Objective: This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. Methods: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses. Results: Atrophy and microstructural damage in the brainstem and cerebellar peduncles and neurochemical abnormalities in the pons were prominent in both preataxic groups, when patients did not differ from controls clinically. MR metrics were strongly associated with ataxia symptoms, activities of daily living, and estimated ataxia duration. A neurochemical measure was the most sensitive metric to preataxic changes in SCA1 (ROC area under the curve [AUC] = 0.95), and a microstructural metric was the most sensitive metric to preataxic changes in SCA3 (AUC = 0.92). Interpretation: Changes in cerebellar afferent and efferent pathways underlie the earliest symptoms of both SCAs. MR metrics collected with a harmonized advanced protocol in the multisite trial setting allow detection of disease effects in individuals before ataxia onset with potential clinical trial utility for subject stratification. ANN NEUROL 2022.
|Original language||English (US)|
|Journal||Annals of Neurology|
|State||Accepted/In press - 2022|
Bibliographical noteFunding Information:
This work was supported by the NIH National Institute of Neurological Disorders and Stroke (grant U01 NS104326). The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (grant P41 EB027061) and the Institutional Center Cores for Advanced Neuroimaging (awards P30 NS076408 and S10 OD017974). Research reported in this publication was also supported by an Academic Investment Research Program award at the University of Minnesota and the National Center for Advancing Translational Sciences of the NIH (award UL1TR000114). A portion of this work was performed in the McKnight Brain Institute of the University of Florida at the National High Magnetic Field Laboratory's Advanced Magnetic Resonance Imaging and Spectroscopy Facility, which is supported by the National Science Foundation (cooperative agreement DMR‐1644779) and the State of Florida and was supported in part by an NIH award (S10 OD021726) for High End Instrumentation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PubMed: MeSH publication types
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