Non-invasive „phenotyping“ of Spinocerebellar Ataxia type 3 (SCA3)

Background: SCA6 is a channelopathy confined to the cerebellum, while SCA3 is a trinucleotide disease that is generalized throughout many brain regions. Together, they account for more than 60% of spinocerebellar ataxias in Germany. By positron emission tomography (PET), we sought to investigate the specific patterns of cerebral glucose metabolism and benzodiazepine receptor binding in SCA3 and SCA6 which might be characteristic for the respective disease.

Patients/Methods: Multitracer PET imaging ([18F]FDG, [11C]FMZ) and MRI were performed in patients with SCA3 (n=8, mean age 52.6±10.3 years) and SCA6 (n=7, 53±13.8 years) and in normal control subjects (n=10, mean age 52.8±9.9 years for [18F]FDG; n=7, mean age 54.3±19.3 years for [11C]FMZ). Patients also were subjected to extensive neuropsychological testing and clinical examination. Individual PET data were transformed to standard brain space, and groups were compared to each other by statistical parametric mapping (SPM).

Results: Patients with SCA3 had an earlier onset (36.1±11.5 vs. 46.2±12.8 years) and a longer duration (13.9±9.7 vs. 8.0±10.5 years) than patients with SCA6; severity of disease as assessed by the Klockgether score was similar in both groups (12.1±5.8 vs. 10.0±4.3). Relative glucose metabolism as measured by [18F]FDG-PET was lowered in frontal areas (SCA3, SCA6), in the cerebellum (SCA6) and in the brainstem (SCA3). Neuronal integrity as measured by [11C]FMZ-PET was severely disturbed in the cerebellum (SCA6) as well as in the culmen (SCA3) and in frontobasal areas (SCA6). These findings show neurodegeneration beyond the cerebellum in SCA6 and are indicative of different pathogenetic patterns in SCA3 and SCA6. Neuropsychological testing detected impairment of visuospatial processing, verbal and working memory as well as executive functions both in SCA3 and SCA6, which in SCA3 correlated to impaired glucose metabolism.

Conclusion: These findings suggest that the clinical phenotype in SCA6 may result from severe neurodegeneration through channel dysfunction. In contrast, in SCA3 neuronal dysfunction seems to play a dominant role in pathogenesis with neurodegeneration occurring at relatively late stages. Most importantly, [11C]FMZ-PET shows a characteristic pattern of altered neuronal integrity within the cerebellum in patients with SCA6 indicating its potential for non-invasive phenotyping of the disease.