Journal of Parkinson's Disease

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.

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: 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. The VPS35 p.D620N variant causes autosomal dominant Parkinson's disease (PD) and has been shown to activate the LRRK2 kinase pathway, resulting in increased Rab substrate phosphorylation in peripheral immune cells and elevated urinary bis(monoacylglycero)phosphate (BMP) levels. Recently, a VPS35 variant of unknown significance (c.959C>T; p.A320V) was described in two late-onset sporadic PD patients. Methods. We ascertained a family from the Canary Islands in which six siblings were chronically exposed to high doses of pesticides. Three siblings developed levodopa-responsive, akinetic-rigid PD, while the other three remained unaffected. Whole-exome sequencing was performed in the three affected siblings. The frequency of the resulting candidate variant was assessed in 23,327 PD patients and 9,235 controls from four independent cohorts. Members of this pedigree and unrelated controls were assessed for LRRK2 kinase activity in monocytes and neutrophils and BMP levels in urine. Results. The three affected siblings were all heterozygous for p.A320V, whereas the three unaffected siblings did not carry the variant. In the combined PD case-control cohort, p.A320V was identified in six patients and one control. However, unlike p.D620N, heterozygous carrier status for p.A320V was not associated with increased LRRK2 kinase activity or elevated urine BMP levels. Conclusions. While VPS35 p.A320V co-segregated with PD in this family, it did not exhibit the characteristic LRRK2-associated biomarker signature observed in VPS35 p.D620N carriers. It is possible that p.A320V exerts a subtle effect on VPS35 function that was not captured by the assays performed and that chronic pesticide exposure contributed to disease penetrance in this pedigree.

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: 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: 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.

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.

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.

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.

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: 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.

Recent evidence suggests that TMEM106B expression is reduced in the brains of patients with Parkinson's disease (PD). However, an association between rare genetic variants in TMEM106B and PD risk has not been previously established. In this work, we investigated the association between rare TMEM106B variants and PD risk. We leveraged whole-genome sequencing data from 22,010 cases and 40,550 controls across diverse ancestries from the Global Parkinson's Genetics Program (GP2), the Accelerating Medicines Partnership in Parkinson's Disease (AMP-PD), and the UK Biobank (UKBB). A total of 4,581 unique rare variants were identified across all groups. No pathogenic or likely pathogenic variants according to ClinVar were observed in any cohort. We found no evidence that rare coding variants in TMEM106B were associated with PD risk, either individually or through cumulative burden. These findings suggest that rare variation in TMEM106B does not play a major role in PD susceptibility across the populations studied.

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: 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: The Progressive Supranuclear Palsy Clinical Deficits Scale (PSP-CDS) is a brief rating scale of clinical severity in PSP. However, its longitudinal performance has not been evaluated. We aimed to assess the ability of the PSP-CDS to track disease progression over time and to compare progression across PSP phenotypes in a real-world Asian cohort. Methods: Patients who met the Movement Disorder Society PSP diagnostic criteria and underwent at least 2 PSP-CDS assessments were recruited from movement disorders clinics in Malaysia. Longitudinal progression was evaluated using linear mixed-effects models. Domain-specific progression and subtype-specific trajectories were also analyzed. Associations between annualized changes in PSP-CDS and Barthel Index (BI) scores were examined. Results: 104 patients (including 59 with PSP-Richardson's syndrome [PSP-RS], 28 with predominant parkinsonism [PSP-P], and 14 with progressive gait freezing [PSP-PGF]) contributed 394 PSP-CDS assessments over a median follow-up of 33.2 months (range, 8.7-73.1 months). PSP-CDS scores increased significantly over time ({beta}=0.126 points/month), corresponding to estimated increases of 1.13 points over 9 months and 2.27 points over 18 months. Subtype-specific analyses demonstrated the fastest progression in PSP-RS (0.156 points/month), followed by PSP-PGF (0.081 points/month) and PSP-P (0.077 points/month). Exploratory domain-level analyses showed that finger dexterity, communication, and dysphagia were the most rapidly worsening domains. Annualized PSP-CDS progression correlated significantly with annualized decline in BI scores (Spearman's {rho}=-0.474, P<0.001). Conclusions: The PSP-CDS is sensitive to longitudinal disease progression in PSP and captures clinically-meaningful functional decline. Its brevity and ability to distinguish differential progression across PSP phenotypes support its utility as a pragmatic outcome measure for routine clinical practice and research.

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.

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.

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.