Investigating neural connectivity of corticomotor networks in ataxia telangiectasia: improving our understanding of the clinical phenotype

Abstract

The human genetic disorder ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative condition occurring in 3 per million live births. The disease is characterised by neurodegeneration, immunodeficiency, radiosensitivity, cell cycle checkpoint defects, genomic instability and cancer predisposition among patients. The most debilitating aspect of the disease is progressive cerebellar ataxia, which represents the hallmark neuropathological condition of A-T.At present, long term therapy to cure or prevent progressive symptoms of A-T are not currently available. While short term treatment to alleviate symptoms associated with immunodeficiency and deficient lung function are available to patients, the predisposition to cancer and the progressive neurodegeneration associated with A-T cannot be prevented with such efforts. To gain a more informed understanding of the A-T condition, research has focused on clinical, genetic and immunological aspects of the disorder; however, minimal attention has been directed towards identifying altered brain structure and function using imaging modalities such as magnetic resonance imaging (MRI).Imaging studies in A-T are limited to structural MRI imaging, where various radiological anomalies in patients are reported as clinical case studies. While these studies provide a detailed focus on the morphological and histopathological conditions of A-T, they provide limited insight into the mechanisms of neurodegeneration and loss of neural motor network connectivity among patients. In other ataxic diseases such as Friedrich's ataxia and spinocerebellar ataxia, the use of high-resolution MRI and diffusion-weighted imaging (DWI) has given valuable insight into the microstructural tissue environment, and the loss of white matter integrity of motor networks due to abnormal neurodevelopmental and/or progressive neurodegenerative conditions associated with the disease.Such imaging approaches have not yet been extended to the study of A-T, and could provide important new information regarding the relationship between the ataxia-telangiectasia gene mutation (ATM) and loss of motor pathway integrity in A-T patients. ivThe key objective of this PhD programme was to investigate white matter integrity and grey matter volume changes associated with A-T using a combination of structural MRI and diffusion-weighted imaging, to pinpoint potential neurodegenerative biomarkers that can be targeted for therapeutic use among young A-T patients. Performing diffusion imaging in children with A-T presents a significant challenge, as spontaneous movement at resting positions form part of the A-T condition, and nonsedated imaging procedures will contribute to excessive motion artefact and limited image quality in diffusion-weighted images. To effectively detect and correct for motion artefacts, a series of data preprocessing and correction steps were introduced to the DWI processing pipeline of A-T images in this project. Whole brain imaging analysis, specifically voxel-based morphometry (based...