Super-Resolution in Clinically Available Spinal Cord MRIs Enables Automated Atrophy Analysis.

BACKGROUND AND PURPOSE: Measurement of the mean upper cervical cord area (MUCCA) is an important biomarker in the study of neurodegeneration. However, dedicated high-resolution scans of the cervical spinal cord are rare in standard-of-care imaging due to timing and clinical usability. Most clinical cervical spinal cord imaging is sagittally acquired in 2D with thick slices and anisotropic voxels. As a solution, previous work describes high-resolution T1-weighted brain imaging for measuring the upper cord area, but this is still not common in clinical care. MATERIALS AND METHODS: We propose using a zero-shot super-resolution technique, SMORE, already validated in the brain, to enhance the resolution of 2D-acquired scans for upper cord area calculations. To incorporate super-resolution in spinal cord analysis, we validate SMORE against high-resolution research imaging and in a real-world longitudinal data analysis. RESULTS: Super-resolved images reconstructed using SMORE showed significantly greater similarity to the ground truth than low-resolution images across all tested resolutions (p<0.001 for all resolutions in PSNR and MSSIM). MUCCA results from super-resolved scans demonstrate excellent correlation with high-resolution scans (r>0.973 for all resolutions) compared to low-resolution scans. Additionally, super-resolved scans are consistent between resolutions (r>0.969), an essential factor in longitudinal analysis. Compared to clinical outcomes such as walking speed or disease severity, MUCCA values from low-resolution scans have significantly lower correlations than those from high-resolution scans. Super-resolved results have no significant difference. In a longitudinal real-world dataset, we show that these super-resolved volumes can be used in conjunction with T1-weighted brain scans to show a significant rate of atrophy (-0.790, p=0.020 vs. -0.438, p=0.301 with low-resolution). CONCLUSIONS: Super-resolution is a valuable tool for enabling large-scale studies of cord atrophy, as low-resolution images acquired in clinical practice are common and available. ABBREVIATIONS: MS=multiple sclerosis; MUCCA=mean upper cervical cord; HR=high-resolution; LR=low-resolution; SR=superresolved; CSC=cervical spinal cord; PMJ=pontomedullary junction; MSSIM=mean structural similarity; PSNR=peak signal-to-noise ratio; EDSS=expanded disability status scale.

Comorbidity and Disease Activity in Multiple Sclerosis.

Importance: Multiple studies suggest that comorbidity worsens clinically relevant outcomes in multiple sclerosis (MS), including the severity of disability at diagnosis and rate of disability worsening after diagnosis. However, less is known regarding the association of comorbidity with measures of disease activity, such as relapse rate and magnetic resonance imaging lesion accrual, which are relevant to clinicians and clinical trialists. Objective: To evaluate the association of comorbidities with disease activity in clinical trials of disease-modifying therapies (DMTs) in populations with MS. Design, Setting, and Participants: A 2-stage meta-analytic approach was used in this cohort study of individual participant data from phase 3 clinical trials of MS DMTs that had 2 years of follow-up and were conducted from November 2001 to March 2018. Data were analyzed from February 2023 to June 2024. Exposure: Comorbidity burden and individual comorbidities present at trial enrollment, including hypertension; hyperlipidemia; functional cardiovascular disease, ischemic heart, cerebrovascular, and peripheral vascular disease; diabetes; autoimmune thyroid and miscellaneous autoimmune conditions; migraine; lung and skin conditions; depression; anxiety; and other psychiatric disorders. Main Outcomes and Measures: The main outcome was evidence of disease activity (EDA) over 2 years of follow-up, defined as confirmed relapse activity, disability worsening, or any new lesions on magnetic resonance imaging. Results: A total of 16 794 participants with MS were included from 17 clinical trials (67.2% female). Over the 2-year follow-up, 61.0% (95% CI, 56.2%-66.3%; I2 = 97.9%) of the pooled trials had EDA. After adjusting for multiple factors, the presence of 3 or more comorbidities was associated with an increased hazard of EDA (adjusted hazard ratio [AHR], 1.14; 95% CI, 1.02-1.28) compared with no comorbidity. Presence of 2 or more cardiometabolic conditions was also associated with an increased hazard of EDA (AHR, 1.21; 95% CI, 1.08-1.37) compared with no cardiometabolic comorbidity. Presence of 1 psychiatric disorder was associated with an increased hazard of EDA (AHR, 1.07; 95% CI, 1.02-1.14). Conclusions and Relevance: In this study, a higher burden of comorbidity was associated with worse clinical outcomes in people with MS, although comorbidity could potentially be a partial mediator of other negative prognostic factors. Our findings suggest a substantial adverse association of the comorbidities investigated with MS disease activity and that prevention and management of comorbidities should be a pressing concern in clinical practice.

A 2-stage model of heterogenous treatment effects for brain atrophy in multiple sclerosis utilizing the MS PATHS research network.

BACKGROUND: Two-stage models of heterogenous treatment effects (HTE) may advance personalized medicine in multiple sclerosis (MS). Brain atrophy is a relatively objective outcome measure that has strong relationships to MS prognosis and treatment effects and is enabled by standardized MRI. OBJECTIVES: To predict brain atrophy outcomes for patients initiating disease-modifying therapies (DMT) with different efficacies, considering the patients' baseline brain atrophy risk measured via brain parenchymal fraction (BPF). METHODS: Analyses included patients enrolled in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network who started DMT and had complete baseline data and ≥ 6-month brain MRI follow-up. All brain MRIs were acquired using standardized acquisition sequences on Siemens 3T scanners. BPF change risk was derived by linear mixed effects models using baseline covariates. Model performance was assessed by predicted versus actual BPF change R2. Propensity score (PS) weighting was used to balance covariates between groups defined by DMT efficacy (high: natalizumab, alemtuzumab, ocrelizumab, and rituximab; moderate: dimethyl fumarate, fingolimod, and cladribine; low: teriflunomide, interferons, and glatiramer acetate). HTE models predicting 1 year change in BPF were built using a weighted linear mixed effects model with low-efficacy DMT as the reference. RESULTS: Analyses included 581 high-, 183 moderate-, and 106 low-efficacy DMT-treated patients. The mean and median number of brain MRI observations per treatment period were 2.9 and 3.0, respectively. Risk model performance R2=0.55. After PS weighting, covariate standardized mean differences were <10 %, indicating excellent balance across measured variables. Changes in BPF between baseline and follow-up were found to be statistically significant (p < 0.001), suggesting a pathological change. Patients with low brain atrophy risk had a similar outcome regardless of DMT selection. In patients with high brain atrophy risk, high- and moderate-efficacy DMTs performed similarly, while a 2-fold worse BPF change was predicted for patients selecting low-efficacy DMTs (p < 0.001). Similar results were observed in a sensitivity analysis adjusting for pseudoatrophy effects in a sub-population of patients treated with natalizumab. CONCLUSIONS: The relative benefit of selecting higher efficacy treatments may vary depending on patients' baseline brain atrophy risk. Poor outcomes are predicted in individuals with high baseline risk who are treated with low-efficacy DMTs.

Evidence of symptom specificity for depression in multiple sclerosis: A two sample Mendelian randomization study.

BACKGROUND: Depression is common and phenotypically heterogenous in multiple sclerosis (MS). MS may increase risk of some but not all affective symptoms or certain symptoms may predispose individuals to higher MS risk. OBJECTIVE: To assess the existence and direction of causality between distinct depressive symptoms and MS using two-sample Mendelian randomization (MR). METHODS: Using summary data from genome-wide association studies, we selected genetic instrument variables (IV) for MS (n = 115,776) and IVs for depressive symptoms (average n = 117,713): anhedonia, altered appetite, concentration, depressed mood, fatigue, inadequacy, psychomotor changes, sleeping problems and suicidality. We performed two-sample MR in either direction using inverse-variance models. Sensitivity analyses included weighted-median and MR-Egger regression. Obesity is a known risk factor for MS and depression; we adjusted for body mass index in multivariable-MR. RESULTS: Genetic liability to MS was associated with anhedonia (IVW estimate per 102: 0.69; 95 % CI: 0.24-1.13; p = 0.002), concentration difficulty (0.66; 0.19-1.13; p = 0.006) and psychomotor changes (0.37; 0.08-0.65; p = 0.01). Results were similar in sensitivity analyses. In the opposite direction, we found no evidence of a causal relationship for any affective symptom on MS risk. CONCLUSIONS: Genetic susceptibility to MS was associated with anhedonia, concentration, and psychomotor-related symptoms, suggesting a specific phenotype of depression in MS.

Quality of life is impaired in myelin oligodendrocyte glycoprotein antibody associated disease.

Background: There is a paucity of studies examining quality of life (QoL) in people with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Methods: A cross-sectional, online, self-administered survey was distributed. Data elements included demographic and clinical characteristics, and QoL in Neurological Disorders (Neuro-QoL) short form questionnaires. Neuro-QoL domain scores were compared to reference populations, yielding standardized T-scores. Symptom severity was categorized as mild, moderate, or severe, using standard Neuro-QoL cut points. Results: A total of 259 participants completed the survey. Neuro-QoL domain impairment was present in a significant proportion of respondents (anxiety: 58.1%, depression: 30.7%, stigma 29.8%, cognition: 58.5%, social function: 57.7%). T-scores were significantly worse than the reference population for anxiety (p<0.001), stigma (p=0.005), cognitive function (p<0.001) and social interactions (p<0.001). There was no clear association between QoL domains and demographics, disease-modifying therapy class, or type of clinical presentation. A relapsing vs monophasic disease course was associated with worse anxiety, stigma, cognition, and social interactions (p<0.05). Conclusion: People with MOGAD may exhibit impairment in multiple domains of QoL. Practicing clinicians should be aware of this burden in MOGAD. Further research is needed to better understand factors associated with QoL impairment in MOGAD.

Individual Prognostication of Disease Activity and Disability Worsening in Multiple Sclerosis With Retinal Layer Thickness z Scores.

BACKGROUND AND OBJECTIVES: Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted z scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS). METHODS: We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted z scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests. RESULTS: In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], p = 3.82e-5). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], p = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], p = 0.04). Compared with raw values with arbitrary cutoffs, applying the z score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score). DISCUSSION: In conclusion, our work demonstrated reference cohort-based z scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.

Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis.

OBJECTIVE: Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS. METHODS: Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression. RESULTS: A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta-analyses identified that in MS, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. INTERPRETATION: Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Synaptic Protein Loss in Extracellular Vesicles Reflects Brain and Retinal Atrophy in People With Multiple Sclerosis.

OBJECTIVES: To assess whether the rate of change in synaptic proteins isolated from neuronally enriched extracellular vesicles (NEVs) is associated with brain and retinal atrophy in people with multiple sclerosis (MS). METHODS: People with MS were followed with serial blood draws, MRI (MRI), and optical coherence tomography (OCT) scans. NEVs were immunocaptured from plasma, and synaptopodin and synaptophysin proteins were measured using ELISA. Subject-specific rates of change in synaptic proteins, as well as brain and retinal atrophy, were determined and correlated. RESULTS: A total of 50 people with MS were included, 46 of whom had MRI and 45 had OCT serially. The rate of change in NEV synaptopodin was associated with whole brain (rho = 0.31; p = 0.04), cortical gray matter (rho = 0.34; p = 0.03), peripapillary retinal nerve fiber layer (rho = 0.37; p = 0.01), and ganglion cell/inner plexiform layer (rho = 0.41; p = 0.006) atrophy. The rate of change in NEV synaptophysin was also correlated with whole brain (rho = 0.31; p = 0.04) and cortical gray matter (rho = 0.31; p = 0.049) atrophy. DISCUSSION: NEV-derived synaptic proteins likely reflect neurodegeneration and may provide additional circulating biomarkers for disease progression in MS.

Metabolomics of Multiple Sclerosis Lesions Demonstrates Lipid Changes Linked to Alterations in Transcriptomics-Based Cellular Profiles.

BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) have a dysregulated circulating metabolome, but the metabolome of MS brain lesions has not been studied. The aims of this study were to identify differences in the brain tissue metabolome in MS compared with controls and to assess its association with the cellular profile of corresponding tissue. METHODS: MS tissues included samples from the edge and core of chronic active or inactive lesions and periplaque white matter (WM). Control specimens were obtained from normal WM. Metabolomic analysis was performed using mass-spectrometry coupled with liquid/gas chromatography and subsequently integrated with single-nucleus RNA-sequencing data by correlating metabolite abundances with relative cell counts, as well as individual genes using Multiomics Factor Analysis (MOFA). RESULTS: Seventeen samples from 5 people with secondary progressive MS and 8 samples from 6 controls underwent metabolomic profiling identifying 783 metabolites. MS lesions had higher levels of sphingosines (false discovery rate-adjusted p-value[q] = 2.88E-05) and sphingomyelins and ceramides (q = 2.15E-07), but lower nucleotide (q = 0.05), energy (q = 0.001), lysophospholipid (q = 1.86E-07), and monoacylglycerol (q = 0.04) metabolite levels compared with control WM. Periplaque WM had elevated sphingomyelins and ceramides (q = 0.05) and decreased energy metabolites (q = 0.01) and lysophospholipids (q = 0.05) compared with control WM. Sphingolipids and membrane lipid metabolites were positively correlated with astrocyte and immune cell abundances and negatively correlated with oligodendrocytes. On the other hand, long-chain fatty acid, endocannabinoid, and monoacylglycerol pathways were negatively correlated with astrocyte and immune cell populations and positively correlated with oligodendrocytes. MOFA demonstrated associations between differentially expressed metabolites and genes involved in myelination and lipid biosynthesis. DISCUSSION: MS lesions and perilesional WM demonstrated a significantly altered metabolome compared with control WM. Many of the altered metabolites were associated with altered cellular composition and gene expression, indicating an important role of lipid metabolism in chronic neuroinflammation in MS.

Structural MRI measures are associated with fatigue severity and persistence in a large, real-world cohort of people with multiple sclerosis.

BACKGROUND: Results of research on radiological hallmarks of multiple sclerosis (MS) fatigue have been conflicting. OBJECTIVE: To investigate the associations of lesion and brain compartment volumes with fatigue severity and persistence in people with multiple sclerosis (PwMS). METHODS: The Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network collects standardized data during routine care of PwMS from 10 healthcare institutions. Magnetic resonance imaging (MRI) predictors included baseline brain parenchymal (BPF) and gray matter fractions (GMF) and T2 lesion volume (T2LV). The Quality of Life in Neurological Disorders (Neuro-QOL) fatigue subscore was analyzed linearly and categorically using T-score cutpoints, with a period of elevated symptoms defined as T-score ⩾ mean + 0.5 SD over follow-up. RESULTS: At baseline, of 4012 participants (average age: 45.6 ± 11.8 years; 73% female; 31% progressive MS), 2058 (51%) had no fatigue, 629 (16%) had mild fatigue, and 1325 (33%) had moderate-to-severe fatigue. One SD greater baseline BPF and GMF were associated with 0.83 (p < 0.001) and 0.38 (p = 0.02) lower values in the baseline Neuro-QOL fatigue T-score. A 1 SD lower log of total T2LV was associated with a 0.49 (p < 0.001) lower baseline fatigue T-score. Higher BPF and lower T2LV at baseline were associated with lower odds of subsequent periods of elevated fatigue. CONCLUSION: Baseline lesion burden and lower generalized whole-brain volumes were associated with MS fatigue in cross-sectional and longitudinal analyses in a large, real-world cohort of PwMS.

Investigating the Prevalence of Comorbidity in Multiple Sclerosis Clinical Trial Populations.

BACKGROUND AND OBJECTIVES: Comorbidity is common in multiple sclerosis (MS) with the most prevalent conditions being depression, anxiety, hypertension, and hyperlipidemia. Limited information regarding the representation of comorbidity status is available from phase III clinical trials in MS leading to concern about the potential underrepresentation of individuals with comorbidity in clinical trials. The objective was to estimate the prevalence of comorbidities in MS clinical trial populations. METHODS: Individual-level data from multiple sponsors were requested for a 2-stage meta-analysis of phase III clinical trials of MS disease-modifying therapies. To ensure consistency of our approach across trials, we followed the Maelstrom retrospective harmonization guidelines. Chronic comorbidities at clinical trial enrollment recommended by the International Advisory Committee on Clinical Trials in MS were considered (depression, anxiety, hypertension, hyperlipidemia, migraine, diabetes, chronic lung disease). Additional comorbidities were also classified. Classification was based on medical history data. Individual comorbidities were summed and categorized as 0, 1, 2, or ≥3. We report the pooled prevalence (95% confidence interval [95% CI]) of comorbidity. The pooled prevalence and prevalence ratios across age, sex, race, disability level, and treatment were also reported. Heterogeneity was assessed using the I2 statistic. RESULTS: Seventeen trials involving 17,926 participants were included. Fourteen trials enrolled participants with relapsing MS (RMS) while 3 enrolled participants with progressive MS (PMS). The distributions of sex, age, and disability level were generally consistent within RMS and PMS trials. When pooled, almost half of trial participants (46.5%) had ≥1 comorbidity (1: 25.0%, 95% CI 23.0-27.0, I2 = 89.9; 2: 11.4% [9.3-14.0], I2 = 96.3; ≥3: 6.0% [4.2-8.4], I2 = 97.7). Depression (16.45% [12.96-20.88], I2 = 98.3) was the most prevalent comorbidity reported, followed by hypertension (10.16% [8.61-11.98], I2 = 93.2). Heterogeneity was high across trials. Older age and female participants were associated with increased number of comorbidities. Older individuals and male participants had a higher prevalence of hyperlipidemia, while older individuals and female participants had a higher prevalence of depression and anxiety. DISCUSSION: Individuals with comorbidities are included in clinical trials, although they may still be underrepresented compared with the general MS population. Given the comorbidity prevalence in the trial populations and studies suggesting an association of comorbidities with disease activity, comorbidity may influence outcomes in clinical trials.

Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease.

Background: Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS. Methods: Global metabolomics was performed in an observational cohort of people with MS followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial, was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2g daily) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory and gut microbiome parameters. Results: In the observational cohort, higher primary bile acid levels at baseline predicted slower whole brain, brain substructure and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not significantly differ between arms (p=0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naïve cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted in the TUDCA arm compared to placebo. Conclusion: Bile acid metabolism in MS is linked with brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration.

Association between demographics, socioeconomics, and disease-related factors and the perception of stigma in people with MS.

BACKGROUND: Stigma is prevalent among individuals with chronic diseases, such as multiple sclerosis (MS) and those with comorbid mental health disorders, but its associated factors are poorly understood. OBJECTIVE: To investigate the prevalence and correlates of stigma in people living with MS. METHODS: We analyzed data from the MS Partners Advancing Technology and Health Solutions (MS PATHS) network, which collected patient information and outcomes during routine clinic visits. We used a multinomial logistic regression model to examine the cross-sectional association between stigma and demographic, socioeconomics, and MS-related factors. RESULTS: We included 11,634 participants. The mean Neuro-QoL stigma T-score was 47.2 ± 8.6, and 17.7% of participants were classified as having moderate to severe stigma using established cutoffs. Multinomial logistic regression models suggest that higher disability levels, progressive form of the disease, shorter duration of the disease, and unemployment were associated with higher stigma while being male, married, undergoing treatment with high-efficacy disease-modifying therapies (DMTs), and being from European MS centers were associated with lower stigma perception. Disability levels, measured by Patient-Determined Disease Steps (PDDS), had the strongest independent association with stigma. CONCLUSION: Stigma remains a relevant issue for people living with MS. Factors, such as physical and cognitive disability, DMT, and employment status may influence the severity of perceived stigma.

Extended interval dosing of ocrelizumab in patients with multiple sclerosis is not associated with meaningful differences in disease activity.

Risk concerns related to ocrelizumab treatment for multiple sclerosis (MS) during the COVID-19 pandemic caused infusion delays with extended interval dosing (EID). We reviewed medical records of patients on ocrelizumab to determine whether EID maintains its effectiveness compared to standard interval dosing (SID). Among 361 patients, 231 (64%) and 123 (34%) had at least one infusion with infusion intervals of ⩾8 months and ⩾12 months, respectively. There were no differences in demographics or clinical profiles between the SID and EID groups. No significant differences between rates of breakthrough activity among relapsing-remitting patients were observed between SID (three patients) and EID (seven patients).

Expanding clinical profiles and prognostic markers in stiff person syndrome spectrum disorders.

OBJECTIVE: To describe the clinical features of a cohort of individuals with stiff person syndrome spectrum disorders (SPSD) and identify potential early predictors of future disability. BACKGROUND: There is a need to better understand the full spectrum of clinical and paraclinical features and long-term impact of SPSD. DESIGN/METHODS: Observational study from 1997 to 2022 at Johns Hopkins. Clinical phenotypes included classic SPS, partial SPS (limb or trunk limited), SPS-plus (classic features plus cerebellar/brainstem involvement), and progressive encephalomyelitis with rigidity and myoclonus (PERM). Outcome measures were modified Rankin scale (mRS) and use of assistive device for ambulation. Multivariate logistic regression was used to assess significant predictors of outcomes. RESULTS: Cohort included 227 individuals with SPSD with mean follow-up of 10 years; 154 classic, 48 SPS-plus, 16 PERM, and 9 partial. Mean age at symptom onset was 42.9 ± 14.1 years, majority were white (69.2%) and female (75.8%). Median time to diagnosis was 36.2 months (longest for SPS-plus and PERM) and 61.2% were initially misdiagnosed. Most had systemic co-morbidities and required assistive devices for ambulation. Female sex (OR 2.08; CI 1.06-4.11) and initial brainstem/cerebellar involvement (OR 4.41; CI 1.63-14.33) predicted worse outcome by mRS. Older age at symptom onset (OR 1.04; CI 1.01-1.06), female sex (OR 1.99; CI 1.01-4.01), Black race (OR 4.14; CI 1.79-10.63), and initial brainstem/cerebellar involvement (OR 2.44; CI 1.04-7.19) predicted worse outcome by use of assistive device. Early implementation of immunotherapy was associated with better outcomes by either mRS (OR 0.45; CI 0.22-0.92) or use of assistive device (OR 0.79; CI 0.66-0.94). CONCLUSIONS: We present the expanding phenotypic variability of this rare spectrum of disorders and highlight potential predictors of future disability.

Agreement Between Published Reference Resources for Neurofilament Light Chain Levels in People With Multiple Sclerosis.

OBJECTIVES: To examine the agreement between published reference resources for neurofilament light chain (NfL) applied to a large population of people with multiple sclerosis (MS). METHODS: Six published reference resources were used to classify NfL in participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network as elevated or normal and to derive age-specific NfL Z-scores. NfL values were classified as elevated if they exceeded the >95th percentile (i.e., Z-score >1.645) of the age-specific reference range. Furthermore, age-specific NfL Z-scores could be derived for 4 of 6 reference resources. RESULTS: NfL measurements were assessed from 12,855 visits of 6,687 people with MS (median 2 samples per individual [range 1-7]). The mean ± SD age was 47.1 ± 11.7 years, 72.1% of participants were female, disease duration was 15.0 ± 10.6 years, body mass index was 28.6 ± 6.9 kg/m2, and serum NfL was 12.87 ± 12.86 pg/mL. Depending on the selection of the reference resource, the proportion of NfL measurements classified as elevated varied from 3.7% to 30.9%. The kappa coefficient across the 6 reference resources used was 0.576 (95% CI 0.571-0.580) indicating moderate agreement. Spearman correlations between Z-scores derived from the various reference resources exceeded 0.90; however, concordance coefficients were lower, ranging from 0.72 to 0.89. DISCUSSION: Interpretation of blood NfL values may vary markedly depending on the selection of the reference resource. Borderline elevated values should be interpreted with caution, and future studies should focus on standardizing NfL measurement and reporting across laboratories/platforms, better characterizing the effects of confounding/influencing factors, and defining the performance of NfL (including as part of multimodal predictive algorithms) for prediction of disease-specific outcomes.

Depression symptoms and cognition in multiple sclerosis: Longitudinal evidence of a specific link to executive control.

BACKGROUND: Depression symptoms are prevalent in multiple sclerosis (MS) and associated with poorer cognition in cross-sectional studies; it is unknown whether changes in depression symptoms track with cognitive changes longitudinally. OBJECTIVE: Investigate whether changes in depression symptoms correspond with cognitive changes over time in MS, and identify specific cognitive functions related to depression symptoms. METHOD: Persons with early relapse-onset MS (n = 165) completed a depression questionnaire (Beck Depression Inventory FastScreen) and tests of cognitive speed, executive control, and memory at baseline and 3-year follow-up. One-way ANOVAs assessed differences in cognitive change across participants with worsened, stable, or improved depression symptoms from baseline to year 3. RESULTS: Change in depression symptoms was related to change in executive control (p = 0.001, ηp2 = 0.08; worsened mood with worsened executive control; improved mood with improved executive control), even when adjusting for cognitive speed (p = 0.002, ηp2 = 0.08). There were no links to cognitive speed (p = 0.826) or memory (p = 0.243). Regarding individual depression symptoms, executive control was related to loss of pleasure and suicidal thoughts. CONCLUSIONS: Executive control tracks with depression symptoms, raising hope that management of mood may improve executive control. The specific link between executive control and anhedonia implicates dysfunctional reward processing as a key component of MS depression.

Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: Post Hoc Analyses of the SPRINT-MS Trial.

BACKGROUND AND OBJECTIVES: Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy in PMS. In this post hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype and (3) associations between OCT and MRI measures of neurodegeneration. METHODS: In the multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (PPMS) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations. RESULTS: One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, p = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, p < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, p = 0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r = 0.27, r = 0.26, and r = 0.20, respectively; p < 0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%. DISCUSSION: Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ibudilast reduces composite ganglion cell + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.

A Phase 1b, Open-Label Study to Evaluate the Safety and Tolerability of the Putative Remyelinating Agent, Liothyronine, in Individuals with MS.

Thyroid hormones are essential during developmental myelination and may play a direct role in remyelination and repair in the adult central nervous system by promoting the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes. Since tri-iodothyronine (T3) is believed to mediate the majority of important thyroid hormone actions, liothyronine (synthetic T3) has the potential to induce reparative mechanisms and limit neurodegeneration in multiple sclerosis (MS). We completed a phase 1b clinical trial to determine the safety and tolerability of ascending doses of liothyronine in individuals with relapsing and progressive MS. A total of 20 people with MS were enrolled in this single-center trial of oral liothyronine. Eighteen participants completed the 24-week study. Our study cohort included mostly women (11/20), majority relapsing MS (12/20), mean age of 46, and baseline median EDSS of 3.5. Liothyronine was tolerated well without treatment-related severe/serious adverse events or evidence of disease activation/clinical deterioration. The most common adverse events included gastrointestinal distress and abnormal thyroid function tests. No clinical thyrotoxicosis occurred. Importantly, we did not observe a negative impact on secondary clinical outcome measures. The CSF proteomic changes suggest a biological effect of T3 treatment within the CNS. We noted changes primarily in proteins associated with immune cell function and angiogenesis. Liothyronine appeared safe and was well tolerated in people with MS. A larger clinical trial will help assess whether liothyronine can promote oligodendrogenesis and enhance remyelination in vivo, limit axonal degeneration, or improve function.