Parkinsonism & Related Disorders

BackgroundFreezing of gait (FOG) is a debilitating symptom of Parkinsons disease (PD) that often worsens with disease progression. Adaptive deep brain stimulation (aDBS) may better target symptom fluctuations and gait impairment, yet most studies have focused on high-frequency stimulation. Low-frequency stimulation may offer additional gait benefits in moderate-to-advanced PD. ObjectiveTo evaluate the efficacy of 60 Hz continuous DBS (cDBS) and the safety, tolerability and feasibility of 60 Hz aDBS. MethodsEight individuals with PD were implanted with bilateral leads in the subthalamic nucleus and the investigational Summit RC+S system (Medtronic, Inc.). 60 Hz aDBS was calibrated to adjust stimulation amplitude based on prolonged beta bursts. Participants completed blinded, randomized testing during a validated FOG-eliciting stepping-in-place task under OFF DBS, 60 Hz cDBS, and 60 Hz aDBS. Cardinal motor signs were assessed using MDS-UPDRS III in each condition, and under clinical 140 Hz cDBS. Results60 Hz cDBS was tolerated acutely by 6 of 8 participants and showed significant shortening of beta burst duration, a pathological neural biomarker of FOG. 60 Hz aDBS was deemed safe and tolerable in this cohort. In participants who demonstrated FOG at baseline, gait improved ON both 60 Hz aDBS and cDBS. However, overall motor symptoms, including tremor, improved only with clinical 140 Hz cDBS. Conclusion60 Hz aDBS and cDBS benefit individuals with baseline FOG but may not achieve broad motor symptom relief of clinically optimized HFS. Identifying individuals most likely to benefit from LFS could enable more personalized DBS programming.

BackgroundThe Montreal Cognitive Assessment (MoCA) is a recommended brief screening tool to detect cognitive impairment in people with Parkinsons disease (PD). ObjectiveTo compare English and Bengali MoCA performance in Bangladeshi individuals with PD in East London. MethodsThis cross-sectional study involved participants completing both English and Bengali MoCA. Analyses included ANCOVA, paired and unpaired t-tests, and Bland-Altman methods in full and age-matched samples. ResultsFifty PD participants and 22 healthy controls (HC) were included in the full analysis. Both groups scored higher on Bengali than English MoCA (mean difference [~]4 points, p<0.001). Age-matched analyses (n= 29 PD and 22 HC) detected PD-control differences with the Bengali but not English version (p=0.02). Bengali scores aligned more closely with multidisciplinary assessments, though mean scores remained below normative cut-offs. ConclusionBengali MoCA improves detection of cognitive differences over English but still overestimates impairment, supporting the need for culturally adapted tools and population-specific cut-offs.

Asymmetric arm swing reduction is a hallmark of early-stage Parkinsons disease (PD). We evaluated wrist sensor-based arm swing measures during free-living gait as digital progression biomarkers in 623 early-stage PD participants and 50 controls monitored continuously for one year (controls) or two years (PD). Biweekly measures were extracted from gait segments without other arm activities. Arm swing measures were reduced in PD, reduced on the most affected side, moderately correlated with clinical motor severity, and highly reliable. In unmedicated participants, most affected side measures declined over one year (standardized response means: -0.32 to -0.78) and two years (-0.51 to -1.10), exceeding an MDS-UPDRS Part III subscore at one year (-0.21) and matching it at two years (-0.83). In medicated participants, arm swing increased on the most affected side, which was associated with higher dopaminergic doses and dyskinesia. Overall, free-living arm swing measures are promising progression biomarkers in early, untreated PD.

Environmental neurotoxins have been implicated in the pathogenesis of Parkinsons disease (PD), with Agent Orange (AO) recognized as a presumptive service-connected exposure among U.S. Veterans. However, prospective data examining potential clinical differences associated with AO exposure remain limited. We conducted a multicenter prospective cohort study of U.S. Veterans with PD to compare demographic and clinical characteristics between individuals with and without a history of AO exposure. Clinical assessments included cognitive testing, motor and non-motor symptom scales, activities of daily living, and a global composite outcome. Among 40 Veterans analyzed, no statistically significant differences were observed between exposed and unexposed groups on univariate analyses. However, trend-level differences suggested lower cognitive performance and greater patient-reported motor disability among AO-exposed Veterans. While exploratory and limited by sample size, these findings suggest potential clinically meaningful distinctions that warrant confirmation in larger cohorts. Improved characterization of PD phenotypes associated with environmental toxin exposure may inform prognostic counselling and care of affected Veterans.

Transcranial temporal interference stimulation (tTIS) is a non-invasive method designed to target deep brain regions, such as the basal ganglia, without affecting overlying cortical areas. This study investigated intermittent theta-burst (iTBS) tTIS effects on symptom severity in Parkinsons disease (PD) and motor learning behavior, a condition associated with - among others - basal ganglia dysfunction. We hypothesized that iTBS-tTIS applied to the right putamen would alleviate PD symptoms and improve motor learning expressed by the contra-lateral hand. This randomized, double-blinded, crossover trial included 19 PD patients (mean age 64 years, 14 males) and 19 age- and sex-matched healthy controls (mean age 68.6 years). Structural MRI data were obtained for each participant, and individualized electric field simulations were performed to predict field strength in the right putamen. The motor part of the Movement Disorder Societys Unified Parkinsons Disease Rating Scale (MDS-UPDRS III) served as a primary outcome parameter, an alternating finger tapping task (aFTT) and Motor learning assessed through a sequential finger-tapping tasks (sFTT) were secondary outcome parameters. ITBS-tTIS significantly reduced MDS-UPDRS motor scores in PD patients and the stimulation induced changes in motor performance correlated with the electric field strength in the targeted putamen region. No significant effects were found for motor performance or motor learning in either group. These findings indicate that iTBS-tTIS in general holds potential as a non-invasive approach for deep brain stimulation in PD.

We describe the design of the first non-pharmacological prevention trials of Parkinsons Disease worldwide: the randomised controlled Slow-SPEED trials. The three trials examine the feasibility and preliminary efficacy of a gamified, remotely administered exercise intervention vs. active control program over 18-36 months in the Netherlands (n=110), United Kingdom (n=110) and United States (n=600). Each trial focuses on a complementary prodromal subgroup: isolated/idiopathic REM sleep behavioural disorder, hyposmia, or LRRK2/GBA1 mutation carriers. These trials will provide unique insights for large-scale Parkinsons Disease prevention studies.

BackgroundLoss of smell commonly predates the diagnosis of Parkinsons disease (PD). However, smell loss has multiple causes, and the relationship between idiopathic anosmia (IA) and PD remains incompletely understood. ObjectivesTo assess the presence of prodromal features of PD in individuals with IA and to examine the relationship between anosmia duration and prodromal features. MethodsWithin the PREDICT-PD study, patients with IA investigated at specialist smell clinics were compared with healthy controls at low risk of PD (HC) and patients with PD. In-person assessments included MDS-UPDRS I-III, functional motor tasks, cognitive tasks, autonomic symptoms, orthostatic hypotension, pain, sleep and mood. We compared these features and PD risk according to the PREDICT-PD algorithm between the groups and examined the relationship between the duration of anosmia and severity of prodromal features using linear regression models. ResultsWe recruited 42 IA, 28 HC and 22 PD participants, matched for age and gender. Overall motor scores were not different between IA and HC. IA had worse cognition, sleep, pain, depressive and some symptoms of dysautonomia than HC, with trends towards worse anxiety scores and higher PD risk scores. Shorter duration of anosmia was negatively correlated with MDS-UPDRS II scores but no other prodromal feature. ConclusionsSome individuals with IA exhibit non-motor features suggestive of prodromal PD. This supports the known association of olfactory dysfunction with subsequent PD but suggests that, even after excluding secondary causes of anosmia, other conditions may underlie anosmia or smell loss may be temporally remote from PD.

Gait impairment (GI) and freezing of gait (FOG) affect 80% of patients with advanced Parkinsons disease. Continuous deep brain stimulation (cDBS) provides limited adaptability to address the episodic nature of FOG due to fixed parameters. Neural biomarkers for adaptive DBS are limited by signal artifacts and poor FOG classification. Wearable inertial measurement units (IMUs) offer a promising alternative by directly measuring signatures of GI&FOG. We developed Kinematic adaptive DBS (KaDBS), the first intelligent system to dynamically modulate stimulation in response to real-time gait metrics. KaDBS integrates bilateral shank-mounted IMUs with an investigational neurostimulator through a wireless architecture enabling step-detection, arrhythmicity calculation, and probabilistic FOG classification. Two control algorithms were implemented: an arrhythmicity model based on stride variability, and a P(FOG) classifier implementing tri-state control based on stepwise freezing probabilities. In the largest KaDBS cohort to date (n=8), we compared OFF, cDBS, KaDBS, and intermittent DBS during harnessed stepping and free walking. KaDBS was safe and well tolerated with no serious adverse events; symptom-free reports were 87.5% and 71.4% for arrhythmicity and P(FOG) models respectively, compared to 50.0% for cDBS. All symptoms were mild, transient, and resolved without intervention. KaDBS significantly reduced percent time freezing versus OFF during stepping-in-place (35.8%, P= 4.80 x 10-3) and free walking (33.4%, p = 9.00 x 10-). Therapeutic effects concentrated in baseline freezers: two participants with 100% time freezing during OFF achieved complete resolution with KaDBS, while non-freezers maintained stable gait. These findings establish KaDBS as a safe, effective approach to personalized neuromodulation for PD.

Parkinsons disease (PD) involves variable patterns of brain atrophy in different motor and cognitive regions that differ across patients in both location and progression rate. Existing clinical tools and single-modal imaging methods can be difficult to analyze how individual patients atrophy will progress. Thus, we developed and evaluated deep learning models capable of understanding the pattern of 216 features of PD patients and predicting future regional brain atrophy in individuals with PD using longitudinal 3D MRI and clinical features. Our models combining long short-term memory (LSTM) networks and deep learning classification models to capture time-dependent changes in 29 PD-related brain volumes. Our model demonstrated accurate prediction of regional brain atrophy. In the classification models, 11 regions achieved AUROC greater than 80%. Regression results showed that our model produces an average MAE of 0.4395 and multiple regions R2 are more than 0.8. In conclusion, PD-related regional brain atrophy can be forecast with high test accuracy in longitudinal research cohort. These proof-of-concept results support the feasibility of developing personalized prognostic tools that integrate longitudinal 3D imaging with clinical data.

BackgroundOculomotor dysfunction is common in parkinsonian syndromes and ataxias, but its impact on patient-reported vision-related quality of life (VQoL) remains insufficiently understood. ObjectivesTo characterize VQoL across parkinsonian syndromes and ataxias and assess the functional significance of specific oculomotor abnormalities in spinocerebellar ataxias. MethodsParticipants were recruited at Massachusetts General Hospital (n=231): 104 with Parkinsons disease (PD), 10 with progressive supranuclear palsy (PSP), 56 with genetically defined ataxias (SCA2, SCA3, SCA6, SCA27B, CANVAS), and 61 healthy controls. VQoL was assessed using a 13-item subset of the Visual Activities Questionnaire targeting depth perception, visual acuity/spatial vision, and visual processing speed. Clinical severity was assessed with the Brief Ataxia Rating Scale and Modified International Cooperative Ataxia Rating Scale, and subjective symptoms with PROM-Ataxia. Group comparisons, correlations, and regression analyses were performed. ResultsAll disease groups reported significantly worse VQoL than controls, with the largest deficits in visual processing speed. PSP showed the greatest impairment across all domains, while PD was less affected. Individuals with SCA3 and SCA6 had significantly lower VQoL across all subcategories. In ataxias, VQoL correlated moderately with PROM-Ataxia and weakly with clinical oculomotor scores. Gaze-evoked nystagmus was the only oculomotor sign independently associated with reduced VQoL. ConclusionsParkinsonian syndromes and ataxias are associated with substantial VQoL impairment, particularly in visual processing speed. Gaze-evoked nystagmus is a key predictor of reduced VQoL in ataxias, highlighting the functional relevance of fixation instability. Patient-reported outcomes and oculomotor assessments are essential for capturing visual disability in clinical care and trials.

BackgroundSensitive outcome measures are critical for evaluating the efficacy of novel treatments for Parkinson disease (PD). Recently, we demonstrated that a tremor detection algorithm could reliably detect and quantify real-life PD tremor from wearable sensor data. Here, we assess the sensitivity to change of sensor-derived daily-life tremor measures over two years in an unmedicated and medicated cohort of persons with early PD. MethodsWe used two-year continuous wrist sensor data (median wear time: 22 hours/day) from the Personalized Parkinson Project (n=462 medicated; n=78 unmedicated at baseline), in combination with annual clinical evaluations of tremor severity. From the raw gyroscope data, we derived previously validated weekly measures for tremor time and power, which were smoothed over time using piecewise linear trend estimation. One- and two-year standardized response means (SRMs) were computed to compare the sensitivity to change between the sensor-derived tremor measures and clinical tremor scores. FindingsIn unmedicated participants with tremor, sensor-derived tremor measures demonstrated a high sensitivity to progression (two-year SRMs ranged from 0.67 to 1.09), which was significantly larger than clinical tremor scores (two-year SRMs ranged from 0.21 to 0.41). In medicated participants, sensor-derived tremor time decreased (two-year SRM of -0.18 in participants with tremor), which was associated with both an increase in dopaminergic medication dose and higher disease duration. In contrast, the sensor-derived tremor power measures and clinical rest tremor scores (measured in the OFF state) increased slightly (two-year SRMs ranging from 0.11 to 0.27). InterpretationPrior to initiation of symptomatic treatment, sensor-derived daily-life tremor measures are substantially more sensitive to disease progression than clinical tremor scores, making them a promising tool to evaluate the efficacy of disease-modifying treatments in early PD.

Parkinsons Disease (PD) is the most prevalent neurodegenerative disorder after Alzheimers, yet its diagnosis largely relies on subjective clinical assessments. Thus, this study proposes a systematic, data-driven approach to accurately classify PD patients using heterogeneous risk factors along with efficient machine learning. Six machine learning algorithms, Support Vector Machine(SVM), Random Forest(RF), Extreme Gradient Boosting(XGBoost), Logistic Regression(LR), K-Nearest Neighbour (KNN), and Decision Tree(DT) were utilized and evaluated their performances to identify the most robust and efficient model with high discrimination power. SVM model outper-formed all other machine learning models, and it has been identified as the highest-quality model to classify PD patients from others with at least 96% accuracy. Further-more, Feature importance was analyzed using SHAP to enhance the interpretability of the proposed model. This study contributes to the integration of artificial intelligence in the healthcare domain, emphasizing the value of data-driven classification modeling techniques in supporting healthcare professionals with accurate, personalized, and actionable insights for high-risk patients. Together, these approaches enhance the precision of early detection of PD, paving the way for more informed clinical decision-making and improved patient care.

ObjectiveTo evaluate whether the presence of orthostatic hypotension (OH) impacts the association between white matter hyperintensity (WMH) volume and motor symptom burden in persons with Parkinsons disease (PWP). MethodsMotor symptom burden in PWP was quantified using the Movement Disorders Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Part III. Total WMH volume was segmented based on high-resolution T1-weighted (T1W) and T2 Fluid Attenuated Inversion Recovery (FLAIR) images. Determination of whether individual participants qualified as having OH was based on orthostatic vital signs. All data were obtained from the Parkinsons Progression Markers initiative (PPMI) dataset. ResultsA total of 218 PWP (mean age, 64.84 {+/-} 9.51) and 50 control participants (mean age, 65.52 {+/-} 11.04) were included in the analyses. WMH volume did not differ significantly between the two groups. 15.1% of the participants in the PD group and only 4% of the control group qualified as having OH. Analysis of covariance determined that in PWP, the association between WMH volume and motor symptom burden was significantly different in participants with OH in comparison to those without OH (steeper in the former group). Follow-up analyses suggested that the effects were strongest for bradykinesia symptoms. Adjusting for disease and symptom duration did not alter results. ConclusionsThe presence of OH in PWP impacts the links between white matter lesion volume and motor symptom burden. These findings may provide a potential mechanism underlying the poorer disease prognosis among PWP with OH.

ATP1A3-related syndromes represent a continuously expanding clinical spectrum and present with an extraordinarily wide range of symptoms. New phenotypes continue to emerge, posing ongoing challenges for both diagnosis and development of treatments. In this context, telemedicine offers a unique opportunity to greatly expand outreach to patients. Remote, high-resolution assessments help refine phenotypic characterization and the identification of novel and intermediate phenotypes. In this study we aimed to determine completion rates and practicality of conducting motor, speech, and neuropsychological assessments entirely via virtual visits. Although the broader recruitment included several ATP1A3-related disorders, this virtual battery was specifically developed for subjects with RDP. Participants with other ATP1A3 phenotypes enrolled in the study contributed to evaluating the overall feasibility of the workflow but were not the target population for the full battery. We recruited individuals with suspected or confirmed diagnosis of ATP1A3-related disorders, along with familial controls, from three participant clinical sites. Participants completed all study procedures through scheduled telemedicine visits using their personal devices (tablets, laptops, smartphones). A total of 59 participants were enrolled, including 46 individuals with suspected or confirmed ATP1A3 variants and 13 family member controls. Among affected patients, 18 had RDP, 12 AHC (Alternating Hemiplegia of Childhood), 4 CAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss), 10 were categorized as "uncertain" and 2 with "mixed" phenotype (RDP/CAPOS and RDP/AHC). The virtual assessment battery included: (i) patient history questionnaire (PHQ), (ii) structured neurological examination adapted for virtual visits, (iii) speech recording, and (iv) extensive neuropsychological assessment. Feasibility was evaluated based on completion rates for each assessment component. Remote neurological, speech and neurocognitive/psychiatric assessments were completed by most participants with ATP1A3 phenotypes, with completion rates of 78% for motor examination and 87% for speech evaluation. The observed pattern of motor and speech impairments were consistent with prior in-person evaluations, supporting the validity and feasibility for both motor and nonmotor features of remote assessment in complex genetic neurological disease.

Importance: Dementia is common in Parkinson's disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. Objective: To investigate whether visual deficits and genetic factors predict PD dementia. Design: Large prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. Setting: Cases were recruited between 2017-2020 at 35 UK PD clinics. Participants: People with PD without dementia at baseline were included. Main outcomes and measures: Visual function was measured using a web-based platform. The main outcome measure was global cognition, measured as the Montreal Cognitive Assessment (MoCA). Blood samples were collected for genetics. Results: 450 patients with PD were included. Mean age of PD patients was 71.7 (SD=7.8), 68% male. Mean baseline MoCA was 27.7 (SD=1.7). 263 patients with PD were classed as poor-vision based on baseline visual tests: mean age 74.4 (SD=6.8) compared to 69.7 (SD=7.5) with good-vision. Poor-vision PD patients had higher rates of progression to mild cognitive impairment (PD-MCI) (HR=2.34, CI=1.58-3.48, pFDR=0.00062, age- and sex-corrected). The combination of genetic factors together with vision influenced outcomes. In good-vision PD patients, high-risk GBA1 gene variants were linked with greater progression to PD-MCI (HR=4.61, CI=1.73-12.28, pFDR=0.0068). Polygenic Risk Score (PRS) for both PD and Alzheimer's disease (AD) also modified cognitive survival when combined with vision status. High PD-PRS was associated with greater progression to PD-MCI in good-vision patients (HR=2.66, CI=1.21-5.81, pFDR=0.0381); and high AD-PRS with greater progression to PD-MCI in poor-vision PD patients (HR=1.91, CI=1.10-3.32, pFDR=0.04999). Combining high PD- and AD-PRS, compared to low PD- and AD-PRS in good-vision PD showed even higher progression to PD-MCI (HR=6.14, CI=1.36-27.83, pFDR=0.046). Simulations showed that adding visual and genetic stratification reduced sample size from n=705 to n=160 for clinical trials. Conclusions and relevance: Poor vision in PD predicts progression to PD-MCI and dementia. This combines with the effects of genetic factors including GBA risk variants and PD- and AD-PRS. These findings can enable enrichment of clinical trials for patients at higher risk of PD dementia, for more efficient trial design for interventions to slow progression.

Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal state for Lewy body disorders, with the highest likelihood of long-term conversion to a clinical diagnosis of either Parkinsons disease (PD) or dementia with Lewy bodies (DLB). There is heterogeneity in the neuropathophysiology of iRBD that may have prognostic significance regarding the ultimate clinical features, and previous research has not focused on iRBD biologically defined as having neuronal synuclein disease (NSD) present. Parkinsons Progression Markers Initiative (PPMI) is a longitudinal, observational, multi-center natural history study. PPMI participants with recently-diagnosed, polysomnogram-confirmed iRBD and who were cerebrospinal fluid neuronal -synuclein seed amplification assay positive without a clinical diagnosis of PD or DLB, were examined for the clinical characteristics of prodromal PD and DLB, including mild cognitive impairment (MCI), subthreshold parkinsonism, and a range of neuropsychiatric, autonomic and sensory symptoms, and compared with a group of internal, robust healthy controls (HCs). iRBD participants (N=197) performed worse cognitively than the HC group (N=136), including on a cognitive summary score (p<0.0003, effect size = 0.41). In addition, the iRBD group was more likely to have subthreshold parkinsonism (odds ratio = 24.5, p<0.0001), neuropsychiatric symptoms (odds ratio = 3.5, p<0.0001), autonomic symptoms (odds ratio = 7.2, p<0.0001) and sensory symptoms (odds ratio = 13.2, p<0.0001) compared with the HCs. In the iRBD group, the most common symptoms or features were hyposmia (75%), pain (54%), urinary problems (52%), constipation (49%), lightheadedness (40%) and anxiety (36%). In contrast, rates of mild cognitive impairment (MCI; 32%), subthreshold parkinsonism (27%) and psychosis (7%) were lower. iRBD participants with an abnormal dopamine transporter SPECT scan (DaTscan) had higher anxiety scores and more frequent antidepressant use than those with a normal DaTscan. Only 10% of iRBD participants met diagnostic criteria for prodromal DLB criteria due to the requirement for MCI as a defining feature. However, treating MCI as just one of five possible clinical domains, multi-domain impairment in wide-ranging combinations affected the majority of iRBD participants. In summary, persons with iRBD and positive CSF neuronal -synuclein testing, but without a clinically-diagnosed neurodegenerative disorder, have cognitive deficits of moderate effect size, and also have elevated rates of subthreshold parkinsonism and symptoms across neuropsychiatric, autonomic, and sensory domains, compared with healthy controls. These findings highlight the importance of assessing multiple clinical domains and symptoms in early biologically-defined synuclein disease without a formal neurodegenerative disease diagnosis, and not anchoring diagnostic criteria solely to motor symptoms or cognitive impairment.

BackgroundAggregation of -synuclein is a central pathological feature of Parkinsons disease (PD), yet reliable and broadly applicable fluid biomarkers reflecting disease-relevant -synuclein biology remain limited. We aimed to establish acetylated -synuclein (Ac-Syn), the predominant proteoform in vivo, as a novel biomarker for PD and to evaluate its diagnostic utility based on a sensitive immunoassay. MethodsUsing a single molecule array technique capable of quantitatively detecting N-terminally acetylated -synuclein, plasma Ac-Syn levels were measured in 110 samples obtained from 52 patients with PD, 24 patients with multiple system atrophy (MSA), and 34 healthy controls (HCs). In a subset of PD patients, plasma Ac-Syn measurements and 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy were performed in the same individuals, enabling direct comparison between these two testing modalities. Ac-Syn levels were also quantified in 91 cerebrospinal fluid (CSF) samples obtained from 51 patients with PD, 25 patients with MSA, and 15 non-parkinsonian disease controls (DCs). ResultsPlasma Ac-Syn levels robustly differentiated PD from both MSA and HCs (p < 0.0001). Receiver operating characteristic analysis demonstrated high diagnostic performance (area under the curve [AUC] = 0.89 for PD vs MSA; AUC = 0.94 for PD vs HCs), comparable to established imaging biomarkers. In the same individuals, plasma Ac-Syn levels correlated with the heart-to-mediastinum ratio derived from MIBG cardiac scintigraphy. CSF Ac-Syn levels also clearly differentiated PD from both MSA and DCs (p < 0.0001), with high diagnostic performance (AUC = 0.85 for PD vs MSA; AUC = 0.93 for PD vs DCs), supporting the biological relevance of plasma Ac-Syn as a biomarker. ConclusionThis study identifies Ac-Syn in plasma as a novel biomarker for PD, enabled by quantitative immunoassay-based detection. Plasma Ac-Syn represents a practical and minimally invasive biomarker that supports biology-based diagnosis of PD and discrimination from MSA.

BackgroundMisdiagnoses of multiple system atrophy (MSA) and Parkinsons disease (PD) remain common due to overlapping clinical features. ObjectiveTo develop and assess a skin -synuclein seed amplification assay (Syn-SAA) for detecting pathological -synuclein and distinguishing MSA from PD. MethodsIn this blinded, cross-sectional study conducted across two laboratories, 308 skin biopsies from 117 participants were analyzed using a standardized Syn-SAA protocol. The cohort included 42 PD, 31 MSA, 30 controls, and 14 with progressive supranuclear palsy (PSP). Biopsies were obtained from up to four anatomical sites and positivity was defined as [&ge;]75% positive replicates. Kinetic parameters were analyzed to differentiate PD and MSA, and clinical features were correlated with Syn-SAA positivity. Fibril morphology from amplified skin samples was compared to postmortem brain using proteinase K digestion and electron microscopy. ResultsSyn-SAA detected synucleinopathy in 86% of PD and 77% of MSA patients, with 90% specificity versus controls and 86% versus PSP. ROC analysis showed that maximum fluorescence (Fmax, AUC = 0.93) and lag time (AUC = 0.91) distinguished PD from MSA at the biopsy level. A 50% mean Fmax cutoff across positive samples accurately differentiated synucleinopathies with 90% sensitivity and 85% specificity. Syn-SAA positivity correlated with RBD in both disorders and with autonomic features in MSA. Amplified fibrils displayed distinct structural and proteolytic profiles between PD and MSA, consistent with brain-derived aggregates. ConclusionSkin Syn-SAA detects pathological -synuclein in living patients with high accuracy and distinguishes MSA from PD based on assay kinetics and fibril strain properties.

Neurodegenerative diseases often feature a prolonged presymptomatic phase during which pathological processes evolve before overt clinical manifestation. In Amyotrophic lateral sclerosis (ALS), defining this prodromal period is critical for identifying early disease features and the optimal window for intervention, yet it remains poorly characterised. In this cross-sectional study, we compared 475 ALS patients with 285 controls recruiting across 20 ALS expert centres in Germany and Switzerland. Participants completed a structured digital questionnaire capturing prodromal complaints, healthcare utilisation, comorbidities, lifestyle factors, and weight changes during the 10 years preceding ALS symptom onset. ALS patients reported substantially higher burden of prodromal complaints than controls (OR=7.50, 95% CI 4.27-13.17; P < 0.001; Padj < 0.001), particularly neuro-motor, sensory, and pain-related symptoms. Prior to symptom onset, ALS patients more frequently consulted neurologists (OR=1.26, CI 1.10-1.44; P < 0.001; Padj = 0.007). Speech therapy consultations were significantly more common among female patients (OR = 2.35, CI 1.05-5.28; P = 0.038) and those with bulbar-onset ALS (OR = 8.67, CI 3.80-19.77; P < 0.001). Prodromal musculoskeletal dysfunction was more frequently reported by ALS patients and exhibited sex- and site-specific patterns. Herniated discs were reported more often by male ALS patients (OR=2.21, CI 1.04-4.68; P = 0.038) and by those with spinal-onset disease (OR=2.32, CI 1.38-3.93; P = 0.002). ALS patients more often completed lower secondary education (OR=1.93, CI 1.24-3.01; P = 0.004; Padj = 0.020) and were more likely to have worked in physically demanding occupations (OR=2.21, CI 1.42-3.43; P < 0.001; Padj = 0.003). Lifestyle factors differed significantly, with higher prior consumption of caffeine (OR=7.21, CI 3.27-15.89; P < 0.001; Padj < 0.001), alcohol (OR=2.25, CI 1.47-3.43; P < 0.001; Padj = 0.002), and cigarettes (OR=1.64, CI 1.20-2.24; P = 0.002) among ALS patients (Padj = 0.011). Weight trajectories differed by sex (P = 0.009), with male ALS patients showing significant loss already during the pre-onset phase (P < 0.001). These findings demonstrate that ALS is preceded by a distinct prodromal phase characterised by mild motor impairment, altered healthcare engagement, and sex- and site-specific patterns in comorbidities, lifestyle, and metabolic change. Characterising these early features of ALS may facilitate earlier diagnosis and enable timely enrolment in clinical trials.

BackgroundRhythmic movement training offers promise as a cognitive and motor intervention tool in Huntingtons disease (HD). HD-DRUM is a tablet-based application for the training of paced movements. Feasibility of 8 weeks of remote HD-DRUM compared with usual-activity control was assessed in a two-arm, randomised controlled trial (RCT) in people with HD. HD-DRUM related changes in quantitative motor and cognitive functions, mood, and brain microstructure were explored. ObjectivesTo assess acceptability of HD-DRUM and feasibility (recruitment, retention, adherence) of an effectiveness RCT. To gain estimates of HD-DRUM-related effect sizes on cognition, motor functions, mood and to explore training mechanism and impact on brain microstructure. MethodsFifty-four individuals with HD, confirmed by genetic testing and/or clinical diagnosis (age, sex, TFC, HD-ISS), were randomised into either HD-DRUM (n = 31) or usual-activity control (n = 23) groups. Participants underwent quantitative motor (q-Motor) and working memory/executive function assessments and diffusion-weighted MRI imaging before and after the 8 weeks period. Group differences of changes in motor and cognitive performance were explored with 95% confidence intervals and those in whole brain microstructure with Tract-Based-Spatial-Statistics of diffusion MRI data. ResultsAcceptability of HD-DRUM, retention, and adherence rates averages were high (>80%) and target recruitment was exceeded. HD-DRUM-related improvements in paced tapping and in brain microstructure, suggestive of a slowing of white matter decline, were observed. ConclusionsHD-DRUM, a remote rhythmic movement app, was feasible and acceptable in people with HD. HD-DRUM holds the potential for a low cost, accessible intervention for maintenance of movements and brain microstructure in HD.