Stage‐Specific Patterns of Imaging and Non‐Motor Biomarkers in Spinocerebellar Ataxia Type 3

ABSTRACT Objective Advancements in disease‐modifying therapies for spinocerebellar ataxia Type 3 (SCA3) underscore the need for robust biomarkers to monitor disease progression and evaluate treatment efficacy. Although motor phenotypes have been well characterized, less is known about non‐motor and imaging‐based features across different disease stages. This study aimed to characterize stage‐specific patterns of non‐motor and imaging biomarkers in SCA3. Methods This cross‐observational study included 229 patients with SCA3 and 104 age‐ and sex‐matched healthy controls from the Organization for Southeast China for cerebellar ataxia research. Non‐motor symptoms were assessed using a battery of neuropsychological tests. Brain volume loss was assessed by 3.0‐Tesla MRI with regions‐of‐interest (ROI)‐based volumetric analysis. Neuroinflammation was quantified in vivo using translocator protein positron emission tomography (TSPO‐PET) with the 18 F‐DPA‐714 radioligand. Additive regression models were fitted to evaluate the cross‐sectional associations between biomarkers and disease stages. Receiver operating curve (ROC) analyses were applied to estimate the discriminative ability of the candidate biomarkers. Results Non‐motor symptoms, including cognitive functions, anxiety, fatigue, depression, and sleep quality, declined after ataxia onset in SCA3. Volume loss in the brainstem and ventral diencephalon diverged from normal controls at 0.7 and 0.2 years before ataxia onset, respectively. Correspondingly, the TSPO signal in the brainstem and ventral diencephalon increased and deviated from normal throughout the disease course. Interpretation Our findings propose a staging model of SCA3 that includes a biomarker stage characterized by multidimensional objective indicators of neurodegeneration and neuroinflammation from pre‐ataxia to ataxia onset. Trial Registration ClinicalTrials.gov identifier: NCT04010214