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Investigating cognitive impairment in multiple sclerosis using myelin water imaging

University of British Columbia

Cognitive impairment is a common symptom in multiple sclerosis (MS) that presents in up to 70% of patients. Cognitive symptoms in MS typically manifest as deficits in attention, memory and/or processing speed, with processing speed being most frequently affected. MS-related cognitive impairment represents a major burden as it can significantly lower quality of life and is a main contributor to unemployment. Conventional magnetic resonance imaging (MRI) with T1-weighted and T2-weighted contrast is the mainstay of MS diagnosis and monitoring. However, conventional MRI is limited in that it is qualitative, lacks biological specificity and correlates poorly with clinical and cognitive status. In contrast, myelin water imaging (MWI) is an advanced MRI technique that measures the signal from water in the myelin bilayers, providing a quantitative myelin-specific measurement (myelin water fraction, MWF). The aim of this thesis is to investigate the relationship between myelin damage and cognitive performance in MS using MWI. First, we demonstrate that MWF in normal appearing white matter (NAWM) was significantly associated with processing speed performance in MS in 3 a priori selected white matter tracts associated with cognition. Next, we show that the relationship between NAWM MWF and cognitive performance extends to additional cognitive domains in a larger cohort. Finally, rather than selecting brain regions a priori, we employed an assumption-free data driven approach using permutation testing to show that myelin damage extent and anatomical location is unique to the cognitive domain being investigated, with greater myelin damage in these regions in cognitively impaired versus cognitively preserved patients. Further, we demonstrate that the severity and spatial extent of myelin damage in cognitive domain-specific white matter regions is strongly associated with cognitive performance. This thesis demonstrates that there is a strong relationship between the location and severity of myelin damage and MS-related cognitive impairment. As the treatment landscape for MS moves toward the development of remyelination therapies, understanding the role of myelin pathology in cognitive symptoms is critical for translating findings to clinical trials. These results also highlight the promise of MWI for monitoring myelin changes and their relationship to cognitive worsening and improvement when investigating new therapies.

Text

2021-11-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76570

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/