| Abstract |
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting the motor system of the central nervous system. The aim of this thesis is to evaluate the potential of structural magnetic resonance imaging (MRI) biomarkers of the brain grey matter (GM) and white matter (WM) for the state and progression of ALS. The thesis has been conducted on behalf of a treatment program on a named patient basis at the University Hospital of Regensburg. 31 patients with written informed consent are compared to a control sample of 34 age-matched healthy participants. Routine MRI scans have been conducted approximately every 3 months and include T1-weighted imaging, diffusion weighted imaging (DWI), and fluid-attenuated inversion recovery (FLAIR) sequences at 1.5 Tesla. The subprojects of the thesis investigate precentral and postcentral cortical thinning (study 1), spread of alterations of fractional anisotropy (FA) across different WM types (study 2), and FLAIR lesion detection (study 3) in the same ALS cohort. Candidate MRI biomarkers are associated with neurophysiological and clinical biomarkers. Statistical analysis includes both cross-sectional and longitudinal analyses. Special focus is set on the individual patient. Cortical thinning is more pronounced in the precentral cortex than in the postcentral cortex. Combinatory biomarker use reveals evident differences in temporal dynamics of cortical thickness, clinical and neurophysiological biomarkers over time. Reduction of FA is consistently detected in the corticospinal tract (CST) and extra motor WM and most pronounced in the brainstem. Spread of FA alterations resembles both dying-forward and dying-back disease propagation and is not linked to patients' clinical or demographic characteristics. WM lesions as detected by FLAIR hyperintensity are more frequent in ALS patients than in controls, most pronounced in the CST, and associated with an inferior survival. Together, the findings of this thesis suggest that MRI biomarkers may contribute to the diagnosis, prognosis and understanding of ALS disease and disease courses on an individual scope. - Contents: (1) Wirth, A.M., Khomenko, A., Baldaranov, D., Kobor, I., Hsam, O., Grimm, T., Johannesen, S., Bruun, T.-H., Schulte-Mattler, W., Greenlee, M.W. & Bogdahn, U. (2018). Combinatory biomarker use of cortical thickness, MUNIX, and ALSFRS-R at baseline and in longitudinal courses of individual patients with amyotrophic lateral sclerosis. frontiers in Neurology, 9:614. DOI: 10.3389/fneur.2018.00614. (2) Wirth, A.M., Khomenko, A., Johannesen, S., Baldaranov, D., Bruun, T.-H., Greenlee, M.W. & Bogdahn, U. (n. d.). Dying-forward or dying-back? White matter type-specific alterations of fractional anisotropy in classical amyotrophic lateral sclerosis. Manuscript submitted for publication. (3) Wirth, A.M., Johannesen, S., Khomenko, A., Baldaranov, D., Bruun, T.-H., Wendl, C., Schuierer, G., Greenlee, M.W., Bogdahn, U. (2019). Value of fluid-attenuated inversion recovery MRI data analyzed by the lesion segmentation toolbox in amyotrophic lateral sclerosis. Journal of Magnetic Resonance Imaging, 50, 552-559. DOI: 10.1002/jmri.26577.
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