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. The 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 on structural MRI) was applied to interrogate and compare grey matter volume in young A-T patients and typically developing age-matched control participants as a preliminary starting point in uncovering neurodegenerative biomarkers in A-T. Tract-based spatial statistics (based on diffusion MRI) was employed to elucidate the white matter microstructure differences between groups, using the diffusion metrics fractional anisotropy (FA) and mean diffusivity (MD) as quantitative measures of tissue integrity. Voxel-wise analyses revealed reduced cerebellar grey matter volume and white matter tract degeneration in pathways projecting from the cerebellum into corticomotor regions among young A-T patients, indicating the need to focus on the corticomotor system in A-T. To assess white matter degeneration quantitatively in A-T corticomotor pathways, white matter fibre tracking and along tract statistical analyses were used to assess FA and MD differences along the length of cortico-ponto-cerebellar, cerebellar-thalamo-cortical, somatosensory and lateral corticospinal pathways between controls and patients. Significant differences in FA and MD were observed along the length of all patient tracts, particularly in locations pertaining to the pre- and postcentral gyrus, thalamus, medial and superior cerebellar peduncles and the spinal cord, suggestive of comprehensive motor pathway degeneration in young A-T patients. Despite numerous histopathological and anatomical studies of degeneration in A-T, the pattern of AT neurodegeneration over time has not been effectively captured. To this end, serial analysis using structural MRI, whole brain imaging methodology and automated volumetric analysis of the basal ganglia (caudate and putamen), thalamus and cerebellum were conducted in A-T MRI data sets spanning two years. Significant changes in white and grey matter integrity were absent in the A-T longitudinal data, however concurrent use of the A-T Neuro Examination Scale Toolkit (A-T NEST) clinical scores during the imaging time frame revealed loss in clinical motor functional scores for some participants, indicating neurodegenerative change in early stages of A-T. These findings highlight the need for high-resolution images to capture significant early neurodegenerative changes in the A-T cohort. In addition, the inclusion of the spinal cord, a prominent area of A-T pathology, for study, and the incorporation of a larger, international collaborative cohort for imaging analysis should be considered in future A-T imaging studies.