Journal of Parkinson’s Disease

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: 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: 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.

Background. Nigrostriatal dopaminergic dysfunction, a biological anchor of Parkinson's disease (PD), is routinely assessed using single-photon emission computed tomography of the dopamine transporter (DaT-SPECT). Dopa decarboxylase (DDC) in cerebrospinal fluid (CSF) is a promising biomarker of dopaminergic dysfunction, but its association with DaT-SPECT has to be demonstrated. Objectives. To investigate the association of CSF DDC with DaT-SPECT. Methods. We first analysed proteomic and DaT-SPECT data from the Parkinson's Progression Markers Initiative (PPMI), including PD (n=891), prodromal PD (n=867) and healthy controls (n=161). We then verified this association in a single-center clinical cohort (UNIPG), including PD/Dementia with Lewy Bodies (DLB) (n=78), atypical parkinsonisms (AP, n=11), other neurodegenerative diseases (OND, n=25) and controls (CTRL, n=40). Here, CSF DDC was measured by a novel fully automated quantitative immunoassay. Results. In PPMI, among 129 proteins assessed, DDC showed the strongest association with DaT-SPECT ({beta} = -0.132, FDR = 6.92 x 10-33). Across PPMI and UNIPG cohorts, DDC correlated with striatal binding ratio (SBR) ({rho} = -0.377, P < 0.001; {rho} = -0.466, P < 0.001, respectively) and accurately discriminated positive from negative scans (AUC 0.811, 95% CI 0.762-0.859; AUC 0.870, 95% CI 0.777-0.963, respectively). In PPMI prodromal cases, higher DDC predicted faster motor progression. In UNIPG, DDC distinguished PD/DLB and AP from OND and CTRL groups (AUC 0.830, 95% CI 0.764-0.896), independently of dopaminergic treatment. Conclusion. CSF DDC reflects nigrostriatal dopaminergic dysfunction, representing a potential quantitative biochemical alternative to DaT-SPECT that might be readily implemented via automated immunoassays.

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.

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: 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.

Background: Peripheral inflammation has been implicated in the pathophysiology of Parkinson's disease (PD), but its relationship with autonomic dysfunction remains unclear. Objectives: To explore the association between peripheral inflammation, assessed by the neutrophil-to-lymphocyte ratio (NLR), and autonomic function in patients with PD. Methods: We retrospectively analyzed 97 patients with PD who underwent 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy and differential blood cell counts. Associations of NLR with early and delayed heart-to-mediastinum (H/M) ratios, washout ratio, and the coefficient of variation of R-R intervals (CVRR) were assessed using Spearman's rank correlation and multivariable linear regression adjusted for age, sex, and disease duration. Results: No significant univariable correlations were observed between NLR and the autonomic measures. In multivariable analysis, higher NLR was associated with a lower early H/M ratio (B = -0.802, 95% CI -1.598 to -0.005, P = 0.049), whereas no significant associations were observed with the delayed H/M ratio, washout ratio, or CVRR. Sensitivity analyses showed a generally consistent direction of association, although the effect estimate was attenuated after exclusion of two influential observations and statistical significance was not consistently retained. Conclusions: Higher NLR was associated with lower early cardiac MIBG uptake after adjustment for age, sex, and disease duration in patients with PD. This exploratory finding raises the possibility of an association between systemic inflammation and sympathetic dysfunction in PD and requires confirmation in larger prospective studies.

Objective: Impulse control disorders (ICDs) are clinically important nonmotor features of Parkinson's disease (PD). Tremor-dominant PD (TD-PD) has been associated with greater cerebello-thalamo-cortical involvement, whereas postural instability/gait difficulty-dominant PD (PIGD-PD) has been linked to more prominent basal ganglia and frontostriatal dysfunction. We therefore examined whether ICD symptoms differ by motor phenotypes. Methods: This cross-sectional study analyzed baseline data from the Parkinson's Precision Medicine Initiative (PPMI). Motor subtype classification was based on Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) criteria. ICD symptoms were assessed using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Current Short Form (QUIP-CS) and evaluated across multiple levels of analysis using the standard screening definition and normalized QUIP-CS scores analyzed categorically and continuously. Temporal-alignment, subgroup, multivariable, and Bayesian analyses were performed to assess the robustness of the primary findings. Results: We analyzed 305 participants (173 TD-PD, 132 PIGD-PD). Screening-defined ICD positivity was similar between subtypes (21.4% vs 21.2%, OR = 1.01, 95% CI 0.58-1.76, p = 0.970). Continuous and categorical normalized QUIP-CS scores likewise did not differ between groups (continuous score: 0.0338 vs 0.0384, p = 0.674; categorical score: 3.5% vs 4.5%, p = 0.632). Temporally aligned, subgroup, and multivariable sensitivity analyses consistently supported the primary finding, and Bayesian analysis provided moderate evidence supporting the null hypothesis (BF01 = 7.21). Conclusions: ICD symptoms do not differ between TD-PD and PIGD-PD motor subtypes in early PD. These findings suggest that motor subtype-associated differences in cerebellar involvement do not substantially influence ICD symptoms in early PD.

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.

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: Cognitive decline in Parkinsons disease (PD) may reflect interacting neurodegenerative and cerebrovascular processes, but their distinct temporal contributions remain unclear. METHODS: Newly diagnosed, untreated PD participants from the PPMI who were cognitively normal at baseline and had at least three years of cognitive follow-ups were included. Linear mixed-effects models examined longitudinal atrophy, white matter hyperintensity (WMH), and clinical trajectories. Mixed-effects models also examined the associations between baseline WMHs and a decline-related atrophy pattern expression score with subsequent multidomain clinical progression. RESULTS: 58 participants experienced cognitive decline and 292 remained cognitively stable. Converters showed faster decline across all cognitive domains, accompanied by faster worsening of motor, gait, neuropsychiatric, sleep-related, and functional symptoms. Converters further showed higher baseline WMH burden without accelerated accumulation, alongside accelerated limbic and subcortical atrophy. Greater baseline WMH burden was associated with differential longitudinal progression in converters across eleven clinical outcomes, including cognition, gait, and functional independence (all q<0.05). Baseline atrophy pattern expression showed similar converter-dependent associations with longitudinal progression across eight outcomes, with the strongest interaction for MoCA (q<0.001). In joint models, atrophy pattern expression retained broader associations with cognitive and motor progression, whereas WMH burden retained more selective associations with neuropsychiatric symptoms and functional independence. DISCUSSION: Cognitive decline in PD was characterized by accelerated neurodegeneration occurring against a background of WMH-related cerebrovascular vulnerability rather than accelerated WMH accumulation, supporting distinct temporal patterns and complementary clinical associations of neurodegenerative and vascular processes with cognitive impairment and broader disease progression in PD.

Blood-based (BB) biomarker investigations in Parkinson disease (PD) and in mild traumatic brain injury (mTBI) have substantially grown over the past decade. High risks for PD in young post-mTBI veterans have been inferred from medical record data using actuarial modeling. However, potential utility of BB biomarkers to quantify risks vs. no risk for PD in young post-mTBI veterans has not been established. Previously we reported post-mTBI veterans performed significantly below the standardized normative scores for their age and education level on specific domains of executive functioning, on par with senior aged individuals with early-stage PD. Here, we examined serum brain-derived neurotropic factor (BDNF), ubiquitin C-terminal hydrolase-L1 (UCH-L1), glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein {beta} (S100B) in association with executive functioning outcomes in search of a bio-cognitive model suitable to differentiate risk from no risk for prodromal PD. A reference range of bio-cognitive cut-points were derived from Area Under the Curve (AUC) sensitivity and specificity methods. Our data revealed two bio-cognitive signatures with reference range cut-points when GFAP was paired with cognitive flexibility / attention scores, and when S100B was paired with categorical / semantic verbal memory scores. Both bio-cognitive signatures revealed prodromal PD risk vs.no-risk parameters that remained relevant for differentiating young veterans who had encountered a past mTBI and those who had not experienced a mTBI. Subjects with early-stage PD who had withstood a mTBI up to 10- to 40-years earlier were also differentiated from those who had no mTBI history. These results indicate the predictive utility of expanding the biomarker field to include reference ranges, cut-points, and specific cognitive domains to estimate risks for PD in a clinic setting. These preliminary data also add value in establishing a quantifiable bio-cognitive risk signature to identify prodromal PD risks in young adults prior to obvious cognitive and motor decline. While encouraging, these data require further follow-up with a larger sample size in a longitudinal design to validate these findings.

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.

Background: Pathogenic variants in GCH1 have been associated with Parkinson's disease (PD), but the clinical phenotype and longitudinal disease course of GCH1-associated PD remain incompletely characterized. Objectives: To characterize the genetic spectrum, clinical phenotype, and longitudinal progression of GCH1-associated PD across multiple populations. Methods: Whole-genome sequencing (WGS) and clinical exome sequencing (CES) data from the Global Parkinson Genetics Program (GP2) were analyzed together with unpublished and published GCH1-associated PD patients. Variant pathogenicity was classified according to ACMG criteria. Demographic, clinical, and longitudinal features were compared between GCH1 P/LP variant carriers and non-carrier PD patients; individuals with known pathogenic variants in PD-associated genes were excluded from both groups. Results: In the GP2 cohort (PD, n=22,825; controls, n=4,453), 16 pathogenic or likely pathogenic (P/LP) GCH1 variants were identified in 58 individuals, including 54 PD patients, one control, and three individuals with other neurodegenerative phenotypes (two with progressive supranuclear palsy and one with dementia with Lewy bodies). In the pooled-ancestry WGS analysis, GCH1 P/LP variants were enriched in PD patients versus controls (0.267% vs 0.023%; OR=11.854; 95% CI=1.620-86.699; p=0.0006). Variant frequencies in PD patients ranged from 0.121% to 0.714% across ancestries. In the CES cohort, P/LP variants were identified in 0.201% of PD patients. After integrating GP2 with additional unpublished and published datasets, 119 GCH1-associated PD patients were analyzed. Compared with noncarriers, carriers of P/LP GCH1 variants had an earlier age at onset (mean [SD], 53.7 [14.8] vs 59.2 [11.7] years; P < .001), lower levodopa equivalent daily dose requirements (mean [SD , 467.5 [331.7] vs 680.3 [466.4] mg/d; P < .001), and a higher frequency of a family history of Parkinson disease (47.6% vs 19.9%; P < .001). Adjusted Cox models showed significant delayed progression to motor fluctuations (HR=0.32, 95% CI=0.16-0.62) and levodopa-induced dyskinesias (HR=0.51, 95% CI=0.30-0.87). Conclusion: GCH1 pathogenic variants were associated with a clinically distinct phenotype characterized by earlier disease onset and slower progression of motor complications. These findings suggest that GCH1 genetic variants may serve as genetic biomarkers for patient stratification and prognosis in PD.

Background: Non-motor symptoms, including sleep and cognitive dysfunction, are major contributors to reduced quality of life in people with Parkinsons disease (PwPD). Dance has been proposed as a promising intervention to improve quality of life in PwPD. Previously, we reported longitudinal trajectories of global cognition following community-based dance; however, little is known about its long-term influence on sleep-related non-motor symptoms and their relationship with global cognitive performance. Objective: We examined the six-year trajectories of sleep and overall non-motor symptom severity among PwPD participating in weekly community-based dance classes compared to a sedentary Reference group. As a secondary objective, we evaluated their association with global cognitive performance as a functional outcome. Methods: This longitudinal observational study followed PwPD engaged in community dance participation as well as a matched sedentary control group from the Parkinsons Progression Markers Initiative database over six years. Generalized estimating equations (GEE) were used to model group-level trends, with sensitivity analyses conducted to assess the robustness of the findings. Results: Non-motor outcomes showed that insomnia worsened significantly within the Reference group (p = .003) but improved among dancers (p = .005), with daytime sleepiness remaining stable across both groups. When sleep was used as a predictor of cognition, global cognitive performance trended to improve in the Dance group (p = .078) and declined mid-period in the Reference group (p = .014). In addition, overall non-motor symptom severity worsened in the Reference group (p = .011) but remained stable in the Dance group. Constipation also worsened significantly in the Reference group (p = .012) compared to the Dance group. Conclusion: The present study demonstrates that community-based dance may support select non-motor symptoms, including insomnia, and cognitive resilience in PwPD. Findings reinforce dance as a valuable, real-world, non-pharmacological approach to slow functional decline in PD.

Peripheral inflammation in Parkinson's disease (PD) remains poorly characterised among carriers of Asian-prevalent LRRK2 G2385R and R1628P variants. We investigated plasma immunoinflammatory markers (i.e., IL-6, TNF-, CCL2, CX3CL1, CCL5, and VCAM-1) via multiplex immunoassay in 240 participants: PD-G2385R (n=53), PD-R1628P (n=58), PD-G2385R+R1628P (n=5), idiopathic PD (iPD; n=62), and controls (n=62), and their clinicobiological correlates including monocyte LRRK2 kinase activity (pRab10Thr73). Compared with iPD and/or controls, TNF-, CCL2, CX3CL1, and CCL5 were lower in PD-G2385R, while IL-6, TNF-, CCL2, and CCL5 were lower in PD-R1628P. Higher LRRK2 kinase activity correlated with lower TNF-. CX3CL1 correlated with greater motor severity in iPD but less disability in both variant groups. CCL5 correlated with less motor complications in PD-G2385R, while IL-6 and VCAM-1 correlated with worse disability and/or cognition in PD-R1628P. These findings suggest that immunoinflammatory profiles and their clinical relevance in PD differ by genotype, with implications for stratification in future immunomodulatory trials.

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.

Importance Alzheimer disease (AD) is frequently accompanied by co-pathologies such as Lewy bodies, intracellular protein aggregates consisting of misfolded -synuclein, ubiquitin and several other proteins. These aggregated proteins contribute to the pathological and clinical heterogeneity of AD and are associated with a more rapid progression. Cerebrospinal fluid (CSF) measurement of aggregated -synuclein or skin biopsy histochemistry are the current biomarkers for Lewy body pathology in individuals with Parkinson's disease and related synucleinopathies but are invasive, not easily scalable for large studies or practical in clinical practice. Neuron-derived extracellular vesicles (nEVs) provide a feasible and tolerable alternative to detect Lewy body pathology. nEVs exit across the blood-brain barrier and deliver neuron-derived proteins into the systemic circulation, offering direct access to brain-level protein concentrations from peripheral blood, not afforded by conventional plasma biomarkers. Objective To use nEVs extracted from plasma to measure brain-derived -synuclein levels as a clinical biomarker of Lewy body pathology and synucleinopathy across clinically and pathologically characterized cohorts. Design, Setting, and Participants This multicohort observational study evaluated plasma nEV-derived -synuclein levels in 1,304 individuals, including 794 (61%) individuals without dementia, 469 (36%) individuals with AD, and 41 (3%) individuals with PD across four cohorts. Postmortem validation was performed from autopsy data in 127 individuals, including 96 (76%) individuals without, and 31 (24%) with, Lewy body pathology. Cerebrospinal fluid (CSF) -synuclein seed amplification assay data were available in a small subset of 54 (4.1%) of the group. Amyloid positron emission tomography (PET) data were available in 901(69.1%) of the total group. Exposure Clinical diagnosis, AD biomarker positivity, Lewy body pathology, CSF -synuclein seed assay status, and amyloid PET positivity. Main Outcomes and Measures Plasma nEV-derived -synuclein levels normalized to CD9 and assessed in relation to clinical diagnosis, AD biomarker status, neuropathologically confirmed Lewy body pathology, CSF seed assay results, and amyloid PET positivity. Results Compared with controls, plasma -synuclein levels from nEVs were significantly elevated among individuals with PD (controls mean 0.51, SD=0.24 vs PD mean=0.69, SD=0.23, P=8.66*10-). nEV-derived -synuclein levels were also significantly higher in P-tau181 and P-tau217 positive individuals with and without cognitive impairment compared to P-tau negative individuals. Elevated nEV-derived -synuclein levels were subsequently validated in individuals with postmortem Lewy body pathology (28.6% higher mean levels, P=0.02). Among 54 individuals with CSF -synuclein seed amplification assay, 8 (15%) were positive and showed a 18.2% increase in mean nEV -synuclein levels compared to individuals with negative -synuclein seed amplification. nEV-derived -synuclein levels were also significantly elevated in amyloid PET positive individuals with and without dementia (5.8% higher mean levels, P=8.50E-03) and clinical AD (9.3% higher mean levels, P=6.38E-12). Conclusions and Relevance Plasma -synuclein levels from nEVs likely reflect underlying synuclein pathology in the brain and have potential as a blood-based biomarker for detecting Lewy body pathology in PD and in AD and related dementias. nEVs cross the blood-brain barrier and carry neuron-derived cargo directly into the bloodstream, thus providing a unique window into brain -synuclein levels that is not accessible through conventional plasma biomarkers.

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.