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Structural alterations of spinocerebellar ataxias type 3: from pre-symptomatic to symptomatic stage

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Abstract

Objectives

To investigate and characterize the structural alterations of the brain in SCA3, and their correlations with the scale for the assessment and rating of ataxia (SARA) and normal brain ATXN3 expression.

Methods

We performed multimodal analyses in 52 SCA3 (15 pre-symptomatic) and healthy controls (HCs) (n = 35) to assess the abnormalities of gray and white matter (WM) of the cerebrum, brainstem, and cerebellum via FreeSurfer, SUIT, and TBSS, and their associations with disease severity. Twenty SCA3 patients (5 pre- and 15 symptomatic) were followed for at least a year. Besides, we uncovered the normal pattern of brain ATXN3 spatial distribution.

Results

Pre-symptomatic patients showed only WM damage, mainly in the cerebellar peduncles, compared to HCs. In the advanced stage, the WM damage followed a caudal-rostral pattern. Meanwhile, continuous nonlinear structure damage was characterized by brainstem volumetric reduction and relatively symmetric cerebellar and basal ganglia atrophy but spared the cerebral cortex, partially explained by the ATXN3 overexpression. The bilateral pallidum, brainstem, and cerebellar peduncles demonstrated a very large effect size. Besides, all these alterations were significantly correlated with SARA; the pons (r = −0.65) and superior cerebellar peduncle (r = −0.68) volume demonstrated a higher correlation than the cerebellum with SARA. The longitudinal study further uncovered progressive atrophy of pons in symptomatic SCA3.

Conclusions

Significant WM damage starts before the ataxia onset. The bilateral pallidum, brainstem, and cerebellar peduncles are the most vulnerable targets. The volume of pons appears to be the most promising imaging biomarker for a longitudinal study.

Trial registration

ClinicalTrial ID: ChiCTR2100045857 (http://www.chictr.org.cn/edit.aspx?pid=55652&htm=4)

Key Points

• Pre- SCA3 showed WM damage mainly in cerebellar peduncles. Continuous brain damage was characterized by brainstem, widespread, and relatively symmetric cerebellar and basal ganglia atrophy.

• Volumetric abnormalities were most evident in the bilateral pallidum, brainstem, and cerebellar peduncles in SCA3.

• The volume of pons might identify the disease progression longitudinally.

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Abbreviations

CAG:

Cytosine-adenine-guanine

DKI:

Diffusion kurtosis imaging

ES:

Effect size

FDR:

False discovery rate

GM:

Gray matter

HCs:

Healthy controls

ICP:

Inferior cerebellar peduncles

Kr:

Radial kurtosis

SARA:

Scale for the assessment and rating of ataxia

SCA3:

Spinocerebellar ataxia type 3

SCP:

Superior cerebellar peduncles

TBSS:

Tract-based Spatial Statistics

WM:

White matter

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Funding

This study has received funding from the National Natural Science Foundation of China (82172015) and the Guangdong Basic and Applied Basic Research Foundation, China (2022A1515011264, 2021A1515012279, and 2020A1515011436).

Author information

Author notes

  1. Haishan Qiu, Chao Wu, and Jiahui Liang contributed equally.

Authors and Affiliations

  1. Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58th, The Second Zhongshan Road, Guangzhou, Guangdong, People’s Republic of China

    Haishan Qiu, Manshi Hu, Yingqian Chen, Zihuan Huang, Zhiyun Yang, **g Zhao & Jian** Chu

  2. Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, 58th, The Second Zhongshan Road, Guangzhou, Guangdong, People’s Republic of China

    Chao Wu

  3. Department of Radiology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, People’s Republic of China

    Jiahui Liang

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  1. Haishan Qiu
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Corresponding authors

Correspondence to **g Zhao or Jian** Chu.

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The scientific guarantor of this publication is Chu Jian**.

Conflict of interest

The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article.

Statistics and biometry

No complex statistical methods were necessary for this paper.

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Written informed consent was obtained from all subjects (patients) in this study.

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Institutional Review Board approval was obtained.

Methodology

• prospective

• cross-sectional study

• performed at one institution

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Haishan Qiu is the first author, and Chao Wu and Jiahui Liang are the co-first authors.

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Qiu, H., Wu, C., Liang, J. et al. Structural alterations of spinocerebellar ataxias type 3: from pre-symptomatic to symptomatic stage. Eur Radiol 33, 2881–2894 (2023). https://doi.org/10.1007/s00330-022-09214-3

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  • DOI: https://doi.org/10.1007/s00330-022-09214-3

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