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Neurochemical abnormalities in premanifest and early spinocerebellar ataxias
Author(s) -
Joers James M.,
Deelchand Dinesh K.,
Lyu Tianmeng,
Emir Uzay E.,
Hutter Diane,
Gomez Christopher M.,
Bushara Khalaf O.,
Eberly Lynn E.,
Öz Gülin
Publication year - 2018
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25212
Subject(s) - neurochemical , spinocerebellar ataxia , psychology , neuroscience , ataxia , neurochemistry , biomarker , medicine , neurology , biology , genetics
Objective To investigate whether early neurochemical abnormalities are detectable by high‐field magnetic resonance spectroscopy (MRS) in individuals with spinocerebellar ataxias (SCAs) 1, 2, 3, and 6, including patients without manifestation of ataxia. Methods A cohort of 100 subjects (N = 18–21 in each SCA group, including premanifest mutation carriers; mean score on the Scale for the Assessment and Rating of Ataxia [SARA] <10 for all genotypes, and 22 matched controls) was scanned at 7 Tesla to obtain neurochemical profiles of the cerebellum and brainstem. A novel multivariate approach (distance‐weighted discrimination) was used to combine regional profiles into an “MRS score.” Results MRS scores robustly distinguished individuals with SCA from controls, with misclassification rates of 0% (SCA2), 2% (SCA3), 5% (SCA1), and 17% (SCA6). Premanifest mutation carriers with estimated disease onset within 10 years had MRS scores in the range of early‐manifest SCA subjects. Levels of neuronal and glial markers significantly correlated with SARA and an Activities of Daily Living score in subjects with SCA. Regional neurochemical alterations were different between SCAs at comparable disease severity, with SCA2 displaying the most extensive neurochemical abnormalities, followed by SCA1, SCA3, and SCA6. Interpretation Neurochemical abnormalities are detectable in individuals before manifest disease, which may allow premanifest enrollment in future SCA trials. Correlations with ataxia and quality‐of‐life scores show that neurochemical levels can serve as clinically meaningful endpoints in trials. Ranking of SCA types by degree of neurochemical abnormalities indicates that the neurochemistry may reflect synaptic function or density. Ann Neurol 2018;83:816–829