Comparing Cognitive Profiles in Older Adults With Multiple Sclerosis and Alzheimer Disease: More Similarities Than Differences.

Background and Objectives: Up to 65% of people with multiple sclerosis (MS) experience disease-related cognitive impairment, but even after decades of research, still very little is known about the cognitive issues among older adults with MS (EwMS; individuals aged 60+). To date, few studies have attempted to characterize cognitive impairment in this group or compare EwMS with those with other neurodegenerative diseases. Our goal was to address this knowledge gap by comparing EwMS with individuals experiencing cognitive impairment due to probable Alzheimer disease (AD) with biomarker confirmation. Methods: We conducted an observational study of individuals seen for routine clinical care at the Cleveland Clinic. After excluding for potential confounding factors, 6 groups were assembled based on the results of their clinical workup and neuropsychological examination: cognitively normal, cognitively normal with MS, mild neurocognitive disorder (due to MS or AD), and major neurocognitive disorder (due to MS or AD). These groups were compared in terms of cognitive test performance, percentage of the group impaired on specific cognitive skills, and rates of cognitive impairment. Results: The sample comprised 140 individuals (64 EwMS and 76 demographically matched individuals from a memory clinic). Among those with mild neurocognitive disorder, differences between MS and AD were marked. However, in those with major neurocognitive disorder, these differences largely disappeared, except persistent performance differences on a measure of rote verbal memory. EwMS outperformed those with AD on memory tests at each level of cognitive impairment. EwMS also exhibited both subcortical and cortical deficits, rather than solely subcortical deficits. Discussion: The overall characterization of the cognitive profile of MS may be different than once described, involving both classically cortical and subcortical functions. Clinically, our results suggest that distinguishing between the cognitive effects of MS and AD at more severe levels of cognitive impairment may be less reliable than once thought. Future work to replicate these findings in other samples and deepen the understanding of cognition in older individuals with MS is needed.

Association Between Disease-Modifying Therapy and Information Processing Speed in Multiple Sclerosis.

BACKGROUND: Cognitive impairment (CI) is common in multiple sclerosis (MS). Processing speed (PS) is often affected, making it an ideal target for monitoring CI. This study aims to evaluate the association between disease-modifying therapy (DMT) use and intensity and longitudinal changes in Processing Speed Test (PST) scores for individuals with MS. METHODS: A retrospective analysis of individual PST scores at a single MS center was conducted. Individuals with 2 or more PST assessments were included. Scores on the PST were compared longitudinally between those who had been on a DMT for 2 or more years and those who had been off a DMT for 2 or more years and between those on high-efficacy DMTs and those on low-/moderate-efficacy DMTs. A linear regression model was approximated to evaluate the rate of cognitive change over time. A propensity score adjustment was conducted using a multivariable logistic regression. RESULTS: The cohort was 642 individuals, 539 on DMT and 103 off DMT. Median age and disease duration was 49.7 (IQR 42.4-57.9) and 16.6 years (IQR 9.3-23.0) in the DMT group, and 58.9 (IQR 52.2-65.3) and 20.0 years (IQR 14.1-31.4) in the non-DMT group. Both cohorts were predominantly female (75% DMT, 79.6% non-DMT), with a mean of 4 assessments (IQR 3-5), and an average monitoring duration of 1.9 years (1.2-2.4) in the DMT group, and 1.8 years (1.4-2.4) in the non-DMT group. After adjusting for multiple factors, DMT status and intensity were not found to be significant predictors of longitudinal PST change. CONCLUSIONS: Neither DMT status nor intensity was a significant predictor of cognitive processing speed over a period of approximately 2 years. Future prospective studies are needed to further support these findings.

Longitudinal myelin content measures of slowly expanding lesions using 7T MRI in multiple sclerosis.

BACKGROUND AND PURPOSE: Slowly expanding lesions (SELs) are thought to represent a subset of chronic active lesions and have been associated with clinical disability, severity, and disease progression. The purpose of this study was to characterize SELs using advanced magnetic resonance imaging (MRI) measures related to myelin and neurite density on 7 Tesla (T) MRI. METHODS: The study design was retrospective, longitudinal, observational cohort with multiple sclerosis (n = 15). Magnetom 7T scanner was used to acquire magnetization-prepared 2 rapid acquisition gradient echo and advanced MRI including visualization of short transverse relaxation time component (ViSTa) for myelin, quantitative magnetization transfer (qMT) for myelin, and neurite orientation dispersion density imaging (NODDI). SELs were defined as lesions showing ≥12% of growth over 12 months on serial MRI. Comparisons of quantitative measures in SELs and non-SELs were performed at baseline and over time. Statistical analyses included two-sample t-test, analysis of variance, and mixed-effects linear model for MRI metrics between lesion types. RESULTS: A total of 1075 lesions were evaluated. Two hundred twenty-four lesions (21%) were SELs, and 216 (96%) of the SELs were black holes. At baseline, compared to non-SELs, SELs showed significantly lower ViSTa (1.38 vs. 1.53, p < .001) and qMT (2.47 vs. 2.97, p < .001) but not in NODDI measures (p > .27). Longitudinally, only ViSTa showed a greater loss when comparing SEL and non-SEL (p = .03). CONCLUSIONS: SELs have a lower myelin content relative to non-SELs without a difference in neurite measures. SELs showed a longitudinal decrease in apparent myelin water fraction reflecting greater tissue injury.

High-resolution diffusion tensor imaging of the fornix predicts memory function in multiple sclerosis.

Background: Cognitive dysfunction is a known symptom of multiple sclerosis (MS), with memory recognized as a frequently impacted domain. Here, we used high-resolution MRI at 7 tesla to build on cross-sectional work by evaluating the longitudinal relationship of diffusion tensor imaging (DTI) measures of the fornix to episodic memory performance. Methods: A sample of 80 people with multiple sclerosis (mean age 51.9 ± 8.1 years; 24% male) underwent baseline clinical evaluation, neuropsychological assessment, and MRI. Sixty-four participants had follow-up neuropsychological testing after 1-2 years. Linear regression was used to assess the relationship of baseline imaging measures to follow-up episodic memory performance, measured using the Selective Reminding Test and Brief Visuospatial Memory Test. A reduced prediction model included cognitive function at baseline, age, sex, and disease course. Results: Radial (ß = -0.222, p < 0.026; likelihood ratio test (LRT) p < 0.018), axial (ß = -0.270, p < 0.005; LRT p < 0.003), and mean (ß = -0.242, p < 0.0139; LRT p < 0.009) diffusivity of the fornix significantly added to the model, with follow-up analysis indicating that a longer prediction interval may increase accuracy. Conclusion: These results suggest that fornix DTI has predictive value specific to memory function in MS and warrants additional investigation in the drive to develop predictors of disease progression.

Choroid plexus volume differentiates MS from its mimics.

This study aimed to determine whether choroid plexus volume (CPV) could differentiate multiple sclerosis (MS) from its mimics. A secondary analysis of two previously enrolled studies, 50 participants with MS and 64 with alternative diagnoses were included. CPV was automatically segmented from 3T magnetic resonance imaging (MRI), followed by manual review to remove misclassified tissue. Mean normalized choroid plexus volume (nCPV) to intracranial volume demonstrated relatively high specificity for MS participants in each cohort (0.80 and 0.76) with an area under the receiver-operator characteristic curve of 0.71 (95% confidence interval (CI) = 0.55-0.87) and 0.65 (95% CI = 0.52-0.77). In this preliminary study, nCPV differentiated MS from its mimics.

INCIDENCE OF MULTIPLE SCLEROSIS IN URUGUAY. A PROSPECTIVE POPULATION-BASED STUDY.

Background The worldwide incidence of multiple sclerosis (MS) is estimated at 0.5-10 cases per 100,000 person-years and is probably increasing. In 2014, a previous study estimated the incidence of multiple sclerosis in Uruguay at 1.2 cases per 100.000 person-years. Objectives We conducted an observational, prospective, population-based study to determine MS incidence from diagnosis in Uruguay. Methods The population studied included people older than 18 years of age, who were living in Uruguay between July 1, 2019, and June 30, 2021. The diagnosis was based on 2017 McDonald criteria. Multiple data sources were employed including neurologists, magnetic resonance imaging centers, laboratories performing oligoclonal band testing, neurophysiology laboratories, neurorehabilitation centers, the institution Fondo Nacional de Recursos, and the MS Patients' Association of Uruguay (EMUR). The capture-recapture method was used to estimate incidence. Results 155 new MS cases were confirmed after review. The median age was 35 (range 18-62). Thirteen patients (8.38%) were diagnosed with late onset MS. The crude incidence rate was 2.89 cases per 100,000 person-years, 3.95 among female and 1.72 among male patients. The incidence rate estimated using the capture-recapture method was 3.18 (95% CI 3.02-3.34). Conclusions According to the Atlas of MS, Uruguay has a low incidence rate (2.0-3.99), even though it is one of the highest in Latin America. Our country aligns with the global trend of increasing incidence. Age and sex distribution were similar to other studies, with a high incidence of patients with late onset multiple sclerosis. The capture-recapture method confirms the exhaustivity of our investigation.

Clinical trials for progressive multiple sclerosis: progress, new lessons learned, and remaining challenges.

Despite the success of disease-modifying treatments in relapsing multiple sclerosis, for many individuals living with multiple sclerosis, progressive disability continues to accrue. How to interrupt the complex pathological processes underlying progression remains a daunting and ongoing challenge. Since 2014, several immunomodulatory approaches that have modest but clinically meaningful effects have been approved for the management of progressive multiple sclerosis, primarily for people who have active inflammatory disease. The approval of these drugs required large phase 3 trials that were sufficiently powered to detect meaningful effects on disability. New classes of drug, such as Bruton tyrosine-kinase inhibitors, are coming to the end of their trial stages, several candidate neuroprotective compounds have been successful in phase 2 trials, and innovative approaches to remyelination are now also being explored in clinical trials. Work continues to define intermediate outcomes that can provide results in phase 2 trials more quickly than disability measures, and more efficient trial designs, such as multi-arm multi-stage and futility approaches, are increasingly being used. Collaborations between patient organisations, pharmaceutical companies, and academic researchers will be crucial to ensure that future trials maintain this momentum and generate results that are relevant for people living with progressive multiple sclerosis.

Imaging chronic active lesions in multiple sclerosis: a consensus statement.

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis (MS) and have implications for non-relapsing biological progression. In recent years, the discovery of innovative magnetic resonance imaging (MRI) and PET derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with MS, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted (T1-w) and T2-w scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification, and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a Consensus Statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this Consensus Statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge.

Geographic Disparities in Access to Neurologists and Multiple Sclerosis Care in the United States.

BACKGROUND AND OBJECTIVES: A shortage of neurology clinicians and healthcare disparities may hinder access to neurologic care. This study examined disparities in geographic access to neurologists and subspecialty multiple sclerosis (MS) care among various demographic segments of the United States. METHODS: Neurologist practice locations from 2022 CMS Care Compare physician data and MS Center locations as defined by the Consortium of Multiple Sclerosis Centers were used to compute spatial access for all U.S. census tracts. Census tract-level community characteristics (sex, age, race, ethnicity, education, income, insurance, % with computer, % without a vehicle, % with limited English, and % with hearing, vision, cognitive, and ambulatory difficulty) were obtained from 2020 American Community Survey 5-year estimates. Rural-urban status was obtained from 2010 rural-urban commuting area codes. Logistic and linear regression models were used to examine access to a neurologist or MS Center within 60 miles and 60-mile spatial access ratios. RESULTS: Of 70,858 census tracts, 388 had no neurologists within 60 miles and 17,837 had no MS centers within 60 miles. Geographic access to neurologists (spatial access ratio [99% CI]) was lower for rural (-80.49%; CI [-81.65 to -79.30]) and micropolitan (-60.50%; CI [-62.40 to -58.51]) areas compared with metropolitan areas. Tracts with 10% greater percentage of Hispanic individuals (-4.53%; CI [-5.23 to -3.83]), men (-6.76%; CI [-8.96 to -4.5]), uninsured (-7.99%; CI [-9.72 to -6.21]), individuals with hearing difficulty (-40.72%; CI [-44.62 to -36.54]), vision difficulty (-13.0%; [-18.72 to -6.89]), and ambulatory difficulty (-15.68%; CI [-19.25 to -11.95]) had lower access to neurologists. Census tracts with 10% greater Black individuals (3.50%; CI [2.93-10.71]), college degree holders (-7.49%; CI [6.67-8.32]), individuals with computers (16.57%, CI [13.82-19.40]), individuals without a vehicle (9.57%; CI [8.69-10.47]), individuals with cognitive difficulty (25.63%; CI [19.77-31.78]), and individuals with limited English (18.5%; CI [16.30-20.73]), and 10-year older individuals (8.85%; CI [7.03-10.71]) had higher spatial access to neurologists. Covariates for access followed similar patterns for MS centers. DISCUSSION: Geographic access to neurologists is decreased in rural areas, in areas with higher proportions of Hispanics, populations with disabilities, and those uninsured. Access is further limited for MS subspecialty care. This study highlights disparities in geographic access to neurologic care.

Longitudinal Disability, Cognitive Impairment, and Mood Symptoms in Patients With Anti-NMDA Receptor Encephalitis.

BACKGROUND AND OBJECTIVES: Longitudinal outcomes in anti-NMDA receptor encephalitis (anti-NMDARe) are still not fully understood and may not be adequately captured with the modified Rankin Scale (mRS), often the sole reported outcome. We aim to characterize longitudinal outcomes in anti-NMDARe using multiple outcome measures. METHODS: This single-center, retrospective, observational study examined outcome measures (mRS and Clinical Assessment Scale in Autoimmune Encephalitis [CASE]) in adults with NMDA receptor-IgG in CSF at short- and long-term follow-ups using linear and logistic regression modeling. Patients with evaluations for cognitive impairment (Montreal Cognitive Assessment/Mini-Mental State Examination), depression (Patient Health Questionnaire-9), and anxiety (General Anxiety Disorder-7) >6 months from symptom onset were correlated with final CASE scores. RESULTS: Thirty-eight patients (76% female, median disease onset age = 28 years, range = 1-75 years) were included. The majority received first-line immunosuppressants (97%) at a median of 3.9 weeks (interquartile range [IQR] = 2.1-9.7) from symptom onset and 68% received second-line therapies. At baseline, median/mean mRS and CASE were 4 (IQR = 3-5) and 12.9 (SD = 7.2), respectively. At short-term follow-up (median = 10 weeks, IQR = 6-17), factors associated with higher CASE and mRS included dysautonomia, coma/lethargy, seizures/status epilepticus, and intensive care unit admission (p < 0.05). At long-term follow-up (median = 70 weeks, IQR = 51-174), median/mean mRS and CASE were 2 (IQR = 1-3) and 4.4 (SD = 4.2), respectively. Only weakness at symptom onset predicted higher mRS scores (odds ratio = 5.6, 95% confidence interval 1.02-30.9, p = 0.047). Despite both mRS and CASE improving from baseline (p < 0.001), only 9 patients (31%) returned to their premorbid function. Among patients with cognitive and mood evaluations >6 months from onset, moderate-severe cognitive impairment (42%), depression (28%), and anxiety (30%) were frequent. Cognitive and depression measures were associated with final CASE subscores (including memory, language, weakness, and psychiatric). DISCUSSION: Multiple clinical factors influenced short-term outcomes, but only onset weakness influenced long-term mRS, highlighting that mRS is predominantly affected by global motor function. Although mRS and CASE improved over time for most patients, these outcome measures did not capture the full extent of long-term functional impairment in terms of mood, cognition, and the ability to return to premorbid function. This emphasizes the need for increased utilization of more nuanced cognitive and mood outcome measures.

Predicting disability and mortality in CV2/CRMP5-IgG associated paraneoplastic neurologic disorders.

BACKGROUND: We aimed to investigate the prognostic factors associated with clinical outcomes in CV2/Collapsin response-mediator protein 5 (CRMP5)-IgG paraneoplastic neurologic disorders (PND). METHODS: This is a retrospective study of patients with CV2/CRMP5-IgG PND evaluated between 2002-2022. We examined the association of clinical variables (including age, clinical phenotype [autoimmune encephalopathy, myelopathy, polyneuropathy/radiculopathy, MG, cerebellar ataxia, chorea, optic neuropathy], cancer) with three clinical outcomes (wheelchair dependence, modified Rankin Scale [mRS], mortality) using univariate logistic regression and Cox proportional hazards modeling. Kaplan-Meier estimates were used to determine the probability of survival. RESULTS: Twenty-seven patients (56% female) with CV2/CRMP5-IgG PND were identified with a median follow-up of 54 months (IQR = 11-102). An underlying tumor was identified in 15 patients (56%) including small cell lung cancer (SCLC) (8, [53%]), thymoma (4, [27%]), and other histologies (3, [20%]). At last follow-up, 10 patients (37%) needed a wheelchair for mobility and this outcome was associated with myelopathy (HR = 7.57, 95% CI = 1.87-30.64, P = 0.005). Moderate-severe mRS = 3-5 was associated with CNS involvement (encephalopathy, myelopathy, or cerebellar ataxia) (OR = 7.00, 95% CI = 1.18-41.36, P = 0.032). The probability of survival 4 years after symptom onset was 66%. Among cancer subtypes, SCLC (HR = 18.18, 95% CI = 3.55-93.04, P < 0.001) was significantly associated with mortality, while thymoma was not. INTERPRETATION: In this retrospective longitudinal study of CV2/CRMP5-IgG PND, patients with CNS involvement, particularly myelopathy, had higher probability of disability. SCLC was the main determinant of survival in this population.

Ibudilast reduces slowly enlarging lesions in progressive multiple sclerosis.

BACKGROUND: Ibudilast has shown beneficial effects on several imaging outcomes in progressive multiple sclerosis (MS). Slowly enlarging lesions are a proposed imaging biomarker of compartmentalized inflammation within chronic active lesions. OBJECTIVE: To assess the treatment effect of ibudilast on slowly enlarging lesion volumes over 96 weeks from a phase II clinical trial of ibudilast (Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). METHODS: In total, 255 participants with progressive MS from 28 sites were randomized to oral ibudilast or placebo. Participants with at least four analyzable magnetic resonance imaging (MRI) were included. Slowly enlarging lesions were quantified using Jacobian determinant maps. A linear model was used to assess the effect of ibudilast. Magnetization transfer ratio within slowly enlarging lesions was assessed to determine the effect of ibudilast on tissue integrity. RESULTS: In total, 195 participants were included in this analysis. Ibudilast significantly decreased slowly enlarging lesion volume (23%, p = 0.003). Ibudilast also reduced magnetization transfer ratio change in slowly enlarging lesions: 0.22%/year, p = 0.04. CONCLUSION: Ibudilast showed a significant effect on baseline volume of lesions that were slowly enlarging and magnetization transfer ratio in slowly enlarging lesions. The results support the use of slowly enlarging lesions for assessment of compartmentalized inflammation represented by chronic active lesions and provide further support for the neuroprotective effects of ibudilast in progressive MS.

Differentiating multiple sclerosis from non-specific white matter changes using a convolutional neural network image classification model.

BACKGROUND: The diagnosis of multiple sclerosis (MS) relies heavily on neuroimaging with magnetic resonance imaging (MRI) and exclusion of mimics. This can be a challenging task due to radiological overlap in several disorders and may require ancillary testing or longitudinal follow up. One of the most common radiological MS mimickers is non-specific white matter disease (NSWMD). We aimed to develop and evaluate models leveraging machine learning algorithms to help distinguish MS and NSWMD. METHODS: All adult patients who underwent MRI brain using a demyelinating protocol with available electronic medical records between 2015 and 2019 at Cleveland Clinic affiliated facilities were included. Diagnosis of MS and NSWMD were assessed from clinical documentation. Those with a diagnosis of MS and NSWMD were matched using total T2 lesion volume (T2LV) and used to train models with logistic regression and convolutional neural networks (CNN). Performance metrices were reported for each model. RESULTS: A total of 250 NSWMD MRI scans were identified, and 250 unique MS MRI scans were matched on T2LV. Cross validated logistic regression model was able to use 20 variables (including spinal cord area, regional volumes, and fractions) to predict MS compared to NSWMD with 68.0% accuracy while the CNN model was able to classify MS compared to NSWMD in two independent validation and testing cohorts with 77% and 78% accuracy on average. CONCLUSION: Automated methods can be used to differentiate MS compared to NSWMD. These methods can be used to supplement currently available diagnostic tools for patients being evaluated for MS.

Associations Between Cognitive Impairment and Neuroimaging in Patients with Multiple Sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is a debilitating inflammatory and neurodegenerative disease which commonly involves cognitive dysfunction. Magnetic resonance imaging (MRI) studies have shown that patients with MS (pwMS) have diffuse patterns of brain atrophy, however, the relationship between the presentation of cognitive dysfunction and brain tissue loss remains understudied. Given the integral function of thalamus as a central nervous system relay center and its involvement in various brain circuits, thalamic atrophy may play a key role in the development and progression of cognitive dysfunction. The purpose of this study is to examine the relationship between cognitive impairment in pwMS and thalamic atrophy. METHODS: A total of 121 pwMS who had neuropsychological testing and quantitative MRI within 1 year of each were retrospectively identified. Grouped LASSO linear regression with 10-fold cross validation was used to estimate each neuropsychological test score with thalamic volume as the focal predictor and all other demographic and MRI metrics as covariates. RESULTS: Rates of impairment ranged from 19% to 44%. Results showed notable associations between thalamic volume and Symbol Digit Modalities Test (ß = 0.11), Brief Visuospatial Memory Test, delayed (ß = 0.12), California Verbal Learning Test, delayed and total (ß = 0.24 and ß = 0.15 respectively), and Trail Making Test Part A (ß = -0.01), after adjusting for covariates. CONCLUSIONS: These findings demonstrate an independent association between thalamic volumes and processing speed and memory performance, after accounting for demographic, clinical, and other MRI variables, among pwMS.

A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis.

BACKGROUND: The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established. OBJECTIVE: The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS. METHODS: Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed. RESULTS: Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female (n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*. CONCLUSION: A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement.

Identification and management of subclinical disease activity in early multiple sclerosis: a review.

IMPORTANCE: Early treatment initiation in multiple sclerosis (MS) is crucial in preventing irreversible neurological damage and disability progression. The current assessment of disease activity relies on relapse rates and magnetic resonance imaging (MRI) lesion activity, but inclusion of other early, often "hidden," indicators of disease activity may describe a more comprehensive picture of MS. OBSERVATIONS: Early indicators of MS disease activity other than relapses and MRI activity, such as cognitive impairment, brain atrophy, and fatigue, are not typically captured by routine disease monitoring. Furthermore, silent progression (neurological decline not clearly captured by standard methods) may occur undetected by relapse and MRI lesion activity monitoring. Consequently, patients considered to have no disease activity actually may have worsening disease, suggesting a need to revise MS management strategies with respect to timely initiation and escalation of disease-modifying therapy (DMT). Traditionally, first-line MS treatment starts with low- or moderate-efficacy therapies, before escalating to high-efficacy therapies (HETs) after evidence of breakthrough disease activity. However, multiple observational studies have shown that early initiation of HETs can prevent or reduce disability progression. Ongoing randomized clinical trials are comparing escalation and early HET approaches. CONCLUSIONS AND RELEVANCE: There is an urgent need to reassess how MS disease activity and worsening are measured. A greater awareness of "hidden" indicators, potentially combined with biomarkers to reveal silent disease activity and neurodegeneration underlying MS, would provide a more complete picture of MS and allow for timely therapeutic intervention with HET or switching DMTs to address suboptimal treatment responses.

Magnetic resonance fingerprinting in multiple sclerosis.

BACKGROUND: In this cross sectional study, we used MRF to investigate tissue properties of normal-appearing white matter, gray matter, and lesions in relapsing remitting MS (n = 21), secondary progressive MS (n = 16) and healthy controls (n = 9). A FISP-based MRF sequence was used for acquisition, imaging time 5 min 15 s. MRF T1 and T2 relaxation times were measured from lesional tissue, normal-appearing frontal white matter, corpus callous, thalamus, and caudate. Differences between healthy controls and MS were examined using ANCOVA adjusted for age and sex. Spearman rank correlations were assessed between T1 and T2 relaxation times and clinical measures. OBJECTIVES: To examine brain T1 and T2 values using magnetic resonance fingerprinting (MRF) in healthy controls and MS. METHODS: The subjects included 21 relapsing-remitting (RR) MS, 16 secondary progressive (SP) MS, and 9 age- and sex-matched HC without manifest neurological disease participating in a longitudinal MRI study. A 3T/ FISP-based MRF sequence was acquired. Regions of interest were drawn for lesions and normal appearing white matter. ANCOVA adjusted for age and sex were used to compare the groups with significance set at 0.05. RESULTS: A step-wise increase in T1 and T2 relaxation times was found between healthy controls, relapsing remitting MS, and secondary progressive MS. Significant differences were found in T1 and T2 between MS and healthy controls in the frontal normal-appearing white matter, corpus callosum, and thalamus (p < 0.04 for all). Significant differences in T1 and T2 between RR and SPMS were found in the frontal normal-appearing white matter and T2 lesions (p < 0.02 for all). T1 relaxation from the frontal normal-appearing white matter correlated with the Expanded Disability Status Scale [ρ = 0.62, p < 0.001], timed 25 foot walk (ρ = 0.45, p = 0.01), 9 hole peg test (ρ = 0.62, p < 0.001), and paced auditory serial addition test (ρ = -0.4, p = 0.01). CONCLUSION: These results suggest that MRF may be a clinically feasible quantitative approach for characterizing tissue damage in MS.

Effect of ibudilast on thalamic magnetization transfer ratio and volume in progressive multiple sclerosis.

BACKGROUND: Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial. OBJECTIVE: To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS. METHODS: A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP). RESULTS: Ibudilast's treatment effect was observed compared to placebo for thalamic MTR (p = 0.03) but not for TV (p = 0.68) while TV correlated with T2 lesion volume (p < 0.001). CDP associated with thalamic MTR (p = 0.04) but not with TV (p = 0.7). CONCLUSION: Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity. CLINICALTRIALS.GOV: NCT01982942.

Long-term trajectories of ambulatory impairment in multiple sclerosis.

BACKGROUND: Ambulatory impairment is a common and complex manifestation of multiple sclerosis (MS), and longitudinal patterns are not well understood. OBJECTIVE: To characterize longitudinal walking speed trajectories in a general MS patient population and in those with early disease (⩽ 5 years from onset), identify subgroups with similar patterns, and examine associations with individual attributes. METHODS: Using a retrospective cohort study design, latent class growth analysis was applied to longitudinal timed 25-foot walk (T25-FW) data from 7683 MS patients, to determine T25-FW trajectories. Associations were evaluated between trajectory assignment and individual attributes. Analyses were repeated for 2591 patients with early disease. RESULTS: In the general patient population, six trajectories were discerned, ranging from very minimal to very high impairment at baseline, with variability in impairment accrual. The clusters with moderate to very high walking impairment were associated with being female, older and Black American, longer symptom duration, progressive course, and depressive symptoms. In the early disease subset, eight trajectories were discerned that included two subgroups that rapidly accrued impairment. CONCLUSION: We identified novel subgroups of MS patients will distinct long-term T25-FW trajectories. These results underscore that socially disadvantaged and economically marginalized MS patients are the most vulnerable for severe ambulatory impairment.