ObjectiveTo evaluate in vivo the co-occurrence of microglial activation and microstructural white matter (WM) damage in the MS brain and to examine their association with clinical disability.Methods 18-kDa translocator protein (TSPO) brain PET imaging was performed for evaluation of microglial activation by using the radioligand [ 11 C](R)-PK11195. TSPO binding was evaluated as the distribution volume ratio (DVR) from dynamic PET images. Diffusion tensor imaging (DTI) and conventional MRI (cMRI) were performed at the same time. Mean fractional anisotropy (FA) and mean (MD), axial, and radial (RD) diffusivities were calculated within the whole normal-appearing WM (NAWM) and segmented NAWM regions appearing normal in cMRI. Fifty-five patients with MS and 15 healthy controls (HCs) were examined. ResultsMicrostructural damage was observed in the NAWM of the MS brain. DTI parameters of patients with MS were significantly altered in the NAWM compared with an age-and sexmatched HC group: mean FA was decreased, and MD and RD were increased. These structural abnormalities correlated with increased TSPO binding in the whole NAWM and in the temporal NAWM (p < 0.05 for all correlations; p < 0.01 for RD in the temporal NAWM). Both compromised WM integrity and increased microglial activation in the NAWM correlated significantly with higher clinical disability measured with the Expanded Disability Status Scale score. ConclusionsWidespread structural disruption in the NAWM is linked to neuroinflammation, and both phenomena associate with clinical disability. Multimodal PET and DTI allow in vivo evaluation of widespread MS pathology not visible using cMRI. PET imaging Insights into disseminated MS brain pathology with multimodal diffusion tensor andThis information is current as of March 2, 2020 Services Updated Information & http://nn.neurology.org/content/7/3/e691.full.html including high resolution figures, can be found at: References http://nn.neurology.org/content/7/3/e691.full.html##ref-list-1 This article cites 39 articles, 7 of which you can access for free at: Subspecialty Collections http://nn.neurology.org//cgi/collection/pet PET http://nn.neurology.org//cgi/collection/multiple_sclerosis Multiple sclerosis http://nn.neurology.org//cgi/collection/dwi DWI following collection(s): This article, along with others on similar topics, appears in the Permissions & Licensing http://nn.neurology.org/misc/about.xhtml#permissions its entirety can be found online at: Information about reproducing this article in parts (figures,tables) or in Reprints http://nn.neurology.org/misc/addir.xhtml#reprintsus Information about ordering reprints can be found online: Academy of Neurology.. All rights reserved. Online

ObjectiveTo evaluate to which extent serum neurofilament light chain (NfL) increase is related to diffusion tensor imaging–MRI measurable diffuse normal-appearing white matter (NAWM) damage in MS.MethodsSeventy-nine patients with MS and 10 healthy controls underwent MRI including diffusion tensor sequences and serum NfL determination by single molecule array (Simoa). Fractional anisotropy and mean, axial, and radial diffusivities were calculated within the whole and segmented (frontal, parietal, temporal, occipital, cingulate, and deep) NAWM. Spearman correlations and multiple regression models were used to assess the associations between diffusion tensor imaging, volumetric MRI data, and NfL.ResultsElevated NfL correlated with decreased fractional anisotropy and increased mean, axial, and radial diffusivities in the entire and segmented NAWM (for entire NAWM ρ = −0.49, p = 0.005; ρ = 0.49, p = 0.005; ρ = 0.43, p = 0.018; and ρ = 0.48, p = 0.006, respectively). A multiple regression model examining the effect of diffusion tensor indices on NfL showed significant associations when adjusted for sex, age, disease type, the expanded disability status scale, treatment, and presence of relapses. In the same model, T2 lesion volume was similarly associated with NfL.ConclusionsOur findings suggest that elevated serum NfL in MS results from neuroaxonal damage both within the NAWM and focal T2 lesions. This pathologic heterogeneity ought to be taken into account when interpreting NfL findings at the individual patient level.

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Purpose of the review Despite the significant progress in the development of disease-modifying treatments for multiple sclerosis (MS), repair of existing damage is still poorly addressed. Current research focuses on stem cell-based therapies as a suitable alternative or complement to current drug therapies. Recent findingsMyelin damage is a hallmark of multiple sclerosis, and novel approaches leading to remyelination represent a promising tool to prevent neurodegeneration of the underlying axon. With increasing evidence of diminishing remyelination capacity of the MS brain with ageing and disease progression, exogenous cell transplantation is a promising therapeutic approach for restoration of oligodendrocyte precursor cell pool reserve and myelin regeneration.