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. 2025 Apr;32(4):e70127.
doi: 10.1111/ene.70127.

Altered Brain Iron Depositions of Spinocerebellar Ataxia Type 3: From Pre-Symptomatic to Symptomatic Stage

Haishan Qiu  1 , Manshi Hu  1 , Chao Jiang  1 , Jiale Wu  1 , Zihuan Huang  1 , Jiahui Liang  2 , Runhua Sha  1 , Wenting Zeng  3 , Chao Wu  4 , Jianping Chu  1 , Jing Zhao  1
Affiliations

Altered Brain Iron Depositions of Spinocerebellar Ataxia Type 3: From Pre-Symptomatic to Symptomatic Stage

Haishan Qiu et al. Eur J Neurol. 2025 Apr.

Abstract

Background: Spinocerebellar ataxia type 3 (SCA3) is a rare hereditary neurodegeneration disease. The iron distribution of SCA3 is poorly understood, yet quantitative susceptibility mapping (QSM) has rarely been used in SCA3.

Methods: We prospectively investigated QSM of SCA3 (19 pre-symptomatic and 41 symptomatic) and 37 healthy controls (HCs) recruited from 2018.05 to 2021.01. Group susceptibility was cross-sectionally compared, and the associations between altered brain iron deposition and clinical symptoms, neurofilament light chain (Nfl), and fractional anisotropy of the bilateral corticospinal tracts and cerebellar peduncles were explored. 12 SCA3 participants were followed for at least a year.

Results: Compared to HCs, bilateral SN were observed with significantly increased susceptibility in pre-symptomatic SCA3. Most of the supratentorial nuclei and the right dental nucleus had increased susceptibility in symptomatic than in pre-symptomatic stage and were partially correlated with symptomatic severity, disease duration, and damaged cerebellar peduncles (p < 0.05) but not Nfl (p > 0.05). The left substantia nigra (SN) demonstrated the highest diagnostic efficacy in identifying pre- (AUC = 0.904) and symptomatic SCA3 (AUC = 0.938). The longitudinal study also confirmed the significant change in the left SN (p < 0.01).

Conclusions: Our in vivo QSM evidence demonstrates disease-specific patterns for brain iron depositions in SCA3. Brain iron deposition abnormality is an early event of the SCA3's occurrence and development. The left SN might be a critical site for the disease's start and development.

Keywords: MRI; quantitative susceptibility mapping; spinocerebellar ataxia type 3; substantia nigra.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
The flow chart of the study. (A) The recruitment of participants. (B) The imaging processing of the QSM, T1‐weighted images and diffusion weighted images. The parcellated cortex (highlighted in red) was overlaid on the QSM images to check the registration results. (C) The final ROI outlining on QSM (globus pallidus in yellow, caudate nucleus in red, thalamus in white, putamen in blue, red nucleus in orange, substantia nigra in gray and dentate nucleus in green) and FA images (superior (blue), middle (red) and inferior (green) cerebellar peduncle). Representative QSM and diffusion weighted image data from an adult (male, 27 years old) are exhibited. BET, Brain Extraction Tool; FA, Fractional anisotropy; HC, Healthy control; HC1, HC group 1; HC2, HC group 2; MNI, Montreal Neurological Institute; pre‐SCA3, Pre‐symptomatic SCA3; QSM, Quantitative susceptibility mapping; ROI, Region of interest; SCA3, Spinocerebellar ataxia type 3; sym‐SCA3, Symptomatic SCA3.
FIGURE 2
FIGURE 2
Iron content (mean magnetic susceptibility value) distributions in brain structures (bilateral PC, CN, THA, GP, PT, RN, SN, and DN) among pre‐, sym‐SCA3 and HCs. CN, Caudate nucleus; DN, Dentate nucleus; GP, globus pallidus; HC, Healthy control; HC1, HC group 1; HC2, HC group 2; PC, Precentral gyrus cortex; pre‐SCA3, Pre‐symptomatic SCA3; PT, Putamen; RN, Red nucleus; SCA3, Spinocerebellar ataxia type 3; SN, Substantia nigra; sym‐SCA3, Symptomatic SCA3; THA, thalamus. *: p < 0.05, false discovery rate corrected; **: p < 0.01, false discovery rate corrected.
FIGURE 3
FIGURE 3
Correlations between susceptibility values of different brain nuclei and the FA values of the impaired fibers. FA, Fractional anisotropy; LCST, Left corticospinal tract; LICP, Left inferior cerebellar peduncle; LSCP, Left superior cerebellar peduncle; MCP, Middle cerebellar peduncles; RCST, Right corticospinal tract; RICP, Right inferior cerebellar peduncle; RSCP, Right superior cerebellar peduncle.
FIGURE 4
FIGURE 4
Correlations between susceptibility values of different brain nuclei and SARA scores (a), disease durations (b), and CAG repetition (c). CAG, Cytosine‐adenine‐guanine; CN, Caudate nucleus; DN, Dentate nucleus; GP, globus pallidus; RN, Red nucleus; SARA scores, the scale for the assessment and rating of ataxia; SN, Substantia nigra.
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