Gene-Related Cerebellar Neurodegeneration in SCA3/MJD: A Case-Controlled Imaging-Genetic Study

Huirong Peng; Xiaochun Liang; Zhe Long; Zhao Chen; Yuting Shi; Kun Xia; Li Meng; Beisha Tang; Rong Qiu; Hong Jiang

doi:10.3389/fneur.2019.01025

Gene-Related Cerebellar Neurodegeneration in SCA3/MJD: A Case-Controlled Imaging-Genetic Study

Front Neurol. 2019 Sep 24:10:1025. doi: 10.3389/fneur.2019.01025. eCollection 2019.

Authors

Huirong Peng¹, Xiaochun Liang¹, Zhe Long², Zhao Chen¹, Yuting Shi¹, Kun Xia³, Li Meng⁴, Beisha Tang^{1

3

5

6

7

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9}, Rong Qiu¹⁰, Hong Jiang^{1

3

5

6

11}

Affiliations

¹ Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
² Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China.
³ Laboratory of Medical Genetics, Central South University, Changsha, China.
⁴ Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.
⁵ National Clinical Research Center for Geriatric Diseases, Central South University, Changsha, China.
⁶ Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China.
⁷ Parkinson's Disease Center, Beijing Institute for Brain Disorders, Beijing, China.
⁸ Collaborative Innovation Center for Brain Science, Shanghai, China.
⁹ Collaborative Innovation Center for Genetics and Development, Shanghai, China.
¹⁰ School of Information Science and Engineering, Central South University, Changsha, China.
¹¹ Department of Neurology, Xinjiang Medical University, Urumchi, China.

Abstract

Background: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is one of the nine polyglutamine (polyQ) diseases and is caused by a CAG repeat expansion within the coding sequence of the ATXN3 gene. Few multimodal imaging analyses of the macro- and micro-structural changes have been performed. Methods: In the present study, we recruited 31 genetically-confirmed symptomatic SCA3/MJD patients and 31 healthy subjects as controls for a multimodal neuroimaging study using structural magnetic resonance imaging (sMRI), proton magnetic resonance spectroscopy (¹H-MRS) and diffusion tensor imaging (DTI). Results: The SCA3/MJD patients displayed a significantly reduced of gray matter volume in the cerebellum, pons, midbrain and medulla, as well as inferior frontal gyrus and insula, and left superior frontal gyrus. The total International Cooperative Ataxia Rating Scale (ICARS) score was inversely correlated with the gray matter volume in the cerebellar culmen, pons and midbrain. The numbers of CAG repeats in the expanded alleles were inversely correlated with the gray matter in the cerebellar culmen. NAA/Cr and NAA/Cho ratio in the middle cerebellar peduncles, dentate nucleus, cerebellar vermis, and thalamus in the SCA3/MJD patients were significantly reduced when compared to that in the normal controls, suggesting neurochemical alterations in cerebellum in the SCA3/MJD patients. Tract-Based Spatial Statistics (TBSS) analysis revealed significant lower volume and mean FA values of the cerebellar peduncles, which inversely correlated with the total scores of ICARS in our patients. Conclusions: In this study, we demonstrated cerebellar degeneration in SCA3/MJD based on tissue volume, neurochemistry, and tissue microstructure. Moreover, the associations between the clinical measures, cerebellar degeneration and genetic variation support a distinct genotype-phenotype relationship in SCA3/MJD.

Keywords: 1HMRS; gray matter; imaging genetics study; spinocerebellar ataxia 3; white matter.