Decreased Peripheral Blood Lymphocytes in Spinocerebellar Ataxia Type 3 Correlate with Disease Severity

Abstract Background The immune system likely plays a role in the pathogenesis of spinocerebellar ataxia type 3 (SCA3). Peripheral blood leukocytes are indicative of the immune status in neurodegenerative diseases. However, alterations in the characteristics of peripheral blood leukocytes at different stages of SCA3 and their potential roles in disease progression remain unclear. Objectives The goal was to identify leukocyte profiles alterations at different stages of SCA3 and analyze their correlation with disease severity. Methods This cross‐sectional study included 150 total ATXN3 expansion carriers (20 pre‐ataxic and 130 ataxic) and 113 healthy controls. Differences in leukocyte profiles were analyzed, and correlations with clinical characteristics were assessed using Spearman and partial correlation. Logistic regression and receiver operating characteristic curve identified independent factors associated with disease severity. Mediation analysis evaluated the effect of lymphocyte counts on the relationship between disease duration and SARA scores. Results Alterations in neutrophil, lymphocyte, eosinophil, and basophil counts were observed across ATXN3 expansion carriers, including those in pre‐ataxic and ataxic stages, compared with healthy controls. Lymphocyte counts negatively correlated with SARA and International Cooperative Ataxia Rating Scale scores, particularly in speech function. Leukocyte, monocyte, and basophil counts were also negatively associated with ataxia scales scores or sub‐item scores. Lymphocyte counts distinguished disease severities, and partially mediated the effect of disease duration on ataxia scale scores in ataxic SCA3. Conclusions Leukocyte profiles alterations at different stages of SCA3 may be closely linked to disease progression and severity. Lymphocyte counts may serve as valuable indicators of disease severity. © 2025 International Parkinson and Movement Disorder Society.