Multiple sclerosis lesions that impair memory map to a connected memory circuit.

BACKGROUND: Nearly 1 million Americans are living with multiple sclerosis (MS) and 30-50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit. METHODS: We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes. RESULTS: Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit. CONCLUSIONS: Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS.

Intersite brain MRI volumetric biases persist even in a harmonized multisubject study of multiple sclerosis.

BACKGROUND AND PURPOSE: Multicenter study designs involving a variety of MRI scanners have become increasingly common. However, these present the issue of biases in image-based measures due to scanner or site differences. To assess these biases, we imaged 11 volunteers with multiple sclerosis (MS) with scan and rescan data at four sites. METHODS: Images were acquired on Siemens or Philips scanners at 3 Tesla. Automated white matter lesion detection and whole-brain, gray and white matter, and thalamic volumetry were performed, as well as expert manual delineations of T1 magnetization-prepared rapid acquisition gradient echo and T2 fluid-attenuated inversion recovery lesions. Random-effect and permutation-based nonparametric modeling was performed to assess differences in estimated volumes within and across sites. RESULTS: Random-effect modeling demonstrated model assumption violations for most comparisons of interest. Nonparametric modeling indicated that site explained >50% of the variation for most estimated volumes. This expanded to >75% when data from both Siemens and Philips scanners were included. Permutation tests revealed significant differences between average inter- and intrasite differences in most estimated brain volumes (P < .05). The automatic activation of spine coil elements during some acquisitions resulted in a shading artifact in these images. Permutation tests revealed significant differences between thalamic volume measurements from acquisitions with and without this artifact. CONCLUSION: Differences in brain volumetry persisted across MR scanners despite protocol harmonization. These differences were not well explained by variance component modeling; however, statistical innovations for mitigating intersite differences show promise in reducing biases in multicenter studies of MS.

Exploring the effect of glatiramer acetate on cerebral gray matter atrophy in multiple sclerosis.

BACKGROUND AND PURPOSE: Cerebral gray matter (GM) atrophy is a proposed measure of neuroprotection in multiple sclerosis (MS). Glatiramer acetate (GA) limits clinical relapses, MRI lesions, and whole brain atrophy in relapsing-remitting MS (RRMS). The effect of GA on GM atrophy remains unclear. We assessed GM atrophy in patients with RRMS starting GA therapy in comparison to a cohort of patients with clinically benign RRMS (BMS). DESIGN/METHODS: We studied 14 patients at GA start [age (mean ± SD) 44.2 ± 7.0 years, disease duration (DD) 7.2 ± 6.4 years, Expanded Disability Status Scale score (EDSS) (median,IQR) 1.0,2.0] and 6 patients with BMS [age 43.0 ± 6.1 years, DD 18.1 ± 8.4 years, EDSS 0.5,1.0]. Brain MRI was obtained at baseline and one year later (both groups) and two years later in all patients in the GA group except one who was lost to follow-up. Semi-automated algorithms assessed cerebral T2 hyperintense lesion volume (T2LV), white matter fraction (WMF), GM fraction (GMF), and brain parenchymal fraction (BPF). The exact Wilcoxon-Mann-Whitney test compared the groups. The Wilcoxon signed rank test assessed longitudinal changes within groups. RESULTS: During the first year, MRI changes did not differ significantly between groups (p > 0.15). Within the BMS group, WMF and BPF decreased during the first year (p = 0.03). Within the GA group, there was no significant change in MRI measures during each annual period (p > 0.05). Over two years, the GA group had a significant increase in T2LV and decrease in WMF (p < 0.05), while GMF and BPF remained stable (p > 0.05). MRI changes in brain volumes (GMF or WMF) in the first year in the GA group were not significantly different from those in the BMS group (p > 0.5). CONCLUSIONS: In this pilot study with a small sample size, patients with RRMS started on GA did not show significant GM or whole brain atrophy over 2 years, resembling MS patients with a clinically benign disease course.

Anti-SARS-CoV-2 monoclonal antibodies for the treatment of active COVID-19 in multiple sclerosis: An observational study.

Monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) received emergency use authorization for the acute treatment of COVID-19. We are not aware of published data on their use in immunosuppressed people with multiple sclerosis (pwMS). We report 23 pwMS (mean age = 49 years, ocrelizumab (n = 19), fingolimod (n = 2), vaccinated with at least an initial series (n = 19)) who received mAb for acute COVID-19. Following mAb receipt, approximately half recovered in <7 days (48%). There were no adverse events or deaths. Use of mAb for pwMS treated with fingolimod or ocrelizumab was not observed to be harmful and is likely helpful for treatment of acute COVID-19.

Serum NfL levels in the first five years predict 10-year thalamic fraction in patients with MS.

BACKGROUND: Serum neurofilament light chain (sNfL) levels are associated with relapses, MRI lesions, and brain volume in multiple sclerosis (MS). OBJECTIVE: To explore the value of early serum neurofilament light (sNfL) measures in prognosticating 10-year regional brain volumes in MS. METHODS: Patients with MS enrolled in the Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study within five years of disease onset who had annual blood samples from years 1-10 (n = 91) were studied. sNfL was measured with a single molecule array (SIMOA) assay. We quantified global cortical thickness and normalized deep gray matter (DGM) volumes (fractions of the thalamus, caudate, putamen, and globus pallidus) from high-resolution 3 T MRI at 10 years. Correlations between yearly sNfL levels and 10-year MRI outcomes were assessed using linear regression models. RESULTS: sNfL levels from years 1 and 2 were associated with 10-year thalamus fraction. Early sNfL levels were not associated with 10-year putamen, globus pallidus or caudate fractions. At 10 years, cortical thickness was not associated with early sNfL levels, but was weakly correlated with total DGM fraction. CONCLUSIONS: Early sNfL levels correlate with 10-year thalamic volume, supporting its role as a prognostic biomarker in MS.

COVID-19 mRNA vaccination leading to CNS inflammation: a case series.

The availability of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), provides hope towards mitigation of the coronavirus disease 2019 (COVID-19) pandemic. Vaccine safety and efficacy has not been established in individuals with chronic autoimmune diseases such as multiple sclerosis (MS). Anecdotal reports suggest that the vaccines may be associated with brain, spinal cord, peripheral nervous system, and cardiac inflammation. Based on the high morbidity and unpredictable course of COVID-19, and the need to achieve herd immunity, vaccination has been recommended for patients with MS. We report clinical and MRI features of seven individuals who received the Moderna (n = 3) or Pfizer (n = 4) SARS-CoV-2 mRNA vaccines. Within one to 21 days of either the first (n = 2) or second (n = 5) vaccine dose, these patients developed neurologic symptoms and MRI findings consistent with active CNS demyelination of the optic nerve, brain, and/or spinal cord. Symptoms included visual loss, dysmetria, gait instability, paresthesias, sphincter disturbance, and limb weakness. Age ranged from 24 to 64 (mean 39.1) years; five were woman (71.4%). The final diagnosis was exacerbation of known stable MS (n = 4, two were receiving disease-modifying therapy at the time of vaccination), new onset MS (n = 2), or new onset neuromyelitis optica (n = 1). All responded to corticosteroid (n = 7) or plasma exchange (n = 1) therapy, with five returning to baseline and two approaching baseline. Large prospective studies are required to further investigate any possible relationship between COVID-19 vaccines and acute CNS demyelination.

Exacerbation of Multiple Sclerosis by BRAF/MEK Treatment for Malignant Melanoma: The Central Vein Sign to Distinguish Demyelinating Lesions From Metastases.

The emergence of immunomodulators as effective cancer treatments has been an important advance in cancer therapy. The combination therapy of BRAF/MEK inhibition with or without anti-CTLA-4 treatment causes an immunostimulatory effect that has greatly reduced death from melanoma. In this article, we present the case of a patient with prior multiple sclerosis (MS) and who later developed metastatic malignant melanoma, had a marked increase of magnetic resonance imaging (MRI) findings after treatment with the combination of trametinib (MEK) and dabrafenib (BRAF), diagnostic question of metastatic disease versus new MS lesions without brain biopsy is discussed. A healthy 49-year-old man was diagnosed with MS in October 2012. He was stable with an oral disease modifying drug until March of 2016 when the patient discovered a lump in his right groin. Biopsy was positive for S100 and BRAF V600 mutation. Combination MEK/BRAF was given and after immunotherapy an MRI showed 25 new gadolinium-enhancing lesions thought to be metastases. A brain biopsy was recommended but neurology and neuroimaging consultation showed that the MRI was consistent with demyelination (oval/ovoid, homogeneous and open-ring enhancement, and predominance of the central vein sign within lesions) rather than metastasis. Treatment for MS has been successful and there has been no return of his melanoma in 4 years. New immunotherapies are lifesaving but the modulation of the immune system can cause unpredictable events such are markedly increased MS activity. The awareness of the diagnostic value of the central vein sign provided a better outcome for this patient and could be a model in the future for others.

Gut Microbiome in Progressive Multiple Sclerosis.

OBJECTIVE: This study was undertaken to investigate the gut microbiome in progressive multiple sclerosis (MS) and how it relates to clinical disease. METHODS: We sequenced the microbiota from healthy controls and relapsing-remitting MS (RRMS) and progressive MS patients and correlated the levels of bacteria with clinical features of disease, including Expanded Disability Status Scale (EDSS), quality of life, and brain magnetic resonance imaging lesions/atrophy. We colonized mice with MS-derived Akkermansia and induced experimental autoimmune encephalomyelitis (EAE). RESULTS: Microbiota ß-diversity differed between MS patients and controls but did not differ between RRMS and progressive MS or differ based on disease-modifying therapies. Disease status had the greatest effect on the microbiome ß-diversity, followed by body mass index, race, and sex. In both progressive MS and RRMS, we found increased Clostridium bolteae, Ruthenibacterium lactatiformans, and Akkermansia and decreased Blautia wexlerae, Dorea formicigenerans, and Erysipelotrichaceae CCMM. Unique to progressive MS, we found elevated Enterobacteriaceae and Clostridium g24 FCEY and decreased Blautia and Agathobaculum. Several Clostridium species were associated with higher EDSS and fatigue scores. Contrary to the view that elevated Akkermansia in MS has a detrimental role, we found that Akkermansia was linked to lower disability, suggesting a beneficial role. Consistent with this, we found that Akkermansia isolated from MS patients ameliorated EAE, which was linked to a reduction in RORγt+ and IL-17-producing γδ T cells. INTERPRETATION: Whereas some microbiota alterations are shared in relapsing and progressive MS, we identified unique bacteria associated with progressive MS and clinical measures of disease. Furthermore, elevated Akkermansia in MS may be a compensatory beneficial response in the MS microbiome. ANN NEUROL 2021;89:1195-1211.

7 T imaging reveals a gradient in spinal cord lesion distribution in multiple sclerosis.

We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.

Regional microglial activation in the substantia nigra is linked with fatigue in MS.

OBJECTIVE: The goal of our study is to assess the role of microglial activation in MS-associated fatigue (MSAF) using [F-18]PBR06-PET. METHODS: Fatigue severity was measured using the Modified Fatigue Impact Scale (MFIS) in 12 subjects with MS (7 relapsing-remitting and 5 secondary progressive) and 10 healthy control participants who underwent [F-18]PBR06-PET. The MFIS provides a total fatigue score as well as physical, cognitive, and psychosocial fatigue subscale scores. Standardized Uptake Value (SUV) 60-90 minute frame PET maps were coregistered to 3T MRI. Voxel-by-voxel analysis using Statistical Parametric Mapping and atlas-based regional analyses were performed. SUV ratios (SUVRs) were global brain normalized. RESULTS: Peak voxel-based level of significance for correlation between total fatigue score and PET uptake was localized to the right substantia nigra (T-score 4.67, p = 0.001). Similarly, SUVRs derived from atlas-based segmentation of the substantia nigra showed significant correlation with MFIS (r = 0.76, p = 0.004). On multiple regression, the right substantia nigra was an independent predictor of total MFIS (p = 0.02) and cognitive MFIS subscale values (p = 0.007), after adjustment for age, disability, and depression. Several additional areas of significant correlations with fatigue scores were identified, including the right parahippocampal gyrus, right precuneus, and juxtacortical white matter (all p < 0.05). There was no correlation between fatigue scores and brain atrophy and lesion load in patients with MS. CONCLUSION: Substantia nigra microglial activation is linked to fatigue in MS. Microglial activation across key brain regions may represent a unifying mechanism for MSAF, and further evaluation of neuroimmunologic basis of MSAF is warranted.

COVID-19 in teriflunomide-treated patients with multiple sclerosis.

The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with multiple sclerosis (MS) who are commonly on long-term immunotherapies. Managing MS during the pandemic remains challenging with little published experience and no evidence-based guidelines. We present five teriflunomide-treated patients with MS who subsequently developed active COVID-19 infection. The patients continued teriflunomide therapy and had self-limiting infection, without relapse of their MS. These observations have implications for the management of MS in the setting of the COVID-19 pandemic.

7T MRI cerebral leptomeningeal enhancement is common in relapsing-remitting multiple sclerosis and is associated with cortical and thalamic lesions.

BACKGROUND: Meningeal inflammation may contribute to gray matter (GM) involvement in multiple sclerosis (MS) and is proposed to manifest as magnetic resonance imaging (MRI) leptomeningeal enhancement (LME). OBJECTIVE: To investigate how LME relates to GM lesions in relapsing-remitting multiple sclerosis (RRMS) at 7T. METHODS: A total of 30 RRMS subjects (age (mean ± standard deviation (SD)): 44.0 ± 11.3 years, 93% on disease-modifying treatment) and 15 controls underwent gadolinium-enhanced three-dimensional (3D) MP2RAGE (magnetization-prepared 2 rapid gradient-echo) and fluid-attenuated inversion recovery (FLAIR) MRI. LME, cortical lesions (CLs), thalamic lesions (TLs), and white matter (WM) lesions were expert-quantified. Wilcoxon rank-sum, two-sample t-tests, Spearman correlations, and regression models were employed. RESULTS: Two-thirds (20/30) of MS subjects and 1/15 controls (6.7%) had LME. LME+ MS subjects had 2.7 ± 1.5 foci, longer disease duration (14.9 ± 10.4 vs. 8.1 ± 5.7 years, p = 0.028), increased CL number (21.5 ± 12.6 vs. 5.5 ± 5.0, p < 0.001) and volume (0.80 ± 1.13 vs. 0.13 ± 0.13 mL, p = 0.002), and increased TL number (3.95 ± 2.11 vs. 0.70 ± 1.34, p < 0.001) and volume (0.106 ± 0.09 vs. 0.007 ± 0.01 mL, p < 0.001) versus LME- subjects. LME focus number correlated more highly with CL (rs = 0.50, p = 0.01) and TL (rs = 0.81, p < 0.001) than WM lesion (rs = 0.34, p > 0.05) volume. Similar LME-CL number associations were observed in unadjusted and WM lesion-adjusted comparisons (both p < 0.001). CONCLUSION: Cerebral LME is common in RRMS at 7T and is independently associated with GM injury. We hypothesize that cerebrospinal fluid (CSF)-related inflammation links cortical and thalamic injury.

Gray matter microglial activation in relapsing vs progressive MS: A [F-18]PBR06-PET study.

Objective: To determine the value of [F-18]PBR06-PET for assessment of microglial activation in the cerebral gray matter in patients with MS. Methods: Twelve patients with MS (7 relapsing-remitting and 5 secondary progressive [SP]) and 5 healthy controls (HCs) had standardized uptake value (SUV) PET maps coregistered to 3T MRI and segmented into cortical and subcortical gray matter regions. SUV ratios (SUVRs) were global brain normalized. Voxel-by-voxel analysis was performed using statistical parametric mapping (SPM). Normalized brain parenchymal volumes (BPVs) were determined from MRI using SIENAX. Results: Cortical SUVRs were higher in the hippocampus, amygdala, midcingulate, posterior cingulate, and rolandic operculum and lower in the medial-superior frontal gyrus and cuneus in the MS vs HC group (all p < 0.05). Subcortical gray matter SUVR was higher in SPMS vs RRMS (+10.8%, p = 0.002) and HC (+11.3%, p = 0.055) groups. In the MS group, subcortical gray matter SUVR correlated with the Expanded Disability Status Scale (EDSS) score (r = 0.75, p = 0.005) and timed 25-foot walk (T25FW) (r = 0.70, p = 0.01). Thalamic SUVRs increased with increasing EDSS scores (r = 0.83, p = 0.0008) and T25FW (r = 0.65, p = 0.02) and with decreasing BPV (r = -0.63, p = 0.03). Putaminal SUVRs increased with increasing EDSS scores (0.71, p = 0.009) and with decreasing BPV (r = -0.67, p = 0.01). On SPM analysis, peak correlations of thalamic voxels with BPV were seen in the pulvinar and with the EDSS score and T25FW in the dorsomedial thalamic nuclei. Conclusions: This study suggests that [F-18]PBR06-PET detects widespread abnormal microglial activation in the cerebral gray matter in MS. Increased translocator protein binding in subcortical gray matter regions is associated with brain atrophy and may link to progressive MS.

The impact of cervical spinal cord atrophy on quality of life in multiple sclerosis.

BACKGROUND: Spinal cord demyelination is common in multiple sclerosis (MS) and has been linked to increased disability and progressive clinical course. Spinal cord atrophy shows an especially close relationship to MS-related physical disability, though the relationship between spinal cord lesions/atrophy and health-related quality of life (QOL) has not been explored. METHODS: 62 patients (53 relapsing MS, 7 secondary progressive, 2 clinically isolated syndrome) from our center underwent 3 T MRI within 30 days of clinical examination and QOL assessment. Upper cervical (C1-C3) spinal cord area (UCCA) was obtained from 3D high-resolution MPRAGE sequences (1 mm isotropic voxels). Cervical spinal cord (C1-C7) lesion count, and cervical and brain T2 hyperintense lesion volumes were calculated. Brain parenchymal fraction (BPF) was obtained from an automated segmentation pipeline. Spearman correlations were assessed between MRI and clinical data. Partial Spearman correlations adjusting for age, disease duration, and BPF assessed the independent association between MRI variables and QOL domains. RESULTS: UCCA showed an inverse relationship with age (r = -0.330, p = .009), disease duration, (r = -0.444, p < .001), and nine-hole peg test (r = -0.353, p = .005). The Upper Extremity Function QOL domain showed the strongest relationship to UCCA (r = 0.333, p = .008), with Lower Extremity Function QOL (r = 0.234, p = .067) and Satisfaction with Social Roles and Activities (r = 0.245, p = .055) correlations bordering significance. The association between UCCA and Upper Extremity QOL remained significant after adjustment for BPF, age, and disease duration. QOL domains reflective of psychological health (Depression, Anxiety, Emotional and Behavioral Dyscontrol, Positive Affect and Wellbeing) showed no relationship to UCCA. Cervical and brain lesion volume related to impairment in Stigma while cervical lesion count was unrelated to NeuroQOL impairment. Brain atrophy correlated with conventional markers of disability and cognition but did not have a significant relationship to QOL. CONCLUSION: Cervical spinal cord volume is independently associated with impaired upper extremity-related QOL in patients with MS. These findings suggest specific clinical relevance of MS-related spinal cord atrophy as compared to brain or cervical spinal cord lesions, or whole brain atrophy.

MRI phenotypes in MS: Longitudinal changes and miRNA signatures.

Objective: To classify and immunologically characterize persons with MS based on brain lesions and atrophy and their associated microRNA profiles. Methods: Cerebral T2-hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were quantified and used to define MRI phenotypes as follows: type I: low T2LV, low atrophy; type II: high T2LV, low atrophy; type III: low T2LV, high atrophy; type IV: high T2LV, high atrophy, in a large cross-sectional cohort (n = 1,088) and a subset with 5-year lngitudinal follow-up (n = 153). Serum miRNAs were assessed on a third MS cohort with 2-year MRI phenotype stability (n = 98). Results: One-third of the patients had lesion-atrophy dissociation (types II or III) in both the cross-sectional and longitudinal cohorts. At 5 years, all phenotypes had progressive atrophy (p < 0.001), disproportionally in type II (BPF -2.28%). Only type IV worsened in physical disability. Types I and II showed a 5-year MRI phenotype conversion rate of 33% and 46%, whereas III and IV had >90% stability. Type II switched primarily to IV (91%); type I switched primarily to II (47%) or III (37%). Baseline higher age (p = 0.006) and lower BPF (p < 0.001) predicted 5-year phenotype conversion. Each MRI phenotype demonstrated an miRNA signature whose underlying biology implicates blood-brain barrier pathology: hsa.miR.22.3p, hsa.miR.361.5p, and hsa.miR.345.5p were the most valid differentiators of MRI phenotypes. Conclusions: MRI-defined MS phenotypes show high conversion rates characterized by the continuation of either predominant neurodegeneration or inflammation and support the partial independence of these 2 measures. MicroRNA signatures of these phenotypes suggest a role for blood-brain barrier integrity.

Spatial distribution of multiple sclerosis lesions in the cervical spinal cord.

Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.

Automatic segmentation of the spinal cord and intramedullary multiple sclerosis lesions with convolutional neural networks.

The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. In particular, a precise delineation of lesions is hindered by a broad heterogeneity of lesion contrast, size, location, and shape. The goal of this study was to develop a fully-automatic framework - robust to variability in both image parameters and clinical condition - for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data of MS and non-MS cases. Scans of 1042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n = 30). Data spanned three contrasts (T1-, T2-, and T2∗-weighted) for a total of 1943 vol and featured large heterogeneity in terms of resolution, orientation, coverage, and clinical conditions. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. CNNs were trained independently with the Dice loss. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg (p ≤ 0.05), a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. In this study, we introduce a robust method to segment the spinal cord and intramedullary MS lesions on a variety of MRI contrasts. The proposed framework is open-source and readily available in the Spinal Cord Toolbox.

A dual modeling approach to automatic segmentation of cerebral T2 hyperintensities and T1 black holes in multiple sclerosis.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) is crucial for in vivo detection and characterization of white matter lesions (WML) in multiple sclerosis (MS). The most widely established MRI outcome measure is the volume of hyperintense lesions on T2-weighted images (T2L). Unfortunately, T2L are non-specific for the level of tissue destruction and show a weak relationship to clinical status. Interest in lesions that appear hypointense on T1-weighted images (T1L) ("black holes") has grown because T1L provide more specificity for axonal loss and a closer link to neurologic disability. The technical difficulty of T1L segmentation has led investigators to rely on time-consuming manual assessments prone to inter- and intra-rater variability. This study aims to develop an automatic T1L segmentation approach, adapted from a T2L segmentation algorithm. MATERIALS AND METHODS: T1, T2, and fluid-attenuated inversion recovery (FLAIR) sequences were acquired from 40 MS subjects at 3 Tesla (3 T). T2L and T1L were manually segmented. A Method for Inter-Modal Segmentation Analysis (MIMoSA) was then employed. RESULTS: Using cross-validation, MIMoSA proved to be robust for segmenting both T2L and T1L. For T2L, a Sørensen-Dice coefficient (DSC) of 0.66 and partial AUC (pAUC) up to 1% false positive rate of 0.70 were achieved. For T1L, 0.53 DSC and 0.64 pAUC were achieved. Manual and MIMoSA segmented volumes were correlated and resulted in 0.88 for T1L and 0.95 for T2L. The correlation between Expanded Disability Status Scale (EDSS) scores and manual versus automatic volumes were similar for T1L (0.32 manual vs. 0.34 MIMoSA), T2L (0.33 vs. 0.32), and the T1L/T2L ratio (0.33 vs 0.33). CONCLUSIONS: Though originally designed to segment T2L, MIMoSA performs well for segmenting T1 black holes in patients with MS.

Whole brain and deep gray matter atrophy detection over 5 years with 3T MRI in multiple sclerosis using a variety of automated segmentation pipelines.

BACKGROUND: Cerebral atrophy is common in multiple sclerosis (MS) and selectively involves gray matter (GM). Several fully automated methods are available to measure whole brain and regional deep GM (DGM) atrophy from MRI. OBJECTIVE: To assess the sensitivity of fully automated MRI segmentation pipelines in detecting brain atrophy in patients with relapsing-remitting (RR) MS and normal controls (NC) over five years. METHODS: Consistent 3D T1-weighted sequences were performed on a 3T GE unit in 16 mildly disabled patients with RRMS and 16 age-matched NC at baseline and five years. All patients received disease-modifying immunotherapy on-study. Images were applied to two pipelines to assess whole brain atrophy [brain parenchymal fraction (BPF) from SPM12; percentage brain volume change (PBVC) from SIENA] and two other pipelines (FSL-FIRST; FreeSurfer) to assess DGM atrophy (thalamus, caudate, globus pallidus, putamen). MRI change was compared by two sample t-tests. Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW) change was compared by repeated measures proportional odds models. RESULTS: Using FreeSurfer, the MS group had a ~10-fold acceleration in on-study volume loss than NC in the caudate (mean decrease 0.51 vs. 0.05 ml, p = 0.022). In contrast, caudate atrophy was not detected by FSL-FIRST (mean decrease 0.21 vs. 0.12 ml, p = 0.53). None of the other pipelines showed any difference in volume loss between groups, for whole brain or regional DGM atrophy (all p>0.38). The MS group showed on-study stability on EDSS (p = 0.47) but slight worsening of T25FW (p = 0.054). CONCLUSIONS: In this real-world cohort of mildly disabled treated patients with RRMS, we identified ongoing atrophy of the caudate nucleus over five years, despite the lack of any significant whole brain atrophy, compared to healthy controls. The detectability of caudate atrophy was dependent on the MRI segmentation pipeline employed. These findings underscore the increased sensitivity gained when assessing DGM atrophy in monitoring MS.

Brain and spinal cord MRI lesions in primary progressive vs. relapsing-remitting multiple sclerosis.

BACKGROUND: Primary progressive (PP) multiple sclerosis (MS) is considered a clinically distinct entity from the spectrum of relapsing-remitting (RR) forms of the disease. OBJECTIVE: To compare the presence of brain and spinal cord lesions between PP and RR subjects. METHODS: We studied people with PPMS [n = 40, 17 (42.5%) men, age 50.7 ±â€¯7.7 years, disease duration 10.1 ±â€¯7.4 years, Expanded Disability Status Scale (EDSS) score 4.6 ±â€¯2.1] and RRMS [n = 40, 12 (30%) men, age 47.9 ±â€¯4.2, disease duration 13.7 ±â€¯5.9, EDSS 1.7 ±â€¯1.3]. MRI of the brain and full spinal cord at 1.5T was analyzed to define patients having: 1. brain only, 2. spinal cord only, or 3. brain and spinal cord MS lesions. RESULTS: Lesions in the brain only were less common in PP (n = 1, 2.5% of people) than RR (n = 10, 25%) (Fisher's exact p = 0.007). Lesions in the spinal cord only (PP: n = 6, 15%, RR: n = 3, 7.5%, p = 0.481) or brain plus spinal cord (PP: n = 33, 83%, RR: n = 27, 68%, p = 0.196) were similar between groups. PP had higher EDSS and timed 25-ft walk (Wilcoxon tests, both p < 0.001), higher age (t-test p = 0.049), lower disease duration (t-test, p = 0.02), and a similar sex ratio (Fisher's exact p = 0.352) vs. RR. CONCLUSIONS: We report a topographic difference in MRI lesion involvement between PPMS and RRMS. Lesions restricted to the brain are more common in RRMS. These findings provide support to the notion that PP may have features distinctive from the RR spectrum of the disease. Longitudinal comparisons and quantitative MRI analysis would be necessary to confirm and extend these results.