Whilst MRI is routinely used for the assessment and diagnosis of multiple sclerosis, there is poor correspondence between clinical disability in primary progressive multiple sclerosis (PPMS) patients and conventional MRI markers of disease activity (e.g., number of enhancing lesions). As PPMS patients show diffuse and global myelin loss, the aim of this study was to evaluate the efficacy of whole-brain myelin water fraction (MWF) imaging in PPMS. Specifically, we sought to use full-brain analysis techniques to: 1) determine the reproducibility of MWF estimates in PPMS brain; 2) compare MWF values in PPMS brain to healthy controls; and 3) establish the relationship between MWF and clinical disability, regionally and globally throughout the brain. Seventeen PPMS patients and seventeen age-matched controls were imaged using a whole-brain multi-component relaxation imaging technique to measure MWF. Analysis of MWF reduction was performed on three spatial levels: 1) histogram; 2) white matter skeleton; and 3) voxel-wise at the single-subject level. From histogram analysis, PPMS patients had significantly reduced global normal appearing white matter MWF (6%, p=0.04) compared to controls. Focal lesions showed lower MWF values than white matter in controls (61%, p<0.001) and patients (59%, p<0.001). Along the white matter skeleton, MWF was diffusely reduced throughout the PPMS brain, with significant correlations between reduced MWF and increased clinical disability (more severe symptoms), as measured by the Expanded Disability Status Scale, within the corpus callosum and frontal, temporal, parietal and occipital white matter. Correlations with the more specific mental and sensory functional system scores were localized to clinically eloquent locations: reduced MWF was significantly associated with increased mental scores in anterior regions (i.e., frontal lobes and genu of the corpus callosum), and increased sensory scores in more posterior regions closer to the sensory cortex. Individual patient MWF maps were also compared to a normative population atlas, which highlighted areas of statistical difference between the individual patient and the population mean. A significant correlation was found between the volume of significantly reduced MWF and clinical disability (p=0.008, R=0.58). Our results show that clinical disability is reflected in particular regions of cerebral white matter that are consistent between subjects, and illustrates a method to examine tissue alteration throughout the brain of individual patients. These results strongly support the use of MWF imaging to evaluate disease activity in PPMS.
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