Movement Disorders

BackgroundMelanocortin 1 receptor (MC1R) is a key regulator of pigmentation. Previous studies have linked MC1R loss-of-function variants to increased risk for Parkinsons disease (PD); however, whether they are associated with PD progression remains unknown. Using data from the Parkinsons Progression Markers Initiative (PPMI) cohort, we aimed to test whether MC1R loss-of-function variants, especially those previously associated with an increased risk of PD, are associated with PD progression and ...

BackgroundLoss of smell commonly predates the diagnosis of Parkinsons disease (PD). However, smell loss has multiple causes, and the relationship between idiopathic anosmia (IA) and PD remains incompletely understood. ObjectivesTo assess the presence of prodromal features of PD in individuals with IA and to examine the relationship between anosmia duration and prodromal features. MethodsWithin the PREDICT-PD study, patients with IA investigated at specialist smell clinics were compared with he...

BackgroundMisdiagnoses of multiple system atrophy (MSA) and Parkinsons disease (PD) remain common due to overlapping clinical features. ObjectiveTo develop and assess a skin -synuclein seed amplification assay (Syn-SAA) for detecting pathological -synuclein and distinguishing MSA from PD. MethodsIn this blinded, cross-sectional study conducted across two laboratories, 308 skin biopsies from 117 participants were analyzed using a standardized Syn-SAA protocol. The cohort included 42 PD, 31 MSA,...

ObjectiveTo evaluate whether the presence of orthostatic hypotension (OH) impacts the association between white matter hyperintensity (WMH) volume and motor symptom burden in persons with Parkinsons disease (PWP). MethodsMotor symptom burden in PWP was quantified using the Movement Disorders Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Part III. Total WMH volume was segmented based on high-resolution T1-weighted (T1W) and T2 Fluid Attenuated Inversion Recovery (FLAIR) images. Det...

IntroductionSex has emerged as a key factor shaping serum metabolomic profiles in idiopathic Parkinsons disease (PD). However, it remains unclear whether sex differences influence circulating metabolic signatures in patients with specific PD-related gene mutations compared to age-matched healthy controls (HCs). MethodsWe conducted an untargeted 1H NMR-based metabolomic analysis of serum in a clinically defined cohort of patients with genetic forms of PD (n = 119) and age- and sex-matched HCs (n...

BackgroundPrognosis and therapeutic management in Parkinsons disease remain challenging due to the diseases heterogeneous progression and symptom presentation and lack of reliable biomarkers to predict individual disease trajectories. ObjectiveTo determine whether baseline blood transcriptomes, analyzed through biologically defined pathway gene sets, contain signatures that distinguish distinct motor and non-motor progression trajectories in Parkinsons disease. MethodsUsing data from the Parki...

Body-first Lewy body disease (LBD) is hypothesized to begin in the peripheral autonomic nervous system, years before nigrostriatal involvement. Isolated REM sleep behaviour disorder (iRBD) is considered prodromal body-first LBD, but the duration of the prodromal phase remains unknown. We aimed to determine the progression rate of cardiac sympathetic denervation using [123I]meta-iodobenzylguanidine (MIBG) scintigraphy and employ the resulting curves to estimate the prodromal period of body-first ...

BackgroundAggregation of -synuclein is a central pathological feature of Parkinsons disease (PD), yet reliable and broadly applicable fluid biomarkers reflecting disease-relevant -synuclein biology remain limited. We aimed to establish acetylated -synuclein (Ac-Syn), the predominant proteoform in vivo, as a novel biomarker for PD and to evaluate its diagnostic utility based on a sensitive immunoassay. MethodsUsing a single molecule array technique capable of quantitatively detecting N-terminall...

BackgroundProgressive supranuclear palsy (PSP) is a rare and devastating tauopathy with limited global data. Given Indias large population, genetic diversity, and clinical heterogeneity, large multicenter datasets are crucial to enrich global understanding of PSP. ObjectiveTo characterize the demographic, clinical, and phenotypic profiles of a large multicenter Indian PSP cohort. MethodsSubjects fulfilling MDS-PSP criteria were prospectively recruited across movement disorders centers (2021-20...

Parkinsons disease genetics remain under-characterized in East Asians. We recruited a Taiwanese case-control cohort (2,245 PD; 2,147 controls), genotyped on the Illumina NeuroBooster Array, and imputed 7.6 million variants using the Taiwan Biobank reference. Logistic-regression GWAS identified genome-wide significant signals at SNCA and MCCC1; we also observed suggestive associations at GCH1, PPARGC1A and GALNT13. Haplotype analyses delineated an East Asian SNCA risk haplotype and confirmed effe...

Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal state for Lewy body disorders, with the highest likelihood of long-term conversion to a clinical diagnosis of either Parkinsons disease (PD) or dementia with Lewy bodies (DLB). There is heterogeneity in the neuropathophysiology of iRBD that may have prognostic significance regarding the ultimate clinical features, and previous research has not focused on iRBD biologically defined as having neuronal synuclein disease (NSD) ...

BackgroundThe SLC25A46 gene encodes a mitochondrial carrier protein previously implicated in neuropathy and optic atrophy. Biallelic variants in SLC25A46 have been described in patients with Parkinsons disease (PD) with optic atrophy, but the evidence supporting a role in PD remains limited. ObjectiveTo assess whether SLC25A46 variants contribute to PD, REM sleep behavior disorder (RBD), or Dementia with Lewy Bodies (DLB). MethodsWe examined common variants using four representative PD genome-...

Asymmetric arm swing reduction is a hallmark of early-stage Parkinsons disease (PD). We evaluated wrist sensor-based arm swing measures during free-living gait as digital progression biomarkers in 623 early-stage PD participants and 50 controls monitored continuously for one year (controls) or two years (PD). Biweekly measures were extracted from gait segments without other arm activities. Arm swing measures were reduced in PD, reduced on the most affected side, moderately correlated with clinic...

Mitochondrial single-nucleotide variants (mtSNVs) can dysregulate cellular bioenergetics and have been increasingly implicated in susceptibility to Parkinsons disease (PD). These variants may impair oxidative metabolism and respiratory chain efficiency, thus contributing to neuronal dysfunction and degeneration. In peripheral blood, mtSNVs may also reflect systemic immunometabolic alterations associated with PD; however, this aspect remains poorly explored, particularly in admixed populations wi...

Parkinsons disease (PD) is a complex neurodegenerative disorder with a substantial genetic influence. To better characterize the genetic landscape of PD in South Africa, we conducted the largest genetic screening to date for pathogenic single nucleotide and copy number variations (CNVs) using genotyping array data from 689 PD probands. We identified 16 unique missense variants, confirming 15 with Sanger sequencing, in 47 individuals across seven well-established PD genes, with GBA1 and PRKN bein...

IntroductionParkinsons disease (PD) affects females and males differently, with differences in prevalence, clinical phenotypes, and therapeutic response, suggesting that biological sex may influence the underlying molecular mechanisms of PD. The extent to which genetic factors may contribute to these differences remains largely unknown. ObjectiveTo investigate sex-specific autosomal genetic factors associated with PD risk. MethodsWe performed a sex-stratified autosomal GWAS meta-analysis lever...

Leucine-rich repeat kinase 2 (LRRK2) variants are the most common cause of inherited Parkinsons disease (PD), and the hyperactivity of the LRRK2 variants represent a validated drug target for PD. The penetration of common LRRK2 variants is incomplete, underscoring the need for molecular biomarkers that predict disease onset and guide therapeutics development. Here, we analyzed large datasets of cerebrospinal fluid (CSF) and urinary proteomics from the Parkinsons Progression Markers Initiative (P...

Environmental neurotoxins have been implicated in the pathogenesis of Parkinsons disease (PD), with Agent Orange (AO) recognized as a presumptive service-connected exposure among U.S. Veterans. However, prospective data examining potential clinical differences associated with AO exposure remain limited. We conducted a multicenter prospective cohort study of U.S. Veterans with PD to compare demographic and clinical characteristics between individuals with and without a history of AO exposure. Cl...

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to affecting motor neuron survival, SMN deficiency impacts multisystem physiology and neurotransmission. Dopaminergic dysfunction has been reported in mouse models of SMA, leading to postural and locomotor impairments that improve upon treatment with L-DOPA and benserazide. However, whether altered dopamine metabolism contributes to clinical sympto...

Parkinsons disease (PD) exhibits substantial clinical and molecular heterogeneity, driven in part by mutations in SNCA, GBA1 and LRRK2 genes. Understanding how these genetic subtypes differ in progression and peripheral transcriptomic profiles may inform personalized prognostic and therapeutic strategies. In this study, we aim to compare disease progression trajectories and blood-based gene expression patterns among SNCA-positive (SNCA+), GBA-positive (GBA+) and LRRK2-positive (LRRK2+), and spor...