Objective:Frequent and objective assessment of ataxia severity is essential for tracking disease progression and evaluating the effectiveness of potential treatments. Wearable-based assessments have emerged as a promising solution. However, existing methods rely on inertial data features directly correlated with subjective and coarse clinician-evaluated rating scales, which serve as imperfect gold standards. This approach may introduce biases and restrict flexibility in feature design. To address these limitations, this study introduces a novel contrastive learning-based model that leverages motor severity differences in wearable inertial data to learn relevant features. Methods:The model was trained on inertial data collected from 87 individuals with diagnostically heterogeneous ataxias and 44 healthy participants performing the finger-to-nose task. A pairwise contrastive loss function was proposed to learn representations capturing relative differences in ataxia severity, which were evaluated through downstream regression and classification tasks. Results:The learned features demonstrated strong cross-sectional (r = 0.84) and longitudinal (r = 0.68) associations with clinical scores and robust measurement reliability (intraclass correlation coefficient = 0.96). Additionally, the model exhibited strong known-group validity, distinguishing between ataxia and healthy phenotypes with an area under the receiver operating characteristic curve of 0.95. Conclusion:The proposed contrastive model captures robust representations of disease severity with reduced reliance on clinical scales, outperforming state-of-the-art methods that derive features directly from clinical scores. Significance:Combining wearable sensors with contrastive learning enables a more objective, scalable, and frequent method for assessing ataxia severity, with the potential to enhance patient monitoring and improve clinical trial efficiency.

IntroductionThe spinocerebellar ataxia composite score (SCACOMS) comprises items from the functional Scale for the Assessment and Rating of Ataxia (f-SARA) and the Clinician Global Impression of Change (CGI-C). In the derivation of SCACOMS, weights reflecting 1-year responsiveness were assigned to each item using partial least squares (PLS) regression modeling. The current objective was to incorporate patient-feedback into the SCACOMS item weights, examine corresponding responsiveness of the composite scale, and discuss potential implications for future use.MethodsItem weights derived by PLS regression were compared to each item's relative importance as assigned by 16 patients with SCA during semi-structured interviews. SCACOMS item weights were adjusted using the following combinations: (1) 50/50 weighted combination of PLS and patient weights and (2) reducing the weight of CGI-C to 20% and averaging individual item weights obtained from each perspective. The 1-year mean to standard deviation ratios (MSDRs) for the resulting reweighted scales were compared, with larger MSDRs indicating greatest sensitivity to disease progression.ResultsThe PLS-derived SCACOMS had the highest MSDR (0.99). When item weights were averaged across the two sources, the resulting MSDR was 0.91. When the weight of CGI-C was set to 20%, reflecting patient preferences for higher weights on the discrete symptoms, the MSDR was 0.79.ConclusionsThis study took a novel approach to enhance the face validity of SCACOMS by incorporating patient feedback into the statistically optimized item weights. The result is the merging of objectively derived item weightings (reflecting optimal scale responsiveness) with patient-assigned relevance. While this update may increase the patient centricity of a composite measure, this comes at the expense of reduced sensitivity. This potential trade-off in sensitivity to detect change should be evaluated in the context of the composite measure's intended use.

The READISCA study aims to prepare for clinical trials in spinocerebellar ataxia types 1 and 3 (SCA1 and SCA3). Hence, we searched for predictive variables of ataxia onset (phenoconversion) and progression. Individuals with SCA1 or SCA3 and controls were enrolled from 2018 to 2021 in the USA and Europe. Clinical scores, MRI measures and neurofilament light chain (NfL) levels were assessed annually for 5 years. In the pre-ataxic group at baseline, we compared phenoconverters with non-converters. A Bayesian mixed model was used to model the longitudinal progression of clinical scores and NfL levels. The impact of data-driven selected baseline variables (demographic, clinical and MRI) on the expected Scale for Assessment and Rating of Ataxia progression was tested. Forty-three controls, 55 SCA1 carriers and 124 SCA3 carriers were included; a subset of the cohort (n = 109) had MRI data. Converters from pre-ataxic to ataxic stages represented 5/22 (22%) and 12/38 (32%) for SCA1 and SCA3, respectively. Converters were more depressed (Patient Health Questionnaire 9: 3.9 ± 2.9 versus 2.3 ± 2.6, P = 0.04), had higher plasma NfL levels (17.6 ± 5.7 versus 11.1 ± 5.9 pg/ml, P < 0.0001), more cerebellar white matter atrophy (1.44% ± 0.12% of total intracranial volume versus 1.54% ± 0.16%, P = 0.032) and more Inventory of Non-Ataxia Signs signs (1.8 ± 1.3 versus 0.7 ± 0.8, P = 0.002). All clinical scores except Cerebellar Cognitive Affective Syndrome significantly worsened during the study. NfL levels significantly increased in non-converters and ataxic SCA3 (1.06 ± 0.33 pg/ml/year, P = 0.002 and 0.57 ± 0.21 pg/ml/year, P = 0.01, respectively) but not in controls and ataxic SCA1 (0.31 ± 0.26 pg/ml/year, P = 0.24 and 0.26 ± 0.42 pg/ml/year, P = 0.55, respectively). In the best predictive model of Scale for Assessment and Rating of Ataxia progression after 1 year (R2 = 0.54), factors linked with faster progression were higher functional stage (P < 0.001), higher Composite Cerebellar Functional Score (P = 0.002) and higher total creatine in cerebellar white matter (P = 0.026). Factors significantly linked to conversion, namely NfL levels, depression and lower motor neuron involvement, differ from those driving disease progression. The NfL levels and lower motor neuron signs could be used as predictors of phenoconversion and MRI variables as ataxia progression predictors. Psychological care should be provided in the pre-ataxic phase of the disease.

BACKGROUND:Clinical trials in spinocerebellar ataxia are currently limited by the large sample sizes required by available clinical endpoints. We aimed to devise a digital composite measure of standing and walking balance using wearable inertial sensors that would require smaller sample sizes. The new score is called the Score of Integrated Balance in Ataxia (SIBA). METHODS:In this study, we developed the SIBA based on a retrospective sample of adults (aged 18-75 years) with spinocerebellar ataxia types 1, 2, 3, or 6, recruited during clinical visits at five sites (four in the USA and one in Cuba) between June 23, 2017, and Aug 21, 2024. Participants were included if they had genetic confirmation of spinocerebellar ataxia, and were able to provide consent, walk 10 m independently without an assistive device, and stand unassisted for 30 s. A cohort of age-specific and sex-matched healthy controls were recruited from family members of the patients. To validate the SIBA, an independent sample of individuals with the same types of ataxias were recruited along with age-matched and sex-matched healthy controls from five centres in the USA (NCT04268147) between June 1, 2019, and April 30, 2024. We performed balance and gait assessments using six wearable sensors (Opal inertial measurement units, APDM Precision Motion, Clario, Portland, OR, USA) on the dorsum of each foot and hand, on the sternum, and on the lower lumbar (trunk) vertebral segments. We used the data from this assessment to develop a composite score from walking at a natural pace for 2 min and standing with feet together and apart for 30 s. We used a multiple criteria decision analysis to weight the relative importance of criteria to guide development of the score. The criteria represented the ability to distinguish groups with known differences, construct validity, reliability, progression, meaningfulness, and concurrent validity. The final composite score integrated two dynamic balance variables from gait (variability of toe-out and double-support time proportion of the gait cycle) and two static balance variables from stance (sway angle root mean square with normal stance width and sway acceleration root mean square with feet together). We compared the SIBA to the Scale for the Assessment and Rating of Ataxia (SARA) for reliability, the ability to distinguish between groups with known differences, construct validity, convergent validity, and the ability to track disease progression. FINDINGS:We included 258 individuals (131 females and 127 males) with spinocerebellar ataxia types 1, 2, 3, or 6 (40 premanifest and 218 ataxic) and 100 healthy controls (45 females and 55 males) in the development study; and 53 individuals (27 females and 26 males) with spinocerebellar ataxia types 1, 2, 3, or 6 and 24 healthy controls (14 females and 10 males) in the validation study. The SIBA showed concurrent validity with the SARA (r=0·736). The SIBA was also reliable (test-retest reliability; intraclass correlation coefficient=0·970), could distinguish between participants and healthy controls (area under the receiver operating characteristic curve [AUROC]=0·956), and related to fall risk (AUROC=0·760) in a validation cohort of ambulatory participants with spinocerebellar ataxia, independent from the larger, score-development cohort. Progression of ataxia over 1 year had an effect size five times larger than the SARA score (0·59 vs 0·11). Based on these estimates, clinical trials using the SIBA would require 88% fewer participants than SARA (171 vs 1491) to detect a 50% reduction in the rate of 1-year progression. INTERPRETATION:SIBA is a suitable digital measure of static and dynamic balance for the most common spinocerebellar ataxias in clinical trials. It may permit clinical trials to be completed more rapidly and with fewer participants. Future trials on responsiveness of the SIBA to interventions are needed in larger cohorts. FUNDING:Biogen, Clario, Pfizer, and the Alexander von Humboldt Foundation.

The dysmetria of thought theory holds that the cerebellum is an integral node in the distributed neural circuits subserving cognition. We tested this theory in four rhesus monkeys with bilateral lesions in cerebellar dentate nuclei (DN), targeting ventral sectors linked with cerebral association cortices engaged in cognitive processing. Lesion localization was confirmed by MRI and histology. DN animals and controls were assessed for motor dexterity (Kuypers’ Task), attention, three-choice discrimination, recognition memory (Delayed Non-Matching to Sample task [DNMS]), working memory (Delayed Recognition Span Task [DRST]) and executive function (Conceptual Set Shifting Task [CSST]). Performance by the DN animals was not significantly different than controls on the Kuypers’ task and DNMS, but as a group they were impaired on DRST and CSST. DN monkeys achieved shorter spans on DRST. Their responses on CSST were more perseverative, and larger lesions produced greater deficits. This study provides the first empirical support for anatomical and functional MRI evidence of a motor-cognitive dichotomy in the cerebellar dentate nucleus. It highlights a within-cognition dichotomy in which cerebellum modulates dorsal stream cognitive functions (spatial awareness; dynamic actions of where and how) characterized by executive functions including working memory but is not engaged in ventral stream cognitive processes (static actions of object identification) exemplified by recognition memory.

The Cerebellar Cognitive Affective / Schmahmann Syndrome scale (CCAS-S) detects cognitive and neuropsychiatric changes in cerebellar disease (CD). It has good sensitivity and specificity, but a false positive rate 5

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.

The Friedreich Ataxia Rating Scale–Activities of Daily Living (FARS-ADL) is a validated and highly utilized measure for evaluating patients with Friedreich Ataxia. While construct validity of FARS-ADL has been shown for spinocerebellar ataxia (SCA), content validity has not been established. Individuals with SCA1 or SCA3 (n = 7) and healthcare professionals (HCPs) with SCA expertise (n = 8) participated in qualitative interviews evaluating the relevance, clarity, and clinical meaningfulness of FARS-ADL for assessment of individuals with SCA. Interviews were recorded, transcribed, coded, and analyzed by ATLAS.Ti v22 software. FARS-ADL concepts most frequently reported by individuals with SCA were difficulty walking (n = 7/7), falls (n = 6/7), speech difficulties (n = 4/7), and swallowing (n = 3/7). Individuals with SCA reported that all FARS-ADL items were relevant; Gait and Walking (n = 7/7), Bladder Function (n = 6/7), and Falling (n = 6/7) were considered extremely relevant. All HCPs (n = 8/8) reported that most FARS-ADL items were relevant to individuals with SCA; Quality of Sitting Position was considered least relevant. HCPs reported meaningful change as 1–2 point score change in individual FARS-ADL items (n = 7/7), 1–3 point change in total score (n = 6/6), and stability on any item and/or total score over ≥ 1 year, depending on SCA subtype (n = 5/8). Cognitive debriefing supported clarity and comprehension of FARS-ADL. Suggested improvements included refining response options for Dressing, Falling, Walking, and Bladder Function items. The findings confirm the content validity of most FARS-ADL items for use in individuals with mild-to-moderate SCA1 and SCA3, and offer suggested improvements for response options.

Cognitive outcome following mild traumatic brain injury (mTBI) vary widely, with many individuals experiencing long-term impairments associated with frontoparietal network dysfunction. Mild TBI patients have demonstrated functional reorganization, suggesting an expansion of activation to cerebellar regions during specific executive functions. In this study, we investigated cerebellar involvement in fluid intelligence processing using a novel fMRI paradigm based on Raven's Progressive Matrices in 51 acute mTBI patients and 61 healthy controls. Despite comparable task accuracy, mTBI patients exhibited significantly increased activation in anterior cerebellar regions, including Vermis III and Cerebellum IV-V. Seed-based functional connectivity analysis further revealed altered cerebellar-frontoparietal interactions in mTBI patients compared to healthy controls. In mTBI patients, connectivity was enhanced with the left lateral prefrontal cortex and lower with the right posterior parietal cortex, which also showed a change from positive to negative connectivity. These findings suggest that the cerebellum is adaptively recruited to maintain cognitive performance, in line with the cerebellar reserve theory. This study provides initial evidence of cerebellar activation during fluid intelligence processing in mTBI, highlighting a potential role for the cerebellum in adaptively interacting with cortical networks to support cognitive function following brain injury.

The triad of cerebellar ataxiology is the cerebellar motor, vestibular, and cerebellar cognitive affective / Schmahmann syndrome (CCAS). The CCAS affective component comprises 5 domains: Attentional control, Emotional control, Autism spectrum, Psychosis spectrum, and Social Skill Set, each with hypermetric / overshoot and hypometric / undershoot poles reflecting the dysmetria of thought and universal cerebellar transform theories. There is no validated screening instrument to assess neuropsychiatric impairments in patients with cerebellar disorders. To examine the psychometric properties of our Cerebellar Neuropsychiatric Rating Scale (CNRS) that explores these symptoms and behaviors in patients with cerebellar disorders, 21 adults with ataxia completed the CNRS and other validation measures: the Behavior Rating Inventory of Executive Function-Adult Version Informant Report, Adult Behavior Checklist, Older Adult Behavior Checklist, Neuropsychiatric Inventory Questionnaire. We examined CNRS internal consistency using Cronbach’s alpha, assessed item to subscale correlations, studied ceiling and floor effects, and convergent construct validity between CNRS and validity measure subscales. Internal consistency was α > 0.70 for each of the five domains. Subscale structure was generally confirmed: 86

BACKGROUND AND PURPOSE:Symptoms indistinguishable from behavioral-variant frontotemporal dementia (bvFTD) can develop in patients with spontaneous intracranial hypotension associated with severe brain sagging. An underlying spinal CSF leak can be identified in only a minority of these patients and the success rate of nondirected treatments, such as epidural blood patching and dural reduction surgery, is low. The disability associated with bvFTD sagging brain syndrome is high and, because of the importance of the venous system in the pathophysiology of CSF leaks in general, we have investigated the systemic venous circulation in those patients with recalcitrant symptoms. MATERIALS AND METHODS:We reviewed the medical records and imaging studies of 21 consecutive patients with bvFTD sagging brain syndrome in whom no spinal CSF leak could be found and who underwent imaging of the systemic venous circulation (MR- or CT-venography). An SIH Disability Assessment Score (SIHDAS) questionnaire was completed to assess the severity of the symptoms. RESULTS:The mean age of the 3 women and 18 men was 50 years (range, 26-68 years). Seven patients were found to have venous stenosis. Endovascular stent placement of moderate to high-grade azygos vein stenosis in 3 patients resulted in prompt and remarkable improvement of symptoms in 2 patients (SIHDAS: very severe disability to no or mild disability) and mild improvement in 1 patient (SIHDAS: very severe disability to severe disability). Treatment of internal jugular vein and inferior vena cava stenosis in 2 patients each did not result in any improvement of symptoms. Endovascular (5 patients) or surgical (2 patients) interruption of multiple epidural spinal venous pathways did not result in any clinical improvement. CONCLUSIONS:The azygos vein is the main conduit between the spinal CSF space and the systemic venous circulation and this study demonstrates that isolated azygos vein stenosis may be a cause of spinal CSF loss and sagging brain syndrome. In this study, the yield of finding a clinically important treatable venous lesion among patients with recalcitrant bvFTD sagging brain syndrome was relatively low (15%). However, high quality and safe noninvasive imaging of the systemic venous system is available, eg, MR-venography, and should be considered for those patients who have exhausted treatments for this devastating condition, focusing on the azygos system.

Spinocerebellar ataxia (SCA) composite score (SCACOMS) is a statistically-derived composite measure comprising weighted items that are sensitive to change during early-stage disease. SCACOMS items and weights include the functional Scale for the Assessment and Rating of Ataxia Gait (12

Late-Onset GM2-Gangliosidoses (LOGG) are rare, neurodegenerative lysosomal disorders that include late-onset Tay-Sachs (LOTS) and Sandhoff disease (LOSD) subtypes. Cerebellar atrophy is common, even in the absence of clinical ataxia, particularly in LOTS. Recent reports have also described brainstem atrophy in LOTS. We assessed brainstem substructure atrophy in LOGG, including LOSD. 10 LOGG patients (7 LOTS, 3 LOSD) and 7 age-matched controls had structural MRI brain imaging. A FreeSurfer brainstem substructure module was used for automatic segmentation and included the pons, medulla, superior cerebellar peduncle (SCP), midbrain, and total brainstem. Clinical ataxia severity was assessed with the LOTS Severity Scale, Brief Ataxia Rating Scale, Friedreich’s Ataxia Rating Scale and Scale for the Assessment and Rating of Ataxia. There were differences between LOGG and controls in the pons (12,785.06 ± 1,603.84 vs. 15,457.14 ± 2,748.41 mm3, p = 0.0069) and SCP (196.93 ± 31.20 vs. 293.57 ± .70.16 mm3, p = 0.0003). In LOTS vs. controls, there was similar pons (p = 0.0055) and SCP atrophy (p = 0.0023). The LOSD group was too small for independent comparisons. There were no significant associations between SCP/pons volume and clinical scales or disease duration. Cerebellar volume, which was analyzed in a previous study by Rowe et al. (2021), was relatively preserved in LOSD compared to the SCP/pons, while in LOTS, the pontocerebellar atrophy profile was dominated by cerebellar atrophy. These findings provide anatomical and clinical insights to the cerebellar/brainstem atrophy observed in LOGG and highlight a need to stratify LOGG by subtypes.

A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to measure disease progression sensitively in clinical trials. Wearable sensors worn continuously during natural behaviour at home have the potential to produce ecologically valid and precise measures of motor function by leveraging frequent and numerous high-resolution samples of behaviour. Here we test whether movement building block characteristics (i.e. submovements), obtained from the wrist and ankle during natural behaviour at home, can capture disease progression sensitively in SCAs and MSA-C, as recently shown in amyotrophic lateral sclerosis and ataxia telangiectasia. Remotely collected cross-sectional (n = 76) and longitudinal (n = 27) data were analysed from individuals with ataxia (SCAs 1, 2, 3 and 6, MSA-C) and controls. Machine learning models were trained to produce composite outcome measures based on submovement properties. Two models were trained on data from individuals with ataxia to estimate ataxia rating scale scores. Two additional models, previously trained entirely on longitudinal amyotrophic lateral sclerosis data to optimize sensitivity to change, were also evaluated. All composite outcomes from both wrist and ankle sensor data had moderate to strong correlations with ataxia rating scales and self-reported function, showed differences between ataxia and control groups with high effect size, and had high within-week reliability. The composite outcomes trained on longitudinal amyotrophic lateral sclerosis data most strongly captured disease progression over time. These data demonstrate that outcome measures based on accelerometers worn at home can capture the ataxia phenotype accurately and measure disease progression sensitively. This assessment approach is scalable and can be used in clinical or research settings with relatively low individual burden.

Hereditary ataxias are progressive neurodegenerative disorders primarily affecting the cerebellum. Since 2009, the Clinical Research Consortium for the Study of Cerebellar Ataxias (CRC-SCA) has studied the natural history of common types of spinocerebellar ataxias (SCAs). The CRC-SCA is a 17-site academic collaboration supported by the National Ataxia Foundation. In 2024, the CRC-SCA expanded its scope by incorporating newly identified late-onset ataxias, including repeat expansion mutations in RFC1 and FGF14 causing Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS) and SCA27B, respectively. These ongoing efforts have enriched the understanding of disease progression and facilitated access to biofluid and neuroimaging data for biomarker discovery, setting the stage for therapeutic development in hereditary ataxias. The CRC-SCA's natural history study and biomarker collection have validated several clinical outcome assessments (COAs) to capture important aspects of hereditary ataxias. We have also developed new COAs for cognitive and patient-reported outcome measures. A key component of the study includes biofluid collection-cerebrospinal fluid, plasma, and serum-to identify molecular biomarkers for disease progression and therapeutic response. Additionally, an incorporated magnetic resonance imaging (MRI) substudy provides critical imaging biomarkers, enhancing our ability to track macro- and microstructural, chemical and functional changes in the cerebellum and relate these to clinical presentations. The comprehensive, longitudinal dataset comprising COAs, biofluid biomarkers, and neuroimaging enhances clinical trial readiness in the field and accelerates therapeutic advancements for hereditary ataxias. This review highlights the collective efforts of CRC-SCA, details the study protocol, and emphasizes the integrity and specificity of the collected data elements.

Spinocerebellar Ataxia type 27B (SCA27B) is caused by an intronic GAA repeat expansion in the fibroblast growth factor 14 (FGF14) gene. The core clinical phenotype is a slowly progressive, adult-onset cerebellar ataxia, often with downbeat nystagmus (DBN) and episodic worsening. We tested whether clinical phenotyping could predict this genetic disorder. We screened the Massachusetts General Hospital Ataxia Center registry (n = 3,182) for patients with a) isolated DBN, b) DBN with ataxia, and c) autosomal dominant cerebellar ataxia (ADCA) that had eluded genetic diagnosis. Patient histories, examinations, and imaging were reviewed. Genetic analysis for FGF14 expansion was performed. Of 65 identified patients, 39 completed genetic testing. Among 14 with isolated DBN, 9 carried an FGF14 repeat expansion (GAA)≥250 (range, 295–461), 1 had a potentially pathogenic allele (247 repeats), and 4 had normal alleles. Among 19 with DBN plus ataxia, 12 tested positive (276–431 repeats), 1 had a suspected pathogenic allele (228 repeats), and 6 had normal alleles. All 4 ADCA patients tested positive (320–483 repeats), as did 2 presymptomatic siblings. Our cohort enriched for suspicion of SCA27B had confirmed or suspected pathogenic FGF14-GAA expansion in 74.4