Imaging Biomarkers in Spinocerebellar Ataxias

Abstract

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder with multisystem involvement and no disease-modifying treatment to date. As targeted therapies move into clinical testing, the need for sensitive imaging biomarkers is critical. This thesis presents a multimodal framework for understanding the structural and microstructural progression of SCA3 and for developing magnetic resonance imaging (MRI) based biomarkers applicable across disease stages. Drawing on cross-sectional and longitudinal data from the European SCA3/Machado– Joseph Disease Initiative (ESMI), this work demonstrates that infratentorial white matter structures—particularly the pons, medulla oblongata, and cerebellar peduncles—showed early and consistent degeneration. Among these, pons volume showed early decline already in pre-symptomatic mutation carriers and showed the highest sensitivity to change, emerging as a robust imaging biomarker across disease stages. Regional atrophy trajectories were modulated by disease severity and duration in distinct, structure-specific patterns. Diffusion tensor imaging showed cerebellar white matter degeneration in cross-sectional comparisons, but high intra-individual variability between visits limited its utility for detecting longitudinal change. Neurofilament light chain (NfL) levels were abnormal decades before clinical onset, but plateaued thereafter and showed limited responsiveness to progression. In contrast, mutant ataxin-3 (ATXN3) concentrations remained relatively constant across the disease course and did not show relevant dynamics. The Scale for the Assessment and Rating of Ataxia (SARA), while widely used clinically, showed lower sensitivity to early progression and exhibited delayed changes relative to imaging markers. To support future biomarker development, a novel method for myelin water estimation was incorporated. While not yet applied in SCA3, it holds great promise for detecting subtle myelin alterations, particularly given the early and pronounced white matter involvement and emerging evidence of oligodendrocyte dysfunction. Together, the findings of this thesis highlight the utility of multimodal imaging for refining disease staging, patient stratification, and identification of suitable imaging biomarkers for clinical trials.