Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disorder characterized by misfolded ataxin-3 aggregation and neuronal intranuclear inclusions. Its primary symptom is progressive ataxia, progressively restricting daily living activities. While repetitive transcranial magnetic stimulation (rTMS) may alleviate symptoms, the effects and mechanisms of specific rTMS paradigms, particularly intermittent and continuous theta burst stimulation (iTBS/cTBS), remain unclear in SCA3. This study therefore aimed to investigate the impacts of iTBS and cTBS on motor coordination, cerebellar neuroinflammation, and autophagy in SCA3 transgenic mice. Thirty 14-week-old SCA3 transgenic mice were randomly divided into sham, cTBS, and iTBS groups. Cerebellar stimulation was delivered at 30

BACKGROUND:No disease-modifying treatments exist for the cerebellar subtype of multiple system atrophy (MSA-C). Because transcranial alternating current stimulation (tACS) has demonstrated safety and efficacy in spinocerebellar ataxia type 3, a cerebellar disorder, we tested whether tACS improves clinical outcomes in MSA-C. METHODS:We conducted a randomized, double-blind, placebo-controlled trial of tACS in MSA-C. Participants received daily 40-minute sessions of 70 Hz, 2 mA tACS or sham stimulation, 5 days/week for 2 weeks. The primary outcome was the change from baseline to 2 weeks in the Unified Multiple System Atrophy Rating Scale (UMSARS) total score. Secondary assessments included the Scale for the Assessment and Rating of Ataxia (SARA), Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT), MSA quality of life (MSA-QoL), gait analysis, and fMRI. RESULTS:The primary endpoint-the change from baseline in UMSARS scores-favored active stimulation: A-tACS -4.48 (4.64) versus S-tACS 0.30 (3.98), with a mean difference of -4.78 (95% CI -6.61 to -2.94), P < 0.001. No treatment-related serious adverse events were reported. Active tACS also improved SARA and gait outcomes but not SCOPA-AUT or MSA-QoL. In exploratory fMRI analyses, no between-group effects survived FDR correction at the whole-connectome edgewise or network-pair level. A subsequent post hoc seed-based screen identified comparatively extensive connectivity-change patterns for Left Frontal Control (ContB.PFClv) and Default Mode (DefaultB.PFCd) parcels; because the seed screen was not corrected across the full 400-seed search space, these findings are hypothesis-generating rather than confirmatory. CONCLUSION:Our results show that tACS produced a statistically significant clinical improvement in MSA-C and was well tolerated. The underlying mechanisms may include enhanced brain network function.

Spinocerebellar ataxia type 3 (SCA3) is a rare monogenic hereditary neurodegenerative disease. It is the most common form of spinocerebellar ataxia worldwide, with diplopia being one of its most frequent symptoms. Diplopia has been reported to be associated with clinical phenotypes and daily living activities in various neurodegenerative diseases. Our objective is to investigate the association between diplopia and the clinical phenotype of SCA3. We conducted a retrospective analysis of 182 patients with SCA3. Participants were categorized into two groups based on the presence or absence of diplopia: the diplopia group and the non-diplopia group. We used the Mann-Whitney U test to analyze phenotypic differences between the groups. We performed univariate and multivariate logistic regression analyses to identify factors associated with diplopia. In this study, the frequency of diplopia among subjects was 45.6

Background Peripheral metabolic dysregulation is increasingly recognized in neurodegenerative disorders, but its contribution to spinocerebellar ataxia type 3 (SCA3) remains unclear. Objectives To characterize peripheral metabolic alterations in SCA3 patients, evaluate their diagnostic potential, and assess their association with SCA3 genotypes/phenotypes. Methods The cross-sectional study enrolled 101 SCA3 patients and 101 healthy controls, assessing the alterations of 24 metabolic markers in peripheral blood. ROC curve analysis was performed to evaluate the capacity of these markers to differentiate SCA3 patients from controls. Spearman's correlations and linear regressions were conducted to explore the relationships between the metabolic markers and SCA3 genotypes/phenotypes. Results TBil, IBil, AST, LDH, HbA1c, Glu, TC, HDL-C, and Apo-A1 were significantly different in SCA3 (FDR-corrected P < 0.05). A panel of five metabolic markers distinguished SCA3 from controls (AUC = 0.879). The finding was validated in an independent SCA3 cohort (AUC = 0.836). Spearman's analysis showed ALT and Urea positively with AAO; bilirubins negatively with CAG; glucose/lipid markers positively with AAO and negatively with CAG; liver markers positively with ICARS (all P < 0.05). Regression analyses revealed that CAG predominantly impacted bilirubin levels (P = 0.001). AAO primarily affected renal function (P = 0.003). Conversely, AAO was significantly influenced by renal function (P = 0.004) and glucose levels (P = 0.003). Furthermore, lipid metabolism increased with disease duration (P = 0.003), and liver function was found to influence ICARS (P = 0.041). Conclusions Peripheral metabolic changes in SCA3 show strong links to genotypes/phenotypes, supporting their clinical and mechanistic relevance.

Abstract Background Spinocerebellar ataxia type 3 (SCA3) is one of the most prevalent hereditary neurodegenerative disorders, with respiratory failure being the leading cause of mortality. Nevertheless, pulmonary function in SCA3 has not been thoroughly characterized, and the underlying mechanisms remain unclear. Methods We conducted pulmonary function tests in both patients and healthy controls, as well as in SCA3 mice and wild-type mice. In participants, we used diaphragm ultrasonography to evaluate diaphragmatic dysfunction. We examined clinical features and inflammatory biomarkers to identify independent associations with pulmonary function. We also performed histopathological and immunohistochemical analyses on lung tissues from SCA3 mice to assess the presence of chronic airway inflammation. Results We enrolled 102 patients and 91 healthy controls for pulmonary function testing. For blood biomarker analyses, SCA3 participants with available blood data were drawn from the same patient cohort and were compared with an independent cohort of 88 age- and sex-matched healthy controls, distinct from the pulmonary-function controls. Compared with controls, patients showed significant reductions in FVC (P < 0.001), FEV1 (P < 0.001), DLco-SB (P = 0.015), and small-airway flow indices (P < 0.05), along with an increased RV/TLC ratio (P < 0.001), indicating subclinical pulmonary dysfunction. Impaired pulmonary function, defined according to prespecified criteria, was identified in 71/102 (69.6%) patients versus 0/91 controls (P < 0.001). Pulmonary impairment was associated with ataxia severity (SARA: OR = 1.196, 95% CI 1.038–1.376; P = 0.013). Diaphragm ultrasound showed preserved diaphragmatic function, whereas systemic inflammatory markers were associated with reduced pulmonary function, with NLR inversely correlated with MEF25 (ρ =–0.272, P = 0.010). In SCA3 mice (n = 4) compared with wild-type mice (n = 3), pulmonary function abnormalities and lung pathology were consistent with airway inflammatory changes. Conclusion SCA3 is associated with early, subclinical pulmonary dysfunction that worsens with disease progression. Chronic inflammation in the small airways may be involved in this process. Our findings underscore the need for early intervention with chest physiotherapy and respiratory training as part of the clinical management of SCA3.

Cognitive impairment (CI) has been reported in spinocerebellar ataxia 3 (SCA3). However, the link between alterations in intrinsic brain activity and cognitive functions remains poorly understood. This study aimed to explore these alterations and their association with cognitive functions to elucidate the pathophysiological mechanisms underlying CI in SCA3. Eighty-four SCA3 patients and 41 healthy controls (HCs) were enrolled. Patients were classified into CI and non-CI groups based on their neuropsychological test performance relative to HCs. We calculated resting-state fMRI (rs-fMRI) metrics, including amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and degree centrality (DC), and compared them between the two patient groups. Whole-brain correlation analyses were used to explore the neural correlates of cognitive deficits by correlating rs-fMRI metrics with composite cognitive z-scores. Compared to SCA3 patients without CI, those with CI showed: (1) increased ALFF in fronto-striatal regions and decreased ALFF in the default mode network; (2) decreased fALFF in the dorsolateral prefrontal cortex but increased fALFF in the supplementary motor area and paracentral lobule; (3) increased ReHo in cerebellar cognitive regions; and (4) reduced DC in the left putamen, insula, and superior frontal gyrus. These alterations were primarily located within the cortico-striato-thalamo-cortical loop and cerebellar cognitive regions. Whole-brain correlation analyses confirmed that these rs-fMRI metric alterations correlated with cognitive performance. Our study revealed distinct patterns of spontaneous brain activity associated with cognitive impairment in SCA3. These findings provide novel imaging evidence for the pathophysiological mechanisms underlying cognitive decline in these patients.

This study developed a wearable gait analysis system to collect gait data from 71 Spinocerebellar Ataxia Type 3 (SCA3) patients and 38 age-, height-, and weight-matched healthy controls (HC). We aimed to identify key gait parameters distinguishing SCA3 from HC and examine their correlations with clinical ataxia scales. Gait variability parameters, including Stride Time SD, Single Support SD, Double Support SD, and Toe-out Angle SD, showed high discriminative power (AUC 0.820–0.840) with large effect sizes. These parameters were significantly correlated with SARA and ICARS total scores, as well as disease duration. They not only effectively separated SCA3 patients from HC but also stratified SCA3 severity into mild and moderate subgroups based on SARA scores. The wearable smart insole system provides reliable gait measurements that correlate with clinical severity, supporting its potential clinical utility for objective assessment of SCA3 progression and severity.

Background Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder, with balance instability as a feature of the disease. Balance instability often manifests before the onset of obvious ataxic symptoms in patients. However, current clinical scales exhibit limited sensitivity in characterizing changes in pre-ataxic patients. Objectives Our research aims to identify appropriate postural characteristics for tracking motor changes in pre-ataxic patients with SCA3 over time. Methods The posturographic platform assessed 102 participants (34 pre-ataxic SCA3 patients, 34 ataxic patients with SCA3, and 34 healthy controls) to measure their postural balance. Multivariate comparative analyses assessed the differential postural characteristics across the three groups. The Taiwanese formula was employed to estimate the age of onset for pre-ataxic patients. A Spearman's rho test was employed to assess correlations between postural characteristics and the time manifestation for pre-ataxic patients. Results Compared to the healthy control group, we observed significant abnormalities in the static posture of pre-ataxic patients (P < 0.01). Compared to the pre-ataxic group, ataxic patients have significant abnormalities in all variables (P < 0.05). The sway range standard deviation (SD), total sway area, and limits of stability were positively correlated with the estimated time to onset. The total sway area is more closely associated with time to manifestation, whereas the sway range SD in the medial-lateral direction of the center of foot pressure is the most sensitive indicator of postural instability in pre-ataxic patients. Conclusion Static posture instability is a sensitive diagnostic parameter that may assist in capturing disease progression in the pre-ataxic stage of SCA3. (c) 2025 International Parkinson and Movement Disorder Society.

Background: Spinocerebellar ataxia type 3 (SCA3) is the most common form of autosomal dominant cerebellar ataxia. Intergenerational genetic instability is a common phenomenon in autosomal dominant genetic disorders, including SCA3, SCA2, and Huntington's disease (HD). Parental gender has been shown to influence genetic instability in offspring, though this remains a point of debate in SCA3. Methods: We enrolled 160 participants from OSCCAR between 2014 and 2023. Genomic DNA was extracted from blood samples using Qiagen's QIAamp kit. The number of CAG repeats in the ATXN3 gene was determined using PCR and Sanger sequencing. We analyzed categorical variables with Chi-square tests, normally distributed variables with independent samples t-tests, and non-normally distributed variables with Mann-Whitney U tests. Multifactorial regression analysis was conducted to evaluate the impact of parental gender on offspring deltaexpanded CAG repeats and genetic anticipation. Results: In 160 parent-offspring transmissions, 129 cases displayed genetic instability, including 95 expansions and 34 contractions. Genetic instability was significantly higher in paternal transmissions (89.87 %) compared to maternal transmissions (71.6 %). The mean expCAG in offspring exceeded that of parents. Among 40 cases with documented anticipation, the mean was 12.95 +/- 8.5 years, with paternal inheritance associated with an earlier onset (t = -4.11, p = 0.001). Parental gender significantly influenced both delta-expCAG (p = 0.012; (3 = 2.71) and offspring anticipation (p = 0.045; (3 = 5.67). Conclusion: Intergenerational genetic instability is highly prevalent in SCA3. Parental gender plays a significant role in determining offspring delta-expCAG and genetic anticipation, with paternal transmission showing greater instability and earlier onset.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder characterized by the accumulation of polyglutamylated ATXN3 protein within neurons, which can potentially compromise the integrity of the brain's glymphatic system. Our objective is to investigate whether glymphatic function is impaired in patients with SCA3 and its clinical relevance. This study recruited 129 SCA3 subjects, including 98 symptomatic (ataxic SCA3) and 31 presymptomatic (preataxic SCA3) individuals, along with 67 healthy controls (HCs). We calculated the index for diffusion tensor image analysis along the perivascular space (DTI-ALPS) across groups and examined its correlation with SCA3 clinical features. Except for the left cerebral hemisphere DTI-ALPS index showing no statistically significant difference between HC and preataxic SCA3, statistically significant differences in ALPS index were observed among the remaining three groups. The DTI-ALPS index decreased in the order HC group > preataxic SCA3 group > ataxic SCA3 group. The Ataxic SCA3 group exhibited a significantly lower DTI-ALPS index than the HC group. The mean DTI-ALPS index showed negative correlations with the Scale for the Assessment and Rating of Ataxia (SARA) scores and International Cooperative Ataxia Rating Scale (ICARS) scores. In this study, we demonstrate that glymphatic waste clearance is impaired in SCA3 and that the magnitude of ALPS-detected dysfunction parallels clinical burden. DTI-ALPS may serve as a potential indicator for evaluating glymphatic system alterations and disease.

BACKGROUND:Spinocerebellar Ataxia Type 3 (SCA3), the most common hereditary ataxia in China, is characterized by progressive gait dysfunction. While quantitative gait analysis provides critical insights into movement disorder management, conventional motion capture systems are often cost-prohibitive and impractical for clinical use. OBJECTIVES:We propose using the markerless Azure Kinect, a cost-effective and portable tool for gait analysis, to detect SCA3-specific gait patterns and identify gait parameters associated with disease severity and duration. METHODS:We enrolled 38 patients with SCA3 patients and 42 healthy controls (HCs). Gait was recorded using an Azure Kinect. Multiple gait parameters were computed and compared with t-tests/Mann-Whitney U tests. The receiver operating characteristic (ROC) analysis identified discriminatory biomarkers, while Pearson's test assessed gait-clinical characteristic associations. RESULTS:Patients with SCA3 exhibited increased mediolateral margins of stability (MOS, p < 0.01), wider step width (p < 0.001), shorter stride length (p = 0.003), slower gait speed (p = 0.007), and reduced hip/knee/ankle joint angles (p < 0.05) compared to HCs. Step width demonstrated the highest diagnostic accuracy (AUC = 0.878, cutoff = 0.197). Increased medial-lateral MOS was negatively correlated with step length (r = -0.52∼-0.45, P < 0.005). Minimal hip frontal angles negatively correlated with SARA scores (r = -0.46, p = 0.004) and disease duration (r = -0.35, p = 0.028), reflecting a progressive cerebellar degeneration. CONCLUSION:In SCA3, gait abnormalities such as increased step width and shortened stride length indicate compensatory adaptations exist to enhance dynamic stability. Step width is identified as a sensitive biomarker for SCA3 screening.

Abstract Background Spinocerebellar ataxia type 3 (SCA3) is a hereditary disease caused by abnormally expanded CAG repeats in the ATXN3 gene. The study aimed to identify potential biomarkers for assessing therapeutic efficacy by investigating the associations between expanded CAG repeat size, brain and spinal cord volume loss, and motor functions in patients with SCA3. Methods In this prospective, cross-observational study, we analyzed 3D T1-weighted MRIs from 92 patients with SCA3 and 42 healthy controls using voxel-based morphometry and region of interest approaches. Associations between expanded CAG repeat size, brain and spinal cord volume loss, and International Cooperative Ataxia Rating Scale (ICARS) scores were investigated using partial correlation and mediation analyses. Sample sizes of potential biomarkers were calculated. Results Compared with healthy controls, SCA3 patients had lower cerebellar volume and cervical spinal cord area. SCA3 patients evolved along a stage-independent decline that began in the cerebellum, progressed to spinal cord, brainstem, thalami, and basal ganglia, and extensive subcortex. Expanded CAG repeat size was associated with right cerebellar lobule IV volume (r = − 0.423, P < 0.001) and cervical spinal cord area (r = − 0.405, P < 0.001), and higher ICARS (r = 0.416, P < 0.001). Mediation analysis revealed an indirect effect of expanded CAG repeat size on ICARS through spinal cord. Sample sizes estimation revealed that a minimum sample size was achieved with spinal cord measures. Conclusions Our results indicate the potential of cervical spinal cord area as a biomarker for disease progression and a minimum sample size estimation in future clinical studies of SCA3.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) and the cerebellar subtype of multiple system atrophy (MSA-C) both manifest with cerebellar ataxia and postural instability in the early stages, leading to considerable clinical overlap and frequent misdiagnosis or delayed intervention. Current diagnostic tools offer limited support when genetic confirmation is unavailable or neuroimaging findings are inconclusive. Clinical rating scales, while commonly used, rely heavily on subjective judgment and lack sensitivity to dynamic monitoring. Therefore, this study aims to develop an interpretable machine learning model based on gait and postural features acquired through wearable sensors, in order to assist in distinguishing SCA3 from MSA-C and to explore their potential as digital biomarkers for clinical application. METHODS: This study included 74 individuals diagnosed with SCA3, 43 individuals with multiple system atrophy of MSA-C, and 45 age-matched healthy controls (HC). All participants were in the mild to moderate stages of disease. Gait and postural control data were collected using a wearable smart insole system, and 98 digital features were extracted. Classification models were developed using XGBoost, LightGBM, random forest, and logistic regression. To enhance model interpretability, SHapley Additive exPlanations (SHAP) were applied to quantify the contribution of each feature and to identify the most informative digital biomarkers. RESULT: Among all models, LightGBM achieved the highest accuracy (95.91%) and ROC-AUC (0.9962). SHAP analysis identified Cadence CV and center of pressure (COP) features under eyes-closed (EC) conditions as top contributors across all models, supporting their potential as digital biomarkers. Gait and postural features provided complementary information. Even at mild to moderate disease stages, individuals with SCA3 and those with MSA-C showed distinguishable motor patterns. Specifically, individuals with SCA3 exhibited greater medio-lateral (ML) postural instability under visual deprivation, while those with MSA-C showed increased variability in gait rhythm, indicating distinct movement phenotypes. CONCLUSION: The integration of gait and postural stability features with interpretable machine learning models enables effective differentiation between SCA3 and MSA-C. It also facilitates the identification of clinically relevant digital biomarkers, supporting early diagnosis and personalized rehabilitation planning in cerebellar ataxia. Clinical trial number NTC04010214.

Spinocerebellar Ataxia type 3 (SCA3) is a widely recognized autosomal dominant disorder characterized by cerebellar ataxia, particularly prevalent in China. Dysphagia frequently arises in SCA3 and other neurological disorders, representing a significant threat to patient survival. Examining the Prevalence of Dysphagia among SCA3 Patients and Its correlation with Clinical phenotype and Disease Progression. We retrospectively analyzed 183 SCA3 patients, divided into dysphagia and non-dysphagia groups. Dysphagia, as an item within INAS, was assessed by ataxia specialists primarily based on patient-reported symptoms, supplemented by caregiver or family input when available. Spearman's rho tested factor associations with dysphagia, logistic regression identified dysphagia risk factors, and multivariable linear regression assessed dysphagia's effect on ataxia severity. Kaplan–Meier curves with first derivative fitting explored dysphagia progression over the disease duration. The study found 77.0

Background Spinocerebellar ataxia type 3 (SCA3) is a common autosomal dominant disorder marked by both cognitive and pulmonary dysfunction. Although a connection between these impairments exists, the mechanisms underlying this relationship are not well understood. In this study, we aim to explore the neural and physiological pathways linking pulmonary and cognitive deficits in SCA3 through multimodal integration. Methods Seventy-six SCA3 patients from the OSCCAR cohort underwent assessments including pulmonary function testing (classified as normal [NPF] or impaired [IPF]), cognitive evaluations (MoCA, MMSE, CVLT-II), and multimodal MRI (3T Siemens). Structural brain volumes were analyzed using CAT12/SPM12, and resting-state functional connectivity was assessed with the CONN toolbox. Mediation analysis was employed to determine whether gray matter volume mediated the relationship between pulmonary and cognitive impairments. Results SCA3 patients with IPF exhibited global cognition and verbal memory that is significantly worse compared to those with NPF. For example, recall-discrimination decreases, intrusions increase, and forget quickly ( p < 0.05). IPF patients also had significant gray matter atrophy, predominantly in temporal regions (β = −0.16 to − 0.91, p < 0.05), extending to the frontal, parietal, insular, and cerebellar areas (β = −0.03 to − 0.34, p < 0.05). Additionally, the connectivity between rITG-medial temporal and intra-cerebellar was impaired (β ≤ −0.21, p < 0.05). Conclusion Pulmonary dysfunction in SCA3 is associated with greater cognitive impairment and cortical gray matter atrophy. Our findings suggest that gray matter volume may serve as a mediator in the pathway linking pulmonary and cognitive dysfunction.

Neuroinflammation plays a recognized role in the pathogenesis of Spinocerebellar Ataxia Type 3 (SCA3). However, the involvement of systemic inflammatory responses in SCA3 remains poorly defined. Our study aimed to characterize peripheral inflammation in patients with SCA3, examine the relationship between peripheral inflammatory biomarkers and clinical/genetic features, and evaluate the diagnostic utility of these markers. The cross-sectional study enrolled 101 patients with SCA3 and 101 healthy controls (HCs). The differences in peripheral inflammatory markers between patients with SCA3 and HCs were assessed. Multivariate linear regressions were used to analyze the associations between blood cell count–derived indices, C-reactive protein (CRP), and clinical/genetic features of SCA3. ROC curves were conducted to assess the potential of these markers to distinguish patients with SCA3 from HCs. Compared to HCs, patients with SCA3 exhibited significantly higher levels of leukocytes, neutrophils, monocytes, platelets, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), systemic inflammatory index (SII), systemic inflammatory composite index (AISI), and CRP (adj. p < 0.05). Age influenced lgCRP, NLR, MLR, and lg(neutrophil-to-platelet ratio) (p < 0.05). CAG affected MLR and AISI (p < 0.05). The combination of BMI, monocytes, NLR, and SII differentiated patients with SCA3 from HCs (AUC = 0.779). Patients with SCA3 display distinct peripheral inflammatory profiles, which correlate with clinical/genetic factors. These peripheral inflammatory markers hold promise as potential tools for diagnosing and monitoring SCA3.

OBJECTIVE:Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, inherited neurodegenerative disorder caused by the expansion of cytosine-adenine-guanine repeats in ATN1. Most studies on DRPLA to date are limited to case reports. We aimed to provide a comprehensive summary of the clinical, genetic, biological, and magnetic resonance imaging characteristics of DRPLA using cross-sectional baseline data. METHODS:This is a cross-sectional observational cohort study. We used an extensive battery of assessments, included clinical phenotypes, genotypes, cognitive performance, biological markers, and magnetic resonance imaging characteristics. RESULTS:We enrolled 116 DRPLA patients, including 96 manifest patients and 20 prodromal patients. We identified a previously unreported ATN1 haplotype consisting of 8 single-nucleotide polymorphisms. Cognitive assessments revealed that 51 manifest patients (96%) and 4 prodromal patients (29%) scored <26 on the Montreal Cognitive Assessment. Manifest patients showed impairments across all cognitive domains, whereas prodromal patients showed deficits only in phonemic fluency. Biological analyses showed significantly elevated plasma neurofilament light levels in manifest patients compared with prodromal patients (P < 0.001) and healthy controls (P < 0.001). Magnetic resonance imaging findings revealed widespread gray matter loss across the whole brain in manifest patients, whereas prodromal patients showed gray matter loss localized to the bilateral cerebellar hemispheres. INTERPRETATION:This is the first DRPLA cohort study to comprehensively report clinical, genetic, cognitive, imaging, and plasma neurofilament light data. This study provides robust data to enhance our understanding of the overall features of DRPLA. We also propose clear definitions for the preclinical stage of DRPLA, and demonstrate the high diagnostic utility of plasma neurofilament light as a biomarker. ANN NEUROL 2025;98:750-761.