Poster No:
131
Submission Type:
Abstract Submission
Authors:
Lachlan Strike1, Sarah Wallis2, Jemimah Harding3, Paul Lockhart4, David Szmulewicz3, Ian Harding1
Institutions:
1QIMR Berghofer Medical Research Institute, Brisbane, Australia, 2School of Psychological Sciences, Monash University, Melbourne, Australia, 3The Bionics Institute, University of Melbourne, Melbourne, Australia, 4Murdoch Children’s Research Institute, The Royal Children’s Hospital, Melbourne, Australia
First Author:
Co-Author(s):
Sarah Wallis
School of Psychological Sciences, Monash University
Melbourne, Australia
Jemimah Harding
The Bionics Institute, University of Melbourne
Melbourne, Australia
Paul Lockhart
Murdoch Children’s Research Institute, The Royal Children’s Hospital
Melbourne, Australia
David Szmulewicz
The Bionics Institute, University of Melbourne
Melbourne, Australia
Introduction:
RFC1-related ataxia is a rare neurodegenerative disorder caused by repeat expansions in the RFC1 gene (Cortese et al., 2019,). Clinically, the disorder comprises cerebellar ataxia, neuropathy, and vestibular areflexia. While the clinical presentation of this disorder is well documented, studies are only now mapping the structural brain changes associated with RFC1-related ataxia (Matos et al., 2021).
Methods:
Participants were 19 individuals with confirmed RFC1 repeat expansions (13/6 M/F, mean age at scan 72 ± 8 years) and 24 controls (15/9 M/F, 73 ± 7 years). Disease severity was quantified using the Scale for the Assessment and Rating of Ataxia (SARA; Schmitz-Hübsch et al., 2006). Whole brain T1- and diffusion-weighted images were collected for each participant on 3T MRI systems at The Alfred Hospital, Melbourne or The Prince of Wales Hospital, Sydney. Volumetric measures were extracted for 106 regions of interest (ROI; 62 cortical, 26 cerebellar, 14 subcortical, 4 brainstem) using FreeSurfer and FastSurfer (Faber et al., 2021; Henschel et al., 2020; Iglesias et al., 2015). Diffusion metrics (i.e., fractional anisotropy [FA], free water [FW]) for 50 white matter ROIs were produced using QSIprep and DIPY (Cieslak et al., 2021; Garyfallidis et al., 2014).
Using R (R Core Team, 2024), multiple linear regression models were used to test for group differences in structural brain measures between individuals with and without RFC1-related ataxia (including covariates: scan age, sex, intracranial volume for volume measures, mean head motion for diffusion measures). Cohen's d was calculated as a measure of effect size (ES) for group differences. Structural brain measures in which group differences were found were carried forward to exploratory analyses examining associations between regional volume/diffusion measures and disease severity (i.e., SARA score). We used the Benjamini–Hochberg procedure to control the false discovery rate for the multiple comparisons (Benjamini & Hochberg, 1995).
Results:
Differences in volume and, to a lesser extent, diffusion measures between individuals with RFC1-related ataxia and controls were evident throughout the brain. Volume differences were most prominent for cerebellar structures (25/26 regional volumes significantly smaller in individuals with RFC1-related ataxia; ES -0.85 [lobule right IX] to -2.63 [lobule left X]). Differences were found for subcortical (left and right thalamus, left hippocampus; ES -0.59 to -0.79) and brainstem volumes (medulla, superior cerebellar peduncle, midbrain; ES -0.68 to -1.42); however, only three cortical ROIs showed group differences (left isthmus cingulate, right lingual, right rostral anterior cingulate, ES -0.64 to -1.07).
Reduced FA in individuals with RFC1-related ataxia compared to controls were found for 11/50 white matter ROIs, including pontine crossing tract, bilateral corticospinal tract, bilateral inferior cerebellar peduncle, bilateral superior cerebellar peduncle, bilateral posterior thalamic radiation, and bilateral fornix/stria terminalis (ES -0.84 to -1.57). Further, increased regional free water diffusion in the RFC1-related ataxia group (relative to controls) was found for five ROIs, including middle cerebellar peduncle, body of corpus callosum, right medial lemniscus, and bilateral inferior cerebellar peduncle (ES 1.03 to 1.65). Associations between structural brain measures and SARA score were not significant following multiple testing correction.
Conclusions:
This study showed brain changes associated with RFC1-related ataxia extend past cerebellar structures into deep grey matter structures and regional white matter integrity. These results highlight the need for larger-scale multi-site collaborative studies to map further morphological change associated with RFC1-related ataxia, to establish the clinical correlates of such change, and to identify metrics sensitive to longitudinal disease progression.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Diffusion MRI Modeling and Analysis
Segmentation and Parcellation 2
Keywords:
Cerebellar Syndromes
Cerebellum
Degenerative Disease
STRUCTURAL MRI
WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC
1|2Indicates the priority used for review
By submitting your proposal, you grant permission for the Organization for Human Brain Mapping (OHBM) to distribute your work in any format, including video, audio print and electronic text through OHBM OnDemand, social media channels, the OHBM website, or other electronic publications and media.
I accept
The Open Science Special Interest Group (OSSIG) is introducing a reproducibility challenge for OHBM 2025. This new initiative aims to enhance the reproducibility of scientific results and foster collaborations between labs. Teams will consist of a “source” party and a “reproducing” party, and will be evaluated on the success of their replication, the openness of the source work, and additional deliverables. Click here for more information.
Propose your OHBM abstract(s) as source work for future OHBM meetings by selecting one of the following options:
I do not want to participate in the reproducibility challenge.
Please indicate below if your study was a "resting state" or "task-activation” study.
Other
Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
Patients
Was this research conducted in the United States?
No
Were any human subjects research approved by the relevant Institutional Review Board or ethics panel?
NOTE: Any human subjects studies without IRB approval will be automatically rejected.
Yes
Were any animal research approved by the relevant IACUC or other animal research panel?
NOTE: Any animal studies without IACUC approval will be automatically rejected.
Not applicable
Please indicate which methods were used in your research:
Structural MRI
Diffusion MRI
For human MRI, what field strength scanner do you use?
3.0T
Which processing packages did you use for your study?
FSL
Free Surfer
Other, Please list
-
DIPY, QSIprep, FastSurfer
Provide references using APA citation style.
Benjamini, Y. (1995). Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society: Series B (Methodological), 57(1), 289–300.
Cieslak, M. (2021). QSIPrep: An integrative platform for preprocessing and reconstructing diffusion MRI data. Nature Methods, 18(7), 775–778.
Cortese, A. (2019). Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nature Genetics, 51(4), 649–658.
Faber, J. (2021). Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3. Movement Disorders: Official Journal of the Movement Disorder Society, 36(10), 2273–2281.
Garyfallidis, E. (2014). Dipy, a library for the analysis of diffusion MRI data. Frontiers in Neuroinformatics, 8.
Henschel, L. (2020). FastSurfer—A fast and accurate deep learning based neuroimaging pipeline. NeuroImage, 219, 117012.
Iglesias, J. (2015). Bayesian segmentation of brainstem structures in MRI. NeuroImage, 113, 184–195.
Matos, P. (2021). Brain Structural Signature of RFC1-Related Disorder. Movement Disorders, 36(11), 2634–2641.
R Core Team. (2024). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing.
Schmitz-Hübsch, T. (2006). Scale for the assessment and rating of ataxia: Development of a new clinical scale. Neurology, 66(11), 1717–1720.
No