Brainstem and striatal volume changes are detectable in under 1 year and predict motor decline in spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 is a progressive neurodegenerative, movement disorder. With potential therapies on the horizon, it is critical to identify biomarkers that (i) differentiate between unaffected and spinocerebellar ataxia Type 1-affected individuals; (ii) track disease progression; and (iii) are directly related to clinical changes of the patient. Magnetic resonance imaging of volumetric changes in the brain may be a suitable source of biomarkers for spinocerebellar ataxia Type 1. In a previous report on a longitudinal study of patients with spinocerebellar ataxia Type 1, we evaluated the volume and magnetic resonance spectroscopy measures of the cerebellum and pons, showing pontine volume and pontine N-acetylaspartate-to-myo-inositol ratio were sensitive to change over time. As a follow-up, the current study conducts a whole brain exploration of volumetric MRI measures with the aim to identify biomarkers for spinocerebellar ataxia Type 1 progression. We adapted a joint label fusion approach using multiple, automatically generated, morphologically matched atlases to label brain regions including cerebellar sub-regions. We adjusted regional volumes by total intracranial volume allowing for linear and power-law relationships. We then utilized Bonferroni corrected linear mixed effects models to (i) determine group differences in regional brain volume and (ii) identify change within affected patients only. We then evaluated the rate of change within each brain region to identify areas that changed most rapidly. Lastly, we used a penalized, linear mixed effects model to determine the strongest brain predictors of motor outcomes. Decrease in pontine volume and accelerating decrease in putamen volume: (i) reliably differentiated spinocerebellar ataxia Type 1-affected and -unaffected individuals; (ii) were observable in affected individuals without referencing an unaffected comparison group; (iii) were detectable within ∼6–9 months; and (iv) were associated with increased disease burden. In conclusion, volumetric change in the pons and putamen may provide powerful biomarkers to track disease progression in spinocerebellar ataxia Type 1. The methods employed here are readily translatable to current clinical settings, providing a framework for study and usage of volumetric neuroimaging biomarkers for clinical trials.