Background Interpretation of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels in blood requires reference ranges from healthy cohorts, accounting for demographic features. Objective To compare serum and plasma NfL and GFAP in healthy individuals, accounting for age, sex, and body mass index (BMI). Methods Adolescents through older adults were recruited at Colorado community events and a senior clinic. A neurologist reviewed self-reported medical histories. Paired serum and EDTA plasma samples were assayed using the Quanterix SR-X Simoa Neuro 4-Plex. Log-linear models estimated percent change per year of age, per BMI unit, and sex ratios. GFAP used a piecewise age model (knot at 30 years). Spearman correlation assessed serum–plasma concordance. Results We enrolled 143 participants (ages = 16.4–85.9; 63.6% female; mean BMI = 26.7). Serum–plasma correlations were strong (NfL ρ = .923; GFAP ρ = .833; both p < .001). In plasma, age was associated with a 2.96% increase in NfL and 2.34% in GFAP per year for ages ≥30. In serum, NfL rose 2.90% and GFAP 2.69% per year (both p < .0001). Conclusion NfL and GFAP are strongly age-dependent and concordant across serum and plasma in healthy individuals. An online calculator provides age-, sex-, and BMI-adjusted reference estimates and serum/plasma conversions.

Background: The association between body mass index (BMI) and cognition, disability, and quality of life (QoL) is controversial in multiple sclerosis (MS). Objectives: We investigated the association between BMI and cognitive function, disability, and QoL in MS. Methods: A cross-sectional secondary analysis of the DISCOMS trial was performed to study the association between BMI and cognition, disability, and QoL. Cognitive function was measured by the symbol digit modalities test (SDMT) and disability was measured based on the expanded disability status scale (EDSS) and patient determined disability steps (PDDS). QoL markers were measured by the Quality of Life in Neurological Disorders. Descriptive and inferential statistics were used to analyze the association between BMI and cognition, disability, and QoL. Results: The study included 253 participants, mostly female (83.8%) and white (89.3%). Their mean BMI was 27.27 (SD = 5.6), and 62% were overweight, obese, or very obese. Controlling for age, gender, and disease-modifying therapy duration, BMI as a continuous or as a categorical variable was not associated with cognitive function as measured by the SDMT or disability as measured by the EDSS and/or the PDDS. EDSS as a dichotomous variable was associated with BMI; 1-unit increase in BMI was associated with a 5.7% increase in the odds of having an EDSS score greater than 4 (β = 0.055, p = 0.045). Higher continuous BMI was associated with physical domains dysfunction; worse fatigue ( p = 0.009), and worse lower extremities function ( p = 0.008), while the very obese group had a higher risk of physical and emotional domain dysfunction than the normal BMI group. Conclusion: The lack of observed associations between BMI and cognitive function or disability in this older MS cohort suggests that the relationship between BMI and clinical outcomes may vary across domains. Nevertheless, the associations identified between BMI and QoL measures emphasize the potential importance of weight management in supporting overall health and well-being among individuals with MS. Trial registration of the primary DISCOMS study: ClinicalTrials.gov NCT03073603.

BACKGROUND:In the DISCOMS (DISCOntinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS)) randomized clinical trial, we could not demonstrate that discontinuing MS DMTs in older, stable adults was not inferior to continuing DMTs. Relapses were rare in both groups, and most new disease activity was one to two new brain magnetic resonance imaging (MRI) lesions unassociated with clinical changes. OBJECTIVE/AIMS:Describe results of the DISCOMS extension study. METHODS:Among 10/19 of the original sites, we enrolled patients who completed DISCOMS; did not reach the primary endpoint during the original trial; and retained original randomized assignment. Participants completed one study visit and brain MRI at least 30 months after original enrollment in DISCOMS. Primary endpoint was time from entry into the primary study to relapse or new brain MRI activity. RESULTS:Mean (SD) total follow-up was 40 (11.7) months. There were no relapses, and new brain MRI lesions (1/30 continuer, 2/44 discontinuers) were uncommon during the extension. Time from primary trial entry to disease event was significantly shorter for subjects in the discontinue group (p = 0.043 from log-rank test). CONCLUSIONS:From entry into DISCOMS extension study, time to new MS activity remained shorter in discontinuers, but relapses were absent and new brain MRI lesions were rare.

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Importance:While the typical onset of multiple sclerosis (MS) occurs in early adulthood, 2% to 10% of cases initially present prior to age 18 years, and approximately 5% after age 50 years. Guidance on approaches to differential diagnosis in suspected MS specific to these 2 age groups is needed. Observations:There are unique biological factors in children younger than 18 years and in adults older than age 50 years compared to typical adult-onset MS. These biological differences, particularly immunological and hormonal, may influence the clinical presentation of MS, resilience to neuronal injury, and differential diagnosis. While mimics of MS at the typical age at onset have been described, a comprehensive approach focused on the younger and older ends of the age spectrum has not been previously published. Conclusions and Relevance:An international committee of MS experts in pediatric and adult MS was formed to provide consensus guidance on diagnostic approaches and key clinical and paraclinical red flags for non-MS diagnosis in children and older adults.

This review presents a summary of the literature on de-escalation and discontinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS), especially as it relates to the aging patient. Currently available DMTs may have less benefit in people with MS who are older, stable and have received years of treatment. Observational studies and interventional trials in people with MS who de-escalate or discontinue their DMTs have demonstrated varied outcomes over the short- to medium-term. Certain factors such as a person’s age, type of DMT, length of treatment, and recent presence of disease activity influence the likelihood of MS activity following discontinuation or de-escalation. Much work remains to be able to accurately predict when it is safe and appropriate for an individual with MS to discontinue or de-escalate from DMTs, though current research has narrowed down the window at which providers should begin to consider these issues.

Long-term use of multiple sclerosis (MS) disease-modifying therapies (DMTs) is standard practice to prevent accumulation of disability. Immunosenescence and other age-related changes lead to an altered risk–benefit ratio for older patients on DMTs. This article reviews recent research on the topic of de-escalation and discontinuation of MS DMTs. Observational and interventional studies have shed light on what happens to patients who de-escalate or discontinue DMTs and the factors, such as age, treatment type, and presence of recent disease activity, that influence outcomes. Though many questions remain, recent findings have been valuable for the development of an evidence-based approach to making de-escalation and discontinuation decisions in MS.

ObjectivesDisease-modifying therapy (DMT) for multiple sclerosis (MS) after natalizumab-associated progressive multifocal leukoencephalopathy (PML) is controversial due to concern for recurrent PML. We describe DMT utilization for over a decade in a patient with MS who survived PML.MethodsCase report.ResultsA 36-year-old woman was diagnosed with MS in 2002 and treated with interferon beta-1a until 2006, when she transitioned to natalizumab due to relapses. She presented in 2012 with 2 months of progressive cognitive and gait concerns and was diagnosed with PML by positive CSF JC virus testing with concordant clinical and MRI findings. She was treated with plasma exchange and then corticosteroids for PML immune reconstitution inflammatory syndrome before starting glatiramer acetate for DMT. She transitioned to dimethyl fumarate in 2013 after MS activity on MRI with negative CSF JC virus testing. Owing to worsening footdrop consistent with progression, she transitioned to ocrelizumab in 2017 and then to ofatumumab in 2020 due to logistics of medication administration. There has been no clinicoradiographic or CSF evidence of recurrent PML.DiscussionDMT selection is challenging for patients with MS who survive PML. We used an escalation approach extending to ocrelizumab and ofatumumab due to MS progression. Anti-CD20 DMTs are a high-efficacy option post-PML.Classification of EvidenceThis provides Class IV evidence. It is a single observational study without controls.

Human microglia play a pivotal role in neurological diseases, but we still have an incomplete understanding of microglial heterogeneity, which limits the development of targeted therapies directly modulating their state or function. Here, we use single-cell RNA sequencing to profile 215,680 live human microglia from 74 donors across diverse neurological diseases and CNS regions. We observe a central divide between oxidative and heterocyclic metabolism and identify microglial subsets associated with antigen presentation, motility and proliferation. Specific subsets are enriched in susceptibility genes for neurodegenerative diseases or the disease-associated microglial signature. We validate subtypes in situ with an RNAscope-immunofluorescence pipeline and high-dimensional MERFISH. We also leverage our dataset as a classification resource, finding that induced pluripotent stem cell model systems capture substantial in vivo heterogeneity. Finally, we identify and validate compounds that recapitulate certain subtypes in vitro, including camptothecin, which downregulates the signature of disease-enriched subtypes and upregulates a signature previously associated with Alzheimer's disease.

OBJECTIVE:Our objectives were to (1) obtain the prevalence and demography of people with multiple sclerosis (MS) in a representative Colorado population, and (2) to assess the utilization of disease-modifying therapy within this prevalent cohort. METHODS:This is a retrospective, observational study of patients that had contact with the University of Colorado Health System from 2012 to 2020. We queried Health Data Compass, a data warehouse, for patient data and applied the MS Prevalence Workgroup Algorithm to generate a prevalent cohort. We calculated prevalence as of 31 December 2020, and stratified by age, sex, race, and ethnicity. Payer information and treatment exposure were obtained from linked claims from the Colorado All Payers Claim Database. Disease-modifying therapies were classified as highly effective and moderately effective based on the clinical trial, TREAT-MS (NCT03500328). RESULTS:From a population of 1,382,821 individuals, 8557 people with MS were captured. Age-adjusted prevalence of MS as of 31 December 2020 was 572.3 per 100,000 with a mean age of 47.36. Prevalence varied between demographic subgroups, with the lowest prevalence in Hispanic men (215.6) and highest in White (824.1) and Black women (820.1). Overall disease-modifying therapy exposure was 62.4%, with increased highly effective therapy use and a corresponding decrease in moderately effective therapy use on a yearly basis. INTERPRETATION:MS is highly prevalent in a representative Colorado cohort. Overall treatment and proportion of highly effective therapy exposure increased significantly during a critical period of MS therapeutic advances, indicating a shift in disease management driven sharply by the availability of on-label anti-CD20 therapy.

Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.

Objective: To assess the effect of sex and age on plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) levels in a healthy control (HC) cohort. Background: Blood NfL levels vary with age and comorbid disorders. The effect of age on blood GFAP has not been investigated. Design/Methods: HC subjects without neurologic disease, cancer, diabetes, and traumatic brain injury were recruited from community and wellness events. Plasma NfL and GFAP were measured using the SR-X Simoa Quanterix platform. Changes in biomarker levels per year of age were estimated and log-linear predictive models generated. Results: 110 of 155 HC samples have been analyzed to date. Age ranges from 16.4 to 59.6 years with the following distribution: 15–19 (11.82%), 20–30 (36.36%), 30–40 (21.82%), 40–50 (15.45%) and 50–60 (14.55%). Sex and racial distribution were female (64.5%), White (78.2%), 15.5% Hispanic, 7.4% Black, 5.5% Asian, 0.9 % American Indian, 1.8 % other. Geometric mean NfL concentrations increased by age, ranging from 2.47 pg/ml (CI: (1.87, 3.29) at 15–19 years to 7.22 pg/ml (CI: (5.97, 8.73) at 50–60 years. Geometric mean GFAP values increased from 49.99 pg/ml (CI: (41.74, 59.87) at 15–19 years to 72.56 pg/ml (CI: (60.16, 87.51) at 50–60 years. Adjusting for age and gender, expected NfL values increased by 2.57% per year (95% CI: (1.90%, 3.25%), p < 0.0001) overall, 2.72% (95% CI:(1.96%, 3.49%), p < 0.0001) in females, and 2.22% (95% CI: (0.87%, 3.58%), p = 0.0018) in males. Expected GFAP increased by 0.94% per year (95% CI: (0.26%, 1.62%), p = 0.0067) overall and by 0.95% (95% CI: (0.11%, 1.80%), p = 0.0273) in females. Conclusions: Utilizing more stringent criteria for HC, our study replicates recent reports on blood NfL levels using national cohorts and provides novel data of plasma GFAP levels across a broad age distribution. Disclosure: Mr. Borko has nothing to disclose. Ms. Barrera has nothing to disclose. Mrs. Ritchie has nothing to disclose. Sean Selva has nothing to disclose. The institution of Stefan Sillau has received research support from Alzheimer's Association. The institution of Stefan Sillau has received research support from Hewitt Family Foundation; State of Colorado. The institution of Stefan Sillau has received research support from PCORI. The institution of Stefan Sillau has received research support from NINR. The institution of Stefan Sillau has received research support from Michael J. Fox Foundation. The institution of Stefan Sillau has received research support from Department of Defense. The institution of Stefan Sillau has received research support from Colorado Department of Public Health and Environment. The institution of Stefan Sillau has received research support from Benign Essential Blepharospasm Research Foundation. Stefan Sillau has a non-compensated relationship as a Statistician with Novartis that is relevant to AAN interests or activities. Stefan Sillau has a non-compensated relationship as a Statistician with Biogen that is relevant to AAN interests or activities. Mr. Engebretson has nothing to disclose. Ms. Seale has stock in Johnson & Johnson. Ms. Valdez has a non-compensated relationship as a Valdez with The Rocky Mountain MS Center non-profit partner that is relevant to AAN interests or activities. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Alvarez has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celgene. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. The institution of an immediate family member of Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Corboy has received personal compensation for serving as an employee of U of Coloado. Dr. Corboy has received personal compensation for serving as an employee of Rocky Mountain MS Center. Dr. Corboy has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Mylan. Dr. Corboy has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squib. Dr. Corboy has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for AAN. Dr. Corboy has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Neurological Association. Dr. Corboy has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Mylan. The institution of Dr. Corboy has received research support from MedDay. The institution of Dr. Corboy has received research support from Novartis. The institution of Dr. Corboy has received research support from NMSS. The institution of Dr. Corboy has received research support from PCORI. The institution of Dr. Corboy has received research support from EMD Serono. The institution of Dr. Shah has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. The institution of Dr. Shah has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Shah has received personal compensation in the range of $5,000-$9,999 for serving as a Educational Speaker with Rocky Mountain MS Center. Dr. Gross has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for AP Expert Group. Diego Silva has received personal compensation for serving as an employee of BMS. Diego Silva has received stock or an ownership interest from BMS. Gregory Owens has nothing to disclose. The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. The institution of Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Sands Anderson PC. The institution of Dr. Piquet has received research support from Rocky Mountain MS Center. The institution of Dr. Piquet has received research support from Novartis. The institution of Dr. Piquet has received research support from Abbvie. The institution of Dr. Piquet has received research support from Roche/Genentech. The institution of Dr. Piquet has received research support from NYU. Dr. Piquet has received publishing royalties from a publication relating to health care. Dr. Piquet has received publishing royalties from a publication relating to health care. Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as a Litigative Consultant with US-Dept HHS/DICP. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Horizon Therapeutics. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alexion. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Reistone Bio. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Antigenomycs. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Chugai. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi Tanabe. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for MedEdicus. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ImCyse. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Clene Nanomedicine. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alexion. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Podoll. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Patterson. The institution of Dr. Bennett has received research support from Novartis. The institution of Dr. Bennett has received research support from Alexion. Dr. Bennett has received intellectual property interests from a discovery or technology relating to health care. Dr. Bennett has received publishing royalties from a publication relating to health care. The institution of Dr. Vollmer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen IDEC. The institution of Dr. Vollmer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech/Roche. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Siranax. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Meyers Squib. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Viela Bios. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. The institution of Dr. Vollmer has received research support from Rocky Mountain MS Center. The institution of Dr. Vollmer has received research support from Biogen. The institution of Dr. Vollmer has received research support from Actelion. The institution of Dr. Vollmer has received research support from Genentech/Roche. The institution of Dr. Vollmer has received research support from Anokion. The institution of Dr. Vollmer has received research support from TG Therapeutics. Dr. Chahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Chahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG. Dr. Chahin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Chahin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Chahin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. The institution of Dr. Chahin has received research support from BIogen. Dr. Nair has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bristol Meyers Squibb. Dr. Nair has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Nair has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for PharMA Foundation. Dr. Nair has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Nair has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Nair has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Nair has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MJH Healthcare. Dr. Nair has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi-Genzyme. The institution of Dr. Nair has received research support from Genentech. The institution of Dr. Nair has received research support from Novartis. The institution of Dr. Nair has received research support from Genentech. The institution of Dr. Nair has received research support from Phrma Foundation. The institution of Dr. Nair has received research support from Bristol Meyers Squibb. The institution of Dr. Nair has received research support from Novartis.

During inflammatory, demyelinating diseases such as multiple sclerosis (MS), inflammation and axonal damage are prevalent early in the course. Axonal damage includes swelling, defects in transport, and failure to clear damaged intracellular proteins, all of which affect recovery and compromise neuronal integrity. The clearance of damaged cell components is important to maintain normal turnover and restore homeostasis. In this study, we used mass spectrometry to identify insoluble proteins within high-speed/mercaptoethanol/sarcosyl-insoluble pellets from purified white matter plaques isolated from the brains of individuals with relapsing–remitting MS (RRMS). We determined that the transmembrane protein 106B (TMEM106B), normally lysosome-associated, is insoluble in RRMS plaques relative to normal-appearing white matter from individuals with Alzheimer’s disease and non-neurologic controls. Relative to wild-type mice, hypomorphic mice with a reduction in TMEM106B have increased axonal damage and lipid droplet accumulation in the spinal cord following myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis. Additionally, the corpora callosa from cuprizone-challenged hypomorphic mice fail to clear lipid droplets efficiently during remyelination, suggesting that when TMEM106B is compromised, protein and lipid clearance by the lysosome is delayed. As TMEM106B contains putative lipid- and LC3-binding sites, further exploration of these sites is warranted.

Emerging evidence is encouraging and suggests that a substantial proportion of patients without antibody responses (due to anti-CD20 therapy or other etiologies) to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines develop T cell responses. However, antigen-specific T cellular responses are notoriously difficult to assess clinically, given the lack of such assays under satisfactory CAP/CLIA regulation, and the laborious nature of the flow cytometric assessment. To evaluate the ability to apply a clinically feasible assay to measure T cellular responses to SARS-CoV-2 mRNA vaccination, we compared flow cytometric and enzyme-linked immunosorbent assay (ELISA) based assays in 24 participants treated with anti-CD20 therapy. T cellular activation (CD69 + CD137+ surface expression, i.e., activation induced markers [AIM]) and intracellular interferon gamma (INFγ) production via flow cytometry was compared to plasma Interferon Gamma Release Assay (IGRA) via ELISA. Plasma INFγ production measured by IGRA correlated with the percent of INFγ-producing AIM positive T cells, supporting the use of IGRA assay as a robust assessment of T cellular response to the SARS-CoV-2 vaccine for B-cell depleted patients that is clinically feasible, time efficient, and cost effective.