The Pattern and Staging of Brain Atrophy in Spinocerebellar Ataxia Type 2 (SCA2): MRI Volumetrics from ENIGMA-Ataxia

Abstract

Objective: Spinocerebellar ataxia type 2 (SCA2) is a rare, inherited neurodegenerative disease characterised by progressive deterioration in both motor coordination and cognitive function. Atrophy of the cerebellum, brainstem, and spinal cord are core features of SCA2, however the evolution and pattern of whole-brain atrophy in SCA2 remain unclear. We undertook a multi-site, structural magnetic resonance imaging (MRI) study to comprehensively characterize the neurodegeneration profile of SCA2.

Methods: Voxel-based morphometry analyses of 110 participants with SCA2 and 128 controls were undertaken to assess groupwise differences in whole-brain volume. Correlations with clinical severity and genotype, and cross-sectional profiling of atrophy patterns at different disease stages, were also performed.

Results: Atrophy in SCA2 relative to controls was greatest (Cohen's d>2.5) in the cerebellar white matter (WM), middle cerebellar peduncle, pons, and corticospinal tract. Very large effects (d>1.5) were also evident in the superior cerebellar, inferior cerebellar, and cerebral peduncles. In cerebellar grey matter (GM), large effects (d>0.8) mapped to areas related to both motor coordination and cognitive tasks. Strong correlations (|r|>0.4) between volume and disease severity largely mirrored these groupwise outcomes. Stratification by disease severity showed a degeneration pattern beginning in cerebellar and pontine WM in pre-clinical subjects; spreading to the cerebellar GM and cerebro-cerebellar/corticospinal WM tracts; then finally involving the thalamus, striatum, and cortex in severe stages.

Interpretation: The magnitude and pattern of brain atrophy evolves over the course of SCA2, with widespread, non-uniform involvement across the brainstem, cerebellar tracts, and cerebellar cortex; and late involvement of the cerebral cortex and striatum.

Figure 1.

Regions of significantly lower volume (voxel-level FWE-corrected p < 0.05) in participants with SCA2 relative to CONT in the (A) whole brain white matter, (B) cerebellar grey matter, and (C) cerebral grey matter. Left: representative slices or cerebellar flatmaps illustrating the areas of significant atrophy in SCA2 subjects. Right: forest plots illustrating regional effects (Cohen’s d > 0.5, reflecting moderate or greater effect size); error bars represent the 95% confidence interval (CI). Slice coordinates are in Montreal Neurological Institute (MNI) space.

Figure 2.

Mapping of structural changes to functional networks in the cerebellum. (A) Cerebellar flatmap of the voxel-level effect size of volume differences in participants with SCA2 vs. CONT in cerebellar grey matter, recalled from Figure 1B. (B) Cerebellar flatmap of the multi-domain task battery (MDTB) functional atlas from King et al. (C) A bar chart of the effect sizes by MDTB region; bar height is the mean effect size within each region, while error bars are the positive 95% CI. The colours of the bars in Panel C match the colours of the regions in Panel B.

Figure 3.

Correlations between regional volume and ataxia severity (SARA score) in SCA2 participants (voxel-level FWE-corrected p < 0.05). (A) SARA vs. white matter volume in the cerebellum and brainstem (left) and cerebrum (right). (B) SARA vs. grey matter volume in the cerebellum (left) and cerebrum (right). Slice coordinates are in MNI space.

Figure 4.

Stratification of the SCA2 cohort based on ataxia severity (SARA score). Voxel-level effect size maps (FWE-corrected p < 0.05) of each SCA2 subgroup relative to CONT. From top to bottom: Pre-Symptomatic (SARA < 3; n = 14); 1^st Quartile (3 ≤ SARA ≤ 9; n = 26); 2^nd Quartile (9 < SARA ≤ 13.5; n = 22); 3^rd Quartile (13.5 < SARA ≤ 18; n = 23); 4^th Quartile (SARA > 18; n = 24). All images show representative slices or flatmaps of the affected tissue type: white matter (left) is at MNI coordinates (−6, −20, −30); cerebellar grey matter (centre) shows the flatmap and slices from MNI coordinates x = −10 and z = −25; cerebral grey matter (right) is at MNI coordinates (−2, +11, +4).

Figure 5.

Stratification of the SCA2 cohort based on CAG repeat length and disease duration. Voxel-level effect size maps (FWE-corrected p < 0.05) of each SCA2 subgroup relative to healthy controls. Top left: CAG repeats and disease duration below the median of each measure (CAG repeats ≤ 40; Duration ≤ 9 y; n = 26). Top right: CAG repeats below the median and disease duration above the median (CAG repeats ≤ 40; Duration > 9 y; n = 21). Bottom left: CAG repeats above the median and disease duration below the median (CAG repeats > 40; Duration ≤ 9 y; n = 15). Bottom right: CAG repeats and disease duration above the median of each measure (CAG repeats > 40; Duration > 9 y; n = 16). Within each cell, representative images appear from the whole-brain white matter (top) at MNI coordinates (−6, −20, −30); the cerebellar grey matter (middle) as the flatmap and slices from MNI coordinates x = −5 and z = −26; and cerebral grey matter (bottom) at MNI coordinates (+2, −18, +4).