IMPORTANCEThe mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood.OBJECTIVE To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. DESIGN, SETTING, AND PARTICIPANTSIn this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021.EXPOSURES According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. MAIN OUTCOMES AND MEASURESMean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models.RESULTS Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, −0.36; 95% CI, −0.60 to −0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, −0.18; 95% CI, −0.34 to −0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. CONCLUSIONS AND RELEVANCEOur study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

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Objectives Neuropathological studies have shown that multiple sclerosis (MS) lesions are heterogeneous in terms of myelin/axon damage and repair as well as iron content. However, it remains a challenge to identify specific chronic lesion types, especially remyelinated lesions, in vivo in patients with MS. Methods We performed 3 studies: (1) a cross‐sectional study in a prospective cohort of 115 patients with MS and 76 healthy controls, who underwent 3 T magnetic resonance imaging (MRI) for quantitative susceptibility mapping (QSM), myelin water fraction (MWF), and neurite density index (NDI) maps. White matter (WM) lesions in QSM were classified into 5 QSM lesion types (iso‐intense, hypo‐intense, hyperintense, lesions with hypo‐intense rims, and lesions with paramagnetic rim legions [PRLs]); (2) a longitudinal study of 40 patients with MS to study the evolution of lesions over 2 years; (3) a postmortem histopathology‐QSM validation study in 3 brains of patients with MS to assess the accuracy of QSM classification to identify neuropathological lesion types in 63 WM lesions. Results At baseline, hypo‐ and isointense lesions showed higher mean MWF and NDI values compared to other QSM lesion types (p < 0.0001). Further, at 2‐year follow‐up, hypo‐/iso‐intense lesions showed an increase in MWF. Postmortem analyses revealed that QSM highly accurately identifies (1) fully remyelinated areas as hypo‐/iso‐intense (sensitivity = 88.89% and specificity = 100%), (2) chronic inactive lesions as hyperintense (sensitivity = 71.43% and specificity = 92.00%), and (3) chronic active/smoldering lesions as PRLs (sensitivity = 92.86% and specificity = 86.36%). Interpretation These results provide the first evidence that it is possible to distinguish chronic MS lesions in a clinical setting, hereby supporting with new biomarkers to develop and assess remyelinating treatments. ANN NEUROL 2022;92:486–502

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Introduction: Graph theory has been applied to study the pathophysiology of multiple sclerosis (MS) since it provides global and focal measures of brain networks properties that are affected by MS. Typically, the connections strength and, consequently, the network(s) properties are computed by counting the number of streamlines (NOS) connecting couples of grey matter regions. However, recent studies have shown that this method is not quantitative. Methods:We evaluated diffusion-based microstructural measures extracted from three different models to assess the network properties in a group of sixty-six MS patients and sixty-four healthy subjects. Besides, we assessed their correlation with patients' disability and with a biological measure of neuroaxonal damage.Results: Graph metrics extracted from connectomes weighted by intra-axonal microstructural components were the most sensitive to MS pathology and the most related to clinical disability. On the other hand, measures of network segregation extracted from the connectomes weighted by maps describing extracellular diffusivity were the most related to serum concentration of neurofilament light chain. Network properties assessed with NOS were neither sensitive to MS pathology nor correlated with clinical and pathological measures of disease impact in MS patients. Conclusion:Using tractometry-derived graph measures in MS patients, we identified a set of metrics based on microstructural components that are highly sensitive to the disease and that provide sensitive correlates of clinical and biological deterioration in MS patients.

Postmortem magnetic resonance imaging (MRI) of the fixed healthy and diseased human brain facilitates spatial resolutions and image quality that is not achievable with in vivo MRI scans. Though challenging—and almost exclusively performed at 7 T field strength—depicting the tissue architecture of the entire brain in fine detail is invaluable since it enables the study of neuroanatomy and uncovers important pathological features in neurological disorders. The objectives of the present work were (1) to develop a 3D isotropic ultra-high-resolution imaging approach for human whole-brain ex vivo acquisitions working on a standard clinical 3 T MRI system; and (2) to explore the sensitivity and specificity of this concept for specific pathoanatomical features of multiple sclerosis. The reconstructed images demonstrate unprecedented resolution and soft tissue contrast of the diseased human brain at 3 T, thus allowing visualization of sub-millimetric lesions in the different cortical layers and in the cerebellar cortex, as well as unique cortical lesion characteristics such as the presence of incomplete/complete iron rims, and patterns of iron accumulation. Further details such as the subpial molecular layer, the line of Gennari, and some intrathalamic nuclei are also well distinguishable.

BackgroundDetecting new and enlarged lesions in multiple sclerosis (MS) patients is needed to determine their disease activity. LeMan‐PV is a software embedded in the scanner reconstruction system of one vendor, which automatically assesses new and enlarged white matter lesions (NELs) in the follow‐up of MS patients; however, multicenter validation studies are lacking.PurposeTo assess the accuracy of LeMan‐PV for the longitudinal detection NEL white‐matter MS lesions in a multicenter clinical setting.Study TypeRetrospective, longitudinal.SubjectsA total of 206 patients with a definitive MS diagnosis and at least two follow‐up MRI studies from five centers participating in the Swiss Multiple Sclerosis Cohort study. Mean age at first follow‐up = 45.2 years (range: 36.9–52.8 years); 70 males.Field Strength/SequenceFluid attenuated inversion recovery (FLAIR) and T1‐weighted magnetization prepared rapid gradient echo (T1‐MPRAGE) sequences at 1.5 T and 3 T.AssessmentThe study included 313 MRI pairs of datasets. Data were analyzed with LeMan‐PV and compared with a manual “reference standard” provided by a neuroradiologist. A second rater (neurologist) performed the same analysis in a subset of MRI pairs to evaluate the rating‐accuracy. The Sensitivity (Se), Specificity (Sp), Accuracy (Acc), F1‐score, lesion‐wise False‐Positive‐Rate (aFPR), and other measures were used to assess LeMan‐PV performance for the detection of NEL at 1.5 T and 3 T. The performance was also evaluated in the subgroup of 123 MRI pairs at 3 T.Statistical TestsIntraclass correlation coefficient (ICC) and Cohen's kappa (CK) were used to evaluate the agreement between readers.ResultsThe interreader agreement was high for detecting new lesions (ICC = 0.97, Pvalue < 10−20, CK = 0.82, P value = 0) and good (ICC = 0.75, P value < 10−12, CK = 0.68, P value = 0) for detecting enlarged lesions. Across all centers, scanner field strengths (1.5 T, 3 T), and for NEL, LeMan‐PV achieved: Acc = 61%, Se = 65%, Sp = 60%, F1‐score = 0.44, aFPR = 1.31. When both follow‐ups were acquired at 3 T, LeMan‐PV accuracy was higher (Acc = 66%, Se = 66%, Sp = 66%, F1‐score = 0.28, aFPR = 3.03).Data ConclusionIn this multicenter study using clinical data settings acquired at 1.5 T and 3 T, and variations in MRI protocols, LeMan‐PV showed similar sensitivity in detecting NEL with respect to other recent 3 T multicentric studies based on neural networks. While LeMan‐PV performance is not optimal, its main advantage is that it provides automated clinical decision support integrated into the radiological‐routine flow.Evidence Level4Technical EfficacyStage 2

Todea et al. Cortical and White Matter Lesions Longitudinal changes in CL and WML count and volume were significantly associated with (i) sustained attention, auditory information, processing speed and flexibility (p < 0.01), (ii) verbal memory (p < 0.01); (iii) verbal fluency (p < 0.05); and (iv) hand-motor function (p < 0.05). Discussion : Changes in cortical and white matter focal damage in early MS patients correlate with global neuroaxonal damage and is associated to cognitive performances.