Journal of Parkinson's Disease

Background: Freezing of gait (FOG) is a disabling and often underrecognized feature of Parkinsons disease (PD). Objective gait analysis may improve characterization of this motor symptom. Objective: To compare quantitative 3D gait parameters in PD with FOG (PDF) and PD without FOG (PDNF) in a routine clinical cohort. Methods: We retrospectively analyzed a sequential sample of 180 patients with PD referred for motion analysis between 2020 and 2024. All patients underwent 3D motion capture in the off-medication state. Eighteen gait outcomes spanning pace, rhythm, postural control, variability, and asymmetry domains were derived from steady-state walking tasks. FOG status was determined using physician documentation and Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) items. Group differences between PDF (n=99) and PDNF (n=81) were evaluated using independent samples t-tests, with outcomes adjusted for disease duration and corrected for multiple comparisons. A secondary analysis among PDF compared those in Hoehn and Yahr (H&Y) stage [≥]III to those in H&Y [≤]II. Results: PDF had longer disease duration, higher OFF MDS-UPDRS III scores, and higher Hoehn and Yahr stage than PDNF but were similar in age and sex. After adjusting for disease duration and multiplicity, PDF demonstrated reduced step length, stride length, and forward velocity, and greater cadence variability, while most postural control, and asymmetry measures were comparable between groups. Among PDF, advanced H&Y stage was associated with impaired pace and rhythm, similar to previous reports among PD in general. Conclusion: In this large, sequential, clinically referred cohort, FOG was associated with more advanced PD and specific impairments in pace and gait variability. These findings support comprehensive 3D gait analysis as an objective tool to better delineate FOG-related gait abnormalities and identify features that may predict FOG, informing targeted interventions.

Introduction: Parkinson's disease is a neurodegenerative disease affecting motor and cognitive function that has a major impact on society. Epidemiological evidence has suggested that the incidence of PD may be increasing; however, the underlying etiology is unclear. Here, we investigated the role of increasingly used antipsychotics in the diagnosis of PD. Methods: We harnessed Merative Marketscan insurance claims databases to conduct a case-control study of 65,275 new cases of PD and 652,364 age-, sex-, and time-matched controls. We estimated associations between exposure and duration of use for antipsychotics adjusted for important confounders using fixed effects logistic regression. We performed sensitivity analyses stratified by the level of D2 receptor inhibition to assess dose-response relationships; a lagged exposure analysis to address confounding by indication; analysis assessing exposure of other psychiatric medications without significant D2 inhibition (bupropion, trazodone, and Z-drugs); analysis assessing exposure of non-psychiatric medications with significant (metoclopramide) or no D2 inhibition (ondansetron). Results: We found cases with PD had elevated odds of antipsychotic exposure. Longer durations of exposure and greater affinity for the D2 receptor were associated with greater associations with PD. There was a dose-response relationship between D2 inhibition activity and increased odds of PD for a similar duration of exposure. There was a dose response relationship between duration of metoclopramide and the odds of PD; however, there was no such relationship between the non-D2 inhibiting control medications. The association between exposure to an antipsychotic and increased odds of PD was present even when the first exposure was 10 years prior to the PD diagnosis date. Conclusion: If these results are causal, antipsychotic use may explain up to 2.4% of all cases of PD. Given the increasing rate of use of these medications, and the concurrent increasing age-adjusted incidence of PD, there is an urgent need for further investigation into this association and greater awareness of the potential risks of these medications in older adults.

We investigated whether people with Parkinson's disease who are dual GBA1+LRRK2 carriers have a milder, LRRK2-like phenotype as previously reported. This was accomplished by comparing clinical features and alpha-synuclein seed amplification assay (SAA) positivity rates between dual GBA1+LRRK2-PD(n=13), GBA1-PD(n=169) and LRRK2-PD(n=175) carriers in a cross-sectional retrospective study of Parkinson's Progression Markers Initiative (PPMI) data. Our results show that GBA1+LRRK2-PD rate(83%) is closer to GBA1-PD rate(87%) rather than LRRK2-PD rate (62%mp-value>0.05). GBA1+LRRK2-PD have both non-motor and motor phenotypic similarity of GBA1-PD(p-value>0.05). This small PPMI cohort indicates that dual GBA1+LRRK2-PD carriers' SAA positivity and phenotype are aligned with GBA1-PD.

Background Sleep disturbances affect up to 60-80% of people with Parkinsons disease (PD) and are associated with worse clinical outcomes and reduced quality of life. Dyskinesia is a common motor complication of dopaminergic therapy, but its relationship with sleep quality remains incompletely defined. Methods Forty-seven people with PD (median age 68 years; 44.7% female; median disease duration 5 years; 38.3% from non-White ethnic background) were assessed for sleep quality on Pittsburgh Sleep Quality Index (PSQI). Dyskinesia was assessed using Movement Disorder Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Part IV items 4.1 and 4.2, and 7-day wearable monitoring with the Parkinsons KinetiGraph (PKG) to derive median dyskinesia score (DK_50) and fluctuation dyskinesia score (FDS). All analyses were conducted using multivariate regression. Associations with sleep quality were adjusted for age, sex, and disease severity (MDS-UPDRS Part III) in Model A; additionally for levodopa equivalent daily dose (LEDD) in Model B; and further for disease duration in Model C. Results In Model A, all four dyskinesia measures were significantly associated with sleep quality. After adjusting for LEDD in Model B, only DK_50 remained a significant predictor of worse sleep (B=0.18, 95CI: 0.003-0.357, P=0.047). With additional adjustment for disease duration in Model C, the association for DK_50 was attenuated (B=0.18, 95%CI: -0.001 to 0.356, P=0.051). Conclusions Wearable-derived continuous dyskinesia burden was independently associated with worse sleep quality, whereas clinician-rated dyskinesia was not, highlighting the added clinical value of objective motor monitoring in PD. Disease duration may partly confound this relationship. Larger prospective studies are warranted.

Background: Reliable biomarkers for Parkinson's disease (PD) pathology detection are essential for research. The alpha-synuclein (aSyn) seed amplification assay (SAA) is a validated biomarker for misfolded aSyn. Objectives: To assess the association between aSyn SAA and LRRK2-related PD (LRRK2-PD) and its link to mitochondrial genetic burden. Methods: We included N=76 LRRK2 p.Gly2019Ser variant carriers (N=22 affected, N=54 unaffected), N=714 patients with idiopathic PD (iPD), and N=411 controls from Norway. We analyzed cerebrospinal fluid (CSF)-based aSyn SAA in N=10 PD patients and N=30 unaffected LRRK2 p.Gly2019Ser carriers, alongside N=6 controls and N=56 iPD patients. A mitochondrial polygenic score (MGS) was derived from genotyping data, using PPMI as an additional cohort (iPD: N=355, LRRK2-PD: N=118). Results: Seeding was observed in 80% of patients with LRRK2-PD, and in one unaffected variant carrier (AUC=0.97, CI 0.92-1.00). In a meta-analysis across two PD cohorts, higher MGS was associated with increased aSyn seeding (pooled beta=0.38, p=0.028). Conclusions: CSF-based aSyn SAA can discriminate between LRRK2-PD and unaffected carriers. Our findings support an association with mitochondrial burden and aSyn seeding.

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) improves levodopa-induced motor complications and cardinal motor symptoms of Parkinson's disease (PD), but stimulation frequency may differentially shape outcomes. This is evident for axial and gait symptoms, which may respond differently to lower-frequency stimulation. Whether frequency-dependent effects extend to cognition remains unclear. Objective: To investigate the cognitive effects of DBS at distinct frequencies in PD. Methods: We conducted a systematic review and meta-analysis (PROSPERO - CRD42024618253). PubMed, Web of Science, and EMBASE were searched for studies assessing cognitive outcomes under different stimulation frequencies. Eight cognitive domains were defined: verbal fluency, cognitive flexibility, executive control, working memory, attention, processing speed, episodic memory, and time processing. Multilevel random-effects meta-analyses were performed, with effect sizes expressed as Hedges' g. Results: Forty-three studies met the inclusion criteria, the majority (n = 31) involving STN-DBS. Twenty-one STN-DBS studies, including 355 patients, were included in the meta-analysis. Compared with HFS ([≥] 130 Hz), lower frequencies (4-80 Hz) were associated with better verbal fluency (g = 0.27) and cognitive flexibility (g = 0.38), with consistent effects across sensitivity and leave-one-out analyses. Accuracy-based executive control measures also favored lower-frequency stimulation. OFF-stimulation comparisons showed a concordant pattern. Evidence for other targets (PPN and NBM) was limited. Conclusions: Lower-frequency STN-DBS was associated with modest benefits in specific cognitive domains compared with HFS. These findings highlight the need for future research to determine how frequency interacts with stimulation location and symptom-specific networks to shape cognitive and cognitive-motor outcomes in PD.

Background The global burden of Parkinson's disease (PD) has increased substantially over recent decades, driven by population ageing and rising age-standardized prevalence. In Africa, accurate estimates remain limited due to a lack of recent, methodologically robust population-based studies. Objectives To determine the current age-standardized and sex-specific prevalence rates of PD in Nigeria. Methods We conducted a 2-stage, cross-sectional population-based door-to-door survey among adults aged [≥]18 years in two densely populated urban local government areas in Lagos State, Nigeria, between April 1, 2024 and January 31, 2025. The first stage involved a household census and screening for parkinsonism using a standardized screening tool. The second stage consisted of in-person clinical assessment and diagnostic confirmation by physicians using established clinical diagnostic criteria. Crude and age-standardized prevalence rates (to the World Health Organization World Standard and European Standard Populations) were calculated. Results 31,009 individuals (52.7% female) from 13,222 households were surveyed, and 70 persons were diagnosed with PD. The crude prevalence ratio was 225.7 per 100,000, with higher prevalence in males (53/14658, 361.6) than females (17/16,351, 104.0). The age-standardized prevalence rate (95% confidence interval) was 193 per 100,000 (150 -- 245) (females: 86 (50 -- 137); males: 277 (207 -- 362)), and increased with advancing age. The diagnostic gap (previously undiagnosed) was 60.0% (42/70). Treatment gap (never treated) was 44/70 (62.9%). Conclusions The age-standardized prevalence of PD is higher than previously reported in sub-Saharan Africa. These findings provide contemporary data to inform updated estimates of disease burden and support health systems planning.

Background: Gait variability is a hallmark of Parkinson's disease (PD) and has been linked to cognitive deficits and fall risk. Rapid eye movement sleep behavior disorder (RBD) is a strong predictor of synucleinopathies, yet evidence for gait changes in RBD is inconsistent. Performing a dual task increases gait variability, an effect that can be quantified using a cost function. Objective: Determine the degree to which dual task cost differs between control, RBD, and PD participants at baseline, and between RBD converters versus non-converters at follow-up. Methods: 46 RBD, 23 control, and 14 PD participants completed standardized gait analysis at baseline. Parameters chosen for analysis included enhanced gait variability index (eGVI), functional ambulation performance (FAP), velocity, step length, cadence, base of support, and double support time. Medical records were surveilled for 3 years following participant enrollment, determining that 6 RBD participants converted to PD or dementia. Baseline gait indices and dual task costs were compared between control, RBD, and PD groups at enrollment, and between RBD stable and RBD converters at follow-up. Results: The PD group had greater eGVI, as well as greater dual task cost for FAP, cadence, width, and double support time. No differences in gait variability were identified between RBD and control groups at baseline. Compared to the stable group, RBD converters had greater dual task cost for FAP, velocity, cadence, and double support time. Conclusions: Increased gait variability during dual task may identify RBD patients at imminent risk of phenoconversion.

BackgroundEffective screening for Parkinson disease (PD) is important for both symptomatic treatment and recruitment into intervention trials. We recently developed a toolkit to quantify PD risk. Here, we examined the PREDIGT models diagnostic performance when deployed at home. MethodsWe contacted 613 subjects following outpatient clinic encounters. Between 2022-2024, 305 participants (range, 40-85 years) were recruited: 93 with typical PD; 66 had other neurological diseases (OND); 146 were neurologically healthy. Two versions of the toolkit were completed: First, an original, 69-item-long questionnaire paired with a 40-scent smell test; thereafter, a simplified, 11-item-long questionnaire and a newly developed, 8-scent smell test. PREDIGT summary scores were calculated for each subject to examine diagnostic classifications. Area-under-the-ROC-curve, sensitivity, specificity, and likelihood ratios were used to evaluate performances and to determine clinically relevant thresholds. ResultsIn both versions, PD patients had higher questionnaire scores and lower smell test scores than neurologically healthy controls (p<0.001); scores for OND subjects ranked at intermediate levels. The simplified questionnaire outperformed the original version in diagnostic accuracy. The abbreviated smell test performed as well as the 40-item version in identifying hyposmia. At a value of 22.94 (range 0-100) for the threshold that separates PD subjects from other participants, the simplified PREDIGT summary score showed a sensitivity of 0.98, a specificity of 0.83, and revealed positive and negative likelihood ratios of 5.88 and 0.02, respectively. InterpretationOur study reveals that unsupervised screening for typical PD can be effectively carried out at home using an 11-item questionnaire and 8-scent smell test.

Increased iron in the substantia nigra has been thought to be a mechanism potentially related to the etiology and/or progression of Parkinson's disease (PD). We hypothesized that genetic variants of HFE, a major iron regulatory gene, would influence substantia nigra iron accumulation in PD. The HFE genotype was obtained from 195 subjects (102 PD and 83 Controls) who participated in the PD biomarker program (PDBP) in central Pennsylvania, United States. For this study, carriers of two SNPs (HFE H63D and/or C282Y) were considered as variants and the others as wildtype. Susceptibility MRI metrics (QSM, R2*) were assessed at baseline, 18, and 36 months. The primary region of interest was the substantia nigra, the key pathology focus of PD. Group differences in substantia nigra QSM and R2* between HFE variants carriers and wildtype were compared between PD patients and controls at baseline and in progression over time using linear mixed-effects model. We also used interaction analyses to explore if HFE genotype impacts clinical measures of PD progression. Of the 102 PD patients, 72 were wildtype, and 30 HFE variant. Of the 83 controls, 56 were wildtype and 27 were HFE variants. There was a total of 451 data points available for analysis. Compared to wildtype patients, patients with HFE variants showed higher baseline substantia nigra QSM (p=0.006), but not higher R2* (p=0.487). Controls had no HFE-dependent differences. Longitudinally, substantia nigra QSM and R2* increased significantly over both 18- and 36-months regardless of HFE status (p's<0.05). Compared to wildtype, PD subjects with HFE variants showed an overall faster increase in R2* (p=0.004) and QSM (p=0.003) over the total 36-month epoch, and this reached the statistical significance for R2* during the first 18-months (p=0.026) and for QSM in 36-months (p=0.005). HFE status showed a significant interaction with motor scales [MDS-UPDRS II (p=0.006), III (p=0.0002)], suggesting a faster symptomatic progression in PD patients with HFE variants compared to wildtype. Although HFE genotype has been shown not to associate with the occurrence of PD, these data demonstrate for the first time that in PD patients substantia nigra iron accumulation and disease progression are affected by HFE genotype. The underlying mechanisms may be important in the progression of PD and the development of personalized treatment.

Abstract Background. Parkinson's disease (PD) is a progressive neurodegenerative disorder of increasing prevalence, with diagnostic accuracy of approximately 26% in early symptomatic patients. There is a need for accurate, non-invasive biomarkers to aid in disease diagnosis. Methods. This proof-of-concept study enrolled 90 participants (PD n = 30, other movement disorders [OM] n = 30, healthy controls [HC] n = 30) at a single institution. Participants completed two 10-minute eye-tracking sessions using the SaccadeDX 250 Hz binocular system. A two-level cascade classifier was fitted using elastic-net feature selection followed by logistic regression on the selected features, validated by 10-fold cross-validation. The cascade distinguished HC from movement disorders (Level 1) and PD from OM (Level 2), with the objective of establishing clinical validity that an eye-tracking signal correlates reliably with PD diagnosis. Results. Level 1 achieved an area under the curve (AUC) of 0.818 (95% CI: 0.71, 0.91), with a sensitivity of 83% and specificity of 63%. Level 2 achieved an AUC of 0.670 (95% CI: 0.52, 0.80), with a sensitivity of 68% and specificity of 63%. End-to-end PD detection achieved an AUC of 0.866 and an accuracy of 83.5%, meeting the prospectively specified accuracy threshold and the proof-of-concept AUC benchmark. Five adverse events were recorded (three cases of dizziness, one of nausea, and one of dry eyes); one participant withdrew from the study. Conclusions. Clinical validity is established: a reproducible eye-tracking signal for PD is detectable using a two-level cascade classifier. A multi-center confirmatory study is warranted before assessment of clinical utility.

Background Neuropsychiatric fluctuations in Parkinson's disease (PD) often accompany motor fluctuations, but their temporal relationship during the acute levodopa response remains unclear. Objectives To determine whether motor and neuropsychiatric responses occur synchronously during the OFF-to-ON transition. Methods Nineteen fluctuating PD patients underwent a high-resolution levodopa challenge with repeated assessments every 10 minutes for 60 minutes after levodopa administration. Motor symptoms (akinesia, rigidity) and neuropsychiatric fluctuations were quantified. Transition times (t25%-t50%-t75%-t100%) and response profiles were analyzed using correlation and clustering approaches. Results Motor and neuropsychiatric transition times were not correlated at any threshold (all FDR-corrected p>0.05; Bayes factors <1), supporting temporal dissociation. Among 18 patients with complete data, clustering revealed synchronous (6/18), neuropsychiatric-preceding (7/18), and motor-preceding (3/18) profiles. Conclusion Motor and neuropsychiatric responses to levodopa during PD fluctuations are partly independent and follow heterogeneous, patient-specific temporal profiles, supporting the search for distinct biomarkers and future individualized adaptative therapies

Background: Lysosomal dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD), particularly among GBA1 mutation carriers. Beyond GBA1, genes such as TMEM175, SCARB2, and CTSB identified in genome-wide association studies (GWAS) are also implicated in lysosomal pathways contributing to PD risk, although their functional effects in patients remain unclear. Proteins encoded by these lysosome-related genes have been explored as potential therapeutic targets in experimental models. Biomarker profiles, including clinical measures, alpha-synuclein seeding activity, lysosomal proteins, and sphingolipids, may facilitate patient stratification and support therapeutic monitoring in future clinical trials. Aim: The aim of this study is to investigate the impact of genetic variants of three lysosomal-related genes (TMEM175, SCARB2, and CTSB) on biomarker profiles in PD with and without GBA1 variants. Cross-sectional data from two German cohorts: the Tuebingen Parkinson Cohort (TUEPAC) and the DESCRIBE PD cohort of the German Center for Neurodegenerative Diseases were used as explorative cohorts, and data from Accelerating Medicines Partnership Parkinson's Disease (AMP-PD) were used as a validation cohort. The ultimate goal is to provide new data for patient stratification based on genetics, which might serve as a readout for target engagement and treatment efficiency assessment. Methods: Three cohorts were analyzed: TUEPAC, DESCRIBE PD, and AMP-PD. TUEPAC and DESCRIBE PD were combined into a single German discovery cohort (TUEPAC-DESCRIBE-PD), while AMP-PD served as an independent validation cohort. Within each cohort, for subgroup analyses, PD patients were classified as the overall PD cohort (PDall), and further stratified by GBA1 mutation status into PD patients without GBA1 mutations (PDGBA1_wildtype), and PD patients carrying GBA1 mutations (PDGBA1). We evaluated cognitive and motor function, as well as depression using the Montreal Cognitive Assessment (MoCA), Unified Parkinson Disease Rating Scale-part III (UPDRS III), and Beck Depression Inventory-II(BDI-II) scales. Analyzed biomarkers included CSF -syn seeding activity using seed amplification assay (SAA), CSF lysosomal protein levels of lysosomal integral membrane protein 2 (LIMP2), also known as SCARB2, cathepsin B (CTSB) and lysosome-associated membrane protein 2 (LAMP2), blood-based enzyme activity of the lysosomal glucocerebrosidase (GCase), and CSF sphingolipid profiles. PD patients carrying risk alleles in TMEM175, SCARB2, and CTSB were compared to non-carriers. Results: Genotype-phenotype correlation analysis in TUEPAC-DESCRIBE-PD and AMP-PD revealed: (1) In PDall, the TMEM175 p.M393T risk variant was nominally associated with decreased cognitive function when adjusted for GBA1 mutation status in TUEPAC-DESCRIBE-PD; this association could not be replicated, although a similar trend was observed in the slightly smaller, but multicentric AMP-PD cohort; TMEM175 p.M393T was not significantly associated with BDI-II or UPDRS-III scores in either cohort. (2) In PDGBA1_wildtype, GCase activity was significantly lower in PD patients with SCARB2 rs6812193 risk allele in TUEPAC-DESCRIBE-PD, while a similar but non-significant trend was observed in AMP-PD; (3) In PDall, CSF levels of CTSB were nominally lower in carriers of CTSB rs1293298 risk allele compared to carriers of CTSB rs1293298 protective allele in TUEPAC-DESCRIBE-PD; in PDGBA1_wildtype, LAMP2 was significantly lower in carriers of CTSB rs1293298 risk allele compared to carriers of CTSB rs1293298 protective allele in TUEPAC-DESCRIBE-PD; (4) In PDall, TMEM175 p.M393T risk allele was nominally associated with altered sphingolipid profiles across both TUEPAC-DESCRIBE-PD and AMP-PD cohorts. Conclusion: These findings demonstrate that genetic variants in lysosomal-related genes (TMEM175, SCARB2, and CTSB) have a functional impact on biomarker profiles in PD patients. Integrating genetic characterization with biochemical profiling provides a framework for patient stratification and may serve as a translational strategy to monitor target engagement and evaluate treatment efficacy in future clinical trials.

Objective To map national Parkinsons disease (PD) research capability to inform an inclusive delivery strategy for a large-scale clinical trial. Background Few people with PD participate in clinical trials, particularly from under-served populations. The Edmond J Safra Accelerating Clinical Trials in PD initiative (EJS ACT-PD) aims to deliver an inclusive multi-arm multi-stage (MAMS) disease modification PD trial. Methods A survey disseminated to National Health Service (NHS) hospitals assessed PD research capability regarding trial experience, rater expertise, trial facilities and specialist investigations. A process was developed to categorise sites into 3 tiers, with tier 1 having the least PD-research capability or experience, and tier 3 being experienced specialist centres. We mapped tiers to PD prevalence, social deprivation and ethnic diversity to identify infrastructure gaps. We developed trial delivery strategies to facilitate rapid and inclusive recruitment. Results Out of 97 survey responses, 43 sites were categorised as tier 1, 33 as tier 2 and 21 as tier 3. Diversity and social deprivation index were higher for tier 3 sites (predominantly urban). A greater proportion of tier 1 and 2 sites were situated in areas of higher PD prevalence (predominantly rural). Ninety one percent of sites reported experience with remote trial delivery methods. Our delivery strategy included: initial trial set-up at tier 3 sites to enable rapid and ethnically diverse recruitment; core funded staff within strategic sites to develop regional solutions for inclusive trial participation and to enable research opportunity provision in areas where currently very little exists, and a hybrid delivery model of in-person and remote study visits, ensuring maximal acceptability and deliverability. Conclusions The mapping of current PD research delivery capability has allowed us to develop a trial delivery strategy that will broaden the provision of research participation opportunity to under-served groups. It has also enabled existing infrastructure to be maximised while mitigating identified gaps.

In both preclinical and clinical studies, transfusions of plasma from young individuals have been reported to ameliorate aspects of neurodegeneration. This study was designed as a preliminary test of the hypothesis that plasma transfusions from young donors might benefit Parkinson's patients. 19 patients were allocated to receive either 2-liters of plasma from young donors, in two doses spaced two days apart, or two doses of placebo. For the next 24 weeks, this double-blind study evaluated changes on a modified MDS-UPDRS scale, along with blood tests and other observations. Adverse events possibly related to transfusion were mild rise in blood pressure and urticaria. A t-test on the changes in the sum of UPDRS subscales 1-3 showed that the plasma patients did better than the placebo patients (p = 0.03*). For patients given yFFP (young Fresh Frozen Plasma), the estimated decrease in the sum of scales 1-3 was 7.1 (95% conf. interval 4.3 to 9.9). Our results give a preliminary indication that young plasma transfusions reduce Parkinson's symptoms and have a place in treatment of these patients. (NCT 04202757).

Importance: The real-world prevalence and the clinical determinants associated with cognitive impairment in diverse patients with Parkinson disease (PD) have been understudied. Objective: To determine the prevalence of cognitive impairment in a diverse PD cohort and explore associations with vascular, motor, and nonmotor factors. Design, setting and participants: Case-only analysis of diverse patients with PD recruited to the East London Parkinson disease project (July 2022 to July 2025) at the Royal London Hospital, a tertiary referral center. Of 237 patients with cognitive status defined by expert, multi-disciplinary, clinical consensus, 223 remained after excluding atypical or secondary parkinsonism, other dementias, and study withdrawal. Exposures: Observational study (no experimental intervention); exposures included vascular risk factors, motor and nonmotor clinical features. Main Outcome(s) and Measure(s): The main outcome was cognitive impairment (PDCI), defined as mild cognitive impairment (PDMCI) or dementia (PDD) by expert clinical consensus based on clinical, imaging, and cognitive screening. Results: Among 223 participants with a median disease duration of 4.0 (1.0-9.0) years, 112 (50.2%) had PDCI, including 62 (27.8%) with PDD and 50 (22.4%) with PDMCI. South Asian ethnicity was associated with PDCI in univariate analysis (OR, 2.30; 95% CI, 1.32-4.00, P = .003) and the association strengthened after adjusting for age, gender, years of education, disease duration and depression scores (OR, 3.60; 95% CI, 1.68-7.69, P < .001). PDCI was associated with increased odds of smoking (OR, 3.62; 95% CI, 1.56-8.41, P = .003) in the adjusted model. Increased odds were also associated with motor severity (Movement Disorders Society Unified Parkinson Disease Rating Scale Part III; OR per point increase 1.07; 95% CI, 1.04-1.10; P < .001), and daytime somnolence score (Epworth Sleepiness Scale; OR per point increase, 1.08; 95% CI, 1.01-1.16; P = .03). Conclusions and Relevance: In this multi-ethnic study of PD using gold-standard expert multidisciplinary consensus, cognitive impairment was common and more prevalent among South Asian individuals. Smoking, greater motor severity, and higher daytime somnolence were associated with increased odds of cognitive impairment.

Purpose: The purpose of this study was to identify subgroups of talkers with Parkinsons disease (PD) with shared tongue, lip, and jaw articulatory amplitude behaviors. The study also sought to identify demographic and clinical features that can distinguish the identified kinematic subgroups. Methods: 53 talkers with PD and 54 controls participated. Articulatory amplitudes of the tongue, lip, and jaw were measured during a paragraph reading task using three-dimensional electromagnetic articulography. Amplitude performance profiles of the tongue, lip, and jaw were established for each talker with PD by referencing their performance to that of controls. These profiles were submitted to a hierarchical cluster analysis to identify kinematic-based subgroups. Amplitude performances were compared across subgroups to determine between-group patterns. Demographic and clinical features (e.g., age, sex, disease duration, selected perceptual speech characteristics, dysarthria severity) were compared across the identified kinematic subgroups. Results: Four main kinematic subgroups with differing amplitude performance profiles were identified. One subgroup exhibited normal to mildly exaggerated or mildly reduced amplitudes and was labeled preclinical subgroup (n = 16). Three subgroups exhibited pronounced amplitude reductions of either the tongue (n = 10), the tongue and lips (n = 12), or the tongue, lips, and jaw (n = 10). In addition, there were five talkers with PD whose performance profiles did not align with the identified four subgroups. Their performance was characterized by either pronounced amplitude exaggerations or mildly reduced jaw and lip amplitudes and exaggerated tongue amplitudes. None of the demographic or clinical features differed significantly between the main four subgroups. Conclusion: Findings suggest that the extent to which hypokinesia manifests within the articulatory subsystem can vary in talkers with PD. Longitudinal studies are needed to determine if these subgroups represent different stages of disease progression or distinctly different manifestations of the disease within the articulatory subsystem.

Background: PD GENEration (NCT04057794, NCT04994015), sponsored by the Parkinson's Foundation in partnership with Aligning Science Across Parkinson's (ASAP) through the Global Parkinson's Genetics Program (GP2), is an international, observational, clinical research study that offers genetic testing and counseling to people living with Parkinson's disease (PwP) at no cost. PD GENEration has aimed to empower PwP and their clinicians with knowledge of their genetic status, to accelerate recruitment into precision medicine trials, and to advance research through data sharing. Since its launch in 2019, the study has expanded to enroll over 32,000 PwP (as of March 31, 2026), from 10 countries across North, Central, and South America, the Caribbean, and Israel. Methods: Over the course of 6 years, PD GENEration has evolved to accommodate the growing scientific and research needs of the Parkinson's community while also increasing the ability to return genetic test results to PwP at a greater scale. Participants with a diagnosis of Parkinson's disease (PD) may enroll in-person or virtually where informed consent and blood sample collection can occur. Samples are analyzed at a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-certified laboratory using whole genome sequencing, with variants curated for a primary panel of seven PD-associated genes. Results are disclosed during a genetic counseling visit, where further testing is offered for two optional additional gene panels. Those who consent undergo analysis of additional genes, and results are returned during a genetic counseling visit for those that test positive for a variant. In addition to returning genetic results to PwP, a central pillar of the study design has been the open sharing of genomic data to advance discovery in PD research in partnership with ASAP and GP2. Discussion: PD GENEration applies a flexible framework, allowing for country specific considerations and the integration of multiple site models, evolving based on participant needs and the prioritization of equity and accessibility. We summarize PD GENEration's implementation and scaling, highlight key accomplishments and lessons learned, and provide guidance for those interested in implementing large-scale clinical genetic testing studies across other diseases and therapeutic domains.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is hypothesized to improve motor symptoms in Parkinson's disease (PD) by suppressing pathologically elevated beta activity and promoting "prokinetic" gamma activity in the cortico-basal ganglia-thalamo-cortical loop. Advances in bidirectional DBS devices have revealed that stimulation can modify gamma oscillations via subharmonic entrainment, though entrainment's therapeutic role remains unclear. Objectives: To identify stimulation parameters that entrain motor cortical and STN gamma oscillations in PD at rest and during movement, and examine their association with motor function. Methods: Sensorimotor cortex and STN field potentials were collected using a bidirectional DBS system in four subjects with PD over a range of stimulation amplitudes and frequencies. Entrainment amplitude at half the stimulation frequency was quantified at rest and during a finger-tapping task in the ON-medication state. The presence or absence of entrainment was studied as a physiomarker of motor symptom severity. Results: The amplitude of stimulation-entrained gamma oscillations was non-linearly related to stimulation intensity and frequency and varied by stimulation contact choice. Entrainment amplitude was highest in precentral gyrus and increased with movement. In the ON-medication state, precentral gyrus gamma entrainment was associated with reduced bradykinesia, dyskinesia, and dystonia. Subthalamic gamma entrainment predicted improved dystonia but was a less significant marker for motor benefit than cortical entrainment. Conclusions: Stimulation-entrained gamma oscillations in the motor network are a physiomarker for optimal DBS response in PD, and could have a role in physiology-guided DBS programming, complementing existing strategies based on suppression of basal ganglia beta activity.

ObjectiveTremor is a common motor symptom of Parkinsons disease (PD) that reduces quality of life. Cortico-cortical paired associative stimulation (ccPAS) is a transcranial magnetic stimulation protocol that induces connective associative plasticity between cortical regions. This study investigated the effects of ccPAS over supplementary motor area (SMA) and primary motor cortex (M1) on SMA-M1 facilitation and tremor severity in individuals with tremor-dominant PD. MethodsFourteen individuals with tremor-dominant PD (mean age 66.5 {+/-} 6.3 years; 5 females) received real and sham ccPAS in separate sessions. SMA-M1 activity and tremor severity were measured before and after ccPAS. Participants were tested OFF dopaminergic medication. ResultsSMA-M1 facilitation increased significantly after real but not sham ccPAS. There was no significant change in tremor severity after either real or sham ccPAS. Tremor severity was not associated with the change in SMA-M1 activity following ccPAS or with baseline SMA-M1 activity. ConclusionsccPAS can increase SMA-M1 facilitation in individuals with tremor-dominant PD. A single session of SMA-M1 ccPAS was insufficient in modulating tremor severity. SignificanceThis study provides preliminary evidence of significant increases in SMA-M1 facilitation from ccPAS in tremor-dominant PD OFF dopamine medication. Future research should explore ccPAS effects ON dopamine medication, and the effects of multi-session ccPAS.