In vivo characterization of cortical and white matter neuroaxonal pathology in early multiple sclerosis

Abstract

Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T1/T2-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ≤5 years) and 24 age-matched healthy controls underwent 7 T T2*-weighted imaging for cortical lesion segmentation and 3 T T1/T2-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions.

Validation of Rapid Magnetic Resonance Myelin Imaging in Multiple Sclerosis

“…Inhomogeneous magnetization transfer ratio in white matter structures correlated with physical disability . Lastly, the T 1 /T 2 ‐weighted ratio has recently been applied clinically to found differences in the cortex and in the white matter of MS patients compared to controls, but its specificity to myelin, primarily in white matter, has been questioned . In addition, the inclusion of the “excess parenchymal water” compartment allows the REMyDI model to account for the presence of the concurrent edema that is associated with MS lesions, which can confound other myelin imaging methods …”

MRI profiling of focal cortical dysplasia using multi‐compartment diffusion models

“…Similarly, we found significant INVF decrease in suspected and confirmed FCD lesions. Both ICVF and INVF have been proposed as biomarkers of highly anisotropic structures, such as neurons nuclei and glia, as suggested by previous studies on multiple sclerosis, 35 Alzheimer disease, 36 and Parkinson disease. 37 The within-lesion decreases are concordant with altered extracellular diffusion and increased extra-neurite volume measures performed on histology samples from surgical resections.…”

<p>Neurite orientation and dispersion density imaging: clinical utility, efficacy, and role in therapy</p>

“…26 In contrast, the cortical lesions of MS are more subtle and difficult to detect on conventional MRI. Accordingly, the finding of reduced ND even in cortical lesions 27 may have further clinical implications for MS. Additionally, the further usefulness of NODDI was indicated for detecting the disease progression of MS, including the change from normalappearing white matter to lesions. 28,29 The viability of a 7-T MRI scanner was also confirmed in MS. 30…”