Identification of robust biomarkers of neuronal and glial metabolic changes in spinocerebellar ataxia type 1, 2, 3 & 7

<p>BACKGROUND: Spinocerebellar ataxias (SCAs) belong to the group of polyglutamine repeat disorders like Huntington disease (HD). SCAs lead primarily to neurodegeneration in the cerebellum and the pons. Even the most sensitive clinical scores would require large number of patients to assess any therapeutic benefit. Therefore, the identification of robust biomarkers is critical to assess disease progression for therapeutic development.</p> <p>METHODS: 1H-NMR spectroscopy (MRS) using an optimized semi-LASER sequence was performed at 3T to determine metabolite concentrations in the vermis and pons of a large cohort of SCA1 (n = 18), SCA2 (n = 13), SCA3 (n = 22) and SCA7 (n = 13), as well as in healthy controls with similar median age (n = 34). Neurochemical profiles of SCA patients were compared to controls and correlated with ataxia rating scores – Scale for the Assessment and Rating of Ataxia (SARA).</p> <p>RESULTS: Compared to controls, SCA patients displayed significantly decreased N-acetylaspartate (NAA) and total NAA (tNAA) likely reflecting neuronal loss, but significantly increased myo-inositol (myo-Ins), a suspected marker of gliosis. SCA patients also showed significantly increased total creatine (creatine + phosphocreatine, tCr) as reported in HD patients and animal models. There was a strong negative correlation between SARA scores and tNAA levels in the pons of SCA2-3-7 patients. tCr correlated with SARA scores in the vermis of SCA1-3 patients. In addition, myo-Ins and Glu correlated with SARA scores in the vermis of SCA3 and SCA2 patients respectively.</p> <p>CONCLUSION: Our data supports preliminary data from a pilot study conducted in SCA1 which now extend to SCA2-3 and 7. Furthermore, the changes in the bioenergetics pool of tCr parallel disease progression and suggest, like in HD, that brain energy deficit is an important component of SCA.</p>