MRI shows a region-specific pattern of atrophy in spinocerebellar ataxia type 2

Abstract

In this study, we used manual delineation of high-resolution magnetic resonance imaging (MRI) to determine the spatial and temporal characteristics of the cerebellar atrophy in spinocerebellar ataxia type 2 (SCA2). Ten subjects with SCA2 were compared to ten controls. The volume of the pons, the total cerebellum, and the individual cerebellar lobules were calculated via manual delineation of structural MRI. SCA2 showed substantial global atrophy of the cerebellum. Furthermore, the degeneration was lobule specific, selectively affecting the anterior lobe, VI, Crus I, Crus II, VIII, uvula, corpus medullare, and pons, while sparing VIIB, tonsil/paraflocculus, flocculus, declive, tuber/folium, pyramis, and nodulus. The temporal characteristics differed in each cerebellar subregion: (1) duration of disease: Crus I, VIIB, VIII, uvula, corpus medullare, pons, and the total cerebellar volume correlated with the duration of disease; (2) age: VI, Crus II, and flocculus correlated with age in control subjects; and (3) clinical scores: VI, Crus I, VIIB, VIII, corpus medullare, pons, and the total cerebellar volume correlated with clinical scores in SCA2. No correlations were found with the age of onset. Our extrapolated volumes at the onset of symptoms suggest that neurodegeneration may be present even during the presymptomatic stages of disease. The spatial and temporal characteristics of the cerebellar degeneration in SCA2 are region specific. Furthermore, our findings suggest the presence of presymptomatic atrophy and a possible developmental component to the mechanisms of pathogenesis underlying SCA2. Our findings further suggest that volumetric analysis may aid in the development of a non-invasive, quantitative biomarker.

Figure 1. Manual delineation of the cerebellar sub-regions

a. Manual delineation of the regions of interest in the cerebellum of a healthy control subject. Individual volumes for the pons, total cerebellum, and hemispheric and vermal subregions were used as the primary endpoints. The cerebellar cortex was subdivided into the anterior lobe (lobules I-V), VI, Crus I, Crus II, VIIB, VIII, tonsil/paraflocculus (IX), and flocculus (X). The vermis was also delineated into the declive (VI), tuber/folium (VII), pyramis (VIII), uvula (IX), and nodulus (X). b. Manual delineation of the cerebellum of a patient with SCA2. In the presence of atrophy, the gaps between the cerebellar lobules (cerebrospinal fluid) were not included in the volumetric measurements. c. Three dimensional reconstruction of the cerebellum using manually delineated regions of interest.

Figure 2. Regional volumes correlate with clinical function in SCA2

log(Age-adjusted volumes) versus functional score (FSFA). Pons (a), the total cerebellum (b), VI (c), Crus I (d), VIIB (e), VIII (f), and corpus medullare (g) correlated (p<0.05) with the UADRS functional score. Other regions did not reach statistical significance (p>0.1).

Figure 3. The time course of the degeneration may differ by region

Log-linear regression line was extrapolated for regions with atrophy that correlated with the duration of disease. The projected regional volume at the onset of disease (duration of disease = 0) suggests that pons, corpus medullare, and the total cerebellum may already be reduced in size at the onset of disease. Crus I, VIII, and uvula trended towards being smaller at the onset of symptoms.

Figure 4. SCA2 selectively affects the anterior-superior cerebellar hemisphere while sparing the posterior-inferior regions

a & b. Coronal view of SCA2 cerebellum. Compared to a neurologically normal cerebellum (c), there is a marked degeneration of the cerebellum even at 6 years of disease duration (b). The degeneration appears to be limited to the anterior-superior regions while the posterior-inferior regions (white dashed circle) are relatively spared during the early stages of disease.