Tetsuo Ashizawa

Objective: Neurochemical levels measured by brain MR spectroscopy (MRS) have been proposed as endpoints for clinical trials in early‐stage spinocerebellar ataxia (SCA) trials. We tested their trial‐readiness by quantifying neurochemicals in three affected brain regions in early‐stage cohorts of SCA2 and SCA3, examining their reproducibility in both patients and controls in a multisite/multivendor setting, and determining if the same neurochemical outcomes can be used as endpoints for different SCA genotypes. Methods: Seventy‐two participants (18 SCA2, mean Scale for the Assessment and Rating of Ataxia (SARA) = 9 +/− 5; 25 SCA3, mean SARA = 10 +/− 6; 29 controls) underwent 3 T scans at four sites using scanners from two vendors and a harmonized MRS protocol. Scans were performed twice with a maximum 2‐week interval. We measured neurochemical concentrations in the cerebellum, pons, and putamen, and assessed their within‐ and between‐site reproducibility and associations with clinician‐ and patient‐reported outcomes. Results: Test–retest coefficients of variance were comparable across sites and vendors, but concentration estimates had to be adjusted for sites to account for small vendor‐based biases. Total N ‐acetylaspartate (tNAA) and glutamate were lower, and myo ‐inositol (mI) and total creatine (tCr) were higher in the cerebellum and pons in both SCAs vs. controls. Pontine tNAA and mI, and cerebellar tNAA, mI, and glutamate levels were significantly different between SCA2 and SCA3, with strong effect sizes (|Cohen's d | = 1.1–2.1). The tNAA/tCr ratio had the strongest associations with clinical outcomes (|r| ≥ 0.5), with stronger associations in the cerebellum for SCA2 and in the pons for SCA3. Interpretation: These data support the use of tNAA and its ratios in a genotype‐specific manner in early‐stage SCA2 and SCA3 trials in the multisite/multivendor setting.

Spinocerebellar ataxias (SCAs) are heterogeneous neurodegenerative disorders with variable phenotypes. Somatosensory evoked potentials (SSEPs) provide insights into the integrity of the dorsal-lemniscal pathway. This study aimed to evaluate SSEP findings in patients with SCA3 and SCA10 and compare their neurophysiological profiles. We conducted a cross-sectional study including 20 SCA3 patients and 20 SCA10 patients under follow-up at a tertiary ataxia clinic in Southern Brazil. Clinical assessment comprised demographic, genetic, and phenotypic characterization, including the Scale for the Assessment and Rating of Ataxia (SARA). SSEPs were recorded bilaterally after median and tibial nerve stimulation, assessing latencies and amplitudes of N9, N20, N21, and P40 potentials, as well as interpotential intervals. Examinations were classified as normal or abnormal, and abnormalities were categorized. Abnormal SSEPs were detected in 18 SCA3 patients (90%) and in 3 SCA10 patients (15%) ( p < 0.001). In SCA3, abnormalities predominantly involved central generators. In contrast, most SCA10 patients exhibited normal SSEPs, with only a few isolated cortical responses and interval abnormalities. No significant associations were found between SSEP abnormalities and demographic, clinical, imaging, or genetic variables in either group. SCA3 shows widespread somatosensory dysfunction, whereas SCA10 patients, particularly in Southern Brazil, show preserved SSEPs consistent with pure cerebellar ataxia. These findings highlight distinct neurophysiological signatures in SCAs, reinforcing their heterogeneity and supporting SSEPs as candidate markers for differential characterization, requiring validation.

Objective: Spinocerebellar ataxia type 3 (SCA3) is a rare, inherited neurodegenerative disease. Here, we profile the spatial spread of atrophy across the whole brain, determine whether brain degeneration preferentially maps onto specific functional networks, and investigate the relationship between cerebellar and cerebral anatomical changes. Methods: Whole-brain grey and white matter (GM and WM) voxel-based morphometry was performed on 408 individuals with SCA3 (82 pre-ataxic) and 293 controls. The SCA3 cohort was stratified by ataxia severity to investigate disease progression, with cerebellar GM atrophy mapped onto a task-based functional atlas. Volume was correlated with disease duration and intensity. Cerebrocerebellar volumetric covariance was assessed to determine whether atrophy was coupled between infra- and supratentorial regions. Results: The pattern of atrophy is spatially consistent but progressive in magnitude across the disease course. The greatest atrophy was found in the pons, cerebellar WM, and cerebellar peduncles; correlations with disease severity and duration were also strongest in these regions. Cerebellar GM atrophy was greatest in functional regions associated with motor execution and planning, attention, and emotional processing. Sparse cerebral cortical atrophy appears only in the most severe disease subgroup, while striatal atrophy begins in the earliest stages. Reduced cerebrocerebellar structural covariance is observed in SCA3 participants versus controls. Interpretation: While cerebellar and brainstem atrophy become more severe, the pattern of atrophy remains largely consistent as SCA3 progresses. Cerebellar GM degeneration occurs in regions associated with motor, cognitive, and affective control, in line with clinical presentation. Cerebellar atrophy is not directly mirrored by cerebral changes.

Background: The Patient‐Reported Outcome Measure of Ataxia (PROM‐Ataxia) has been validated cross‐sectionally but not longitudinally.Objective: We aimed to validate PROM‐Ataxia as a measure of patient experience of disease over time, examine overall and domain‐specific progression, and test convergent validity with other clinical outcome assessments (COAs).Methods: We derived PROM‐Ataxia data from 176 patients with spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, or 10 in the Clinical Research Consortium for the Study of Cerebellar Ataxia at baseline and 1 year. We classified patients' ataxia severity stage (“severity”) according to the Friedreich's Ataxia Rating Scale Functional Staging into mild, moderate, and severe subgroups. Analyses of the entire cohort and by severity subgroup included internal consistency, sensitivity to disease severity, predictive modeling of score changes, correlations with COAs: Brief Ataxia Rating Scale, Scale for Assessment and Rating of Ataxia, Fatigue Severity Scale, Cerebellar Cognitive Affective Syndrome scale, EuroQol 5‐Dimension, and responsiveness to disease progression.Results: The PROM‐Ataxia exhibited high internal consistency and correlated with other COAs. Scores demonstrated sensitivity to disease severity and evolving patient experience. Progression was sigmoidal, with the greatest change in moderate patients. Compared with other COAs, PROM‐Ataxia captured the most change. Mental features worsened fastest in mild patients, physical in moderate patients, and activities of daily living in severe patients.Conclusion: PROM‐Ataxia is more sensitive to change than ataxia COAs, captures the evolution of patients' experience of disease over 1 year, and reveals domain‐specific progression. Studies of larger cohorts and different ataxia diagnoses over longer periods may provide insights to further enhance clinical care and research. © 2025 International Parkinson and Movement Disorder Society.

Background: Clinical trials for upcoming disease‐modifying therapies of spinocerebellar ataxias (SCA), a group of rare movement disorders, lack endpoints sensitive to early disease progression, when therapeutics will be most effective. In addition, regulatory agencies emphasize the importance of biological outcomes. Objectives: READISCA, a transatlantic clinical trial readiness consortium, investigated whether advanced multimodal magnetic resonance imaging (MRI) detects pathology progression over 6 months in preataxic and early ataxic carriers of SCA mutations. Methods: A total of 44 participants (10 SCA1, 25 SCA3, and 9 controls) prospectively underwent 3‐T MR scanning at baseline and a median [interquartile range] follow‐up of 6.2 [5.9–6.7] months; 44% of SCA participants were preataxic. Blinded analyses of annual changes in structural, diffusion MRI, MR spectroscopy, and the Scale for Assessment and Rating of Ataxia (SARA) were compared between groups using nonparametric testing. Sample sizes were estimated for 6‐month interventional trials with 50% to 100% treatment effect size, leveraging existing large cohort data (186 SCA1, 272 SCA3) for the SARA estimate. Results: Rate of change in microstructural integrity (decrease in fractional anisotropy, increase in diffusivities) in the middle cerebellar peduncle, corona radiata, and superior longitudinal fasciculus significantly differed in SCAs from controls ( P < 0.005), with high effect sizes (Cohen's d = 1–2) and moderate‐to‐high responsiveness (|standardized response mean| = 0.6–0.9) in SCAs. SARA scores did not change, and their rate of change did not differ between groups. Conclusions: Diffusion MRI is sensitive to disease progression at very early‐stage SCA1 and SCA3 and may provide a >5‐fold reduction in sample sizes relative to SARA as endpoint for 6‐month‐long trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Currently doctors rely on tools such as the Unified Parkinson’s Disease Rating Scale (MDS-UDPRS) and the Scale for the Assessment and Rating of Ataxia (SARA) to make diagnoses for movement disorders based on clinical observations of a patient’s motor movement. Observation-based assessments however are inherently subjective and can differ by person. Moreover, different movement disorders show overlapping symptoms, challenging neurologists to make a correct diagnosis based on eyesight alone. In this work, we create an intelligent interface to highlight movements and gestures that are indicative of a movement disorder to observing doctors. First, we analyzed the walking patterns of 43 participants with Parkinson’s Disease (PD), 60 participants with ataxia, and 52 participants with no movement disorder to find ten metrics that can be used to distinguish PD from ataxia. Next, we designed an interface that provides context to the gestures that are relevant to a movement disorder diagnosis. Finally, we surveyed two neurologists (one who specializes in PD and the other who specializes in ataxia) on how useful this interface is for making a diagnosis. Our results not only showcase additional metrics that can be used to evaluate movement disorders quantitatively but also outline steps to be taken when designing an interface for these kinds of diagnostic tasks.

Background: Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated.Objectives: To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life.Methods: Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi‐variable linear regression models to examine the factors contributing to fatigue as well as the association between fatigue and quality of life.Results: Fatigue was most prevalent in SCA3 (52.6%), followed by SCA1 (36.7%), SCA6 (35.7%), and SCA2 (35.6%). SCA cases with fatigue had more severe ataxia and worse depressive symptoms. In SCA3, those with fatigue had a longer disease duration and longer pathological CAG repeat numbers. In multi‐variable models, depressive symptoms, but not ataxia severity, were associated with more severe fatigue. Fatigue, independent of ataxia and depression, contributed to worse quality of life in SCA3 and SCA6 at baseline, and fatigue continued affecting quality of life throughout the disease course in all types of SCA.Conclusions: Fatigue is a common symptom in SCAs and is closely related to depression. Fatigue significantly impacts patients' quality of life. Therefore, screening for fatigue should be considered a part of standard clinical care for SCAs.

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

Background: Video recordings of neurological examinations are often used in clinical trials. The Scale for Assessment and Rating of Ataxia (SARA) is a widely used clinical scale for ataxic patients. Despite several advantages of video ratings, correlation between live ratings and remote video‐ratings has not been systematically investigated.Objective: To compare live and remote video assessment of SARA.Methods: Full SARA examinations of 69 patients with cerebellar ataxia were recorded on video. Live rating from site investigators were compared with remote video rating of three experienced ataxia clinicians using Bland–Altman analysis.Results: Live and remote video ratings showed a high level of agreement for the complete score (bias = 0.09, with standard deviation = 2.00) and all single SARA items (bias <0.20 for all items).Conclusion: Remote video ratings of SARA are a reliable means to assess severity of ataxia.

Background: Severe reduced synaptic density was observed in spinocerebellar ataxia (SCA) in postmortem neuropathology, but in vivo assessment of synaptic loss remains challenging.Objective Spinocerebellar ataxia type 3: The objective of this study was to assess in vivo synaptic loss and its clinical correlates in spinocerebellar ataxia type 3 (SCA3) patients by synaptic vesicle glycoprotein 2A (SV2A)‐positron emission tomography (PET) imaging.Methods: We recruited 74 SCA3 individuals including preataxic and ataxic stages and divided into two cohorts. All participants received SV2A‐PET imaging using ¹⁸F‐SynVesT‐1 for synaptic density assessment. Specifically, cohort 1 received standard PET procedure and quantified neurofilament light chain (NfL), and cohort 2 received simplified PET procedure for exploratory purpose. Bivariate correlation was performed between synaptic loss and clinical as well as genetic assessments.Results: In cohort 1, significant reductions of synaptic density were observed in cerebellum and brainstem in SCA3 ataxia stage compared to preataxic stage and controls. Vermis was found significantly involved in preataxic stage compared to controls. Receiver operating characteristic (ROC) curves highlighted SV2A of vermis, pons, and medulla differentiating preataxic stage from ataxic stage, and SV2A combined with NfL improved the performance. Synaptic density was significantly negatively correlated with disease severity in cerebellum and brainstem (International Co‐operative Ataxia Rating Scale: ρ ranging from −0.467 to −0.667, P ≤ 0.002; Scale of Assessment and Rating of Ataxia: ρ ranging from −0.465 to −0.586, P ≤ 0.002). SV2A reduction tendency of cerebellum and brainstem identified in cohort 1 was observed in cohort 2 with simplified PET procedure.Conclusions: We first identified in vivo synaptic loss was related to disease severity of SCA3, suggesting SV2A PET could be a promising clinical biomarker for disease progression of SCA3. © 2023 International Parkinson and Movement Disorder Society.