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.

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

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

Abstract Background: Parkinson's disease (PD) genetics has been predominantly studied in Western European and North American populations, leaving Central Europe underrepresented. We aimed to characterise the genetic architecture of PD in the V4 countries (Slovakia, Czech Republic, Hungary, and Poland). Methods: The CEGEMOD study combined a systematic review of published PD genetic studies from the V4 region with prospective genetic screening of 1373 patients. All participants underwent genotyping array screening, while genetically unresolved patients with early-onset or familial PD underwent whole-exome sequencing analysis. Variants were interpreted using current clinical standards and validated using Sanger sequencing. Results: The systematic review identified 48 eligible studies reporting pathogenic or risk variants in PD patients from the V4 countries. In the prospective cohort, pathogenic, likely pathogenic, or established risk variants were identified in 157/1373 patients (11.4%). GBA1 variants accounted for the majority of findings, mostly driven by the two GBA1:p.(Thr408Met) and p.(Glu365Lys) mild common risk variants, followed by LRRK2, PRKN, POLG, PLA2G6, and ATP1A3. Whole-exome sequencing provided an additional 5% diagnostic yield in genetically unresolved high-risk patients. Our findings also demonstrate substantial disparities in genetic research across Central Europe. Conclusions: This study provides the largest genetic characterisation of PD in Central Europe to date. The CEGEMOD study expands knowledge of the regional genetic landscape, supports the implementation of genetic testing in clinical practice, and establishes an important resource for future precision medicine and collaborative PD genetics research.

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.

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.

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.

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

LRRK2 is implicated in Parkinson's disease (PD) microbiome-gut-brain axis. We compared plasma lipopolysaccharide-binding protein (LBP) and soluble CD14 (sCD14), markers of gut permeability and endotoxin exposure, in PD patients with/without LRRK2 p.G2385R and/or p.R1628P, and controls, and examined their associations with systemic inflammation and clinical severity. Neither marker differed between groups. Across PD patients, LBP correlated with higher IL-6, TNF- and worse motor function, while sCD14 correlated with higher IL-6, CCL5 and worse constipation. These findings highlight the clinical relevance of endotoxin-related immune signaling in PD, without LRRK2 risk variant-specific associations and identify LBP as an emerging marker of inflammatory burden.

Background: Problematic Internet use (PIU) has been scarcely investigated in Parkinson's disease (PD). Objectives: To estimate the prevalence of PIU symptoms in PD using a specific screening instrument and to explore the clinical characteristics of these individuals. Methods: Two-stage observational study in a Movement Disorders clinic. In Evaluation 1, participants with PD were screened by the Brazilian Portuguese Nine-Item Problematic Internet Use Questionnaire-Short Form (BR-PIUQ-SF-9). In Evaluation 2, screening-positive participants underwent an exploratory assessment of Internet use. Results: 16.7% of participants with PD were positive for the BR-PIUQ-SF-9. The median Internet use time among these positive-screened participants was 5.5 hours per day. Most of them had impulsive-compulsive behaviors, and somatic concern, anxiety, and depressive mood were common psychiatric symptoms. Conclusions: Approximately one in six participants screened positive for PIU symptoms. Impulsive-compulsive behaviors and depressive symptoms were frequent among those undergoing subsequent exploratory assessment.

Background: Parkinsons disease (PD) has a prolonged prodromal phase, but minimally invasive molecular biomarkers distinguishing manifest PD from prodromal synucleinopathy remain insufficiently characterized. Isolated REM sleep behavior disorder (iRBD) represents a high-risk prodromal condition and provides an opportunity to investigate early blood-based transcriptional alterations. Objective: To identify peripheral blood transcriptomic signatures distinguishing healthy controls (HC), individuals with iRBD, and patients with PD, and to explore whether longitudinal iRBD samples exhibit movement toward a PD-like transcriptional state. Methods: Peripheral blood RNA-seq data were analyzed using harmonized metadata, DESeq2 differential-expression analysis, internally validated machine-learning models, PD-like projection, and integrated biomarker-panel prioritization. Independent baseline samples were used for cross-sectional differential-expression and machine-learning analyses. iRBD follow-up and post-conversion observations were excluded from baseline model development and reserved for exploratory longitudinal analyses. Results: Baseline analyses included 71 independent samples: 20 HC, 31 iRBD, and 20 PD. An additional 19 iRBD follow-up observations, including three post-conversion observations, were available for exploratory analyses. Differential-expression analysis identified 170 FDR-significant genes in PD versus HC and 85 in PD versus iRBD, compared with one FDR-significant gene in iRBD versus HC. Internal machine-learning validation showed stronger discrimination of manifest PD, with a best ROC-AUC of 0.883 for HC versus PD and 0.889 for iRBD versus PD. Discrimination between HC and iRBD was weak, with a best ROC-AUC of 0.584. PD-like projection scores were lowest in HC, highest in PD, and heterogeneous among baseline iRBD samples. Follow-up iRBD samples showed an exploratory upward shift in the mean PD-like projection score. Integrated prioritization produced a 24-gene PD candidate panel and a 24-gene exploratory iRBD panel, with genes in each panel supported by machine-learning feature-stability evidence and differential expression analysis. Conclusions: Manifest PD was associated with a distinct peripheral blood transcriptional signature, whereas iRBD-associated alterations were substantially weaker and more heterogeneous. The prioritized panels represent candidates for independent technical and external validation and should not yet be interpreted as clinically validated diagnostic or prognostic tests.

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

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: Motor complications, such as motor fluctuations and Levodopa-induced dyskinesias (LID), significantly impair quality of life in persons with Parkinson's disease (PD) on long-term Levodopa treatment. Predicting their onset is crucial for tailored patient care. Objectives: To develop and evaluate machine learning (ML) models to forecast the onset of new motor fluctuations and LID in PD patients within three years from baseline assessment, and to assess how training cohort composition influences performance. Methods: A comprehensive ML workflow with repeated Nested Grid Search Cross-Validation was applied to real-world clinical data from a multicentric cohort of 247 PD patients. ML models were rigorously evaluated on the clinically relevant subgroup free of motor complications at baseline. SHAP analysis provided model explainability. Results: Models achieved moderate predictive power for both LID (SVC: MCC 0.28 {+/-} 0.14) and motor fluctuations (Voting MCC = 0.32 {+/-} 0.18). For LID prediction, the strongest predictors were the Levodopa Equivalent Daily Dose (LEDD), baseline motor fluctuations, and duration of Levodopa therapy, with risk increasing significantly above a LEDD threshold of 300-400 mg. A critical ablation study revealed that excluding patients with pre-existing complications caused a collapse in model sensitivity, highlighting their essential role in defining the upper bound of predicted risk. Conclusions: The model-based risk assessment is consistent with established clinical factors. Inclusion of the full spectrum of disease severity, including patients with pre-existing motor complications, in the training set is essential for achieving a robust probabilistic risk scale and reliable model calibration for new-onset prediction.

Background: Motor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing. Methods: The cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinson`s Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex. Results: The mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. {beta}=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. {beta}=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. {beta}=0.15, 95% CI [0.00, 0.29], p=0.044). Conclusion: These findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.

Estimating Parkinson's disease (PD) risk years before diagnosis remains an unmet need. We applied a validated machine learning classifier for REM sleep behavior disorder (RBD) detection to 7-day wrist accelerometry data in 87,975 UK Biobank participants followed for 10 years. Participants in the highest RBD risk stratum (>99th percentile) had an approximately fivefold increased hazard of incident PD compared with the lowest-risk group (0-90th percentile), with a dose-dependent relationship across the full score distribution. Among non-converters, higher RBD risk was associated with baseline cognitive deficits and longitudinal enrichment of autonomic and psychiatric prodromal features. The association with incident PD remained independent of PD polygenic risk score, while RBD score and genetic risk were synergistic. The combined high-risk group achieved a positive likelihood ratio of 7.91, approximately threefold higher than questionnaire-based RBD screening. These findings support wrist accelerometry as a scalable approach for prodromal PD risk enrichment in population screening.