Parkinsonism & Related Disorders

Background: Parkinson's disease is a progressive neurodegenerative condition, often associated with motor complications, neuropsychiatric symptoms, and increased care costs in advanced stages. Neuromodulation, especially deep brain stimulation, represents a therapeutic alternative for selected patients. Objective: To characterize the clinical, epidemiological, therapeutic, and economic profile of patients with Parkinson's disease followed at a tertiary center and to estimate the proportion of individuals eligible for neuromodulation. Methods: A cross-sectional descriptive study included 4,060 patients with idiopathic Parkinson disease followed from January 2022 to December 2025. Demographic data, clinical characteristics, functional scales, therapeutic regimen, eligibility criteria for neuromodulation, and cost-effectiveness estimates were analyzed. Comparisons with data from the literature were performed using appropriate statistical tests, considering a significance of p<0.05. Results: The sample was predominantly male, with a median age of 69 years, and a median time of evolution of 8 years. Motor complications occurred in 58.4% of the patients, a frequency higher than that described in general populations. In all, 893 patients were considered eligible for neuromodulation, corresponding to 22.0% of the sample. The economic analysis estimated a reduction in annual costs after neuromodulation, with an average saving of R$ 8,247 per patient/year and an incremental cost-effectiveness ratio of R$ 46,505 per QALY. Conclusion: The study population presented a clinical profile compatible with advanced Parkinson's disease, a high frequency of motor complications and a significant proportion of patients potentially eligible for neuromodulation. The data suggest a possible clinical and economic benefit of the structured incorporation of this therapeutic strategy.

Background: Huntington's disease (HD) is an inherited neurodegenerative disorder primarily associated with motor and psychiatric manifestations. No disease-modifying treatment currently exists, with vesicular monoamine transporter type-2 inhibitors (VMAT2i's) being the only FDA-approved therapy for motor features in HD. Previous studies evaluated the antichorea effects of VMAT2i's but did not address its effects on non-choreiform features. Objectives: This study aimed to characterize the effect of VMAT2i's on hyperkinetic, hypokinetic and total hypokinetic subscores of the UHDRS motor assessment in patients with motor-manifest HD from the Enroll-HD research platform. Methods: Data from 622 participants were analyzed. Linear mixed effects models were constructed to compare the rates of change of choreiform and non-choreiform motor scores before and after the initiation of a VMAT2i. We calculated and plotted the direction, magnitude and significance of VMAT2i administration on the rates of change of motor subscores. A similar analysis was performed investigating the effect of antipsychotic medications on motor subscales in HD. Results: VMAT2i's reversed progression of hyperkinesis but significantly increased the rates of change in the hypokinetic and total hypokinetic subscores. Antipsychotics also displayed efficacy in reversing progression of chorea but did not significantly influence progression of hypokinesis. Conclusions: The initiation of VMAT2i's was associated with an improvement in hyperkinesis but was associated with worsening of other motor features of HD. Hypokinesis increases progressively in HD and is correlated with functional impairment and global decline. Therefore, the use of VMAT2i's to treat motor features in HD should be a nuanced decision, considering its multipronged impact.

Background: Levodopa is time-critical in hospitalized Parkinson disease. Whether dosing fidelity depends on care setting or documented access status is unclear. Objectives: To quantify levodopa dosing fidelity, test ICU exposure with clustering-aware methods, and test whether documented access type is associated with delayed or omitted dosing. Methods: Retrospective cohort study using MIMIC-IV (2011-2022). Adults with Parkinson disease and [&ge;]1 scheduled levodopa dose contributed 1,665 admissions and 39,322 doses. ICU exposure was tested with a patient-clustered GEE model. Among ICU-exposed doses, access type (normal, tube feeding, parenteral nutrition, NPO) was modeled in one fully adjusted model and tested for specificity, restricted to the ICU, against an active-comparator medication (statins). Results: Of 39,322 doses, 79.8% were on time by the primary 60-minute definition; a symmetric {+/-}15-minute definition classified 68.8% as mistimed. ICU exposure was not associated with delayed or omitted dosing after clustering (patient-clustered OR, 0.87; 95% CI, 0.74-1.01). Among ICU-exposed doses, NPO was associated with delayed or omitted dosing (adjusted OR, 1.89; 95% CI, 1.36-2.62) and tube feeding with lower odds (adjusted OR, 0.62; 95% CI, 0.42-0.92; P < .001). The comparator medication showed a directionally consistent but inconclusive interaction (OR, 1.27-1.28; 92 patients). A route-order association was not observed among immediate-release formulations (OR, 0.72; 4 patients). Conclusions: ICU admission alone was not associated with dosing unreliability after clustering. Among ICU-exposed doses, access type, not a single pooled category, was associated with dosing reliability; a comparator-medication check, valid only in the ICU, was directionally consistent but inconclusive.

We report here, based on Parkinson's Progression Markers Initiative (PPMI) data, on the Cerebrospinal Fluid (CSF) profile of a group of 12 Parkinson's Disease (PD) subjects with the prototypical p.A53T SNCA mutation, comparing them to 36 matched Healthy Controls (HCs) and 36 idiopathic PD (iPD) cases. We furthermore assessed the CSF profile of 7 asymptomatic carriers of this mutation. There was no significant difference between the 3 groups of A53T-PD, HC and iPD in total alpha synuclein (a-syn) levels, beta-amyloid 1-42, total-Tau and p-Tau, although A53T-PD subjects tended to have slightly lower beta-amyloid 1-42, total-Tau and especially total a-syn levels. All A53T-PD cases had a positive CSF a-syn Seeding Amplification Assay (SAA). Four out of 7 asymptomatic carriers also had a positive SAA, in 3 without motor symptoms or signs and absence of clear prodromal manifestations. Conversion to motoric manifestations has occurred in one out of these 3 subjects, 8 years after SAA positivity, while one other subject only has hyposmia 8 years later. Overall, these results indicate that at least in early stages of PD, CSF Alzheimer's Disease profiles are not significantly different in A53T-PD compared to HCs or iPD, while the CSF a-syn SAA is universally positive in this group. Furthermore, the assay may be positive in asymptomatic carriers at a time with no prodromal manifestations and many years before motor disease onset, opening a window into very early stages of disease pathobiology and opportunities for early therapeutic intervention.

Background: Common side effects of dopamine replacement therapy (DRT) for Parkinson's Disease (PD) are addiction-like impulse control disorders, including compulsive gambling. Gambling products such as slot machines prominently feature reward-paired audiovisual stimuli, which can promote riskier choices on laboratory gambling tasks in both humans and rodents. In rats, risky decision making in the presence of reward-paired cues is dependent on dopamine D3 receptor activity and is increased by ropinirole, a D2/3 receptor agonist with a higher affinity for D3 receptors. In humans, it remains uncertain whether cue-induced risky choice is amplified by dopamine agonism. Methods: We tested effects of DRT on cue-induced risky choice in 62 patients with PD (34 on levodopa monotherapy, 27 on levodopa and dopamine agonists). Patients performed two versions of a risky decision-making task: one with and one without reward-paired sensory cues, both ON and OFF DRT. A group of 36 age-matched controls completed the same task versions without DRT. Results: Across all groups, participants made riskier choices when the task included reward-paired sensory cues. Levodopa monotherapy did not affect risky decision-making. However, a combination of levodopa and dopamine agonists increased risky choices specifically in the uncued version of the task, making performance indistinguishable from that on the cued task. Conclusions: Dopamine agonists combined with levodopa promote risk-taking even in the absence of reward-paired cues. This could translate into risky reward-seeking behaviors that are decoupled from contextual factors.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's Disease (PD), but identifying optimal stimulation contacts is time-intensive. Beta-band activity (13-35 Hz) from local field potentials (LFP) correlates with motor symptoms and attenuation by dopaminergic therapy and DBS supports its role as a programming biomarker. The recently introduced Electrode Identifier (EI) feature of Medtronic PerceptTM neurostimulators may facilitate beta-guided contact selection. Objective: To evaluate whether pseudo-monopolar STN beta power obtained using EI predicts optimal stimulation contacts and compare its performance with reconstructed bipolar recordings and MPR. Methods: LFPs were recorded in 69 patients using EI and Electrode Survey (ES). Prediction accuracy was assessed using predefined ranking rules and compared with clinically selected contacts. Agreement between EI, ES, and MPR was evaluated. Motor outcome was assessed using MDS-UPDRS-III. Results: EI predicted clinically selected contacts above chance (TOP1: 45%, p = 0.010; TOP2-80: 57%, p = <0.001), whereas ES exceeded chance only under more inclusive selection criteria (TOP1: 38%, p = 0.073; TOP2-80: 55%, p = 0.0021). Accuracy did not differ between methods (TOP1: p = 0.720; TOP2-80: p = 1.000). EI showed highest agreement with MPR and tended to select ventral contacts. Neither method predicted motor outcome, although EI-matched contacts showed a trend toward greater improvement. Due to technical constraints, one-third of EI recordings were excluded. Conclusions: Pseudo-monopolar STN beta power provides clinically relevant information for DBS contact selection with performance comparable to bipolar approaches. Further improvements are needed before clinical implementation.

Background: Lysosomal dysfunction has been implicated in Parkinson's disease (PD) pathogenesis. However, lysosomal polygenic risk scores (lyso-PRS) have not been evaluated extensively in PD across populations. Objectives: (1) Evaluation of lyso-PRS (lyso-PRS) performance for PD risk across populations; (2) Comparison of lyso-PRS across idiopathic PD (iPD), GBA1-PD, non-manifesting GBA1 carriers (NMC), and healthy controls (HC) in the European population. (3) Assessment of the lyso-PRS association with clinical outcomes in the PD patients of European population. Methods: We analyzed Neurobooster array data from the Global Parkinson's Genetics Program (GP2) dataset, including 32,054 iPD cases and 18,188 healthy controls across ten ancestries. Results: (1) lyso-PRS performed best in Europeans (European-GP2 test cohort: AUC = 0.602, p = 2.02e-172; European-TUEPAC validation cohort: AUC = 0.632, p = 5.34e-20) and worse in other populations (AUC: 0.51-0.59, p<0.05). (2) In the European population, the lyso-PRS distinguished GBA1-PD from HC (AUC = 0.621, p = 7.83e-71) and from NMC (AUC = 0.621, p = 1.05e-18). (3) In the European-GP2 cohort, higher lyso-PRS was significantly associated with earlier age at onset ({beta}=-0.21, p=0.022) and higher Unified Parkinson's Disease Rating Scale (UPDRS) scores ({beta}=0.32-1.13, all p < 0.05). Conclusions lyso-PRS was associated with iPD and GBA1-PD status, with the strongest predictive performance in the European population, underscoring the need to improve accuracy in other ancestries. In the European population, the lyso-PRS showed associations with clinical features; however, not all findings were replicated in the validation cohort, highlighting the need for further investigation in large and diverse cohorts.

Transcranial alternating current stimulation (tACS) is a promising noninvasive intervention for modulating pathological brain oscillations in Parkinson's disease (PD). To evaluate its clinical and neurophysiological efficacy, we searched five databases (Web of Science, PubMed, Scopus, Google Scholar and APA PsycInfo) up to August 31, 2025, for trials employing tACS in patients with idiopathic PD. Risk of bias was assessed using the RoB 2 and ROBINS-I tools. Random-effects meta-analyses were used to calculate standardized (SMD) and unstandardized mean differences (MD) with 95% confidence intervals (CIs). We included 10 studies (184 patients with PD, mean age: 64.9, mean disease duration: 5.2 years) in the qualitative review and seven trials (146 patients with PD, mean age: 65.6, mean disease duration: 5 years) in the meta-analysis. No statistically significant differences favoring active tACS over control were found in overall motor severity (UPDRS: SMD = 0.21, 95% CI [-0.10, 0.52], p = 0.097), tremor (SMD = -0.40, 95% CI [-1.97, 1.17], p = 0.478), or a neurophysiological marker of inhibitory response, represented by short intracortical inhibition (MD = 0.00, 95% CI [-0.40, 0.41], p = 0.971). The prediction intervals indicated substantial uncertainty, and significant between-study heterogeneity was observed, particularly for tremor outcomes (I2 = 86.1%). This variability and limitation in evidence quality is largely driven by small sample sizes, highly heterogeneous stimulation protocols, and varying outcome assessments. Systematically, tACS was generally well-tolerated, with no serious adverse events reported across the included studies; however, formal safety assessment was beyond the scope of this review. Current exploratory evidence shows a lack of consistent improvements in motor symptoms or functions in PD largely due to protocol-level heterogeneity. Future studies should consistently assess the MDS-UPDRS III post-tACS and report its specific subscores alongside neurophysiological measures to enable robust meta-analyses.

Background: Individuals with isolated REM sleep behaviour disorder (iRBD) show motor and cognitive dysfunction prior to clinical -synucleinopathy. Performance instability may represent an earlier marker of neurodegeneration but remains underexplored using digital tests. Objectives: To assess baseline and longitudinal differences in motor and cognitive performance and examine performance variability in iRBD and related phenotypes. Methods: Three PD-risk-stratified prodromal cohorts (normosmic probable RBD (pRBD), hyposmic pRBD and polysomnography-confirmed iRBD (PSG-iRBD)) were compared with healthy controls. Participants completed the BRadykinesia Akinesia Incoordination (BRAIN) test, Distal Finger Tapping (DFT) test, and Trail Making Test (TMT) remotely. Motor outcomes included kinesia score (KS), akinesia time (AT), and incoordination score (IS); cognitive outcomes included TMT-A/B reaction times and executive function. Baseline differences were analysed using age- and sex-adjusted logistic regression, longitudinal change using linear mixed-effects models, and variability using the mean of squared successive differences (MSSD) and heteroscedastic modelling. Results: At baseline, PSG-iRBD participants showed greater motor and cognitive impairment than controls, hyposmic pRBD demonstrated intermediate deficits and normosmic pRBD participants showed milder but significant impairments. Linear mixed-effects models showed no change in motor trajectories across all groups, while executive function declined significantly in PSG-iRBD (p=0.001). However, variance modelling showed widespread variability. Cognitive variability was elevated in PSG-iRBD and hyposmic pRBD participants (MSSD p<0.035), and heteroscedastic modelling captured significant visit-specific motor instability across all prodromal cohorts on the BRAIN test (all p<0.02). Conclusions: Performance variability precedes measurable linear decline across PD-risk stratified groups. Remote digital testing offers a scalable framework to capture this early instability.

Background: The locus coeruleus-norepinephrine (LC-NE) system is affected early in Parkinson's disease (PD) and is associated with various non-motor symptoms. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising non-invasive approach for improving PD symptoms, and it has been hypothesized that its action is linked to the LC-NE brainstem system; however, its neurophysiological mechanisms remain poorly understood. Objective: Given the close relationship between LC-NE activity and pupil dynamics, pupillometry may provide a non-invasive measure of LC-related activity during taVNS. This monocentric, single-blinded, sham-controlled study investigated the impact of taVNS on pupillary response as an indicator of taVNS effects at the level of the brainstem. Methods: Twenty-one patients with PD and 18 age-matched healthy controls were included. Real and sham stimulation were applied in a randomized cross-over design, and pupil size was continuously recorded. A local-global auditory processing task, which elicits arousal-related responses to auditory irregularities, was incorporated as a control condition to evaluate pupil responsiveness associated with LC-NE system activity. Results: Real taVNS elicited greater pupil dilation than sham stimulation, with a significant effect emerging 2710--3640 ms after stimulation onset in patients with PD. In contrast, no significant difference was found between real and sham stimulation in healthy controls. The local-global auditory processing task elicited larger pupil responses to deviant than non-deviant stimuli in both groups, indicating intact LC-NE reactivity. Conclusion: TaVNS elicited a significant pupillary response in individuals with PD but not in healthy older adults, providing evidence of physiological responsiveness to taVNS in PD.

Background Parkinson disease (PD) is associated with increased sedentary time and reduced cardiorespiratory fitness, making exercise an important component of disease management. Although exercise improves cardiorespiratory fitness, individuals with PD vary substantially in their response to exercise. Sedentary time may contribute to this variability, yet whether sedentary time modifies the response to intervention and varying exercise intensities within an intervention is unknown. We examined whether sedentary time interacted with 6 months of moderate-intensity or high-intensity aerobic exercise on maximal oxygen consumption (VO2max) in individuals with PD. Methods This secondary analysis used data from the SPARX phase 2 randomized clinical trial including 128 de novo PD patients assigned to high- or moderate-intensity treadmill exercise, or usual care for 6 months. Interactions between randomized group and post-randomization 6-months average sedentary time were assessed for associations with 6-month change in VO2max by using linear regression models corresponding to Analysis of Covariance (ANCOVA) models with interaction. Results The interaction between exercise intensity and sedentary behavior on 6-month change in VO2max in the moderate-intensity group compared with usual care was not significant ({beta}: -1.78, 95% CI: -3.76 to 0.20, p-value: 0.08), although the sensitivity analysis restricted to complete cases showed a significant interaction where each 10% increase in 6-months average sedentary time was associated with a 2.51 mL/kg/min decrease in VO2max change in the moderate-intensity group compared with usual care ({beta}: -2.51, 95% CI: -4.53 to -0.48, p-value: 0.02). There was no significant interaction between exercise intensity and sedentary behavior on 6-month change in VO2max in the high-intensity group compared with usual care ({beta}: -1.46, 95% CI: -4.74 to 1.83, p-value: 0.38). The sensitivity analysis showed similar results. Conclusions These hypothesis-generating, preliminary findings suggest that sedentary time may modify the response to exercise among individuals participating in moderate-intensity aerobic exercise. Future adequately powered randomized controlled trials are needed to confirm these findings and determine whether sedentary behavior should be considered when prescribing exercise for individuals with PD.

Background: Cognitive impairment in Parkinson disease (PD) significantly affects patients ability to perform instrumental activities of daily living (IADLs). However, neuropsychiatric symptoms, which are highly prevalent in PD, may also contribute to functional impairments. In this study, we investigated the independent contributions of cognitive and neuropsychiatric symptoms to functional impairments and tested whether mood mediates cognition-function associations. Methods: We examined 104 patients from the Quebec Parkinson Network and replicated analyses in a sample of 144 patients from an independent online cohort. Participants completed the Penn Parkinsons Daily Activities Questionnaire (PDAQ), a validated patient-reported measure designed to capture cognition-dependent IADLs, standard cognitive tests (executive function, attention, working memory), and neuropsychiatric questionnaires (apathy, depression, impulsivity, and anhedonia). Regression models tested the independent and combined effects of cognition and neuropsychiatric symptoms on PDAQ; mediation analyses explored mechanistic pathways. Results: Both cognitive performance and neuropsychiatric symptoms were independently associated with PDAQ scores and the proportion of variance explained by neuropsychiatric symptoms was comparable to that explained by cognitive performance. Furthermore, depression and impulsivity partially confounded the relationship between cognitive performance and PDAQ and impulsivity partially mediated this relationship. The independent associations between neuropsychiatric symptoms and PDAQ were replicated in the replication sample. Conclusion: These results indicate that impairments in cognitive IADLs reflect contributions of both cognition and neuropsychiatric changes and suggest that trials using measures of IADLs as an outcome measure should also carefully assess and control for neuropsychiatric symptoms.

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for Parkinson's disease (PD). G2019S, the most common pathogenic variant, has been linked to milder motor symptoms, but the effects of other LRRK2 variants on disease trajectory remain incompletely characterized. R1441G, the second most common pathogenic variant, co-occurs with the PD risk variant M1646T on a shared haplotype. Whether this haplotype confers a distinct rate of motor progression has not been established. Methods: We analyzed up to 12 years of longitudinal data from 603 participants in the Parkinson's Progression Markers Initiative (PPMI) with PD and available whole-genome sequencing data: 394 sporadic PD, 169 G2019S carriers, 20 R1441G+M1646T carriers, and 20 M1646T carriers. Motor symptom progression (MDS-UPDRS III) was assessed using linear mixed-effects models with genotype-by-time interactions, adjusted for age at onset, disease duration at baseline, sex, race, baseline score, and levodopa equivalent daily dose. Results: R1441G+M1646T carriers exhibited 76% slower progression in OFF-state MDS-UPDRS III than sporadic PD (0.50 vs. 2.04 points/year; {beta}=-1.54 [95% CI: -2.48, -0.60]; p=0.001). G2019S carriers exhibited 26% slower progression (1.52 points/year; {beta}=-0.52 [-0.99, -0.06]; p=0.03). M1646T carriers did not differ from sporadic PD (p=0.60). Slower progression in R1441G+M1646T carriers was characterized by attenuated bradykinesia (64% slower; p=0.008), axial decline (76% slower; p=0.002), and a lack of orofacial symptom progression (p<0.001). R1441G+M1646T carriers also exhibited 55% slower self-reported motor decline (MDS-UPDRS II; p=0.04) Conclusions: R1441G+M1646T carriers exhibit substantially slower motor progression than sporadic PD while M1646T carriers do not.

The genetics of Parkinsons disease (PD) in underrepresented populations remain poorly characterized, potentially overlooking population-specific contributions. We analyzed 461 Chilean PD cases from a movement disorders center. Pathogenic, likely pathogenic, or GBA1 risk variants were identified in 58 individuals (12.6%), mainly in LRRK2 (50%) and GBA1 (44.8%), while PRKN, SNCA, and SQSTM1 collectively represented 5.2%. All LRRK2 variants were p.G2019S, with an overall frequency of 6.3%, the highest reported in South America, and enrichment of Ashkenazi Jewish ancestry at this locus. These findings characterize the genetic landscape of PD in Chile and support its relevance for LRRK2-targeted studies.

Background An X-linked levodopa-responsive parkinsonism-epilepsy syndrome has been associated with PGK1, and the gene lies within the previously suspected PD locus PARK12. Objective To examine the association of common and rare PGK1 variants with PD. Methods We analyzed common and rare variants from Accelerated Medicines Partnership - Parkinsons Disease (AMP-PD) and UK Biobank (UKBB, total N=4,523 PD cases, 19,736 proxy cases, and 390,532 controls). To account for the X-linked location of PGK1, we used sex-stratified, combined regression models and optimized sequence Kernel association (SKAT-O) tests, followed by meta-analysis using MetaSKAT. Results We found no association between common or rare PGK1 variants and PD in sex-stratified or combined analyses, including after cross-cohort meta-analysis. Conclusion Although we did not find evidence supporting an association between PGK1 and PD, very rare pathogenic PGK1 variants may still contribute to syndromic parkinsonism. Future research could explore larger datasets to further examine this potential association.

Background: People with Parkinsons disease (PD) experience substantial psychosocial burden, but the extent of their concern about the future is not well characterized. Objective: The objective of the present study is to characterize concerns about the future among people with PD (PwP), with an emphasis on the clinical and demographic correlates of future-oriented concerns. Methods: A survey in the online Fox Insight study platform asked PwP to rate their degree of concern about the future across seven domains: quality of life, disease progression, healthcare needs, social relationships, financial responsibilities, stigma, and specific symptoms. Relationships among uncertainty and demographic and clinical features, such as age of onset, gender, and disease severity, were examined. Latent class analysis was conducted to identify patterns of fear/uncertainty. Results: Among 3372 respondents, concerns about the future were common and spanned cognitive, functional, social, and symptom-related domains. Concerns about future cognitive impairment, independence, mobility, and disease progression were most prominent. Women and individuals with young-onset PD reported higher levels of concern than other groups. Latent class analysis revealed two clear patterns, including a high-concern subgroup with elevated worry across nearly all domains. Fewer than half of respondents had discussed these concerns with a healthcare professional. Conclusion: Future-related concerns are common among people with PD but is not routinely explored in clinical care. Greater attention to these concerns, especially for young-onset individuals and women, may help clinicians offer more timely and supportive guidance.

In Parkinson's disease (PD), early phase clinical trials of disease-modifying agents generally use the MDS-UPDRS Part III as the primary outcome measure of motor function, which typically requires a large sample and/or a long (12-18 months) treatment duration, even if a substantial treatment effect is assumed. This is due to the rather slow rate of early PD progression relative to the variability of the MDS-UPDRS Part III assessments. Using placebo-arm data from four recent large Phase 2 trials of early-stage PD (SPARK, PASADENA, PADOVA and LUMA), the sample size needed to detect a range of assumed treatment effects on MDS-UPDRS Part III progression was estimated. The trial sample size estimates obtained for MDS-UPDRS Part III and for smartphone-based sensor-derived motor functional composite (MFC) endpoints were compared using an approach based on relative responsiveness to disease progression. The calculations were also implemented in an interactive, publicly accessible application. Powering a one-year trial using the MFC1 endpoint, derived from three active assessments (6-minute walk, U-turn and Hand Pronation-Supination), or the MFC2, which adds 60-Second Typing, was projected to reduce the required sample size by more than half relative to the MDS-UPDRS Part III, assuming equivalent proportional treatment effects.

Background Parkinson's disease (PD), the most common neurodegenerative movement disorder, is commonly thought of as an aging and sporadic disease; however, 5-14% of individuals experience disease onset before the age of 50 years (early-onset PD; EOPD) and about 20% have a positive family history. In the case of both EOPD and people with a family history of PD, evidence suggests higher rates of a disease-causing genetic contribution. Objectives Our goal was to perform a variant screening of seven PD-related genes and 21 genes associated with related parkinsonian disorders to identify pathogenic/likely pathogenic variants and variants of uncertain significance within EOPD and family-history-positive individuals within the Latin American Research Consortium on the Genetics of PD (LARGE-PD). Methods We performed short-read whole-genome sequencing on a subset of 263 individuals with EOPD and/or a familial history of PD who had no known pathogenic PD variant in genotyping data. Results Of the analyzed individuals, a monogenic burden in primary and secondary PD genes due to pathogenic or likely pathogenic variants for PD was observed in 4.7%, an additional 5.5% had pathogenic or likely pathogenic variants for Gaucher's disease, and 2.7% had known risk variants in GBA1. Conclusions By expanding the reported spectrum of disease-associated variants in a Latin American population, we identified previously unreported or underrepresented variants that would likely be missed by array-based or targeted screening approaches and contribute to the characterization of EOPD and familial PD in Latin America.

BackgroundThe relationship between essential tremor (ET) and Parkinsons disease (PD) remains controversial. Beyond viewing ET as a discrete risk factor for PD, recent frameworks propose that an ET phenotype may represent a clinical presentation of prodromal PD (pPD), consistent with the current reconceptualization of ET as a syndrome. Whether co-occurring subtle motor signs alter pPD probability in ET remains unknown. MethodsUsing the MDS research criteria, we calculated pPD probability in a large cohort of ET patients with and without subtle motor signs (rest tremor, hypomimia, isolated rigidity, reduced arm swing, altered repetitive movements, global slowing). Multivariable regression was used to identify independent predictors of pPD probability. ResultsAmong 599 ET patients (median disease duration: 12 years), only 6 (1.0%) met criteria for probable pPD. Although ET patients with subtle motor signs exhibited higher continuous pPD probability scores than those without, the frequency of possible or probable pPD did not differ significantly between groups. In multivariable regression, neither ET nor individual subtle motor signs, but hypomimia, were independent predictors of pPD probability, which was primarily driven by older age and male sex. ConclusionsLong-standing ET, whether isolated or accompanied by subtle motor signs, is not associated with pPD, with the possible exception of co-occurring hypomimia.

Introduction: Parkinson's Disease (PD) motor features typically begin unilaterally, but it remains unclear whether dominant versus non-dominant side motor symptoms differentially affect lateralized aspects of fine motor control. Methods: We recruited 16 right-handed participants with mild, asymmetric PD (8 primarily left-side affected, 8 primarily right-side affected) and 10 age-matched controls to complete a bimanual tablet task in which one hand draws a stylus to targets (leveraging trajectory control mechanisms) while the other hand simultaneously stabilizes a stylus over a stationary target (leveraging stabilizing control mechanisms). The styli are connected via a resistance band to mimic internal forces that arise during asymmetric, bimanual activities of daily living. Results: Both PD groups demonstrated preserved trajectory control in their dominant hand relative to controls (p > .072), but significantly impaired stabilizing control in their non-dominant hand (p < .022), with the largest deficits observed in the left-side PD group. Trajectory control performance significantly correlated with an overall measure of motor severity (r(14) = .69; p = .004), while stabilizing control did not (p = .56). Discussion: These findings suggest that left- and right-side motor symptoms in early PD produce distinct patterns of functional impairment (rather than simple contralateral analogs) that may be related to underlying lateralized motor control mechanisms. This work highlights a potential gap in standard clinical motor assessments, which may not adequately capture non-dominant side stabilizing deficits in early PD.