Fixel-Based Analysis of Diffusion Imaging as a Quantitative Marker of Disease State in Spinocerebellar Ataxia

Objective: Spinocerebellar ataxias (SCAs) are a group of genetically heterogeneous neurodegenerative diseases causing progressive deterioration and reduced quality of life. Therapeutic advances have been limited by a lack of sensitive anatomic, functional, or diffusion imaging-based biomarkers. This study aimed to identify white matter differences in the brains of preataxic and early-stage SCA1 and SCA3 mutation carriers using diffusion magnetic resonance imaging data from a multisite trial setting. Methods: Fixel-based analysis was used to estimate microscopic fiber density, macroscopic fiber-bundle cross-section, and a combined fiber density and fiber-bundle cross-section measure within 45 cerebral and cerebellar tracts. Multivariate ANOVAs compared controls (n = 16), pre-ataxic (n = 10 SCA1, n = 24 SCA3), and ataxic patients (n = 14 SCA1, n = 36 SCA3). Clinical variables were correlated with fixel metrics and receiver operating characteristic analyses identified white matter tracts sensitive to distinguishing controls from pre-ataxic SCA1 and SCA3. Results: We found widespread white matter deficits in pre-ataxic and ataxic patients compared to controls with regard to fiber density, fiber-bundle cross-section, and combined measures, all of which were associated with clinical measures of ataxia severity. We also found the combined fiber density and fiber-bundle cross-section measure from cerebellar tracts distinguished controls from pre-ataxia with high sensitivity and specificity for both SCA1 (receiver operating characteristic area under the curve = 0.96) and SCA3 (area under the curve = 0.97). The receiver operating characteristic analyses revealed that cerebellar tracts resulted in greater area under the curve than cortico-spinal and transcallosal tracts. Interpretation: These results demonstrate that fixel metrics offer sensitive disease-specific measures of early SCA disease state that correlate with standard clinical measures. Trial Registration: Clinical Trial Readiness for SCA1 and SCA3 (READISCA), NCT03487367. https://clinicaltrials.gov/ct2/show/NCT03487367.