In vivo assessment of neurodegeneration in Spinocerebellar Ataxia type 7

Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease characterized by progressive cerebellar ataxia and retinal degeneration. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering our ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments. In this cross-sectional study, we aimed to identify imaging measures of neurodegeneration, which may more accurately reflect SCA7 severity and progression. We analyzed diffusion tensor imaging (DTI) data collected from a cohort of 13 SCA7 patients and 14 healthy volunteers using two recent methodological advances: 1) a diffusion tensor-based image registration technique, and 2) a dual-compartment DTI model to control for the potential increase in extracellular CSF-like water due to neurodegeneration. These methodologies allowed us to assess both volumetric and microstructural abnormalities in both white and gray matter brain-wide in SCA7 patients for the first time. To measure tissue volume, we performed diffusion tensor-based morphometry (DTBM) using the tensor-based registration. To assess tissue microstructure, we computed the parenchymal mean diffusivity (pMD) and parenchymal fractional anisotropy (pFA) using the dual compartment model. This model also enabled us to estimate the parenchymal volume fraction (pVF), a measure of parenchymal tissue volume within a given voxel. While DTBM and pVF revealed tissue loss primarily in the brainstem, cerebellum, thalamus, and a subset of cerebral white matter tracts in patients, pMD and pFA detected microstructural abnormalities brain-wide (p < 0.05, FWE corrected; Hedge’s g > 1). This distinction was meaningful in terms of motor symptom severity, as we found that patient scores on the Scale for the Assessment and Rating of Ataxia correlated most strongly with cerebellar pVF (r = - 0.66, p = 0.015) and global white matter pFA (r = −0.64, p = 0.018). Since this contrast between focal tissue loss and global microstructural abnormality has previously been described in neuropathology, we believe the approach employed here is well suited for the in-vivo assessment of neurodegeneration. Moving forward, this approach could be applied to characterize the full spatiotemporal pattern of neurodegeneration in SCA7, and potentially develop an accurate imaging biomarker of disease progression.HighlightsDTI study reveals brain-wide differences between SCA7 patients and controls.DTI dual-compartment model controls for increased CSF-like free water in patients.Tensor-based deformations show SCA7 tissue loss extends beyond cerebellum.Focal atrophy, but global microstructural abnormalities were observed in SCA7.Ataxia most correlated with cerebellar atrophy, global microstructural abnormality.