Longitudinal changes in DTI-ALPS index are associated with clinical progression and brainstem atrophy in...

The perivascular and neurofluid-related tissue environment is implicated in neurodegeneration, but its clinical relevance in spinocerebellar ataxia type 3 (SCA3) remains unclear. We investigated alterations in diffusion tensor image analysis along the perivascular space (DTI-ALPS) across disease stages, and its longitudinal associations with clinical progression and brain atrophy.

We included 129 SCA3 (44 preclinical, 85 ataxic) at baseline, 51 with longitudinal follow-up, and 78 controls. Cross-sectional, longitudinal, and structural equation modeling (SEM) analyses examined group differences, clinical correlates, progression, associations with regional brain volumes, and relationships among age, genetic burden, DTI-ALPS index, brainstem volume, and severity.

DTI-ALPS index was reduced in SCA3 and showed stage-dependent pattern. Ataxic SCA3 exhibited lower DTI-ALPS index than preclinical SCA3 and controls, whereas preclinical SCA3 did not differ from controls. Lower DTI-ALPS index was associated with greater clinical severity (r = -0.208, p < 0.05) and reduced volumes of the brainstem, thalamus, hippocampus, caudate, amygdala, pallidum, and putamen (p < 0.05). SEM showed that lower DTI-ALPS index was associated with greater clinical severity (β = -0.151, p < 0.05) and reduced brainstem volume (β = 0.160, p < 0.05). Longitudinally, lower baseline DTI-ALPS index was associated with faster clinical progression (β = -2.59, p < 0.01).

Reduced DTI-ALPS index emerged predominantly during SCA3 symptomatic stage and was associated with greater severity, brainstem atrophy, and faster longitudinal disease progression. These findings supported DTI-ALPS index as a promising imaging marker for characterizing disease-related tissue environment changes and providing adjunctive prognostic information in SCA3.