(Whole Brain MS) Macromolecular Imaging of White and Gray Matter Pathology in Multiple Sclerosis

MRI is a vital component of MS work-up, providing noninvasive evidence of MS lesions on T1/T2-weighted images, detecting active inflammatory lesions, and measuring brain atrophy to assess neurodegeneration. Consequently, largely owing to the location of MRI-visible lesions, MS has long been considered a white matter (WM) disease. Recent years of post-mortem and ultra-high field MRI research, however, have generated strong evidence of significant and complicated gray matter (GM) involvement in MS, resulting in the reclassification of MS as a whole-brain disease. Similar to WM, a primary target of MS pathology in GM is myelin (~50%/~15% of WM/GM dry weight, respectively), the protective sheath insulating the penetrating axons within GM and extending brain connectivity all the way to the neuronal bodies. Demyelination in GM occurs independently from WM and may begin several years earlier in the course of disease than in WM. GM demyelination diminishes information-processing capacity necessary to develop and maintain cognitive functions. GM pathology is likely responsible for much of the disability, particularly for the cognitive decline seen in up to 65% of MS patients. Consistent with the above findings for GM disease, cognitive impairment may occur early in the disease11 and may be predictive of conversion from clinically isolated syndrome (CIS) to clinically definite MS. Thus, studying associations between imaging measures of GM disease and cognitive performance can establish GM-based imaging correlates predicting the disease course and accurately assessing treatment results.
The primary aim of this project is to determine whether our new macromolecular measures optimized for whole brain (GM+WM) imaging predict neurocognitive impairment in MS patients. We will apply them along with existing imaging measures in a series of MS subjects and healthy controls to determine whether the novel methods will yield estimates of whole-brain MS disease burden that predict cognitive impairment more accurately. The successful clinical validation of the new markers will show that it provides more relevant measures of GM+WM disease associated with cognitive deficits than conventional MRI. The availability of such objective, imaging-based measures may fundamentally change the evaluation of cognitive performance. Thus, this study may realign the capabilities of MRI with the demands for biomarkers generated by our most current understanding of MS as a “whole-brain" disease.