Intrinsic and extrinsic contributors to subregional thalamic volume loss in multiple sclerosis.

OBJECTIVE: To evaluate the intrinsic and extrinsic microstructural factors contributing to atrophy within individual thalamic subregions in multiple sclerosis using in vivo high-gradient diffusion MRI. METHODS: In this cross-sectional study, 41 people with multiple sclerosis and 34 age and sex-matched healthy controls underwent 3T MRI with up to 300 mT/m gradients using a multi-shell diffusion protocol consisting of eight b-values and diffusion time of 19 ms. Each thalamus was parcellated into 25 subregions for volume determination and diffusion metric estimation. The soma and neurite density imaging model was applied to obtain estimates of intra-neurite, intra-soma, and extra-cellular signal fractions for each subregion and within structurally connected white matter trajectories and cortex. RESULTS: Multiple sclerosis-related volume loss was more pronounced in posterior/medial subregions than anterior/ventral subregions. Intra-soma signal fraction was lower in multiple sclerosis, reflecting reduced cell body density, while the extra-cellular signal fraction was higher, reflecting greater extra-cellular space, both of which were observed more in posterior/medial subregions than anterior/ventral subregions. Lower intra-neurite signal fraction in connected normal-appearing white matter and lower intra-soma signal fraction of structurally connected cortex were associated with reduced subregional thalamic volumes. Intrinsic and extrinsic microstructural measures independently related to subregional volume with heterogeneity across atrophy-prone thalamic nuclei. Extrinsic microstructural alterations predicted left anteroventral, intrinsic microstructural alterations predicted bilateral medial pulvinar, and both intrinsic and extrinsic factors predicted lateral geniculate and medial mediodorsal volumes. INTERPRETATION: Our results might be reflective of the involvement of anterograde and retrograde degeneration from white matter demyelination and cerebrospinal fluid-mediated damage in subregional thalamic volume loss.

The cognitive relevance of non-lesional damage to cortical networks in people with multiple sclerosis.

BACKGROUND: Cognitive impairment, a common and debilitating symptom in people with multiple sclerosis (MS), is especially related to cortical damage. However, the impact of regional cortical damage remains poorly understood. Our aim was to evaluate structural (network) integrity in lesional and non-lesional cortex in people with MS, and its relationship with cognitive dysfunction. METHODS: In this cross-sectional study, 176 people with MS and 48 healthy controls underwent MRI, including double inversion recovery and diffusion-weighted scans, and neuropsychological assessment. Cortical integrity was assessed based on fractional anisotropy (FA) and mean diffusivity (MD) within 212 regions split into lesional or non-lesional cortex, and grouped into seven cortical networks. Integrity was compared between people with MS and controls, and across cognitive groups: cognitively-impaired (CI; ≥ two domains at Z ≤ - 2 below controls), mildly CI (≥ two at - 2 < Z ≤ - 1.5), or cognitively-preserved (CP). RESULTS: Cortical lesions were observed in 87.5% of people with MS, mainly in ventral attention network, followed by limbic and default mode networks. Compared to controls, in non-lesional cortex, MD was increased in people with MS, but mean FA did not differ. Within the same individual, MD and FA were increased in lesional compared to non-lesional cortex. CI-MS exhibited higher MD than CP-MS in non-lesional cortex of default mode, frontoparietal and sensorimotor networks, of which the default mode network could best explain cognitive performance. CONCLUSION: Diffusion differences in lesional cortex were more severe than in non-lesional cortex. However, while most people with MS had cortical lesions, diffusion differences in CI-MS were more prominent in non-lesional cortex than lesional cortex, especially within default mode, frontoparietal and sensorimotor networks.

Characterization of cortico-meningeal translocator protein expression in multiple sclerosis.

Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. Positron emission tomography targeting the 18 kDa mitochondrial Translocator Protein (TSPO) is a molecular-specific approach to quantify immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. The aim of this study was to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratio values sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (p = 0.007, by linear regression). Immunohistochemistry, validated using in-situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator Protein immunostaining was detected on meningeal major histocompatibility complex (MHC)-class II + macrophages and cortical activated MHC-class II + transmembrane protein (TMEM)119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.

The effect of ibudilast on thalamic volume in progressive multiple sclerosis.

BACKGROUND: Thalamic volume loss is known to be associated with clinical and cognitive disability in progressive multiple sclerosis (PMS). OBJECTIVE: To investigate the treatment effect of ibudilast on thalamic atrophy more than 96 weeks in the phase 2 trial in progressive(MS Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). METHODS: A total of 231 participants were randomized to either ibudilast (n = 114) or placebo (n = 117). Thalamic volume change was computed using Bayesian Sequence Adaptive Multimodal Segmentation tool (SAMseg) incorporating T1, fluid-attenuated inversion recovery (FLAIR), and fractional anisotropy maps and analyzed with a mixed-effects repeated-measures model. RESULTS: There was no significant difference in thalamic volumes between treatment groups. On exploratory analysis, participants with primary progressive multiple sclerosis (PPMS) on placebo had a 0.004% greater rate of thalamic atrophy than PPMS participants on ibudilast (p = 0.058, 95% confidence interval (CI) = -0.008 to <0.001). Greater reductions in thalamic volumes at more than 96 weeks were associated with worsening multiple sclerosis functional composite (MSFC-4) scores (p = 0.002) and worsening performance on the symbol digit modality test (SDMT) (p < 0.001). CONCLUSION: In a phase 2 trial evaluating ibudilast in PMS, no treatment effect was demonstrated in preventing thalamic atrophy. Participants with PPMS exhibited a treatment effect that trended toward significance. Longitudinal changes in thalamic volume were related to worsening of physical and cognitive disability, highlighting this outcome's clinical importance.

Detection of grey matter microstructural substrates of neurodegeneration in multiple sclerosis.

Multiple sclerosis features complex pathological changes in grey matter that begin early and eventually lead to diffuse atrophy. Novel approaches to image grey-matter microstructural alterations in vivo are highly sought after and would enable more sensitive monitoring of disease activity and progression. This cross-sectional study aimed to assess the sensitivity of high-gradient diffusion MRI for microstructural tissue damage in cortical and deep grey matter in people with multiple sclerosis and test the hypothesis that reduced cortical cell body density is associated with cortical and deep grey-matter volume loss. Forty-one people with multiple sclerosis (age 24-72, 14 females) and 37 age- and sex-matched healthy controls were scanned on a 3 T Connectom MRI scanner equipped with 300 mT/m gradients using a multi-shell diffusion MRI protocol. The soma and neurite density imaging model was fitted to high-gradient diffusion MRI data to obtain estimates of intra-neurite, intra-cellular and extra-cellular signal fractions and apparent soma radius. Cortical and deep grey-matter microstructural imaging metrics were compared between multiple sclerosis and healthy controls and correlated with grey-matter volume, clinical disability and cognitive outcomes. People with multiple sclerosis showed significant cortical and deep grey-matter volume loss compared with healthy controls. People with multiple sclerosis showed trends towards lower cortical intra-cellular signal fraction and significantly lower intra-cellular and higher extra-cellular signal fractions in deep grey matter, especially the thalamus and caudate, compared with healthy controls. Changes were most pronounced in progressive disease and correlated with the Expanded Disability Status Scale, but not the Symbol Digit Modalities Test. In multiple sclerosis, normalized thalamic volume was associated with thalamic microstructural imaging metrics. Whereas thalamic volume loss did not correlate with cortical volume loss, cortical microstructural imaging metrics were significantly associated with thalamic volume, and not with cortical volume. Compared with the short diffusion time (Δ = 19 ms) achievable on the Connectom scanner, at the longer diffusion time of Δ = 49 ms attainable on clinical scanners, multiple sclerosis-related changes in imaging metrics were generally less apparent with lower effect sizes in cortical and deep grey matter. Soma and neurite density imaging metrics obtained from high-gradient diffusion MRI data provide detailed grey-matter characterization beyond cortical and thalamic volumes and distinguish multiple sclerosis-related microstructural pathology from healthy controls. Cortical cell body density correlates with thalamic volume, appears sensitive to the microstructural substrate of neurodegeneration and reflects disability status in people with multiple sclerosis, becoming more pronounced as disability worsens.

In vivo characterization of microglia and myelin relation in multiple sclerosis by combined 11C-PBR28 PET and synthetic MRI.

BACKGROUND: The in vivo relation between microglia activation and demyelination in multiple sclerosis is still unclear. OBJECTIVE: We combined 11C-PBR28 positron emission tomography and rapid estimation of myelin for diagnostic imaging (REMyDI) to characterize the relation between these pathological processes in a heterogeneous MS cohort. METHODS: 11C-PBR28 standardized uptake values normalized by a pseudo-reference region (SUVR) were used to measure activated microglia. A voxelwise analysis compared 11C-PBR28 SUVR in the white matter of 38 MS patients and 16 matched healthy controls. The relative difference in SUVR served as a threshold to classify patients' lesioned, perilesional and normal-appearing white matter as active or inactive. REMyDI was acquired in 27 MS patients for assessing myelin content in active and inactive white matter and its relationship with SUVR. Finally, we investigated the contribution of radiological metrics to clinical outcomes. RESULTS: 11C-PBR28 SUVR were abnormally higher in several white matter areas in MS. Myelin content was lower in active compared to inactive corresponding white matter regions. An inverse correlation between SUVR and myelin content was found. Radiological metrics correlated with both neurological and cognitive impairment. CONCLUSION: our data suggest an inverse relation of microglia activation and myelination, particularly in perilesional white matter tissue.

Axonal and myelin changes and their inter-relationship in the optic radiations in people with multiple sclerosis.

Background: The imaging g-ratio, estimated from axonal volume fraction (AVF) and myelin volume fraction (MVF), is a novel biomarker of microstructural tissue integrity in multiple sclerosis (MS). Objective: To assess axonal and myelin changes and their inter-relationship as measured by g-ratio in the optic radiations (OR) in people with MS (pwMS) with and without previous optic neuritis (ON) compared to healthy controls (HC). Methods: Thirty pwMS and 17 HCs were scanned on a 3Tesla Connectom scanner. AVF and MVF, derived from a multi-shell diffusion protocol and macromolecular tissue volume, respectively, were measured in normal-appearing white matter (NAWM) and lesions within the OR and used to calculate imaging g-ratio. Results: OR AVF and MVF were decreased in pwMS compared to HC, and in OR lesions compared to NAWM, whereas the g-ratio was not different. Compared to pwMS with previous ON, AVF and g-ratio tended to be higher in pwMS without prior ON. AVF and MVF, particularly in NAWM, were positively correlated with retinal thickness, which was more pronounced in pwMS with prior ON. Conclusion: Axonal measures reflect microstructural tissue damage in the OR, particularly in the setting of remote ON, and correlate with established metrics of visual health in MS.

Positive Predictive Value of MOG-IgG for Clinically Defined MOG-AD Within a Real-World Cohort.

Myelin oligodendrocyte glycoprotein antibody associated disease (MOG-AD) is a CNS demyelinating disease, typically presenting with optic neuritis, transverse myelitis, and/or ADEM-like syndromes. The positive predictive value (PPV) of MOG-IgG testing by live cell-based assay was reported to be 72% in a study performed at the Mayo Clinic using a cut-off of 1:20. PPV may vary depending upon the tested population, thus supporting further investigation of MOG-IgG testing at other centers. In this real-world institutional cohort study, we determined the PPV of serum MOG-IgG for clinically defined MOG-AD in our patient population. The Massachusetts General Brigham Research Patient Data Registry database was queried for patients with positive serum MOG-IgG detection, at least once, between January 1, 2017 and March 25, 2021. All were tested via the MOG-IgG1 fluorescence-activated cell sorting assay (Mayo Laboratories, Rochester, MN). MOG-IgG positive cases were reviewed for fulfillment of typical MOG-AD clinical features, determined by treating neurologists and study authors. Of 1,877 patients tested, 78 (4.2%) patients tested positive for MOG-IgG with titer ≥1:20, and of these, 67 had validated MOG-AD yielding a PPV of 85.9%. Using a ≥1:40 titer cutoff, 65 (3.5%) tested positive and PPV was 93.8%. Three MOG positive cases had a prototypical multiple sclerosis diagnosis (RRMS n = 2, titers 1:20 and 1:40; PPMS n = 1; 1:100). The treating diagnosis for one RRMS patient with a 1:40 titer was subsequently modified to MOG-AD by treating neurologists. Validated diagnoses of the remaining positive patients without MOG-AD included: migraine (n = 2, titers 1:20, 1:100), inclusion body myositis (n = 1, titer 1:100), autoimmune encephalitis (n = 2, titers 1:20, 1:20), hypoxic ischemic brain injury (n = 1, titer 1:20), IgG4-related disease (n = 1, titer 1:20), and idiopathic hypertrophic pachymeningitis (n = 1, titer 1:20). In our cohort, the PPV for MOG-IgG improved utilizing a titer cut-off of ≥1:40. The presence of positive cases with and without demyelinating features, emphasizes a need for testing in the appropriate clinical context, analysis of titer value and clinical interpretation.

Associations between corpus callosum damage, clinical disability, and surface-based homologous inter-hemispheric connectivity in multiple sclerosis.

Axonal damage in the corpus callosum is prevalent in multiple sclerosis (MS). Although callosal damage is associated with disrupted functional connectivity between hemispheres, it is unclear how this relates to cognitive and physical disability. We investigated this phenomenon using advanced measures of microstructural integrity in the corpus callosum and surface-based homologous inter-hemispheric connectivity (sHIC) in the cortex. We found that sHIC was significantly decreased in primary motor, somatosensory, visual, and temporal cortical areas in a group of 36 participants with MS (29 relapsing-remitting, 4 secondary progressive MS, and 3 primary-progressive MS) compared with 42 healthy controls (cluster level, p < 0.05). In participants with MS, global sHIC correlated with fractional anisotropy and restricted volume fraction in the posterior segment of the corpus callosum (r = 0.426, p = 0.013; r = 0.399, p = 0.020, respectively). Lower sHIC, particularly in somatomotor and posterior cortical areas, was associated with cognitive impairment and higher disability scores on the Expanded Disability Status Scale (EDSS). We demonstrated that higher levels of sHIC attenuated the effects of posterior callosal damage on physical disability and cognitive dysfunction, as measured by the EDSS and Brief Visuospatial Memory Test-Revised (interaction effect, p < 0.05). We also observed a positive association between global sHIC and years of education (r = 0.402, p = 0.018), supporting the phenomenon of "brain reserve" in MS. Our data suggest that preserved sHIC helps prevent cognitive and physical decline in MS.

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.

Comprehensive diffusion MRI dataset for in vivo human brain microstructure mapping using 300 mT/m gradients.

Strong gradient systems can improve the signal-to-noise ratio of diffusion MRI measurements and enable a wider range of acquisition parameters that are beneficial for microstructural imaging. We present a comprehensive diffusion MRI dataset of 26 healthy participants acquired on the MGH-USC 3 T Connectome scanner equipped with 300 mT/m maximum gradient strength and a custom-built 64-channel head coil. For each participant, the one-hour long acquisition systematically sampled the accessible diffusion measurement space, including two diffusion times (19 and 49 ms), eight gradient strengths linearly spaced between 30 mT/m and 290 mT/m for each diffusion time, and 32 or 64 uniformly distributed directions. The diffusion MRI data were preprocessed to correct for gradient nonlinearity, eddy currents, and susceptibility induced distortions. In addition, scan/rescan data from a subset of seven individuals were also acquired and provided. The MGH Connectome Diffusion Microstructure Dataset (CDMD) may serve as a test bed for the development of new data analysis methods, such as fiber orientation estimation, tractography and microstructural modelling.

Cortical and phase rim lesions on 7 T MRI as markers of multiple sclerosis disease progression.

In multiple sclerosis, individual lesion-type patterns on magnetic resonance imaging might be valuable for predicting clinical outcome and monitoring treatment effects. Neuropathological and imaging studies consistently show that cortical lesions contribute to disease progression. The presence of chronic active white matter lesions harbouring a paramagnetic rim on susceptibility-weighted magnetic resonance imaging has also been associated with an aggressive form of multiple sclerosis. It is, however, still uncertain how these two types of lesions relate to each other, or which one plays a greater role in disability progression. In this prospective, longitudinal study in 100 multiple sclerosis patients (74 relapsing-remitting, 26 secondary progressive), we used ultra-high field 7-T susceptibility imaging to characterize cortical and rim lesion presence and evolution. Clinical evaluations were obtained over a mean period of 3.2 years in 71 patients, 46 of which had a follow-up magnetic resonance imaging. At baseline, cortical and rim lesions were identified in 96% and 63% of patients, respectively. Rim lesion prevalence was similar across disease stages. Patients with rim lesions had higher cortical and overall white matter lesion load than subjects without rim lesions (P = 0.018-0.05). Altogether, cortical lesions increased by both count and volume (P = 0.004) over time, while rim lesions expanded their volume (P = 0.023) whilst lacking new rim lesions; rimless white matter lesions increased their count but decreased their volume (P = 0.016). We used a modern machine learning algorithm based on extreme gradient boosting techniques to assess the cumulative power as well as the individual importance of cortical and rim lesion types in predicting disease stage and disability progression, alongside with more traditional imaging markers. The most influential imaging features that discriminated between multiple sclerosis stages (area under the curve±standard deviation = 0.82 ± 0.08) included, as expected, the normalized white matter and thalamic volume, white matter lesion volume, but also leukocortical lesion volume. Subarachnoid cerebrospinal fluid and leukocortical lesion volumes, along with rim lesion volume were the most important predictors of Expanded Disability Status Scale progression (area under the curve±standard deviation = 0.69 ± 0.12). Taken together, these results indicate that while cortical lesions are extremely frequent in multiple sclerosis, rim lesion development occurs only in a subset of patients. Both, however, persist over time and relate to disease progression. Their combined assessment is needed to improve the ability of identifying multiple sclerosis patients at risk of progressing disease.

Quantitative 7-Tesla Imaging of Cortical Myelin Changes in Early Multiple Sclerosis.

Cortical demyelination occurs early in multiple sclerosis (MS) and relates to disease outcome. The brain cortex has endogenous propensity for remyelination as proven from histopathology study. In this study, we aimed at characterizing cortical microstructural abnormalities related to myelin content by applying a novel quantitative MRI technique in early MS. A combined myelin estimation (CME) cortical map was obtained from quantitative 7-Tesla (7T) T 2 * and T1 acquisitions in 25 patients with early MS and 19 healthy volunteers. Cortical lesions in MS patients were classified based on their myelin content by comparison with CME values in healthy controls as demyelinated, partially demyelinated, or non-demyelinated. At follow-up, we registered changes in cortical lesions as increased, decreased, or stable CME. Vertex-wise analysis compared cortical CME in the normal-appearing cortex in 25 MS patients vs. 19 healthy controls at baseline and investigated longitudinal changes at 1 year in 10 MS patients. Measurements from the neurite orientation dispersion and density imaging (NODDI) diffusion model were obtained to account for cortical neurite/dendrite loss at baseline and follow-up. Finally, CME maps were correlated with clinical metrics. CME was overall low in cortical lesions (p = 0.03) and several normal-appearing cortical areas (p < 0.05) in the absence of NODDI abnormalities. Individual cortical lesion analysis revealed, however, heterogeneous CME patterns from extensive to partial or absent demyelination. At follow-up, CME overall decreased in cortical lesions and non-lesioned cortex, with few areas showing an increase (p < 0.05). Cortical CME maps correlated with processing speed in several areas across the cortex. In conclusion, CME allows detection of cortical microstructural changes related to coexisting demyelination and remyelination since the early phases of MS, and shows to be more sensitive than NODDI and relates to cognitive performance.

Electronic pill bottles to monitor and promote medication adherence for people with multiple sclerosis: A randomized, virtual clinical trial.

OBJECTIVE: We perform a randomized trial to test the impact of electronic pill bottles with audiovisual reminders on oral disease modifying therapy (DMT) adherence in people with MS (PwMS). METHODS: Adults with multiple sclerosis (MS) taking an oral DMT were randomized 1:1 for 90 days to remote smartphone app- and pill bottle-based (a) adherence monitoring, or (b) adherence monitoring with audiovisual medication reminders. Optimal adherence was defined as the proportion of doses taken ±3 h of the scheduled time. Numbers of missed pills and pills taken early, on time, late, and extra were recorded. A multivariable regression model tested possible associations between optimal adherence and age, MS duration, cognitive functioning, and number of daily prescription pills. RESULTS: 85 participants (66 female; mean age 44.9 years) took dimethyl/diroximel fumarate (n = 49), fingolimod (n = 26), or teriflunomide (n = 10). Optimal adherence was on average higher in the monitoring with reminders arm (71.4%) than the monitoring only arm (61.6%; p = 0.033). In a multivariable model, optimal adherence was less likely in younger participants (p < 0.001) and those taking more daily prescription pills (p < 0.001). In the monitoring only arm, 4.0% of doses were taken early, 61.6% on time, 5.6% late, 4.4% in excess, and 24.4% were missed. In the reminders arm, these proportions were 3.4%, 71.4%, 3.7%, 8.7%, and 12.8%, respectively. CONCLUSION: We map real-world oral DMT adherence patterns using mHealth technology. PwMS who received medication reminders had higher optimal adherence. Nonadherence was more nuanced than simply missing pills. Developing strategies to improve adherence remains important in longitudinal MS care.

Scan-rescan repeatability of axonal imaging metrics using high-gradient diffusion MRI and statistical implications for study design.

Axon diameter mapping using diffusion MRI in the living human brain has attracted growing interests with the increasing availability of high gradient strength MRI systems. A systematic assessment of the consistency of axon diameter estimates within and between individuals is needed to gain a comprehensive understanding of how such methods extend to quantifying differences in axon diameter index between groups and facilitate the design of neurobiological studies using such measures. We examined the scan-rescan repeatability of axon diameter index estimation based on the spherical mean technique (SMT) approach using diffusion MRI data acquired with gradient strengths up to 300 mT/m on a 3T Connectom system in 7 healthy volunteers. We performed statistical power analyses using data acquired with the same protocol in a larger cohort consisting of 15 healthy adults to investigate the implications for study design. Results revealed a high degree of repeatability in voxel-wise restricted volume fraction estimates and tract-wise estimates of axon diameter index derived from high-gradient diffusion MRI data. On the region of interest (ROI) level, across white matter tracts in the whole brain, the Pearson's correlation coefficient of the axon diameter index estimated between scan and rescan experiments was r = 0.72 with an absolute deviation of 0.18 µm. For an anticipated 10% effect size in studies of axon diameter index, most white matter regions required a sample size of less than 15 people to observe a measurable difference between groups using an ROI-based approach. To facilitate the use of high-gradient strength diffusion MRI data for neuroscientific studies of axonal microstructure, the comprehensive multi-gradient strength, multi-diffusion time data used in this work will be made publicly available, in support of open science and increasing the accessibility of such data to the greater scientific community.

Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis.

BACKGROUND: Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in progressive MS. OBJECTIVE: To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS. METHODS: In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable. RESULTS: The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were r = 0.52 and r = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum (p = 0.76) or CSF (p = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed. CONCLUSION: Ibudilast treatment was not associated with a change in either serum or CSF NfL.

The relevance of multiple sclerosis cortical lesions on cortical thinning and their clinical impact as assessed by 7.0-T MRI.

OBJECTIVE: This study aimed to investigate at 7.0-T MRI a) the role of multiple sclerosis (MS) cortical lesions in cortical tissue loss b) their relation to neurological disability. METHODS: In 76 relapsing remitting and 26 secondary progressive MS patients (N = 102) and 56 healthy subjects 7.0-T T2*-weighted images were acquired for lesion segmentation; 3.0-T T1-weighted structural scans for cortical surface reconstruction/cortical thickness estimation. Patients were dichotomized based on the median cortical lesion volume in low and high cortical lesion load groups that differed by age, MS phenotype and degree of neurological disability. Group differences in cortical thickness were tested on reconstructed cortical surface. Patients were evaluated clinically by means of the Expanded Disability Status Scale (EDSS). RESULTS: Cortical lesions were detected in 96% of patients. White matter lesion load was greater in the high than in the low cortical lesion load MS group (p = 0.01). Both MS groups disclosed clusters (prevalently parietal) of cortical thinning relative to healthy subjects, though these regions did not show the highest cortical lesion density, which predominantly involved frontal regions. Cortical thickness decreased on average by 0.37 mm, (p = 0.002) in MS patients for each unit standard deviation change in white matter lesion volume. The odds of having a higher EDSS were associated with cortical lesion volume (1.78, p = 0.01) and disease duration (1.15, p < 0.001). CONCLUSION: Cortical thinning in MS is not directly related to cortical lesion load but rather with white matter lesion volume. Neurological disability in MS is better explained by cortical lesion volume assessment.

Response to ibudilast treatment according to progressive multiple sclerosis disease phenotype.

OBJECTIVE: Determine whether a treatment effect of ibudilast on brain atrophy rate differs between participants with primary (PPMS) and secondary (SPMS) progressive multiple sclerosis. BACKGROUND: Progressive forms of MS are both associated with continuous disability progression. Whether PPMS and SPMS differ in treatment response remains unknown. DESIGN/METHODS: SPRINT-MS was a randomized, placebo-controlled 96-week phase 2 trial in both PPMS (n = 134) and SPMS (n = 121) patients. The effect of PPMS and SPMS phenotype on the rate of change of brain atrophy measured by brain parenchymal fraction (BPF) was examined by fitting a three-way interaction linear-mixed model. Adjustment for differences in baseline demographics, disease measures, and brain size was explored. RESULTS: Analysis showed that there was a three-way interaction between the time, treatment effect, and disease phenotype (P < 0.06). After further inspection, the overall treatment effect was primarily driven by patients with PPMS (P < 0.01), and not by patients with SPMS (P = 0.97). This difference may have been due to faster brain atrophy progression seen in the PPMS placebo group compared to SPMS placebo (P < 0.02). Although backward selection (P < 0.05) retained age, T2 lesion volume, RNFL, and longitudinal diffusivity as significant baseline covariates in the linear-mixed model, the adjusted overall treatment effect was still driven by PPMS (P < 0.01). INTERPRETATION: The previously reported overall treatment effect of ibudilast on worsening of brain atrophy in progressive MS appears to be driven by patients with PPMS that may be, in part, because of the faster atrophy progression rates seen in the placebo-treated group.

Prospective growth and developmental outcomes in infants born to mothers with multiple sclerosis.

BACKGROUND: The importance of supporting pregnancy-related decisions in multiple sclerosis (MS) patients has increasingly been recognized and hence the need for prospective data on pregnancy and pediatric outcomes in this patient population. OBJECTIVE: To assess prospective growth and developmental outcomes of infants born to mothers with multiple sclerosis (IMS). METHODS: PREG-MS is a prospective multicenter cohort study in New England, United States. We followed 65 women with MS and their infants with up to 12 months consistent pediatric follow-up. Pediatric, neurologic, and demographic information was obtained via structured telephone interviews and validated with medical records. RESULTS: No differences in infant weights and lengths with World Health Organization (WHO) 50th percentile standards were observed (p > 0.05). However, larger head circumference (HC) measurements than WHO standards were reported in cohort infants (p < 0.05). There was no association between HC and markers of maternal MS activity, demographic, or social factors. No irreversible pediatric developmental abnormalities were observed. CONCLUSION: This first prospective study on pediatric anthropometry in IMS suggests a possible increase in HC compared to WHO standards without an increase in irreversible developmental abnormalities. The observations are exploratory and require confirmation with larger prospective studies in diverse groups of MS patients.

Optical coherence tomography outcomes from SPRINT-MS, a multicenter, randomized, double-blind trial of ibudilast in progressive multiple sclerosis.

BACKGROUND: The SPRINT-MS trial demonstrated benefit of ibudilast on brain atrophy over 96 weeks in progressive multiple sclerosis (MS). Optical coherence tomography (OCT) was performed in all trial participants. OBJECTIVE: Report the OCT results of the SPRINT-MS trial. METHODS: OCT was obtained at baseline and every 6 months using spectral domain OCT and analyzed by an OCT reading center. Change in each OCT outcome measure by treatment group was estimated using linear mixed models. RESULTS: Change in pRNFL thickness was +0.0424 uM/year (95% confidence interval (CI): -0.3091 to 0.3939) for ibudilast versus -0.2630 uM (95% CI: -0.5973 to 0.0714) for placebo (n = 244, p = 0.22). Macular volume change was -0.00503 mm3/year (-0.02693 to 0.01688) with ibudilast versus -0.03659 mm3/year (-0.05824 to -0.01494) for placebo in the Spectralis cohort (n = 61, p = 0.044). For the Cirrus cohort, macular volume change was -0.00040 mm3/year (-0.02167, 0.020866) with ibudilast compared to -0.02083 mm3/year (-0.04134 to -0.00033) for placebo (n = 183, p = 0.1734). Ganglion cell-inner plexiform layer thickness change, available from Cirrus, was -0.4893 uM/year (-0.9132, -0.0654) with ibudilast versus -0.9587 uM/year (-1.3677, -0.5498) with placebo (n = 183, p = 0.12). CONCLUSION: Retinal thinning in MS may be attenuated by ibudilast. Sample size estimates suggest OCT can be a viable outcome measure in progressive MS trials if a therapy has a large treatment effect. TRIAL REGISTRATION: NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.