The impact of cigarette smoking on cognitive processing speed and brain atrophy in multiple sclerosis.

BACKGROUND: Smoking is associated with an increased risk of multiple sclerosis (MS) and disability worsening. The relationship between smoking, cognitive processing speed, and brain atrophy remains uncertain. OBJECTIVE: To quantify the impact of smoking on processing speed and brain volume in MS and to explore the longitudinal relationship between smoking and changes in processing speed. METHODS: A retrospective study of MS patients who completed the processing speed test (PST) between September 2015 and March 2020. Demographics, disease characteristics, smoking history, and quantitative magnetic resonance imaging (MRI) were collected. Cross-sectional associations between smoking, PST performance, whole-brain fraction (WBF), gray matter fraction (GMF), and thalamic fraction (TF) were assessed using multivariable linear regression. The longitudinal relationship between smoking and PST performance was assessed by linear mixed modeling. RESULTS: The analysis included 5536 subjects of whom 1314 had quantitative MRI within 90 days of PST assessment. Current smokers had lower PST scores than never smokers at baseline, and this difference persisted over time. Smoking was associated with reduced GMF but not with WBF or TF. CONCLUSION: Smoking has an adverse relationship with cognition and GMF. Although causality is not demonstrated, these observations support the importance of smoking cessation counseling in MS management.

Detecting isolated cognitive relapses in persons with MS.

BACKGROUND: The existence of isolated cognitive relapses (ICRs) in persons with MS (PwMS) has been debated. OBJECTIVE: To examine relapses with decline on Symbol Digit Modalities Test (SDMT) but no change on Expanded Disability Status Scale (EDSS). METHODS: This 3-year prospective cohort study identified PwMS experiencing a relapse with decrease on SDMT. Participants with SDMT decline/stable EDSS were labeled "ICR," while those with a corresponding decrease on EDSS were classified "Relapse with Cognitive Decline (RCD)." Two definitions of SDMT decline were explored: (1) ⩾ 8 points, and (2) ⩾ 4 points. Logistic regression was used to analyze the relationship between ICR and RCD. RESULTS: The full cohort had 592 participants: 83 experienced relapses; 22 (26.5%) had an SDMT decrease of ⩾ 8 points; 14 (63.6%) met ICR criteria. Logistic regression (X2(1) = 5.112, p = 0.024) using demographics and disease characteristics explained 28.4% of the variance in ICR versus RCD. Only the MS Neuropsychological Questionnaire was associated with ICR (odds ratio (OR): 8.6; 95% confidence interval (CI): 1.1-16.4) 40 relapsing participants with SDMT decrease of ⩾ 4 points were identified: 26 (65%) had a stable EDSS (ICR). Logistic regression did not find any variable predictive of ICR. CONCLUSION: This prospective study demonstrates evidence of ICR in PwMS.

Interpreting change on the Symbol Digit Modalities Test in people with relapsing multiple sclerosis using the reliable change methodology.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is increasingly utilized in clinical trials. A SDMT score change of 4 points is considered clinically important, based on association with employment anchors. Optimal thresholds for statistically reliable SDMT changes, accounting for test reliability and measurement error, are yet to be applied to individual cases. OBJECTIVE: The aim of this study was to derive a statistically reliable marker of individual change on the SDMT. METHODS: This prospective, case-control study enrolled 166 patients with multiple sclerosis (MS). SDMT scores at baseline, relapse, and 3-month follow-up were compared between relapsing and stable patient groups. Using data from the stable group and three previously published studies, candidate thresholds for reliable decline were calculated and validated against other tests and a clinically meaningful anchor-cognitive relapse. RESULTS: Candidate thresholds for reliable decline at the 80% confidence level varied between 6 and 11 points. An SDMT change of 8 or more raw score points was deemed to offer the best balance of discriminatory power and external validity for estimating cognitive decline. CONCLUSION: This study illustrates the feasibility and usefulness of reliable change methodology for identifying statistically meaningful cognitive decline that could be implemented to identify change in individual patients, for both clinical management and clinical trial outcomes.

Vascular comorbidity is associated with lower brain volumes and lower neuroperformance in a large multiple sclerosis cohort.

OBJECTIVE: The objective of this study is to assess the association between vascular comorbidity burden with clinical and imaging features of disease burden in a large population of people with multiple sclerosis (MS). METHODS: We included participants from the MS Partners Advancing Technology Health Solutions (MS PATHS) cohort. We evaluated if vascular comorbidities (diabetes, hypertension, and dyslipidemia) or a composite sum of comorbidities was associated with MS characteristics, including objective neurologic function assessments and quantitative brain magnetic resonance imaging (MRI) measurements in propensity score-weighted models. RESULTS: In total, 11,506 participants (6409 (55%) with brain MRI) were included. Individuals with 2+ vascular comorbidities had slower walking speed (standard deviation (SD) = -0.49; 95% confidence interval (CI) = -0.78, -0.19; p = 0.001), slower manual dexterity (SD = -0.41; 95% CI = -0.57, -0.26; p < 0.0001), and fewer correct scores on cognitive processing speed (SD = -0.11; 95% CI = -0.20, -0.02; p = 0.02) versus those with no comorbidities. Those with 2+ had lower brain parenchymal (-0.41%, 95% CI = -0.64, -0.17) and gray matter fractions (-0.30%, 95% CI = -0.49, -0.10), including reduced cortical (-10.10 mL, 95% CI = -15.42, -4.78) and deep (-0.44 mL, 95% CI = -0.84, -0.04) gray matter volumes versus those with no comorbidity. CONCLUSION: Increased vascular comorbidity burden was associated with clinical and imaging markers of neurologic dysfunction and neurodegeneration in MS. Strategies to optimize comorbidity management in people with MS are warranted.

Age of hypertension onset in multiple sclerosis patients.

BACKGROUND/OBJECTIVE: Hypertension (HTN) is common in multiple sclerosis (MS), and it is associated with poorer outcomes. We sought to characterize HTN age at onset (AAO) by MS status. METHODS/RESULTS: There were 130,050 incident HTN patients, among whom there were 892 MS patients. We conducted multivariable linear regression adjusting for patient attributes. Sex- and race-stratified models were conducted. HTN AAO did not differ in patients with and without MS (p = 0.17). Similar null associations were observed in the sex- and race-specific analyses. CONCLUSION: While there are complex relationships between HTN and MS, there are no differences in HTN AAO by MS status.

Patient reported outcomes and performance metrics at diagnosis of secondary progressive multiple sclerosis.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) usually evolves into secondary progressive multiple sclerosis (SPMS). Recognition of SPMS is important because of prognostic and treatment implications. OBJECTIVE: The objective of this study is to determine distributions of patient-reported outcomes (PROs) and the Timed 25-Foot Walk (T25FW) at SPMS diagnosis and describe the evolution of these metrics in patients with SPMS. METHODS: A tertiary MS center clinical database was queried to identify patients with RRMS and SPMS. PRO data including performance scales (PS), Patient Health Questionnaire-9 (PHQ-9), European Quality of Life-5-Dimensions (EQ-5D), and the T25FW were extracted. Descriptive statistics were calculated at SPMS diagnosis, and score trajectories were modeled. Cox proportional hazards modeling was used to estimate hazard ratios for time to SPMS diagnosis. RESULTS: Among 5,558 patients identified, 164 were diagnosed with SPMS between January 2008 and June 2016. At SPMS diagnosis, the mean outcome values were T25FW = 12.5 seconds (standard deviation, SD = 10.7), PS = 15.6 (SD = 6.5), PHQ-9 = 6.8 (SD = 4.2), and EQ-5D = 0.63 (SD = 0.20). Distinct patterns were observed in the measures leading up to SPMS diagnosis. Higher age, male gender, longer disease duration, and greater disability were associated with an increased hazard of SPMS diagnosis. CONCLUSION: Longitudinal monitoring of PROs and performance metrics may help identify those at higher risk of near-term SPMS.

Quantifying cognition and fatigue to enhance the sensitivity of the EDSS during relapses.

BACKGROUND: Cognition is affected by relapses in persons with multiple sclerosis (PwMS), yet the Expanded Disability Status Scale (EDSS) does not readily detect cognitive changes. OBJECTIVE: The objective of this study is to improve the detection of cognitive decline during relapses, by incorporating the Symbol Digit Modalities Test (SDMT) into the cerebral Functional System Score (CFSS) of the EDSS. METHODS: This prospective study recruited PwMS from three dedicated MS centers. All subjects had EDSS, SDMT, and Fatigue Severity Scale (FSS) administered. Subjects experiencing a relapse were assigned to the relapse group (RG). Matched controls from the larger cohort were assigned to the stable group (SG). RG and SG subjects underwent the same evaluation at relapse and 3 months later. Our main outcomes were a modified CFSS (m-CFSS) and modified EDSS (m-EDSS), incorporating SDMT and FSS, accounting for cognitive performance and fatigue rating, during relapse. RESULTS: The full cohort included 592 subjects; 80 qualified for RG and 72 were matched to the SG. The m-CFSS was significantly higher than CFSS at baseline (median = 2 vs. median = 0, p < 0.001) and relapse (median = 2 vs. median = 1, p < 0.001). The m-EDSS was higher than EDSS (median 3.0 vs. 2.5, p = 0.02) at relapse, where 35 RG subjects (43.8%) had higher m-EDSS than EDSS at relapse. CONCLUSION: This study demonstrates that incorporating the SDMT and FSS improves the accuracy of the EDSS, by accounting for cognitive changes, during relapse activity.

Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60.

BACKGROUND: The risk-benefit ratio of continuing immunomodulating disease-modifying therapy (DMT) in older multiple sclerosis (MS) patients is unknown. OBJECTIVE: To evaluate clinical and patient-reported outcomes after stopping DMT in older MS patients. METHODS: Retrospective, observational study identifying patients from our MS clinics who were aged over 60 and on DMT > 2 years. Cause-specific Cox proportional hazards regression modeled time to discontinuation and time to reinitiation of therapy. Pre- and post-discontinuation comparisons of Performance Scales (PS), Timed 25-Foot Walk, and Patient Health Questionnaire-9 (PHQ9) were analyzed using linear mixed models. RESULTS: A total of 600 patients were included, with 178 (29.7%) discontinuing. Discontinuers were 2.2 years older, had 3.2 years longer disease duration, and 1.6 years lesser treatment exposure. Providers initiated discontinuation more than patients (68.0%). Only one clinical relapse occurred in discontinuers. A proportion (10.7%) reinitiated DMT. Provider-initiated discontinuers restarted less often (hazard ratio (HR): 0.34; 95% confidence interval (CI): 0.12-0.9). In discontinuers, relapsing-remitting patients had lower PS on average than primary progressive. Provider-initiated discontinuation was associated with lower PS than patient- initiated discontinuation. PHQ9 scores appeared higher in those stopping intravenous (IV) therapies than interferons. Lower PS and PHQ9 indicate better outcomes. CONCLUSION: Most patients over age 60, who discontinued DMT, remained off DMT. This study provides real-world data that may guide clinicians considering discontinuing DMT.

Influence of hypertension, diabetes, hyperlipidemia, and obstructive lung disease on multiple sclerosis disease course.

BACKGROUND: Comorbidities are known to affect multiple sclerosis (MS) patients in a number of ways, including delaying time to diagnosis and reducing health-related quality of life. OBJECTIVE: To determine the impact of hypertension, hyperlipidemia, diabetes mellitus, and obstructive lung disease on disease course in MS patients. METHODS: The Knowledge Program is a database linked to our electronic medical record allowing capture of patient and clinician reported outcomes. Through Knowledge Program query and chart review, we identified all relapsing-remitting MS patients seen between 1 January 2010 and 29 May 2012 and acquired their magnetic resonance imaging (MRI) results and comorbidities. Linear and logistic regression models with adjustment for important covariates were used to determine whether the comorbidities affected outcomes over a 3-year period. RESULTS: Hypertension, diabetes, and obstructive lung disease, but not hyperlipidemia, impacted clinical outcomes, including walking speed, self-reported disability, and depression. Hypertension had the greatest effect. The presence of multiple comorbidities had a cumulative effect on clinical outcomes. MRI outcomes were unaffected by comorbidities. CONCLUSION: This 3-year longitudinal study revealed that all comorbidities tested except hyperlipidemia impacted clinical outcomes and a cumulative effect with multiple comorbidities was observed. Consideration of comorbid conditions is essential in MS patient care.

Factors associated with clinically significant increased walking time in multiple sclerosis: results of a survival analysis of short-term follow-up data from a clinical database.

BACKGROUND: Because multiple sclerosis (MS) is variable and unpredictable, if symptom worsening could be predicted, patients may feel better prepared to manage changes in function. OBJECTIVE: The objective of this paper is to study the prediction of walking impairment in MS. METHODS: We retrieved data for all MS patients at our center (2008-2009), including baseline and follow-up timed 25-foot walk (T25FW) times. We assessed the incidence of ≥20% worsening in T25FW by developing two survival models: (1) disease course and (2) Multiple Sclerosis Performance Scales (MSPS) score. The outcome was days until ≥20% worsening in T25FW. Covariates were disease subtype, years since diagnosis, Patient Health Questionnaire-9 (PHQ-9) score, and demographics. Data were interval censored; missing data were handled with multiple imputation. RESULTS: Of 1544 patients, 309 (20%) experienced ≥20% worsening T25FW. For disease course, time to worsening was significantly shorter for secondary progressive vs. relapsing-remitting disease (p < 0.001). For MSPS, patients with lower baseline MSPS scores progressed more slowly (p = 0.001). In both models, sex, baseline T25W, and time since diagnosis were significantly associated with worsening. In the disease course model, PHQ 9 score may be related to worsening (p = 0.07). CONCLUSION: These findings suggest factors associated with worsening in T25FW and a potential approach to establishing indicators associated with clinically significant change.

The patient-reported wearing-off phenomenon with monoclonal antibody treatments for multiple sclerosis.

Background: Many patients report a wearing-off phenomenon with monoclonal antibody treatment for multiple sclerosis in which perceived benefits wear off before the next dose is due. Objectives: To determine prevalence of the wearing-off effect, symptoms experienced, impact on treatment satisfaction, and associated patient characteristics. Methods: Patients receiving natalizumab, ocrelizumab, ofatumumab, or rituximab at a tertiary multiple sclerosis center were invited to take an online survey interrogating their monoclonal antibody experience. Additional history and patient characteristic data were collected. Logistic regression was used to determine if patient characteristics predicted the wearing-off effect and linear regression to evaluate the impact of the wearing-off effect on treatment satisfaction. The models were adjusted for age, disease duration, race, sex, body mass index, education, and depression as measured by the Patient Health Questionnaire-9. Results: We received 258 qualifying responses and 141 (54.7%) patients reported the wearing-off phenomenon. The most common symptom was fatigue (47.7%). Higher Patient Health Questionnaire-9 scores were significantly associated with the wearing-off phenomenon (OR = 1.02, p = 0.005). The wearing-off effect (ß = -0.52, p = 0.04) and higher Patient Health Questionnaire-9 (ß = -0.09, p < 0.01) scores were associated with significantly reduced treatment satisfaction. Conclusion: The wearing-off phenomenon is common, associated with depression, and reduces treatment satisfaction. Research addressing mitigation strategies is needed.

Progressive Encephalomyelopathy in an Older Man: A Case Report From the National Multiple Sclerosis Society Case Conference Proceedings.

We present a case of subacute onset progressive encephalomyelopathy in a 77-year-old man with symmetric lateral column signal abnormalities on spinal MRI. We discuss the differential and presumptive final diagnosis along with a review of the postulated disease immunopathogenesis.

Common Social and Health Disparities Contribute to Racial Differences in Ambulatory Impairment in Multiple Sclerosis.

BACKGROUND: We previously reported more rapid accrual of ambulatory impairments in Black compared to White individuals with relapsing remitting multiple sclerosis (RRMS) and higher body mass index (BMI). Hypertension and lower neighborhood socioeconomic status (SES) were associated with greater impairment, irrespective of race. We hypothesize that these common social and health inequities may explain a substantial portion of the racial differences in ambulation in American individuals with RRMS. METHODS: Causal mediation analyses investigated baseline and change-over-time mediators of ambulatory impairment differences between 1795 Black and White individuals with RRMS using a retrospective cohort study comprised of electronic health record data from 8491 clinical encounters between 2008 and 2015 where Timed 25-Foot Walk (T25FW) speeds without assistive devices were recorded. The hypothesis was that BMI, neighborhood SES, and hypertension were possible mediators. RESULTS: At baseline, Black individuals with RRMS (n = 175) had significantly slower T25FW speeds (5.78 vs 5.27 ft/s), higher BMI, a higher prevalence of hypertension, and they were more likely to live in lower-income neighborhoods than White individuals (n = 1,620). At baseline, a significant proportion (33.7%; 95% CI, 18.9%-59.4%) of the T25FW difference between Black and White individuals was indirectly due to a higher BMI (12.5%), hypertension burden (9.5%), and living in lower-income neighborhoods (11.2%). Once baseline mediation relationships were accounted for, there were no significant longitudinal mediation relationships. CONCLUSIONS: The findings implicate social and health disparities as prominent drivers of ambulatory differences between Black and White individuals with RRMS, suggesting that wellness and health promotion are essential components of MS care, particularly for Black individuals.

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.

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.

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.

Multidisciplinary lifestyle interventions for neurological disorders during the Silent phase (MINDS) study: a multi-omics randomized controlled trial protocol.

INTRODUCTION: Given the prevalence and staggering cost of neurological disorders, there is dire need for effective early detection and intervention tools. Emerging evidence suggests that multidisciplinary lifestyle interventions (MLI) may mitigate the risk and progression of neurological disorders. The objectives of this protocol are (1) to test the impact of MLI on the progression of neurological disorders and (2) to identify multi-omic biomarkers for early stages of neurological disease and the impact of MLIs on these biomarkers. METHODS AND ANALYSIS: We present the Multidisciplinary lifestyle Interventions for Neurological Disorders during the Silent phase (MINDS) protocol, a randomized controlled trial of MLI in neurologically healthy older adults (≥ 50 years old) exhibiting elevated risk for common neurological disorders: stroke, epilepsy, Parkinson's Disease, or Alzheimer's disease and related dementias. Participants will be randomly assigned to intervention (n = 100) or control (n = 100) groups. The intervention group will receive 3 months of weekly 2-hour sessions on diet education, yoga, music therapy, and cognitive skills training. The participants' neurological health and engagement in relevant lifestyle practices will be assessed at regular intervals for 12 months. Neuroimaging and samples for multi-omic analyses will be collected at baseline, and at 3 months and 12 months after enrollment. Primary outcomes will be signs of progression of the neurological disorder risk that qualified them for study enrollment or a clinical diagnosis of the disorder. Secondary and exploratory outcomes will be based on self-reported health and multi-omic data. Data analysis will include between-group and longitudinal within-group analyses. PERSPECTIVES: The MINDS protocol and trial aims to clarify the impact of MLI on the progression of neurological disorder risk or diagnosis in older adults and to identify biomarkers that can be used to confirm MLI efficacy. The ability to validate the impact of MLI on neurological disorder progression based on biomarker data allows the identification of individuals most likely to benefit from such therapies in the early stages of neurological disease. TRIAL REGISTRATION: The trial is registered on the National Institutes of Health (NIH) ClinicalTrials.gov (NCT05984056) site. It was registered on August 2nd, 2023. The trial has full approval of the Cleveland Clinic Internal Review Board.

Long term benefit of multiple sclerosis treatment: an investigation using a novel data collection technique.

BACKGROUND: The Knowledge Program (KP) is an initiative to collect self-reported patient data and objective clinician assessments electronically at each outpatient clinical encounter. Available outcomes include the EuroQoL-5D (EQ5D), Patient Health Questionnaire-9 (PHQ9), Multiple Sclerosis Performance Scales (MSPS), and the timed 25-foot walk (T25FW). OBJECTIVE: This study was designed to use the KP to investigate the long-term benefits of early treatment (ET) in multiple sclerosis (MS). METHODS: The KP was queried for patients with relapsing-remitting MS or secondary progressive MS who were ≥ 5 years from symptom onset. ET was defined as treatment with an approved agent for ≥ 3 of the first five years after symptom onset. Propensity scores for ET were calculated based on early clinical characteristics. Patients were divided into propensity score quintiles and linear regression models were constructed to determine the treatment effect sizes and confidence intervals. RESULTS: From the 1082 patients that met entry criteria, 453 patients (41.9%) received ET. Those patients receiving ET showed significantly better scores on the EQ5D index, PHQ9, and MSPS, but only in the upper three propensity quintiles. For the T25FW, ET did not result in significantly better times in any quintile. CONCLUSIONS: These results suggest that ET of MS is beneficial but the effect appears modest.

Chronic cerebrospinal venous insufficiency as a cause of multiple sclerosis: controversy and reality.

OPINION STATEMENT: Multiple sclerosis (MS) is a relapsing and progressive disorder of the central nervous system. It is characterized most commonly by episodes of clinical worsening, followed by clinical improvement. Pathologically, MS is associated with focal areas of myelin destruction, inflammation, and axonal transection ("demyelinating plaques") in the brain and spinal cord. Traditionally, MS has been considered an autoimmune disorder, with the primary pathophysiology arising from an errant immune system. Recent work has raised the possibility that MS is not caused primarily by an immune abnormality but may instead arise from venous anomalies affecting the jugular and/or azygos venous systems. This condition has been called chronic cerebrospinal venous insufficiency (CCSVI). It has been proposed that CCSVI may be pathogenic in MS, causing venous back pressure and iron deposition, with a secondary immune response. Some investigators have proceeded to unblinded nonrandomized angioplasty and stenting procedures in patients with CCSVI, with anecdotal reports of symptom improvement. Because of conflicting data on the presence of CCSVI and the absence of controlled trials of CCSVI intervention, the current standard of clinical care is neither to evaluate multiple sclerosis (MS) patients for CCSVI anomalies, nor to intervene with procedures to alter such anomalies. There is intense interest and ongoing work to evaluate the presence of venous anomalies in MS patients as well as in normal controls and patients with other neurologic conditions; to characterize such anomalies, if present; and to further understand whether the concept of a "backpressure" pathology is borne out by the evidence. If CCSVI is indeed a pathogenic mechanism for some subset of the MS population, this would dramatically change the focus of attention for therapeutic endeavors and monitoring for this population and would bring MS therapeutics firmly into the area of vascular intervention. On the other hand, the history of MS research contains many novel and potentially paradigm-shifting ideas that were later disproved by other investigators.