Assessment of Cerebral and Cerebellar White Matter Microstructure in Spinocerebellar Ataxias 1, 2, 3, and 6 Using Diffusion MRI

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Development of imaging biomarkers for rare neurodegenerative diseases such as spinocerebellar ataxia (SCA) is important to non-invasively track progression of disease pathology and monitor response to interventions. Diffusion MRI (dMRI) has been shown to identify cross-sectional degeneration of white matter (WM) microstructure and connectivity between healthy controls and patients with SCAs, using various analysis methods. In this paper, we present dMRI data in SCAs type 1, 2, 3, and 6 and matched controls, including longitudinal acquisitions at 12–24-month intervals in a subset of the cohort, with up to 5 visits. The SCA1 cohort also contained 3 premanifest patients at baseline, with 2 showing ataxia symptoms at the time of the follow-up scans. We focused on two aspects: first, multimodal evaluation of the dMRI data in a cross-sectional approach, and second, longitudinal trends in dMRI data in SCAs. Three different pipelines were used to perform cross-sectional analyses in WM: region of interest (ROI), tract-based spatial statistics (TBSS), and fixel-based analysis (FBA). We further analyzed longitudinal changes in dMRI metrics throughout the brain using ROI-based analysis. Both ROI and TBSS analyses identified higher mean (MD), axial (AD), and radial (RD) diffusivity and lower fractional anisotropy (FA) in the cerebellum for all SCAs compared to controls, as well as some cerebral alterations in SCA1, 2, and 3. FBA showed lower fiber density (FD) and fiber crossing (FC) regions similar to those identified by ROI and TBSS analyses. FBA also highlighted corticospinal tract (CST) abnormalities, which was not detected by the other two pipelines. Longitudinal ROI-based analysis showed significant increase in AD in the middle cerebellar peduncle (MCP) for patients with SCA1, suggesting that the MCP may be a good candidate region to monitor disease progression. The patient who remained symptom-free throughout the study displayed no microstructural abnormalities. On the other hand, the two patients who were at the premanifest stage at baseline, and showed ataxia symptoms in their follow-up visits, displayed AD values in the MCP that were already in the range of symptomatic patients with SCA1 at their baseline visit, demonstrating that microstructural abnormalities are detectable prior to the onset of ataxia.

Original languageEnglish (US)
Article number411
JournalFrontiers in Neurology
StatePublished - Jun 4 2020

Bibliographical note

Funding Information:
We thank the participants in this study, members of the US Clinical Research Consortium for Studies of Cerebellar Ataxias (CRC-SCA) for referring participants to our study, and the staff of the Center for Magnetic Resonance Research (CMRR) for maintaining and supporting the MR system. Funding. This work was supported by the Bob Allison Ataxia Research Center, Jay D. Schlueter Ataxia Research Fund, and National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS070815. The CMRR was supported by the National Institute of Health (NIH) grants P41 EB027061, P30 NS076408, and S10 OD017974-01. Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1 TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
© Copyright © 2020 Park, Joers, Guo, Hutter, Bushara, Adanyeguh, Eberly, Öz and Lenglet.


  • SCA1
  • SCA2
  • SCA3
  • SCA6
  • Spinocerebeflar ataxias
  • diffusion MRI

PubMed: MeSH publication types

  • Journal Article


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