Genome sequence analyses identify novel risk loci for multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses.

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. METHODS: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. FINDINGS: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. INTERPRETATION: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. FUNDING: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

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.

Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy.

OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024.

Frequency and outcomes of gastrostomy insertion in a longitudinal cohort study of atypical parkinsonism.

BACKGROUND: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) show a high prevalence and rapid progression of dysphagia, which is associated with reduced survival. Despite this, the evidence base for gastrostomy is poor, and the optimal frequency and outcomes of this intervention are not known. We aimed to characterise the prevalence and outcomes of gastrostomy in patients with these three atypical parkinsonian disorders. METHOD: We analysed data from the natural history and longitudinal cohorts of the PROSPECT-M-UK study with up to 60 months of follow-up from baseline. Survival post-gastrostomy was analysed using Kaplan-Meier survival curves. RESULTS: In a total of 339 patients (mean age at symptom onset 63.3 years, mean symptom duration at baseline 4.6 years), dysphagia was present in >50% across all disease groups at baseline and showed rapid progression during follow-up. Gastrostomy was recorded as recommended in 44 (13%) and performed in 21 (6.2%; MSA 7, PSP 11, CBS 3) of the total study population. Median survival post-gastrostomy was 24 months compared with 12 months where gastrostomy was recommended but not done (p = 0.008). However, this was not significant when correcting for age and duration of symptoms at the time of procedure or recommendation. CONCLUSIONS: Gastrostomy was performed relatively infrequently in this cohort despite the high prevalence of dysphagia. Survival post-gastrostomy was longer than previously reported, but further data on other outcomes and clinician and patient perspectives would help to guide use of this intervention in MSA, PSP and CBS.

Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose-Driven Approach.

The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A pathogenic variant in RAB32 causes autosomal dominant Parkinson's disease and activates LRRK2 kinase.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD. Methods: Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed. Findings: We found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase. Interpretation: Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD. Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

Two sample Mendelian Randomisation using an outcome from a multilevel model of disease progression.

Identifying factors that are causes of disease progression, especially in neurodegenerative diseases, is of considerable interest. Disease progression can be described as a trajectory of outcome over time-for example, a linear trajectory having both an intercept (severity at time zero) and a slope (rate of change). A technique for identifying causal relationships between one exposure and one outcome in observational data whilst avoiding bias due to confounding is two sample Mendelian Randomisation (2SMR). We consider a multivariate approach to 2SMR using a multilevel model for disease progression to estimate the causal effect an exposure has on the intercept and slope. We carry out a simulation study comparing a naïve univariate 2SMR approach to a multivariate 2SMR approach with one exposure that effects both the intercept and slope of an outcome that changes linearly with time since diagnosis. The simulation study results, across six different scenarios, for both approaches were similar with no evidence against a non-zero bias and appropriate coverage of the 95% confidence intervals (for intercept 93.4-96.2% and the slope 94.5-96.0%). The multivariate approach gives a better joint coverage of both the intercept and slope effects. We also apply our method to two Parkinson's cohorts to examine the effect body mass index has on disease progression. There was no strong evidence that BMI affects disease progression, however the confidence intervals for both intercept and slope were wide.

A programme evaluation of 'First Steps': A peer-conceived, developed and led self-management intervention for people after a Parkinson's diagnosis.

OBJECTIVE: A diagnosis of Parkinson's often leads to uncertainty about the future and loss of perceived control. Peer support may offer a means to address these concerns and promote self-management. DESIGN: A programme evaluation of the feasibility and potential effects of 'First Steps', utilising a pragmatic step wedge approach. Comparing First Steps (intervention) to (control) conditions.Setting: In the community at four sites in southern England.Participants: Newly diagnosed (≤ 12months) people with Parkinson's.Intervention: First Steps was a 2-day peer-conceived, developed and led intervention to support self-management.Main measures: At 0, 12 and 24 weeks anxiety and depression (Hospital, Anxiety and Depression Scale, HADS), daily functioning (World Health Organisation Disability Assessment Schedule, WHODAS), physical activity, quality of life (EQ5D), carer strain and service utilisation were assessed. RESULTS: Between February 2018 and July 2019, 36 participants were enrolled into intervention and 21 to control conditions, all were included in statistical analysis. Lost to follow up was n = 1 (intervention) and n = 1 adverse event was reported (control, unrelated). Of the 36 allocated to the intervention n = 22 participants completed both days of First Steps during the study period. Completion of outcome measures was >95% at 24 weeks. Small effects favouring the intervention were found for HADS (odds ratio (OR) = 2.06, 95% confidence interval (CI) 0.24:17.84), Carer Strain Index (OR = 2.22, 95% CI 0.5:9.76) and vigorous (d = 0.42, 95% CI -0.12:0.97) and total physical activity (d = 0.41, 95% CI -0.13:0.95). EQ5D, WHOSDAS and service utilisation, was similar between groups. CONCLUSIONS: First Steps was feasible and safe and we found potential to benefit physical activity, mental health and carer strain. Further research with longer-term follow up is warranted.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

Neuronally Derived Extracellular Vesicle α-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease.

IMPORTANCE: Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase. OBJECTIVE: To investigate whether α-synuclein in neuronally derived serum-extracellular vesicles identifies individuals at risk of developing PD and related dementia. DESIGN, SETTING, and PARTICIPANTS: This retrospective, cross-sectional multicenter study of serum samples included the Oxford Discovery, Marburg, Cologne, and Parkinson's Progression Markers Initiative cohorts. Participants were recruited from July 2013 through August 2023 and samples were analyzed from April 2022 through September 2023. The derivation group (n = 170) included participants with isolated rapid eye movement sleep behavior disorder (iRBD) and controls. Two validation groups were used: the first (n = 122) included participants with iRBD and controls and the second (n = 263) included nonmanifest GBA1N409S gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD. Overall the study included 199 participants with iRBD, 20 hyposmic participants with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBA1N409S gene carriers, 21 GBA1N409S gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1, participants with polysomnographically confirmed iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included. Among 580 potential participants, 4 were excluded due to alternative diagnoses. EXPOSURES: Clinical assessments, imaging, and serum collection. MAIN OUTCOME AND MEASURES: L1CAM-positive extracellular vesicles (L1EV) were immunocaptured from serum. α-Synuclein and syntenin-1 were measured by electrochemiluminescence. Area under the receiver operating characteristic (ROC) curve (AUC) with 95% CIs evaluated biomarker performance. Probable prodromal PD was determined using the updated Movement Disorder Society research criteria. Multiple linear regression models assessed the association between L1EV α-synuclein and prodromal markers. RESULTS: Among 576 participants included, the mean (SD) age was 64.30 (8.27) years, 394 were male (68.4%), and 182 were female (31.6%). A derived threshold of serum L1EV α-synuclein distinguished participants with iRBD from controls (AUC = 0.91; 95% CI, 0.86-0.96) and those with more than 80% probability of having prodromal PD from participants with less than 5% probability (AUC = 0.80; 95% CI, 0.71-0.89). Subgroup analyses revealed that specific combinations of prodromal markers were associated with increased L1EV α-synuclein levels. Across all cohorts, L1EV α-synuclein differentiated participants with more than 80% probability of having prodromal PD from current and historic healthy control populations (AUC = 0.90; 95% CI, 0.87-0.93), irrespective of initial diagnosis. L1EV α-synuclein was increased in at-risk participants with a positive cerebrospinal fluid seed amplification assay and was above the identified threshold in 80% of cases (n = 40) that phenoconverted to PD or related dementia. CONCLUSIONS AND RELEVANCE: L1EV α-synuclein in combination with prodromal markers should be considered in the stratification of those at high risk of developing PD and related Lewy body diseases.

Embedding Patient Input in Outcome Measures for Long-Term Disease-Modifying Parkinson Disease Trials.

BACKGROUND: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. OBJECTIVES: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. METHODS: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. RESULTS: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. CONCLUSIONS: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Subthalamic nucleus shows opposite functional connectivity pattern in Huntington's and Parkinson's disease.

Huntington's and Parkinson's disease are two movement disorders representing mainly opposite states of the basal ganglia inhibitory function. Despite being an integral part of the cortico-subcortico-cortical circuitry, the subthalamic nucleus function has been studied at the level of detail required to isolate its signal only through invasive studies in Huntington's and Parkinson's disease. Here, we tested whether the subthalamic nucleus exhibited opposite functional signatures in early Huntington's and Parkinson's disease. We included both movement disorders in the same whole-brain imaging study, and leveraged ultra-high-field 7T MRI to achieve the very fine resolution needed to investigate the smallest of the basal ganglia nuclei. Eleven of the 12 Huntington's disease carriers were recruited at a premanifest stage, while 16 of the 18 Parkinson's disease patients only exhibited unilateral motor symptoms (15 were at Stage I of Hoehn and Yahr off medication). Our group comparison interaction analyses, including 24 healthy controls, revealed a differential effect of Huntington's and Parkinson's disease on the functional connectivity at rest of the subthalamic nucleus within the sensorimotor network, i.e. an opposite effect compared with their respective age-matched healthy control groups. This differential impact in the subthalamic nucleus included an area precisely corresponding to the deep brain stimulation 'sweet spot'-the area with maximum overall efficacy-in Parkinson's disease. Importantly, the severity of deviation away from controls' resting-state values in the subthalamic nucleus was associated with the severity of motor and cognitive symptoms in both diseases, despite functional connectivity going in opposite directions in each disorder. We also observed an altered, opposite impact of Huntington's and Parkinson's disease on functional connectivity within the sensorimotor cortex, once again with relevant associations with clinical symptoms. The high resolution offered by the 7T scanner has thus made it possible to explore the complex interplay between the disease effects and their contribution on the subthalamic nucleus, and sensorimotor cortex. Taken altogether, these findings reveal for the first time non-invasively in humans a differential, clinically meaningful impact of the pathophysiological process of these two movement disorders on the overall sensorimotor functional connection of the subthalamic nucleus and sensorimotor cortex.

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

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

Investigating gait-responsive somatosensory cueing from a wearable device to improve walking in Parkinson's disease.

Freezing-of-gait (FOG) and impaired walking are common features of Parkinson's disease (PD). Provision of external stimuli (cueing) can improve gait, however, many cueing methods are simplistic, increase task loading or have limited utility in a real-world setting. Closed-loop (automated) somatosensory cueing systems have the potential to deliver personalised, discrete cues at the appropriate time, without requiring user input. Further development of cue delivery methods and FOG-detection are required to achieve this. In this feasibility study, we aimed to test if FOG-initiated vibration cues applied to the lower-leg via wearable devices can improve gait in PD, and to develop real-time FOG-detection algorithms. 17 participants with Parkinson's disease and daily FOG were recruited. During 1 h study sessions, participants undertook 4 complex walking circuits, each with a different intervention: continuous rhythmic vibration cueing (CC), responsive cueing (RC; cues initiated by the research team in response to FOG), device worn with no cueing (NC), or no device (ND). Study sessions were grouped into 3 stages/blocks (A-C), separated by a gap of several weeks, enabling improvements to circuit design and the cueing device to be implemented. Video and onboard inertial measurement unit (IMU) data were analyzed for FOG events and gait metrics. RC significantly improved circuit completion times demonstrating improved overall performance across a range of walking activities. Step frequency was significantly enhanced by RC during stages B and C. During stage C, > 10 FOG events were recorded in 45% of participants without cueing (NC), which was significantly reduced by RC. A machine learning framework achieved 83% sensitivity and 80% specificity for FOG detection using IMU data. Together, these data support the feasibility of closed-loop cueing approaches coupling real-time FOG detection with responsive somatosensory lower-leg cueing to improve gait in PD.

Genetic meta-analysis of levodopa induced dyskinesia in Parkinson's disease.

The genetic basis of levodopa-induced-dyskinesia (LiD) is poorly understood, and there have been few well-powered genome-wide studies. We performed a genome-wide survival meta-analyses to study the effect of genetic variation on the development of LiD in five separate longitudinal cohorts, and meta-analysed the results. We included 2784 PD patients, of whom 14.6% developed LiD. We found female sex (HR = 1.35, SE = 0.11, P = 0.007) and younger age at onset (HR = 1.8, SE = 0.14, P = 2 × 10-5) increased the probability of developing LiD. We identified three genetic loci significantly associated with time-to-LiD onset. rs72673189 on chromosome 1 (HR = 2.77, SE = 0.18, P = 1.53 × 10-8) located at the LRP8 locus, rs189093213 on chromosome 4 (HR = 3.06, SE = 0.19, P = 2.81 × 10-9) in the non-coding RNA LINC02353 locus, and rs180924818 on chromosome 16 (HR = 3.13, SE = 0.20, P = 6.27 × 10-9) in the XYLT1 locus. Based on a functional annotation analysis on chromosome 1, we determined that changes in DNAJB4 gene expression, close to LRP8, are an additional potential cause of increased susceptibility to LiD. Baseline anxiety status was significantly associated with LiD (OR = 1.14, SE = 0.03, P = 7.4 × 10-5). Finally, we performed a candidate variant analysis of previously reported loci, and found that genetic variability in ANKK1 (rs1800497, HR = 1.27, SE = 0.09, P = 8.89 × 10-3) and BDNF (rs6265, HR = 1.21, SE = 0.10, P = 4.95 × 10-2) loci were significantly associated with time to LiD in our large meta-analysis.

Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative.

BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.

HLA in isolated REM sleep behavior disorder and Lewy body dementia.

Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27-1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95%CI = 1.12-1.41, p = 8.76e-05), 70Q (OR = 0.81, 95%CI = 0.72-0.91, p = 3.65e-04) and 71R (OR = 1.21, 95%CI = 1.08-1.35, p = 1.35e-03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.

Genetic meta-analysis of levodopa induced dyskinesia in Parkinson's disease.

Importance: Forty percent of Parkinson's disease patients develop levodopa-induced-dyskinesia (LiD) within 4 years of starting levodopa. The genetic basis of LiD remains poorly understood, and there have been few well powered studies. Objective: To discover common genetic variants in the PD population that increase the probability of developing LiD. Design setting and Participants: We performed survival analyses to study the development of LiD in 5 separate longitudinal cohorts. We performed a meta-analysis to combine the results of genetic association from each study based on a fixed effects model weighting the effect sizes by the inverse of their standard error. The selection criteria was specific to each cohort. We studied individuals that were genotyped from each cohort and that passed our analysis specific inclusion criteria. Main Outcomes and Measures: We measured the time for PD patients on levodopa treatment to develop LiD as defined by reaching a score higher or equal than 2 from the MDS-UPDRS part IV, item 1, which is equivalent to a range of 26%-50% of the waking time with dyskinesia. We carried out a genome-wide analysis of the hazard ratio and the association of genome-wide SNPs with the probability of developing LiD using cox proportional hazard models (CPH). Results: This study included 2,784 PD patients of European ancestry, of whom 14.6% developed LiD. Consistent with previous studies, we found female gender (HR = 1.35, SE = 0.11, P = 0.007) and younger age at onset (HR = 1.8, SE = 0.14, P = 2 × 10 -5 ) to increase the probability of developing LiD. We identified three loci significantly associated with time-to-LiD onset. rs72673189 on chromosome 1 (HR = 2.77, SE = 0.18, P = 1.53 × 10 -8 ) located in the LRP8 locus, rs189093213 on chromosome 4 (HR = 3.06,, SE = 0.19, P = 2.81 × 10 -9 ) in the non-coding RNA LINC02353 locus, and rs180924818 on chromosome 16 (HR = 3.13, SE = 0.20, P = 6.27 × 10 -9 ) in the XYLT1 locus. Subsequent colocalization analyses on chromosome 1 identified DNAJB4 as a candidate gene associated with LiD through a change in gene expression. We computed a PRS based on our GWAS meta-analysis and found high accuracy to stratify between PD-LID and PD (AUC 83.9). We also performed a stepwise regression analysis for baseline features selection associated with LiD status. We found baseline anxiety status to be significantly associated with LiD (OR = 1.14, SE = 0.03, P = 7.4 × 10 -5 ). Finally, we performed a candidate variant analysis and found that genetic variability in ANKK1 ( rs1800497 , Beta = 0.24, SE = 0.09, P = 8.89 × 10 -3 ) and BDNF ( rs6265 , Beta = 0.19, SE = 0.10, P = 4.95 × 10 -2 ) loci were significantly associated with time to LiD in our large meta-analysis. Conclusion: In this association study, we have found three novel genetic variants associated with LiD, as well as confirming reports that variability in ANKK1 and BDNF loci were significantly associated with LiD probability. A PRS nominated from our time-to-LiD meta-analysis significantly differentiated between PD-LiD and PD. In addition, we have found female gender, young PD onset and anxiety to be significantly associated with LiD.

Network connectivity and structural correlates of survival in progressive supranuclear palsy and corticobasal syndrome.

There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.