Poster No:
87
Submission Type:
Abstract Submission
Authors:
Jason Robertson1, Ian Harding2,3, Carlos Hernandez-Castillo1
Institutions:
1Dalhousie University, Halifax, Nova Scotia, Canada, 2QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia, 3School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
First Author:
Co-Author(s):
Ian Harding, Ph.D.
QIMR Berghofer Medical Research Institute|School of Translational Medicine, Monash University
Brisbane, Queensland, Australia|Melbourne, Victoria, Australia
Introduction:
Spinocerebellar ataxias (SCAs) are rare genetic disorders that result in loss of motor coordination primarily affecting gait, balance, speech, swallowing, and fine motor control. More than forty SCA disorders have been classified to date, of which SCA2 and SCA3 are among the most prevalent. These specific SCAs result from expanded CAG triplet repeats in the respective causative gene, creating a mutated protein that causes progressive atrophy preferentially in the spinal cord, cerebellum, and brainstem. Historically, neuroimaging studies of SCAs have relied on relatively small samples due to their rarity, limiting statistical power, generalisability, and characterisation of inter-individual variability. The ENIGMA-Ataxia working group addresses these limitations by aggregating MRI data from SCA cohorts worldwide to perform large-scale, well-powered inference of brain atrophy in these rare diseases.
Methods:
MRI, demographic, and clinical data were collected from 14 global partner sites and two partner consortia. The final dataset contained 128 SCA2 subjects with 110 age- and sex-matched healthy controls; and 339 SCA3 subjects with 276 controls. MRI data consisted of T1-weighted structural scans; clinical data included the Scale for Assessment and Rating of Ataxia (SARA), disease duration, and number of CAG repeats in the target gene. The MRI data were processed using volume-based morphometry (VBM) of both grey matter (GM) and white matter (WM). Whole-brain assessments of volume changes in the SCA2 and SCA3 cohorts were undertaken relative to their respective control groups, correcting for site, age, and head size. Stratified analyses were then undertaken in five subgroups defined by ataxia severity, and regressions were calculated between volume and each of the three clinical variables.
Results:
In both SCA2 and SCA3, the earliest and largest magnitude of atrophy occurred in the cerebellar WM and brainstem, especially the pons. Many key WM tracts linking the spine, cerebellum, and cerebrum, including the corticospinal tract, medial lemniscus, and cerebral and cerebellar peduncles were heavily affected. Consistent atrophy, lower in intensity compared to the WM, was visible throughout the cerebellar GM in both diseases. In SCA2 only, WM atrophy also encompassed the superior fronto-occipital fasciculus, superior corona radiata, and internal capsule, underlying cortical motor areas; by contrast, in SCA3 only, GM atrophy was evident in the bilateral caudate nuclei and putamen. Overall atrophy effect size was lower in SCA3 compared to SCA2.
Substantial differences between SCA2 and SCA3 were observed in the stratified WM analysis. In SCA2, WM atrophy is first evident in the cerebellar WM and pons in the pre-ataxic stage, progressively expanding over worsening disease stages to encompass the cerebellar-cerebral pathways. By contrast, in SCA3, the WM atrophy also begins in the cerebellum and brainstem, and becomes more severe in these areas, but does not progressively expand with disease severity. Meanwhile, GM loss in both SCA2 and SCA3 progressively encompassed the entire cerebellum and select regions of the cerebrum; while the cerebral regions affected differed slightly between SCA2 and SCA3, results were sparse.
Significant regressions with SARA were found in both disease groups and generally mirrored their respective groupwise results, with the SCA2 subjects showing stronger negative relationships between volume and SARA. In SCA3, correlations with disease duration largely mirrored those with SARA, whereas in SCA2, results were sparse. No correlations were observed with CAG repeats in either disease.
Conclusions:
This study represents the first results from a long-term project to better characterize and understand common SCA disorders. We have found that, while the principal involvement of the cerebellum and brainstem is unsurprisingly common to both disorders, the progression and pattern varied considerably between them.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Genetics:
Neurogenetic Syndromes 2
Keywords:
Cerebellum
Congenital
Degenerative Disease
DISORDERS
Movement Disorder
Spinal Cord
STRUCTURAL MRI
White Matter
Other - Ataxia; SCA
1|2Indicates the priority used for review
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