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BackgroundTraumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications.MethodsWe studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education).ResultsYears of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1).ConclusionsLifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.

Introduction: Cognitive impairment is a debilitating symptom in people with multiple sclerosis (MS). Most of the neuropsychological tasks have little resemblance to everyday life. There is a need for ecologically valid tools for assessing cognition in real-life functional contexts in MS. One potential solution would involve the use of virtual reality (VR) to exert finer control over the task presentation environment; however, VR studies in the MS population are scarce. Objectives: To explore the utility and feasibility of a VR program for cognitive assessment in MS. Methods: A VR classroom embedded with a continuous performance task (CPT) was assessed in 10 non-MS adults and 10 people with MS with low cognitive functioning. Participants performed the CPT with distractors (i.e., WD) and without distractors (i.e., ND). The Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II), and a feedback survey on the VR program was administered. Results: People with MS exhibited greater reaction time variability (RTV) compared to non-MS participants, and greater RTV in both WD and ND conditions was associated with lower SDMT. Conclusions: VR tools warrant further research to determine their value as an ecologically valid platform for assessing cognition and everyday functioning in people with MS.

BackgroundIn multiple sclerosis (MS), telemedicine improves access to specialized medical care; however, barriers remain, including universal access and effective implementation. Focusing on telerehabilitation, ie, remotely delivered physical therapy, our goal was to identify barriers to telerehabilitation implementation and factors associated with patients completing telerehabilitation physical therapy treatment.MethodsQuantitative data included a review of electronic health records of patients with MS treated at the University of California San Francisco Physical Therapy Faculty Practice. We extracted demographic, clinical, and transit-related factors. For patients who scheduled an initial evaluation, we recorded the number of follow-ups, cancellations, completed physical therapy goals, and discharges. Qualitative data included interviews with 3 board-certified neurologic physical therapists and patients' perspectives recorded in the subjective portion of physical therapy notes.ResultsWe identified 111 patients with at least 1 visit (in-person or telerehabilitation) to physical therapy (82 women; mean ± SD age, 54.2 ± 12.7 years). Patients with no disability (Expanded Disability Status Scale [EDSS] score, 0) were 73% less likely to schedule a follow-up appointment (in-person or telerehabilitation) than those with some disability (EDSS score, >0) (odds ratio, 0.27; 95% CI, 0.09-0.75; P = .012). Neurologic physical therapists identified reduced travel burden and scheduling flexibility as benefits of telerehabilitation vs in-person visits. Barriers to telerehabilitation included low technological literacy, cognitive impairment, and fall risk. Patients described scheduling conflicts and pain/illness as barriers to telerehabilitation.ConclusionsPatients with no disability were least likely to complete physical therapy treatment via telerehabilitation. Although both benefits and barriers to completing physical therapy via telerehabilitation are present, the neurologic physical therapists were supportive of a hybrid model for physical therapy.

Background and objectivesPatients with multiple sclerosis (MS) transition from oral sphingosine-1-receptor (S1P) modulators to anti-CD20 therapies for several circumstances. Optimal timing of this transition is uncertain, given competing concerns of rebound disease activity and ensuring immune reconstitution. The objective of this study was to evaluate the relationship between inflammatory activity and the transition period from fingolimod to anti-CD20 therapies in a real-world MS cohort.MethodsMedical records were reviewed for all patients at our center transitioning from fingolimod to rituximab or ocrelizumab between 2010 and October 2020. Time periods reviewed were the following: before fingolimod discontinuation, interval between fingolimod and anti-CD20 treatments, and after the first anti-CD20 infusion. The primary outcome was clinical relapses; MRI activity, time to absolute lymphocyte count (ALC) recovery, and infections were secondary. Clinical and demographic factors significant in univariable analyses were included in multivariable analyses.ResultsTransition data were available for 108 patients (68.5% women, 68.5% relapsing-remitting MS, mean age 44.6 years). The median (interquartile range) interval between fingolimod and anti-CD20 therapy was 28 (1-115.2) days. Six of 51 patients (11.8%) with intervals >1 month and 0/57 patients with shorter intervals experienced a relapse (MRI confirmed) within 6 months of fingolimod discontinuation. In the year following anti-CD20 initiation, 4/108 patients (3.7%) experienced a relapse (median 214.5 days after infusion). An additional 7% of those undergoing contrast-enhanced MRIs developed Gd+ lesions. ALC normalized following treatment switch in 89/92; the interval between treatments was unrelated to ALC recovery or infection.DiscussionDelaying anti-CD20 start to monitor ALC after S1P modulator discontinuation may not be necessary and could increase rebound risk. ALC monitoring could instead occur after a rapid switch to anti-CD20 treatment.

ObjectiveA major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS).MethodsFrom a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion.ResultsPatients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p

BackgroundSleep disturbances are commonly reported by people with multiple sclerosis (PwMS). However, optimal management of sleep disturbances is uncertain, and objective studies of sleep quality in PwMS are scarce.ObjectivesTo determine the effect of exogenous melatonin on sleep quality and sleep disturbances in PwMS.MethodsThirty adult PwMS reporting sleep difficulties were recruited in a randomized, controlled, double-blind cross-over study. They took either melatonin or placebo for 2 weeks, and the opposite for the following 2 weeks. During weeks 2 and 4, an actigraph was used to capture mean total sleep time and sleep efficiency. Patient-reported outcomes (PROs) were collected at weeks 0, 2 and 4.ResultsMelatonin use significantly improved mean total sleep time (p = 0.03), with a trend towards higher sleep efficiency (p = 0.06). No PROs were significantly different; there was a trend for melatonin use to decrease mean Insomnia Severity Index score (p = 0.07), improve Pittsburgh Sleep Quality Index sleep quality component (p = 0.07), and improve NeuroQoL-Fatigue (p = 0.06). No other PROs showed differences between melatonin and placebo; nor did step count measured by actigraphy (all p > 0.45).ConclusionThese results provide preliminary evidence that melatonin, a low-cost, over-the-counter supplement, could improve objective measures of sleep quality in PwMS.

The purpose of this study was to compare the preliminary effects of movement pattern training (MoveTrain) versus strengthening/flexibility (standard) treatment on hip and pelvic biomechanics in patients with chronic hip-related groin pain. This is a secondary analysis of data collected during a pilot randomized clinical trial. Thirty patients with hip pain, between the ages of 15 and 40 years, were randomized to MoveTrain or standard. Both groups completed 10 treatment sessions over 12 weeks along with a daily home exercise program. Three-dimensional motion analysis was used to collect kinematic and kinetic data of the pelvis and hip during a single-leg squat task at pretreatment and immediately posttreatment. Compared with the standard group, the MoveTrain group demonstrated smaller hip adduction angles (P =.006) and smaller hip external adduction moments (P =.008) at posttreatment. The desired changes to hip joint biomechanics, as found in this study, may require specificity in training that could allow health care professionals to better customize the rehabilitation of patients with hip pain. These findings can also be applied to the design and implementation of future clinical trials to strengthen our understanding of the long-term implications of different rehabilitation techniques for patients with hip pain. [ABSTRACT FROM AUTHOR]

Telehealth services complement in-person neurologic care. The American Academy of Neurology supports patient access to telehealth services regardless of location, coverage for telehealth services by all subscriber benefits and insurance, equitable provider reimbursement, simplified state licensing requirements easing access to virtual care, and expanding telehealth research and quality initiatives. The roles and responsibilities of providers should be clearly delineated in telehealth service models.

BackgroundIn persons with multiple sclerosis (MS), the Expanded Disability Status Scale (EDSS) is the criterion standard for assessing disability, but its in-person nature constrains patient participation in research and clinical assessments.ObjectiveThe aim of this study was to develop and validate a scalable, electronic, unsupervised patient-reported EDSS (ePR-EDSS) that would capture MS-related disability across the spectrum of severity.MethodsWe enrolled 136 adult MS patients, split into a preliminary testing Cohort 1 (n = 50), and a validation Cohort 2 (n = 86), which was evenly distributed across EDSS groups. Each patient completed an ePR-EDSS either immediately before or after a MS clinician's Neurostatus EDSS evaluation.ResultsIn Cohort 2, mean age was 50.6 years (range = 26-80) and median EDSS was 3.5 (interquartile range (IQR) = [1.5, 5.5]). The ePR-EDSS and EDSS agreed within 1-point for 86% of examinations; kappa for agreement within 1-point was 0.85 (p

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood-brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein-Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.

IntroductionSelf-administered in-home digital therapeutics could expand access to cognitive rehabilitation for individuals with multiple sclerosis (MS), over half of whom experience cognitive impairment (CI). However, feasibility in an MS population must be clarified. This study was conducted to assess the feasibility of deploying a videogame-like digital treatment for CI in MS, including initial efficacy and barriers to adherence.MethodsIn this pilot study, 21 participants with MS completed an in-clinic baseline neurological evaluation. Cognitive tests included paper-and-pencil Brief International Cognitive Assessment for Multiple Sclerosis [BICAMS-which included the Symbol Digit Modalities Test (SDMT)] and other unsupervised tablet-based tests (including Match: an unsupervised test of executive functions and processing speed, developed at UCSF; and the Cogstate MS Battery). Participants then completed an in-home, tablet-based, videogame-like investigational digital treatment (Project: EVO™) for 25 min daily, 5 days weekly, for 4 weeks. This was followed by a repeat in-clinic evaluation.ResultsOf the 21 participants (mean [standard deviation, SD] age 53.8 [11.6] years, median Expanded Disability Status Scale (EDSS) 2.5 [SD 2.0, IQR [2-3.5]]) enrolled to use the digital therapeutic at home (mean [SD] SDMT z score: - 0.21 [1.16]), 18 completed the study, during which they completed an average of 19.7 days (median [SD]: 20.5 [8.4]). Overall, 78% of these 18 participants completed 75% of prescribed days (i.e., at least 15), and 50% completed all 20 days or more. Over the 4-week period, scores of processing speed improved significantly (based on one-sided t test), including SDMT (p = 0.003) and Match (p = 0.006). The Cogstate DET test (psychomotor function) also increased (p = 0.006). Mean increase in SDMT was 3.6 points. Male sex, not being employed, and higher baseline anxiety all were significantly associated with greater improvement in SDMT over the 4-week period. Interestingly, lower baseline cognitive scores were associated with greater number of sessions completed (e.g., SDMT: p = 0.003, R2 = 0.44). Adjusting for employment, a proxy for time available, did not significantly improve the model fit.DiscussionDeploying an in-home digital tool to improve processing speed in MS is feasible, and shows preliminary efficacy. A larger, randomized controlled clinical trial is ongoing.

The goal of this review is to apply an evolutionary lens to understanding the origins of multiple sclerosis (MS), integrating three broad observations. First, only humans are known to develop MS spontaneously. Second, humans have evolved large brains, with characteristically large amounts of metabolically costly myelin. This myelin is generated over long periods of neurologic development-and peak MS onset coincides with the end of myelination. Third, over the past century there has been a disproportionate increase in the rate of MS in young women of childbearing age, paralleling increasing westernization and urbanization, indicating sexually specific susceptibility in response to changing exposures. From these three observations about MS, a life history approach leads us to hypothesize that MS arises in humans from disruption of the normal homeostatic mechanisms of myelin production and maintenance, during our uniquely long myelination period. This review will highlight under-explored areas of homeostasis in brain development, that are likely to shed new light on the origins of MS and to raise further questions about the interactions between our ancestral genes and modern environments.

The goal of this review is to apply an evolutionary lens to understanding the origins of multiple sclerosis (MS), integrating three broad observations. First, only humans are known to develop MS spontaneously. Second, humans have evolved large brains, with characteristically large amounts of metabolically costly myelin. This myelin is generated over long periods of neurologic development-and peak MS onset coincides with the end of myelination. Third, over the past century there has been a disproportionate increase in the rate of MS in young women of childbearing age, paralleling increasing westernization and urbanization, indicating sexually specific susceptibility in response to changing exposures. From these three observations about MS, a life history approach leads us to hypothesize that MS arises in humans from disruption of the normal homeostatic mechanisms of myelin production and maintenance, during our uniquely long myelination period. This review will highlight under-explored areas of homeostasis in brain development, that are likely to shed new light on the origins of MS and to raise further questions about the interactions between our ancestral genes and modern environments.

PurposeHuman females have a unique duration of post-reproductive longevity, during which sex-specific mechanisms ma influence later-life mechanisms of neuronal resilience and vulnerability. The maintenance of energy metabolism, through the oxidative phosphorylation (OXPHOS) apparatus, is essential for brain health. Given the known association between reproductive period (years from menarche to menopause) and cognitive aging, we examined the hypothesis that cumulative estrogen exposure across the lifetime may be associated with differential methylation of genes in the OXPHOS pathway.MethodsUsing DNA methylation patterns in the post-mortem dorsolateral prefrontal cortex (DLPFC) of 426 women prospectively followed until death in the Religious Orders Study and Rush Memory and Aging Project, we examined the relationship between reproductive period (subtracting age at menarche from age at menopause) and DNA methylation of a published set of autosomal OXPHOS genes previously implicated in stroke susceptibility. We then performed an unsupervised analysis of methylation levels across the Hallmark pathways from the Molecular Signatures Database.ResultsWe observed a strong association between reproductive period and DNA methylation status across OXPHOS CpGs. We replicated this association between reproductive period and DNA methylation in a much larger set of OXPHOS genes in our unsupervised analysis. Here, reproductive period also showed associations with methylation in genes related to E2F, MYC and MTORC1 signaling, fatty acid metabolism and DNA repair.ConclusionThis study provides evidence from both a supervised and unsupervised analyses, that lifetime cumulative endogenous steroid exposures may play a role in maintenance of post-menopausal cellular balance, including in brain tissue.

We have witnessed major successes in the development of effective immunomodulatory therapies capable of reducing adaptive immune-mediated myelin damage in MS over the last 30 years. However, until it is possible to prevent MS or initiate treatment before it has already caused lesions there is a need to repair myelin damage to prevent further axonal loss. The past decade has brought remarkable advances in our understanding of oligodendrocyte biology and the related search for remyelinating therapies in humans. In this review, we first outline the basic biology of central nervous system myelin and remyelination, including a discussion of the major identified pathways and targets that might help yield CNS remyelinating drugs. In conjunction, we provide an overview of techniques that have helped identify compounds capable of promoting oligodendrocyte precursor cell differentiation and myelination. This includes the methods for both initial in vitro screening and subsequent in vivo confirmation of the target. We then review methods proposed to quantify human remyelination in vivo, including visual evoked potentials and putative imaging modalities. As the remyelination era approaches, with the announcement of the first positive trial in remyelination, we are now tasked with answering new questions regarding patient-specific factors (e.g., age) that may influence the extent and optimal therapeutic window for remyelination.

ObjectiveTo optimally leverage the scalability and unique features of the electronic health records (EHR) for research that would ultimately improve patient care, we need to accurately identify patients and extract clinically meaningful measures. Using multiple sclerosis (MS) as a proof of principle, we showcased how to leverage routinely collected EHR data to identify patients with a complex neurological disorder and derive an important surrogate measure of disease severity heretofore only available in research settings.MethodsIn a cross-sectional observational study, 5,495 MS patients were identified from the EHR systems of two major referral hospitals using an algorithm that includes codified and narrative information extracted using natural language processing. In the subset of patients who receive neurological care at a MS Center where disease measures have been collected, we used routinely collected EHR data to extract two aggregate indicators of MS severity of clinical relevance multiple sclerosis severity score (MSSS) and brain parenchymal fraction (BPF, a measure of whole brain volume).ResultsThe EHR algorithm that identifies MS patients has an area under the curve of 0.958, 83% sensitivity, 92% positive predictive value, and 89% negative predictive value when a 95% specificity threshold is used. The correlation between EHR-derived and true MSSS has a mean R(2) = 0.38±0.05, and that between EHR-derived and true BPF has a mean R(2) = 0.22±0.08. To illustrate its clinical relevance, derived MSSS captures the expected difference in disease severity between relapsing-remitting and progressive MS patients after adjusting for sex, age of symptom onset and disease duration (p = 1.56×10(-12)).ConclusionIncorporation of sophisticated codified and narrative EHR data accurately identifies MS patients and provides estimation of a well-accepted indicator of MS severity that is widely used in research settings but not part of the routine medical records. Similar approaches could be applied to other complex neurological disorders.

A case of anteromedial leg pain diagnosed and treated for 10 years as "shin splints" (medial tibial stress syndrome) is described. A history and examination was performed focused on anatomy, biomechanics, and peripheral nerves. Detailed sensory testing was performed in the painful area, and imaging was obtained to confirm the diagnosis. The clinical investigation was consistent with dynamic stenosis of the left L4-5 intervertebral foramen, causing a mixed partial mononeuropathy of the L4 spinal nerve that presented as pain and hypersensitivity in the anteromedial shin. Manual therapy maneuvers intended to open the intervertebral foramen led to resolution of the pain and sensory deficits. After three additional treatments performed within a month, resolution was maintained for >3 years. This case highlights how concepts from preclinical studies, coupled with basic anatomical, neurological, and biomechanical investigations, can be critical for accurate diagnosis and treatment for a case previously considered unresponsive to care. [ABSTRACT FROM AUTHOR]