Multi-Modal Digital Monitoring of Disease Symptoms in Spinocerebellar Ataxia

The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of rare, autosomal dominant neurodegenerative disorders characterized by progressive degeneration of the cerebellum and its connecting pathways. The four most common subtypes (SCA1, SCA2, SCA3, and SCA6) are caused by expanded polyglutamine-coding CAG repeats, and collectively account for the majority of dominantly inherited ataxias worldwide. The cardinal feature across subtypes is progressive ataxia affecting gait, stance, limb coordination, and speech, frequently accompanied by oculomotor abnormalities and, in some subtypes, extracerebellar signs such as spasticity, peripheral neuropathy, and parkinsonism. Symptoms typically begin in adulthood and progress over many years, leading to severe disability and reduced life expectancy. The principal means of measuring ataxia severity is the Scale for the Assessment and Rating of Ataxia (SARA), which is the most widely applied clinical outcome assessment (COA) for genetic ataxias and has been used as the primary endpoint in large natural history cohorts and randomized controlled trials. Although the SARA has demonstrated good inter-rater reliability and has been validated across multiple SCA subtypes, it is inherently subjective and semi-quantitative, requires trained personnel to administer, and may not be sufficiently sensitive to detect incremental but clinically meaningful changes over short follow-up intervals. Movement-associated symptoms are a core feature of SCA and have a substantial negative impact on quality of life. Impairments in gait and balance contribute to falls and loss of independence, while dysarthria and impaired limb coordination affect communication and activities of daily living. Because these assessments are conducted infrequently, typically in a clinic setting, they may not accurately represent an individual's true functional status during everyday life. However, the increasing understanding of disease pathomechanisms and the development of gene-targeting and other novel therapeutic approaches have raised expectations for disease-modifying treatments. The key challenge in developing new therapeutics for SCA and other neurological disorders is that current disease assessment is largely subjective and requires in-person, in-clinic evaluation. Digital measures, such as those proposed in this study, can provide objective, sensitive, and real-world assessments of how individuals are functioning. A growing body of evidence demonstrates that digital biomarkers derived from body-worn inertial sensors can quantify ataxia-specific gait and balance impairments, and correlate strongly with clinician-rated SARA scores. Beyond gait and balance, multi-modal digital assessment of speech, hand function, and oculomotor control may capture complementary domains of cerebellar dysfunction that are affected in SCA. Acoustic analysis of speech can quantify dysarthria, finger tapping can characterize upper-limb bradykinesia and dysrhythmia, and oculomotor testing can capture saccadic and antisaccadic abnormalities that are characteristic of cerebellar disease. Thus, a system that can objectively, sensitively, and frequently monitor multiple clinical domains (motor, speech, and oculomotor function) is necessary to understand the pattern of evolving impairment in individuals with SCA and to support the identification of endpoint measures for therapeutic trials. This study will evaluate the feasibility of a multi-modal digital monitoring platform in a cohort of individuals with SCA and will characterize the relationship between digital measures and established clinical and patient reported outcomes.