Associations Between CAG Repeat Size, Brain and Spinal Cord Volume Loss, and Motor Symptoms in Spinocerebellar Ataxia Type 3: a Cohort Study

Overview

Journal Orphanet J Rare Dis

Publisher Biomed Central

Date 2025 Jan 24

PMID 39849568

Authors

Zhi-Xian Ye

Xuan-Yu Chen

Meng-Cheng Li

Xin-Yuan Chen

Yu-Sen Qiu

Ru-Ying Yuan

Zhi-Li Chen

Min-Ting Lin

Jian-Ping Hu

Ying Fu

Wan-Jin Chen

Ning Wang

Shi-Rui Gan

Affiliations

Soon will be listed here.

Abstract

Background: Spinocerebellar ataxia type 3 (SCA3) is a hereditary disease caused by abnormally expanded CAG repeats in the ATXN3 gene. The study aimed to identify potential biomarkers for assessing therapeutic efficacy by investigating the associations between expanded CAG repeat size, brain and spinal cord volume loss, and motor functions in patients with SCA3.

Methods: In this prospective, cross-observational study, we analyzed 3D T1-weighted MRIs from 92 patients with SCA3 and 42 healthy controls using voxel-based morphometry and region of interest approaches. Associations between expanded CAG repeat size, brain and spinal cord volume loss, and International Cooperative Ataxia Rating Scale (ICARS) scores were investigated using partial correlation and mediation analyses. Sample sizes of potential biomarkers were calculated.

Results: Compared with healthy controls, SCA3 patients had lower cerebellar volume and cervical spinal cord area. SCA3 patients evolved along a stage-independent decline that began in the cerebellum, progressed to spinal cord, brainstem, thalami, and basal ganglia, and extensive subcortex. Expanded CAG repeat size was associated with right cerebellar lobule IV volume (r = - 0.423, P < 0.001) and cervical spinal cord area (r = - 0.405, P < 0.001), and higher ICARS (r = 0.416, P < 0.001). Mediation analysis revealed an indirect effect of expanded CAG repeat size on ICARS through spinal cord. Sample sizes estimation revealed that a minimum sample size was achieved with spinal cord measures.

Conclusions: Our results indicate the potential of cervical spinal cord area as a biomarker for disease progression and a minimum sample size estimation in future clinical studies of SCA3.

References

Fahl C, Branco L, Bergo F, DAbreu A, Lopes-Cendes I, Franca Jr M . Spinal cord damage in Machado-Joseph disease. Cerebellum. 2014; 14(2):128-32. DOI: 10.1007/s12311-014-0619-7. View

Romero J, Coupe P, Giraud R, Ta V, Fonov V, Park M . CERES: A new cerebellum lobule segmentation method. Neuroimage. 2016; 147:916-924. DOI: 10.1016/j.neuroimage.2016.11.003. View

Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-59. DOI: 10.1007/BF00308809. View

Maas R, Teerenstra S, Toni I, Klockgether T, Schutter D, van de Warrenburg B . Cerebellar Transcranial Direct Current Stimulation in Spinocerebellar Ataxia Type 3: a Randomized, Double-Blind, Sham-Controlled Trial. Neurotherapeutics. 2022; 19(4):1259-1272. PMC: 9059914. DOI: 10.1007/s13311-022-01231-w. View

Schulz J, Borkert J, Wolf S, Schmitz-Hubsch T, Rakowicz M, Mariotti C . Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6. Neuroimage. 2009; 49(1):158-68. DOI: 10.1016/j.neuroimage.2009.07.027. View

Nighoghossian N, Trouillas P . Hyperbaric oxygen in the treatment of acute ischemic stroke: an unsettled issue. J Neurol Sci. 1997; 150(1):27-31. DOI: 10.1016/s0022-510x(97)05398-7. View

Guo J, Chen H, Biswal B, Guo X, Zhang H, Dai L . Gray matter atrophy patterns within the cerebellum-neostriatum-cortical network in SCA3. Neurology. 2020; 95(22):e3036-e3044. DOI: 10.1212/WNL.0000000000010986. View

Ye Z, Bi J, Qiu L, Chen X, Li M, Chen X . Cognitive impairment associated with cerebellar volume loss in spinocerebellar ataxia type 3. J Neurol. 2023; 271(2):918-928. DOI: 10.1007/s00415-023-12042-0. View

Pyatigorskaya N, Yahia-Cherif L, Valabregue R, Gaurav R, Gargouri F, Ewenczyk C . Parkinson Disease Propagation Using MRI Biomarkers and Partial Least Squares Path Modeling. Neurology. 2020; 96(3):e460-e471. DOI: 10.1212/WNL.0000000000011155. View

Burk K, Abele M, Fetter M, Dichgans J, Skalej M, Laccone F . Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain. 1996; 119 ( Pt 5):1497-505. DOI: 10.1093/brain/119.5.1497. View

10.

Durr A, Stevanin G, Cancel G, Duyckaerts C, Abbas N, Didierjean O . Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol. 1996; 39(4):490-9. DOI: 10.1002/ana.410390411. View

11.

Maas R, van Gaalen J, Klockgether T, van de Warrenburg B . The preclinical stage of spinocerebellar ataxias. Neurology. 2015; 85(1):96-103. DOI: 10.1212/WNL.0000000000001711. View

12.

Faber J, Schaprian T, Berkan K, Reetz K, Franca Jr M, de Rezende T . Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3. Mov Disord. 2021; 36(10):2273-2281. PMC: 9521507. DOI: 10.1002/mds.28610. View

13.

Evert B, Vogt I, Kindermann C, Ozimek L, de Vos R, Brunt E . Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains. J Neurosci. 2001; 21(15):5389-96. PMC: 6762679. View

14.

Jacobi H, Tezenas du Montcel S, Bauer P, Giunti P, Cook A, Labrum R . Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol. 2015; 14(11):1101-8. DOI: 10.1016/S1474-4422(15)00202-1. View

15.

Schmitz-Hubsch T, Tezenas Du Montcel S, Baliko L, Berciano J, Boesch S, Depondt C . Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006; 66(11):1717-20. DOI: 10.1212/01.wnl.0000219042.60538.92. View

16.

Leotti V, de Vries J, Oliveira C, de Mattos E, Meerman G, Brunt E . CAG Repeat Size Influences the Progression Rate of Spinocerebellar Ataxia Type 3. Ann Neurol. 2020; 89(1):66-73. DOI: 10.1002/ana.25919. View

17.

Rezende T, Paiva J, Martinez A, Lopes-Cendes I, Pedroso J, Barsottini O . Structural signature of SCA3: From presymptomatic to late disease stages. Ann Neurol. 2018; 84(3):401-408. DOI: 10.1002/ana.25297. View

18.

Seidel K, Siswanto S, Brunt E, den Dunnen W, Korf H, Rub U . Brain pathology of spinocerebellar ataxias. Acta Neuropathol. 2012; 124(1):1-21. DOI: 10.1007/s00401-012-1000-x. View

19.

Guo J, Jiang Z, Biswal B, Zhou B, Xie D, Gao Q . Hypothalamic Atrophy, Expanded CAG Repeat, and Low Body Mass Index in Spinocerebellar Ataxia Type 3. Mov Disord. 2022; 37(7):1541-1546. DOI: 10.1002/mds.29029. View