omicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases.

Treatments for neurodegenerative disorders remain rare, but recent FDA approvals, such as lecanemab and aducanumab for Alzheimer disease (MIM: 607822), highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use summary-data-based Mendelian randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer disease, 3 amyotrophic lateral sclerosis (MIM: 105400), 5 Lewy body dementia (MIM: 127750), 46 Parkinson disease (MIM: 605909), and 9 progressive supranuclear palsy (MIM: 601104) target genes passing multiple test corrections (pSMR_multi < 2.95 × 10-6 and pHEIDI > 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics, classifying 41 novel targets, 3 known targets, and 115 difficult targets (of these, 69.8% are expressed in the disease-relevant cell type from single-nucleus experiments). Our novel class of genes provides a springboard for new opportunities in drug discovery, development, and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as riluzole in Alzheimer disease. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community.

Increased CSF DOPA Decarboxylase Correlates with Lower DaT-SPECT Binding: Analyses in Biopark and PPMI Cohorts.

BACKGROUND: Recent studies identified increased cerebrospinal fluid (CSF) DOPA decarboxylase (DDC) as a promising biomarker for parkinsonian disorders, suggesting a compensation to dying dopaminergic neurons. A correlation with 123I-FP-CIT-SPECT (DaT-SPECT) imaging could shed light on this link. OBJECTIVE: The objective is to assess the relationship between CSF DDC levels and DaT-SPECT binding values. METHODS: A total of 51 and 72 Parkinson's disease (PD) subjects with available DaT-SPECT and CSF DDC levels were selected from the PPMI and Biopark cohorts, respectively. DDC levels were analyzed using proximity extension assay and correlated with DaT-SPECT striatal binding ratios (SBR). All analyses were corrected for age and sex. RESULTS: CSF DDC levels in PD patients correlated negatively with DaT-SPECT SBR in both putamen and caudate nucleus. Additionally, SBR decreased with increased DDC levels over time in PD patients. CONCLUSION: CSF DDC levels negatively correlate with DaT-SPECT SBR in levodopa-treated PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.

BACKGROUND: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. OBJECTIVES: Our goal was to investigate the effects of genetic variants on risk and time to LID. METHODS: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. RESULTS: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147). CONCLUSIONS: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genetic risk factor clustering within and across neurodegenerative diseases.

Overlapping symptoms and co-pathologies are common in closely related neurodegenerative diseases (NDDs). Investigating genetic risk variants across these NDDs can give further insight into disease manifestations. In this study we have leveraged genome-wide single nucleotide polymorphisms and genome-wide association study summary statistics to cluster patients based on their genetic status across identified risk variants for five NDDs (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia and frontotemporal dementia). The multi-disease and disease-specific clustering results presented here provide evidence that NDDs have more overlapping genetic aetiology than previously expected and how neurodegeneration should be viewed as a spectrum of symptomology. These clustering analyses also show potential subsets of patients with these diseases that are significantly depleted for any known common genetic risk factors suggesting environmental or other factors at work. Establishing that NDDs with overlapping pathologies share genetic risk loci, future research into how these variants might have different effects on downstream protein expression, pathology and NDD manifestation in general is important for refining and treating NDDs.

Large-scale rare variant burden testing in Parkinson's disease.

Parkinson's disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson's disease. To address this gap, we investigated the rare genetic component of Parkinson's disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson's disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson's disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson's disease. To date, this is the largest analysis of rare genetic variants in Parkinson's disease.

A cross-sectional study of α-synuclein seed amplification assay in Alzheimer's disease neuroimaging initiative: Prevalence and associations with Alzheimer's disease biomarkers and cognitive function.

INTRODUCTION: Alzheimer's disease (AD) pathology is defined by ß-amyloid (Aß) plaques and neurofibrillary tau, but Lewy bodies (LBs; 𝛼-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed. METHODS: A validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aß and tau biomarkers, risk-factors, genetics, and cognitive trajectories. RESULTS: SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aß burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive. DISCUSSION: SAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression. HIGHLIGHTS: SAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aß burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.

Intra- and inter-hemispheric network dynamics supporting object recognition and speech production.

We built normative brain atlases that animate millisecond-scale intra- and inter-hemispheric white matter-level connectivity dynamics supporting object recognition and speech production. We quantified electrocorticographic modulations during three naming tasks using event-related high-gamma activity from 1,114 nonepileptogenic intracranial electrodes (i.e., non-lesional areas unaffected by epileptiform discharges). Using this electrocorticography data, we visualized functional connectivity modulations defined as significant naming-related high-gamma modulations occurring simultaneously at two sites connected by direct white matter streamlines on diffusion-weighted imaging tractography. Immediately after stimulus onset, intra- and inter-hemispheric functional connectivity enhancements were confined mainly across modality-specific perceptual regions. During response preparation, left intra-hemispheric connectivity enhancements propagated in a posterior-to-anterior direction, involving the left precentral and prefrontal areas. After overt response onset, inter- and intra-hemispheric connectivity enhancements mainly encompassed precentral, postcentral, and superior-temporal (STG) gyri. We found task-specific connectivity enhancements during response preparation as follows. Picture naming enhanced activity along the left arcuate fasciculus between the inferior-temporal and precentral/posterior inferior-frontal (pIFG) gyri. Nonspeech environmental sound naming augmented functional connectivity via the left inferior longitudinal and fronto-occipital fasciculi between the medial-occipital and STG/pIFG. Auditory descriptive naming task enhanced usage of the left frontal U-fibers, involving the middle-frontal gyrus. Taken together, the commonly observed network enhancements include inter-hemispheric connectivity optimizing perceptual processing exerted in each hemisphere, left intra-hemispheric connectivity supporting semantic and lexical processing, and inter-hemispheric connectivity for symmetric oral movements during overt speech. Our atlases improve the currently available models of object recognition and speech production by adding neural dynamics via direct intra- and inter-hemispheric white matter tracts.

Genome-Wide Meta-Analysis of Cerebrospinal Fluid Biomarkers in Alzheimer's Disease and Parkinson's Disease Cohorts.

BACKGROUND: Amyloid-ß, phosphorylated tau (p-tau), and total tau (t-tau) in cerebrospinal fluid are established biomarkers for Alzheimer's disease (AD). In other neurodegenerative diseases, such as Parkinson's disease (PD), these biomarkers have also been found to be altered, and the molecular mechanisms responsible for these alterations are still under investigation. Moreover, the interplay between these mechanisms and the diverse underlying disease states remains to be elucidated. OBJECTIVE: To investigate genetic contributions to the AD biomarkers and assess the commonality and heterogeneity of the associations per underlying disease status. METHODS: We conducted genome-wide association studies (GWASs) for the AD biomarkers on subjects from the Parkinson's Progression Markers Initiative, the Fox Investigation for New Discovery of Biomarkers, and the Alzheimer's Disease Neuroimaging Initiative, and meta-analyzed with the largest AD GWAS. We tested heterogeneity of associations of interest between different disease statuses (AD, PD, and control). RESULTS: We observed three GWAS signals: the APOE locus for amyloid-ß, the 3q28 locus between GEMC1 and OSTN for p-tau and t-tau, and the 7p22 locus (top hit: rs60871478, an intronic variant for DNAAF5, also known as HEATR2) for p-tau. The 7p22 locus is novel and colocalized with the brain DNAAF5 expression. Although no heterogeneity from underlying disease status was observed for the earlier GWAS signals, some disease risk loci suggested disease-specific associations with these biomarkers. CONCLUSIONS: Our study identified a novel association at the intronic region of DNAAF5 associated with increased levels of p-tau across all diseases. We also observed some disease-specific genetic associations with these biomarkers. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

Long-Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease.

BACKGROUND: Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants. OBJECTIVES: To identify complex structural variants in PRKN using long-read sequencing. METHODS: We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole-genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP-PD) and United Kingdom (UK)-Biobank datasets. RESULTS: Multiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long-read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression. CONCLUSIONS: This is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long-read sequencing for structural variant analysis in unresolved young-onset PD cases. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Developmental organization of neural dynamics supporting auditory perception.

PURPOSE: A prominent view of language acquisition involves learning to ignore irrelevant auditory signals through functional reorganization, enabling more efficient processing of relevant information. Yet, few studies have characterized the neural spatiotemporal dynamics supporting rapid detection and subsequent disregard of irrelevant auditory information, in the developing brain. To address this unknown, the present study modeled the developmental acquisition of cost-efficient neural dynamics for auditory processing, using intracranial electrocorticographic responses measured in individuals receiving standard-of-care treatment for drug-resistant, focal epilepsy. We also provided evidence demonstrating the maturation of an anterior-to-posterior functional division within the superior-temporal gyrus (STG), which is known to exist in the adult STG. METHODS: We studied 32 patients undergoing extraoperative electrocorticography (age range: eight months to 28 years) and analyzed 2,039 intracranial electrode sites outside the seizure onset zone, interictal spike-generating areas, and MRI lesions. Patients were given forward (normal) speech sounds, backward-played speech sounds, and signal-correlated noises during a task-free condition. We then quantified sound processing-related neural costs at given time windows using high-gamma amplitude at 70-110 Hz and animated the group-level high-gamma dynamics on a spatially normalized three-dimensional brain surface. Finally, we determined if age independently contributed to high-gamma dynamics across brain regions and time windows. RESULTS: Group-level analysis of noise-related neural costs in the STG revealed developmental enhancement of early high-gamma augmentation and diminution of delayed augmentation. Analysis of speech-related high-gamma activity demonstrated an anterior-to-posterior functional parcellation in the STG. The left anterior STG showed sustained augmentation throughout stimulus presentation, whereas the left posterior STG showed transient augmentation after stimulus onset. We found a double dissociation between the locations and developmental changes in speech sound-related high-gamma dynamics. Early left anterior STG high-gamma augmentation (i.e., within 200 ms post-stimulus onset) showed developmental enhancement, whereas delayed left posterior STG high-gamma augmentation declined with development. CONCLUSIONS: Our observations support the model that, with age, the human STG refines neural dynamics to rapidly detect and subsequently disregard uninformative acoustic noises. Our study also supports the notion that the anterior-to-posterior functional division within the left STG is gradually strengthened for efficient speech-sound perception after birth.

Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease.

OBJECTIVE: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide 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. METHODS: In an effort to study sex-specific genetic factors associated with PD, we explored 2 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. RESULTS: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). INTERPRETATION: 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 cases 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 female patients. ANN NEUROL 2021;90:41-48.

A population scale analysis of rare SNCA variation in the UK Biobank.

Parkinson's disease (PD) is a complex neurodegenerative disease with a variety of genetic and environmental factors contributing to disease. The SNCA gene encodes for the alpha-synuclein protein which plays a central role in PD, where aggregates of this protein are one of the pathological hallmarks of disease. Rare point mutations and copy number gains of the SNCA gene have been shown to cause autosomal dominant PD, and common DNA variants identified using Genome-Wide Association Studies (GWAS) are a moderate risk factor for PD. The UK Biobank is a large-scale population prospective study including ~500,000 individuals that has revolutionized human genetics. Here we assessed the frequency of SNCA variation in this cohort and identified 30 subjects carrying variants of interest including duplications (n = 6), deletions (n = 6) and large complex likely mosaic events (n = 18). No known pathogenic missense variants were identified. None of these subjects were reported to be a PD case, although it is possible that these individuals may develop PD at a later age, and whilst three had known prodromal features, these did not meet defined clinical criteria for being considered 'prodromal' cases. Seven of the 18 large complex carriers showed a history of blood based cancer. Overall, we identified copy number variants in the SNCA region in a large population based cohort without reported PD phenotype and symptoms. Putative mosaicism of the SNCA gene was identified, however, it is unclear whether it is associated with PD. These individuals are potential candidates for further investigation by performing SNCA RNA and protein expression studies, as well as promising clinical trial candidates to understand how duplication carriers potentially escape PD.

The Parkinson's Disease DNA Variant Browser.

BACKGROUND: Parkinson's disease (PD) is a genetically complex neurodegenerative disease with ~20 genes known to contain mutations that cause PD or atypical parkinsonism. Large-scale next-generation sequencing projects have revolutionized genomics research. Applying these data to PD, many genes have been reported to contain putative disease-causing mutations. In most instances, however, the results remain quite limited and rather preliminary. Our aim was to assist researchers on their search for PD-risk genes and variant candidates with an easily accessible and open summary-level genomic data browser for the PD research community. METHODS: Sequencing and imputed genotype data were obtained from multiple sources and harmonized and aggregated. RESULTS: In total we included a total of 102,127 participants, including 28,453 PD cases, 1650 proxy cases, and 72,024 controls. CONCLUSIONS: We present here the Parkinson's Disease Sequencing Browser: a Shiny-based web application that presents comprehensive summary-level frequency data from multiple large-scale genotyping and sequencing projects https://pdgenetics.shinyapps.io/VariantBrowser/. Published © 2021 This article is a U.S. Government work and is in the public domain in the USA. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Accelerating Medicines Partnership: Parkinson's Disease. Genetic Resource.

BACKGROUND: Whole-genome sequencing data are available from several large studies across a variety of diseases and traits. However, massive storage and computation resources are required to use these data, and to achieve sufficient power for discoveries, harmonization of multiple cohorts is critical. OBJECTIVES: The Accelerating Medicines Partnership Parkinson's Disease program has developed a research platform for Parkinson's disease (PD) that integrates the storage and analysis of whole-genome sequencing data, RNA expression data, and clinical data, harmonized across multiple cohort studies. METHODS: The version 1 release contains whole-genome sequencing data derived from 3941 participants from 4 cohorts. Samples underwent joint genotyping by the TOPMed Freeze 9 Variant Calling Pipeline. We performed descriptive analyses of these whole-genome sequencing data using the Accelerating Medicines Partnership Parkinson's Disease platform. RESULTS: The clinical diagnosis of participants in version 1 release includes 2005 idiopathic PD patients, 963 healthy controls, 64 prodromal subjects, 62 clinically diagnosed PD subjects without evidence of dopamine deficit, and 705 participants of genetically enriched cohorts carrying PD risk-associated GBA variants or LRRK2 variants, of whom 304 were affected. We did not observe significant enrichment of pathogenic variants in the idiopathic PD group, but the polygenic risk score was higher in PD both in nongenetically enriched cohorts and genetically enriched cohorts. The population analysis showed a correlation between genetically enriched cohorts and Ashkenazi Jewish ancestry. CONCLUSIONS: We describe the genetic component of the Accelerating Medicines Partnership Parkinson's Disease platform, a solution to democratize data access and analysis for the PD research community. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article is a U.S. Government work and is in the public domain in the USA.

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

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

Differences in the Presentation and Progression of Parkinson's Disease by Sex.

BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.

Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia.

Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

Long-term satisfaction after extraoperative invasive EEG recording.

This retrospective cohort study investigated 53 patients with drug-resistant focal epilepsy and identified factors predictive of long-term satisfaction of patients and families following extraoperative intracranial EEG (iEEG) recording. The mixed model analysis assessed the utility of intracranial EEG (iEEG) predictor variables, including the seizure-onset zone (SOZ), modulation index (MI), and naming-related high-gamma activity. Modulation index, quantifying the coupling between high-frequency activity at >80 Hz and local slow wave at 3-4 Hz, effectively functions as a surrogate marker of the burden of interictal spike-and-slow-wave discharges. The mixed model specifically incorporated 'subtraction-MI', defined as the subtraction of mean z-score normalized MI across all preserved sites from that across all resected sites. Auditory naming-related high-gamma activity at 70-110 Hz is a biomarker to characterize the underlying language and speech function. The model incorporated 'maximum resected high-gamma', defined as the high-gamma percent change largest among sites included in the resected language-dominant hemispheric region. The model also incorporated the clinical and imaging profiles of given patients. The analysis revealed that complete removal of SOZ (p = 0.003) and younger patient age (p = 0.040) were independently associated with greater satisfaction. Neither 'subtraction-MI' nor 'maximum naming-related high-gamma' showed a significant and independent association with long-term satisfaction in our patient cohort. The observed impact of complete resection of SOZ and early surgery can be considered when counseling candidates for epilepsy surgery.

Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson's disease.

BACKGROUND: Classical randomisation of clinical trial patients creates a source of genetic variance that may be contributing to the high failure rate seen in neurodegenerative disease trials. Our objective was to quantify genetic difference between randomised trial arms and determine how imbalance can affect trial outcomes. METHODS: 5851 patients with Parkinson's disease of European ancestry data and two simulated virtual cohorts based on public data were used. Data were resampled at different sizes for 1000 iterations and randomly assigned to the two arms of a simulated trial. False-negative and false-positive rates were estimated using simulated clinical trials, and per cent difference in genetic risk score (GRS) and allele frequency was calculated to quantify variance between arms. RESULTS: 5851 patients with Parkinson's disease (mean (SD) age, 61.02 (12.61) years; 2095 women (35.81%)) as well as simulated patients from virtually created cohorts were used in the study. Approximately 90% of the iterations had at least one statistically significant difference in individual risk SNPs between each trial arm. Approximately 5%-6% of iterations had a statistically significant difference between trial arms in mean GRS. For significant iterations, the average per cent difference for mean GRS between trial arms was 130.87%, 95% CI 120.89 to 140.85 (n=200). Glucocerebrocidase (GBA) gene-only simulations see an average 18.86%, 95% CI 18.01 to 19.71 difference in GRS scores between trial arms (n=50). When adding a drug effect of -0.5 points in MDS-UPDRS per year at n=50, 33.9% of trials resulted in false negatives. CONCLUSIONS: Our data support the hypothesis that within genetically unmatched clinical trials, genetic heterogeneity could confound true therapeutic effects as expected. Clinical trials should undergo pretrial genetic adjustment or, at the minimum, post-trial adjustment and analysis for failed trials.

Penetrance of Parkinson's Disease in LRRK2 p.G2019S Carriers Is Modified by a Polygenic Risk Score.

BACKGROUND: Although the leucine-rich repeat kinase 2 p.G2019S mutation has been demonstrated to be a strong risk factor for PD, factors that contribute to penetrance among carriers, other than aging, have not been well identified. OBJECTIVES: To evaluate whether a cumulative genetic risk identified in the recent genome-wide study is associated with penetrance of PD among p.G2019S mutation carriers. METHODS: We included p.G2019S heterozygote carriers with European ancestry in three genetic cohorts in which the mutation carriers with and without PD were selectively recruited. We also included the carriers from two data sets: one from a case-control setting without selection of mutation carriers and the other from a population sampling. Associations between polygenic risk score constructed from 89 variants reported recently and PD were tested and meta-analyzed. We also explored the interaction of age and PRS. RESULTS: After excluding eight homozygotes, 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34; 95% confidence interval: [1.09, 1.64] per +1 standard deviation; P = 0.005). In addition, associations with polygenic risk score and penetrance were stronger in the younger participants (main effect: odds ratio 1.28 [1.04, 1.58] per +1 standard deviation; P = 0.022; interaction effect: odds ratio 0.78 [0.64, 0.94] per +1 standard deviation and + 10 years of age; P = 0.008). CONCLUSIONS: Our results suggest that there is a genetic contribution for penetrance of PD among p.G2019S carriers. These results have important etiological consequences and potential impact on the selection of subjects for clinical trials. © 2020 International Parkinson and Movement Disorder Society.