MRI quantification of multiple sclerosis pathology

Abstract: Background: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease and a common cause of neurologic disability. MS pathology is characterized by demyelination, neuroaxonal loss and atrophy. Magnetic Resonance Imaging (MRI) is an essential tool in diagnosing and monitoring MS, but its clinical value could be even further expanded by more advanced and quantitative MRI methods, which may also provide additional pathophysiological insights. Purpose: The overall aim of this thesis was to quantify MS pathology using volumetric brain MRI, ultra-high field brain and cervical spinal cord MRI as well as a newly developed rapid myelin imaging technique in relation to cognitive and physical MS disability. Study I, a prospective 17-year longitudinal study of 37 MS participants with 23 age/sex- matched healthy controls for comparison at the last follow-up. Longitudinal volumetric brain 1.5 Tesla MRI during the second half of the study showed that lesion accumulation and corpus callosum atrophy were the most strongly associated neuroanatomical correlates of cognitive disability, with the lesion fraction being an independent predictor of cognitive performance 8.5 years later. Study II, a prospective cross-sectional study of 35 MS participants and 11 age-matched healthy controls using 3 and 7 Tesla MRI. The study demonstrated involvement of both grey and white matter in MS, not only the brain but also the cervical spinal cord, associated with MS disability. Lesions appeared in proximity to the cerebrospinal fluid (CSF), with special predilection to the periventricular and grey matter surrounding the central canal in secondary progressive MS. Study III, a prospective in vivo (71 MS participants and 21 age/sex-matched healthy controls) and ex vivo (brain tissue from 3 MS donors) study at 3 Tesla, showed that a new clinically approved and feasible rapid myelin imaging technique correlates well with myelin stainings and produces robust in vivo myelin quantification that is related to both current and future cognitive and physical disability in MS. Study IV, an in-depth topographical analysis based on Study III, mapped the distribution of demyelination, both in vivo and ex vivo, in the periventricular and perilesional regions of the brain. A gradient of demyelination with predominance near the CSF spaces was seen. Measures of clinical disability were consistently and more strongly associated with the myelin content in normal-appearing tissue compared to the intralesional myelin content. Conclusions: Lesions and atrophy contribute to cognitive and physical disability in MS but to a varying degree, likely dependent on the relative involvement of white vs. grey matter. Both focal lesions/demyelination as well as diffuse demyelination in normal-appearing white matter shows an apparent gradient from the CSF, which differ between relapsing-remitting and progressive MS subtypes/phases. The growing utility and clinical availability of advanced and quantitative MRI techniques holds promise for improved monitoring of MS pathology and likely represents a vital tool for assessing the efficacy of potential remyelinating/reparative therapies in MS.

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