early motor PD. The presence of reduced striatal DAT binding based on visual reads of single photon emission tomography (SPECT) scans in early motor PD subjects was an independent predictor of faster decline in UPDRS Parts II and III as compared to subjects with scans without evidence of dopaminergic deficit (SWEDD) over 24 months. The EMA issued in 2018 a full Qualification Opinion for the use of DAT as an enrichment biomarker in PD trials targeting subjects with early motor symptoms. Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and exclude subjects who are unlikely to progress clinically from being exposed to novel test therapeutics.

Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives To identify the genetic determinants of PD age at onset. Methods Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. Results We estimated that the heritability of PD age at onset attributed to common genetic variation was similar to 0.11, lower than the overall heritability of risk for PD (similar to 0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. (c) 2019 International Parkinson and Movement Disorder Society

ObjectiveWe sought to identify an abbreviated test of impaired olfaction amenable for use in busy clinical environments in prodromal (isolated REM sleep behavior disorder [iRBD]) and manifest Parkinson disease (PD).MethodsEight hundred ninety individuals with PD and 313 controls in the Discovery cohort study underwent Sniffin’ Stick odor identification assessment. Random forests were initially trained to distinguish individuals with poor (functional anosmia/hyposmia) and good (normosmia/super-smeller) smell ability using all 16 Sniffin’ Sticks. Models were retrained using the top 3 sticks ranked by order of predictor importance. One randomly selected 3-stick model was tested in a second independent PD dataset (n = 452) and in 2 iRBD datasets (Discovery n = 241, Marburg n = 37) before being compared to previously described abbreviated Sniffin’ Stick combinations.ResultsIn differentiating poor from good smell ability, the overall area under the curve (AUC) value associated with the top 3 sticks (anise/licorice/banana) was 0.95 in the Development dataset (sensitivity 90%, specificity 92%, positive predictive value 92%, negative predictive value 90%). Internal and external validation confirmed AUCs ≥0.90. The combination of the 3-stick model determined poor smell, and an RBD screening questionnaire score of ≥5 separated those with iRBD from controls with a sensitivity, specificity, positive predictive value, and negative predictive value of 65%, 100%, 100%, and 30%.ConclusionsOur 3-Sniffin’-Stick model holds potential utility as a brief screening test in the stratification of individuals with PD and iRBD according to olfactory dysfunction.Classification of EvidenceThis study provides Class III evidence that a 3-Sniffin’-Stick model distinguishes individuals with poor and good smell ability and can be used to screen for individuals with iRBD.

Parkinson’s disease (PD) is a complex neurodegenerative disorder. Males are on average ∼1.5 times more likely to develop PD compared to females. Over the years genome-wide association studies (GWAS) have identified numerous genetic risk factors for PD, however it is unclear whether genetics contribute to disease etiology in a sex-specific manner.In an effort to study sex-specific genetic factors associated with PD, we explored two large genetic datasets from the International Parkinson’s Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases.In total 19 genome-wide significant regions were identified, and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWASes was identified (rg=0.877) and heritability estimates were identical between male and female PD cases (∼20%).We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus females.

Background Little is known about decline in lung function in Parkinson's disease (PD). To assess these changes, we assessed the changes in lung function that occurred over 12 months in patients on standard PD therapy as part of the observational cohort of an open-label study of inhaled levodopa (CVT-301) in PD. Methods PD patients on stable oral PD therapy and no chronic respiratory disease had spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) measured at 3, 6, 9, and 12 months. Results 106 patients (81.5%) in the observational cohort on no investigational therapy completed the study. Mean FEV1 declined at 12 months from 2.88L at baseline with a mean change of −0.11L, greater than the −0.030–0.045L/year observed in healthy, non-smokers aged 60–70 years. FVC declined from 3.77L (mean change −0.19L); FEV1/FVC ratio remained relatively constant. DLCO mean change was −0.48 mL/min/mmHg from a baseline of 24.24 mL/min/mmHg. This change in DLCO, while not significant, was similar to that seen in non-smokers aged 60–70 years (DLCO -0.42–0.63 mL/min/mmHg/year). Decreases in alveolar volume (VA) and inspiratory vital capacity (IVC) rather than the transfer coefficient (DLCO/VA) were observed. Conclusions PD patients had greater declines in FEV1, and FVC, but not in DLCO, compared to healthy non-smokers of similar age. Declines in FEV1 and FVC with little change in FEV1/FVC, and decline in VA and IVC with little change in DLCO/VA, suggest these changes were due to decreases in lung volume and are compatible with progressive PD-associated respiratory muscle weakness. Trial registration ClinicalTrials.gov (NCT02352363 Registered January 26, 2015 [ https://clinicaltrials.gov/ct2/show/NCT02352363 ]) and EudraCT (2014-003799-22).

Early-onset Parkinson’s disease (EOPD) can be caused by biallelic mutations in PRKN, DJ1 and PINK1. However, while the identification of novel genes is becoming increasingly challenging, new insights into EOPD genetics have important relevance for understanding the pathways driving disease pathogenesis. Here, using extended runs of homozygosity (ROH) >8Mb as a marker for possible autosomal recessive inheritance, we identified 90 EOPD patients with extended ROH. Investigating rare, damaging homozygous variants to identify candidate genes for EOPD, 81 genes were prioritised. Through the assessment of biallelic (homozygous and compound heterozygous) variant frequencies in cases and controls from three independent cohorts totalling 3,381 PD patients and 2,463 controls, we identified two biallelic MIEF1 variant carriers among EOPD patients. We further investigated the role of disease-associated variants in MIEF1 which encodes for MID51, an outer mitochondrial membrane protein, and found that putative EOPD-associated variants in MID51 preferentially disrupted its oligomerization state. These findings provide further support for the role of mitochondrial dysfunction in the development of PD. Together, we have used genome-wide homozygosity mapping to identify potential EOPD genes, and future studies incorporating expanded datasets and further functional analyses will help to determine their roles in disease aetiology.

Olfactory loss, motor impairment, anxiety/depression, and REM-sleep behaviour disorder (RBD) are prodromal Parkinson’s disease (PD) features. PD risk prediction models typically dichotomize test results and apply likelihood ratios (LRs) to scores above and below cut-offs. We investigate whether LRs for specific test values could enhance classification between PD and controls. PD patient data on smell (UPSIT), possible RBD (RBD Screening Questionnaire), and anxiety/depression (LADS) were taken from the Tracking Parkinson’s study (n = 1046). For motor impairment (BRAIN test) in PD cases, published data were supplemented (n = 87). Control data (HADS for anxiety/depression) were taken from the PREDICT-PD pilot study (n = 1314). UPSIT, RBDSQ, and anxiety/depression data were analysed using logistic regression to determine which items were associated with PD. Gaussian distributions were fitted to BRAIN test scores. LRs were calculated from logistic regression models or score distributions. False-positive rates (FPRs) for specified detection rates (DRs) were calculated. Sixteen odours were associated with PD; LRs for this set ranged from 0.005 to 5511. Six RBDSQ and seven anxiety/depression questions were associated with PD; LRs ranged from 0.35 to 69 and from 0.002 to 402, respectively. BRAIN test LRs ranged from 0.16 to 1311. For a 70% DR, the FPR was 2.4% for the 16 odours, 4.6% for anxiety/depression, 16.0% for the BRAIN test, and 20.0% for the RBDSQ. Specific selections of (prodromal) PD marker features rather than dichotomized marker test results optimize PD classification. Such optimized classification models could improve the ability of algorithms to detect prodromal PD; however, prospective studies are needed to investigate their value for PD-prediction models.

OBJECTIVETo discover genetic determinants of Parkinson disease (PD) motor subtypes, including Tremor Dominant (TD) and Postural Instability/Gait Difficulty (PIGD) forms.METHODSIn 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining two complementary outcome traits derived from the Unified Parkinson’s Disease Rating Scale (UPDRS), including dichotomous motor subtype (TD vs. PIGD) or a continuous tremor / PIGD score ratio. Logistic or linear regression models were adjusted for sex, age of onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.RESULTSAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199347, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = −0.04, 95% CI = −0.07, 0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6×10−7), which harbors an independent risk allele for essential tremor.CONCLUSIONSMultiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

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 e4 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 e4 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.

BackgroundHyposmia, motor impairment and probable REM-sleep behaviour disorder (RBD) are markers for Parkinson’s disease (PD). Proposed PD risk prediction models have dichotomised test results and applied likelihood ratios (LRs) to scores above and below cut-offs. We investigate whether LRs for specific test values could enhance prediction models.MethodsSmell and probable RBD data for PD patients were taken from the Tracking Parkinson’s study (n=1046). For motor impairment previously published data were supplemented (n=87). PREDICT-PD pilot study participants were the controls. Smell, motor impairment and RBD were assessed using the University of Pennsylvania Smell Identification Test (UPSIT), the Bradykinesia-Akinesia Incoordination (BRAIN) test and the REM sleep behaviour disorder Screening Questionnaire (RBDSQ). UPSIT and RBDSQ data were analysed using logistic regression to determine which items were predictive of PD, or using total scores. Gaussian distributions were fitted to BRAIN test scores. LRs were calculated from logistic regression models or from score distributions. False-positive rates (FPRs) for specified detection rates (DRs) were calculated.ResultsLogistic regression modelling yielded a greater range of LRs. 16 odours were associated with PD; LRs ranged from 0.005-5511. 6 RBDSQ questions were associated with PD; LRs ranged from from 0.34-69. BRAIN test LRs ranged from 0.16-1311. For a 70% DR the FPR for the 16 odours was 2.4%, for 50% DRs, the BRAIN test FPR was 6.6% and 12.2% for the RBDSQ.ConclusionsMaximising information on PD markers can potentially improve the ability of algorithms to detect PD by generating LRs with a larger range of values than using dichotomised results.

Background Hyposmia is an early feature in neurodegenerative diseases, most notably Parkinson’s Disease (PD). Using abbreviated smell tests could provide a cost-effective means for large-scale hyposmia screening. It is unclear whether short smell tests can effectively detect hyposmia in patient populations. Objectives To test the ability of short smell combinations to ‘pre-screen’ for probable hyposmia in people with PD and target administration of more extensive tests, such as the University of Pennsylvania Smell Identification Test (UPSIT). Methods We assessed the screening performance of a short 4 smell combination previously derived from use of the 40-item UPSIT in healthy older people and its ability to detect hyposmia in a large cohort of PD patients. Results The novel 4 smell combination included Menthol, Clove, Onion and Orange and had a sensitivity of 87.1% (95% confidence interval: 84.9%-89.2%) and specificity of 69.7% (63.3%-75.5%) for detecting hyposmia in patients with PD. A different (also novel) 4-item combination developed using a data driven approach in PD patients only achieved 81.3% (78.2%-84.4%) sensitivity for equivalent specificity. Conclusions A short 4 smell combination derived from a healthy population demonstrated high sensitivity to detect those with hyposmia and PD.

Importance\ud \ud Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied.\ud \ud Objective\ud \ud To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD.\ud \ud Design, Setting, Participants\ud \ud This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019.\ud \ud Main Outcomes and Measures\ud \ud Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures.\ud \ud Results\ud \ud A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P

Imatinib, a tyrosine kinase inhibitor, is the mainstay of treatment for resected high-risk (adjuvant and metastatic) gastrointestinal stromal tumour (GIST) - a rare form of sarcoma. There has been recent research into the neuroprotective role and modulation of dopaminergic neurones by imatinib through the abl pathway in Parkinson's disease (PD). We describe two patients from a single cancer centre with concurrent diagnoses of PD and metastatic GIST receiving imatinib and standard PD management. The cases highlight a potential reduction in PD progression using Unified Parkinson's Disease Rating Scale. Further research into repurposing of imatinib for PD may provide additional management options for this neurodegenerative illness.

Background: \ud 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.\ud \ud Literature Review: \ud 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.\ud \ud Cases: \ud 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.\ud \ud Conclusions: \ud The levodopa motor response varies in definite PD. Explanations other than diagnostic inaccuracy should be explored.

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.

ObjectiveTo assess genetic modifiers of Parkinson’s disease (PD) age at onset (AAO) penetrance in individuals carrying common and rare LRRK2 risk allelesMethodsWe analysed reported genetic modifier DNM3 rs2421947 in 724 LRRK2 p.G2019S heterozygotes using linear regression of AAO. We meta-analysed our data with previously published data (n=754). VAMP4 is in close proximity to DNM3 and is associated with PD. We analysed the effect of the rs11578699 VAMP4 variant on pG2019S penetrance in 786 LRRK2 p.G2019S heterozygotes. We also evaluated the impact of VAMP4 variants using AAO regression in 4882 patients with PD carrying a common LRRK2 risk variant (rs10878226).ResultsThere was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699. Our linear regression AAO of 724 p.G2019S carriers showed no relationship between DNM3 rs2421947 and AAO (beta = −1.19, p = 0.55, n =708). Meta-analysis with previously published data did not indicate a significant effect on AAO (beta = −2.21, p = 0.083, n = 1304), but there was significant heterogeneity in the analyses of new and previously published data. VAMP4 rs11578699 was nominally associated with AAO in patients dichotomized by the common LRRK2 risk variant rs10878226 (beta=1.68, se=0.81 p=0.037).InterpretationAnalysis of DNM3 in previously unpublished data does not show an interaction between DNM3 and LRRK2 G2019S for AAO, however the inter-study heterogeneity may indicate ethnic-specific effects of DNM3 rs2421947. Analysis of sporadic PD patients stratified by the PD risk variant rs10878226 indicates a possible interaction between LRRK2 and VAMP4.

BackgroundDementia 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.MethodsSystematic 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.Results44 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-β pathology was moderate or severe in over half. Amyloid-β 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-β 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.ConclusionsWhile significant α-synuclein pathology is the main substrate of dementia in PD, coexistent pathologies are common. In particular, tau and amyloid-β 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.

BACKGROUND: The detection of prodromal Parkinson's disease (PD) is desirable to test drugs with neuroprotective potential, but will be affected by known disease variations.OBJECTIVE: To assess the prevalence of four key non-motor prodromal PD markers, and evaluate the sensitivity of case detection when non-motor screening tools for prodromal PD are implemented in an early clinical PD cohort.METHODS: Hyposmia (University of Pennsylvania smell identification test ≤15th centile or Sniffin' Sticks at or ≤10th centile corrected for age and sex), rapid-eye movement sleep behaviour disorder (RBD questionnaire >4), constipation (6) were recorded in recent onset PD cases, and proposed non-motor screening criteria applied.RESULTS: In 1,719 PD cases, mean age 68.6 years (SD 8.1), 65.5% male, mean disease duration 1.3 years (SD 0.9), 72.2% were hyposmic, 43.3% had RBD, 22.1% depression, and 21.5% constipation. 11.6% of cases had no key non-motor features, 38.8% one, 32.1% two, 15.5% three, and 2.0% all four. Increasing numbers of non-motor features were associated with younger age (p = 0.019), higher motor scores (p < 0.001), more postural instability gait difficulty (PIGD) (p < 0.001), greater cognitive impairment (p < 0.001) and higher total non-motor burden (p < 0.001). Cases with hyposmia alone were younger (p < 0.001), had less severe cognitive (p = 0.006) and other non-motor features (p < 0.001). All screening criteria selected younger patients (p = 0.001, p < 0.001), three of four greater overall non-motor burden (p = 0.005, p < 0.001), and inclusion of RBD more cognitive impairment (p = 0.003, p = 0.001) and PIGD (p = 0.004, p = 0.001).CONCLUSIONS: Varying sensitivity levels, and age and phenotype selectivity, are found when different non-motor screening methods to detect prodromal PD are applied to an early clinical PD cohort.

Background Although levodopa is the most effective oral PD therapy, many patients experience motor fluctuations, including sudden loss of dose effect and delayed benefit. CVT-301 is a levodopa inhalation powder with the potential for rapid onset of action. The objective of this study was to evaluate CVT-301 self-administered by PD patients to relieve OFF episodes. Methods PD patients with ≥2 hours per day of OFF time despite oral levodopa ≥4 times per day were randomized to CVT-301 or placebo for 4 weeks, to be used up to 3 times per day for OFF episodes. After 2 weeks, the study-drug dose was escalated from 35 to 50 mg. The primary end point was mean change in UPDRS Part III score from a predose OFF state to the average of postdose scores obtained at 10, 20, 30, and 60 minutes, as assessed in-clinic at the end of week 4. Home diaries were recorded. Results Eighty-six patients used the study drug at an average frequency of 2.1 times per day for CVT-301 and for placebo. At 4 weeks, least-squares mean change in UPDRS Part III score favored CVT-301 by 7.0 points (P < 0.001). A treatment effect was evident at 10 minutes. At 4 weeks, least-squares mean OFF-time change from baseline favored CVT-301 by 0.9 hours per day (P = 0.045). The most frequently reported adverse events in the CVT-301 group were dizziness, cough, and nausea, each in 7% (3 of 43 patients). Conclusions CVT-301 self-administered during OFF episodes provided rapid improvement of motor function, and daily OFF time was significantly reduced at the higher dose. CVT-301 was generally safe and well-tolerated. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Background Anecdotal reports suggested that a specialized physiotherapy technique developed in France (the Bleton technique) improved primary cervical dystonia. We evaluated the technique in a randomized trial. Methods A parallel-group, single-blind, two-centre randomized trial compared the specialized outpatient physiotherapy programme given by trained physiotherapists up to once a week for 24 weeks with standard physiotherapy advice for neck problems. Randomization was by a central telephone service. The primary outcome was the change in the total Toronto Western Spasmodic Torticollis Rating (TWSTR) scale, measured before any botulinum injections that were due, between baseline and 24 weeks evaluated by a clinician masked to treatment. Analysis was by intention-to-treat. Results 110 patients were randomized (55 in each group) with 24 week outcomes available for 84. Most (92%) were receiving botulinum toxin injections. Physiotherapy adherence was good. There was no difference between the groups in the change in TWSTR score over 24 weeks (mean adjusted difference 1.44 [95% CI -3.63, 6.51]) or 52 weeks (mean adjusted difference 2.47 [-2.72, 7.65]) nor in any of the secondary outcome measures (Cervical Dystonia Impact Profile-58, clinician and patient-rated global impression of change, mean botulinum toxin dose). Both groups showed large sustained improvements compared to baseline in the TWSTR, most of which occurred in the first four weeks. There were no major adverse events. Subgroup analysis suggested a centre effect. Conclusion There was no statistically or clinically significant benefit from the specialized physiotherapy compared to standard neck physiotherapy advice but further trials are warranted.

Background\ud \ud Parkin related Parkinson's disease (PD) is differentiated from idiopathic PD by absent or sparse Lewy bodies, and preserved olfaction. The significance of single Parkin mutations in the pathogenesis of PD is debated.\ud \ud Objectives\ud \ud To assess olfaction results according to Parkin mutation status. To compare the prevalence of Parkin single heterozygous mutations in patients diagnosed with PD to the rate in healthy controls in order to establish whether these single mutations could be a risk factor for developing PD.\ud \ud Methods\ud \ud Parkin gene mutation testing was performed in young onset PD (diagnosed

Background: L-dopa responsiveness in Parkinson's disease (PD) varies, but the clinical correlates and significance of this are ill-defined. Methods: Patients were assessed before and after their usual morning L-dopa dose, using the MDS Unified PD Rating Scale Part 3 (MDS UPDRS 3), and rated as definite responders (≥24.5% improvement) or limited responders (Results: 1007 cases, mean age 66.1 years (SD 9.1) at diagnosis, were assessed 3.4 (SD 0.9) years after diagnosis. The L-dopa response was definite in 614 cases (61.0%), median reduction in MDS UPDRS 3 scores was 42.0%, (IQR 33.3, 53.1), and was limited in 393 cases (39.0%), median reduction in MDS UPDRS 3 scores 11.5% (IQR 4.3, 18.2). Definite responders were younger (66.3 years at study entry, SD 9.3) than limited responders (69.2 years, SD 8.4, p < 0.001). The MDS UPDRS 3 score at study entry in definite responders (21.0, SD 10.5) was significantly lower than in limited responders (24.7, SD 13.4, p < 0.001). The MDS UPDRS 3 increase over 18 months was less in definite responders at 3.0 (SD 10.4), compared to limited responders (6.4, SD 11.0, p < 0.001). The levodopa equivalent daily dose (LEDD) was not significantly different at study entry (definite responders 317 mg, SD 199, vs limited responders 305 mg, SD 191, p = 0.53). However, LEDD was significantly higher at the time of the L-dopa challenge test in definite responders (541 mg, SD 293) compared to limited responders (485 mg, SD 215, p = 0.01). Responsiveness to L-dopa was unaffected by the challenge test dose (p = 0.54). Conclusions: The main determinants of variation in the L-dopa response in early PD are age and motor severity. A limited L-dopa response is associated with faster motor progression.

Increasing evidence supports an extensive and complex genetic contribution to Parkinson’s disease (PD). Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age of onset are largely unknown. Here we performed an age of onset GWAS based on 28,568 PD cases. We estimated that the heritability of PD age of onset due to common genetic variation was ~0.11, lower than the overall heritability of risk for PD (~0.27) likely in part because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni corrected significant effect at other known PD risk loci, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. In addition, we identified that GBA coding variant carriers had an earlier age of onset compared to non-carriers. Notably, SNCA, TMEM175, SCARB2, BAG3 and GBA have all been shown to either directly influence alpha-synuclein aggregation or are implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci such as GCH1, MAPT and RAB7L1/NUCKS1 (PARK16) did not show a significant effect on age of onset of PD. While for some loci, this may be a measure of power, this is clearly not the case for the MAPT locus; thus genetic variability at this locus influences whether but not when an individual develops disease. We believe this is an important mechanistic and therapeutic distinction. Furthermore, these data support a model in which alpha-synuclein and lysosomal mechanisms impact not only PD risk but also age of disease onset and highlights that therapies that target alpha-synuclein aggregation are more likely to be disease-modifying than therapies targeting other pathways.

In the past 4 years, two adjunctive treatment options to levodopa have been licensed for use in the UK in patients with Parkinson's disease (PD) and motor fluctuations: opicapone, a third-generation catechol-O-methyl transferase inhibitor, and safinamide, a monoamine oxidase B inhibitor. This clinical consensus outlines the practical considerations relating to motor fluctuations and managing wearing-off in patients with PD, and provides a clinical insight to adjunctive treatment options, including opicapone and safinamide. Practice-based opinion was provided from a multidisciplinary steering Group of eight UK-based movement disorder and PD specialists, including neurologists, geriatricians and a nurse specialist, from England, Scotland and Wales.