Clinical outcomes after use of checkpoint inhibitor immunotherapies in people with multiple sclerosis.

Background: Immune checkpoint inhibitors (ICIs) represent a novel class of agents approved for the treatment of several cancers and progressive multifocal leukoencephalopathy (PML). However, due to the risk of autoimmune side effects, their use in people with autoimmune diseases such as multiple sclerosis (MS) has been limited. Objective: To characterize outcomes in a cohort of adults with MS who received ICIs. Methods: A single-center retrospective review of medical record data was performed for people with MS treated with ICIs. Results: Seven people with MS were identified, with a mean (SD) age at ICI use of 55.4 (13.7) years and a mean MS duration of 18.2 (12.2) years. Six were treated for cancer; 1 was treated for PML. After mean (SD) follow-up of 1.76 (2.15) years after ICI, outcomes are: no evidence of disease (2), residual metastatic disease (1), death due to cancer (1), death due to PML (1), and lost to follow-up (2). Notably, 0 out of 7 patients experienced an MS relapse; two out of six had new asymptomatic demyelinating magnetic resonance imaging lesions. In the three patients with expanded disability status scale (EDSS) scores at baseline and follow-up, EDSS remained stable (mean delta 0.13). Conclusion: In this cohort, no people with MS experienced clinical relapses and one-third experienced asymptomatic radiological activity following ICI treatment.

Cognitive function influences cognitive-motor interference during dual task walking in multiple sclerosis.

BACKGROUND: Both physical and cognitive impairments are common in people with multiple sclerosis (PwMS). Performing a cognitive task while walking (i.e., dual-task walking) can introduce cognitive-motor interference (CMI), resulting in changes in walking performance. The association between the levels of cognitive impairment and of CMI in MS remains unclear. OBJECTIVES: To examine the association between cognitive functioning and differences in walking performance arise between single- and dual-task walking. METHODS: Ninety-five PwMS performed self-preferred pace walking and dual-task walking. The gait parameters recorded were used to compute dual task costs (DTC) as a metric of CMI. Cognitive functioning was assessed using Match, an unsupervised test developed based on the Symbol Digit Modalities Test. Participants were categorized as higher (HCF) and lower cognitive functioning (LCF) based on a Match z-score < -1.5. RESULTS: LCF group had elevated DTC for stride velocity, relative to the HCF group. Higher DTC for stride velocity was associated with lower cognition, as assessed by Match test. CONCLUSION: The findings support the hypothesis that CMI is associated with cognitive functioning in PwMS.

A Closed-Loop Falls Monitoring and Prevention App for Multiple Sclerosis Clinical Practice: Human-Centered Design of the Multiple Sclerosis Falls InsightTrack.

BACKGROUND: Falls are common in people with multiple sclerosis (MS), causing injuries, fear of falling, and loss of independence. Although targeted interventions (physical therapy) can help, patients underreport and clinicians undertreat this issue. Patient-generated data, combined with clinical data, can support the prediction of falls and lead to timely intervention (including referral to specialized physical therapy). To be actionable, such data must be efficiently delivered to clinicians, with care customized to the patient's specific context. OBJECTIVE: This study aims to describe the iterative process of the design and development of Multiple Sclerosis Falls InsightTrack (MS-FIT), identifying the clinical and technological features of this closed-loop app designed to support streamlined falls reporting, timely falls evaluation, and comprehensive and sustained falls prevention efforts. METHODS: Stakeholders were engaged in a double diamond process of human-centered design to ensure that technological features aligned with users' needs. Patient and clinician interviews were designed to elicit insight around ability blockers and boosters using the capability, opportunity, motivation, and behavior (COM-B) framework to facilitate subsequent mapping to the Behavior Change Wheel. To support generalizability, patients and experts from other clinical conditions associated with falls (geriatrics, orthopedics, and Parkinson disease) were also engaged. Designs were iterated based on each round of feedback, and final mock-ups were tested during routine clinical visits. RESULTS: A sample of 30 patients and 14 clinicians provided at least 1 round of feedback. To support falls reporting, patients favored a simple biweekly survey built using REDCap (Research Electronic Data Capture; Vanderbilt University) to support bring-your-own-device accessibility-with optional additional context (the severity and location of falls). To support the evaluation and prevention of falls, clinicians favored a clinical dashboard featuring several key visualization widgets: a longitudinal falls display coded by the time of data capture, severity, and context; a comprehensive, multidisciplinary, and evidence-based checklist of actions intended to evaluate and prevent falls; and MS resources local to a patient's community. In-basket messaging alerts clinicians of severe falls. The tool scored highly for usability, likability, usefulness, and perceived effectiveness (based on the Health IT Usability Evaluation Model scoring). CONCLUSIONS: To our knowledge, this is the first falls app designed using human-centered design to prioritize behavior change and, while being accessible at home for patients, to deliver actionable data to clinicians at the point of care. MS-FIT streamlines data delivery to clinicians via an electronic health record-embedded window, aligning with the 5 rights approach. Leveraging MS-FIT for data processing and algorithms minimizes clinician load while boosting care quality. Our innovation seamlessly integrates real-world patient-generated data as well as clinical and community-level factors, empowering self-care and addressing the impact of falls in people with MS. Preliminary findings indicate wider relevance, extending to other neurological conditions associated with falls and their consequences.

Well-being at midlife: Correlates of mental health in ambulatory menopausal women with multiple sclerosis.

BACKGROUND: A majority of women with multiple sclerosis (MS) are diagnosed prior to menopause, yet their experiences during this transition are not well characterized. OBJECTIVES: To explore associations between mental health, sleep, and other quality of life metrics, and vasomotor symptoms (VMSs) in ambulatory, menopausal women with MS. METHODS: A secondary analysis was performed of baseline data from two trials enrolling ambulatory peri/postmenopausal women with MS: NCT02710214 (N = 24, bothersome VMS) and NCT04002934 (ongoing, N = 35, myelin repair). Measures analyzed were 36-Item Short-Form Survey (SF-36) (primary scale: general mental health), subjective sleep quality (Pittsburg Sleep Quality Index), VMS (daily diary, interference), mood (Center for Epidemiologist Studies-Depression Scale (CES-D)), walking impairment (timed 25-foot walk (T25FW)), and global disability (Expanded Disability Status Scale (EDSS)). RESULTS: Participants' characteristics (N = 59) were: mean age 51.8 years (SD = 3.4), mean disease duration 11.3 years (SD = 7.6), median EDSS 3.0 (IQR = 2.0-4.0). Mental health was associated with better sleep quality (rho = -0.41, p = 0.019) and better mood (rho = -0.75, p < 0.001), but not with EDSS or T25FW (rho < 0.20, p > 0.10). Worse sleep quality also correlated with more frequent VMS (rho = 0.41, p = 0.02) and VMS interference (rho = 0.59, p < 0.001). CONCLUSIONS: Findings suggest that optimizing sleep quality, mood, and hot flash quantity/interference could substantially improve mental health in menopausal women with MS-and highlight an important care gap in this population.

Re-WRAP (Remyelination for women at risk of axonal loss and progression): A phase II randomized placebo-controlled delayed-start trial of bazedoxifene for myelin repair in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a major cause of disability in young and middle-aged people, and myelin repair therapies are needed to slow or potentially reverse this damage. Bazedoxifene (BZA) is a selective estrogen receptor modulator identified in a novel high-throughput unbiased screen for its remyelinating potential, and its remyelinating effects were demonstrated in pre-clinical models. METHODS: This is a single-center, double blind, randomized, controlled, delayed-start Phase 2 clinical trial (NCT04002934) investigating the remyelinating effects of BZA relative to placebo. Female patients with relapsing-remitting MS, aged 45-60 years (or > 40 if post-menopausal), and ambulatory status (EDSS 0-6 inclusive), will be recruited into a clinical trial with 2 arms of identical design, except that the "Chronic Optic Neuropathy" arm requires additional inclusion criteria of electrophysiological evidence of prior visual pathway demyelination. Clinical, electrophysiological, and imaging evaluations will occur at baseline, 3 months, and 6 months. The primary outcome is change in Myelin Water Fraction (MWF) on MRI within the corpus callosum. Secondary outcomes are: visual evoked potential (VEP) P100 latency, novel digital measures of cognition and activity, and patient reported outcomes. Tertiary outcomes are: safety and tolerability. DISCUSSION: BZA has strong preclinical effects on myelin repair, and in the general population demonstrated benefits in treating postmenopausal osteoporosis. Together, these findings support the rationale for an RCT testing BZA in women with MS, evaluating established neuroimaging and neurovisual measures of myelin repair. Additionally, validating novel digital tools could increase sensitivity to change and inform the duration and design of future clinical trials.

Clinical course of multiple sclerosis and patient experiences during breast cancer treatment.

BACKGROUND: Over one-third of multiple sclerosis (MS) patients are post-menopausal women, the primary demographic affected by breast cancer. After breast cancer diagnosis, there is little information about patients' clinical experiences with both diseases. OBJECTIVE: Utilize a case series of MS patients diagnosed with breast cancer to characterize oncologic and MS trajectories, and generate novel insights about clinical considerations using qualitative analysis. METHODS: A single-center retrospective review was performed on medical record data of patients with MS and breast cancer. Thematic analysis was used to characterize experiences with the concurrent diagnoses. RESULTS: For the 43 patients identified, mean age was 56.7 years at cancer diagnosis and MS duration was 16.5 years. Approximately half were treated with MS disease modifying therapy at cancer diagnosis, and half of these subsequently discontinued or changed therapy. Altogether 14% experienced MS relapse(s) during follow-up (with 2 relapses in the first 2 years), with mean annualized relapse rate of 0.03. Cohort Expanded Disability Status Scale (EDSS) scores remained stable during follow-up. Qualitative insights unique to this population were identified regarding immunosuppression use and neurologic symptoms. CONCLUSIONS: MS relapses were infrequent, and there was modest progression during breast cancer treatment. Oncologic outcomes were comparable to non-MS patients with similarly staged cancer.

Plasma Markers of Neurologic Injury and Inflammation in People With Self-Reported Neurologic Postacute Sequelae of SARS-CoV-2 Infection.

BACKGROUND AND OBJECTIVES: The biologic mechanisms underlying neurologic postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are incompletely understood. METHODS: We measured markers of neurologic injury (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and soluble markers of inflammation among a cohort of people with prior confirmed SARS-CoV-2 infection at early and late recovery after the initial illness (defined as less than and greater than 90 days, respectively). The primary clinical outcome was the presence of self-reported CNS PASC symptoms during the late recovery time point. We compared fold changes in marker values between those with and without CNS PASC symptoms using linear mixed-effects models and examined relationships between neurologic and immunologic markers using rank linear correlations. RESULTS: Of 121 individuals, 52 reported CNS PASC symptoms. During early recovery, those who went on to report CNS PASC symptoms had elevations in GFAP (1.3-fold higher mean ratio, 95% CI 1.04-1.63, p = 0.02), but not NfL (1.06-fold higher mean ratio, 95% CI 0.89-1.26, p = 0.54). During late recovery, neither GFAP nor NfL levels were elevated among those with CNS PASC symptoms. Although absolute levels of NfL did not differ, those who reported CNS PASC symptoms demonstrated a stronger downward trend over time in comparison with those who did not report CNS PASC symptoms (p = 0.041). Those who went on to report CNS PASC also exhibited elevations in interleukin 6 (48% higher during early recovery and 38% higher during late recovery), monocyte chemoattractant protein 1 (19% higher during early recovery), and tumor necrosis factor α (19% higher during early recovery and 13% higher during late recovery). GFAP and NfL correlated with levels of several immune activation markers during early recovery; these correlations were attenuated during late recovery. DISCUSSION: Self-reported neurologic symptoms present approximately 4 months after SARS-CoV-2 infection are associated with elevations in markers of neurologic injury and inflammation at earlier time points. Some inflammatory pathways seem to be involved months after acute infection. Additional work will be needed to better characterize these processes and to identify interventions to prevent or treat this condition.

Podoplanin is a negative regulator of Th17 inflammation.

Recent data indicate that there are different subpopulations of Th17 cells that can express a regulatory as opposed to an inflammatory gene signature. The transmembrane glycoprotein PDPN is critical in the development of multiple organs including the lymphatic system and has been described on T cells in mouse models of autoimmune Th17 inflammation. Here, we demonstrate that unlike in mice, PDPN+ T cells induced under classic Th17-polarizing conditions express transcription factors associated with Th17 cells but do not produce IL-17. Moreover, these cells express a transcriptional profile enriched for immunosuppressive and regulatory pathways and express a distinct cytokine profile compared with potentially pathogenic PDPN- Th17 cells. Ligation of PDPN by its ligand CLEC-2 ameliorates the Th17 inflammatory response. IL-17 secretion is restored with shRNA gene silencing of PDPN. Furthermore, PDPN expression is reduced via an Sgk1-mediated pathway under proinflammatory, high sodium chloride conditions. Finally, CD3+PDPN+ T cells are devoid of IL-17 in skin biopsies from patients with candidiasis, a prototypical Th17-driven skin disease. Thus, our data support the hypothesis that PDPN may serve as a marker of a nonpathogenic Th17 cell subset and may also functionally regulate pathogenic Th17 inflammation.

B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by autoimmune-mediated demyelination and neurodegeneration. The CNS of patients with MS harbors expanded clones of antigen-experienced B cells that reside in distinct compartments including the meninges, cerebrospinal fluid (CSF), and parenchyma. It is not understood whether this immune infiltrate initiates its development in the CNS or in peripheral tissues. B cells in the CSF can exchange with those in peripheral blood, implying that CNS B cells may have access to lymphoid tissue that may be the specific compartment(s) in which CNS-resident B cells encounter antigen and experience affinity maturation. Paired tissues were used to determine whether the B cells that populate the CNS mature in the draining cervical lymph nodes (CLNs). High-throughput sequencing of the antibody repertoire demonstrated that clonally expanded B cells were present in both compartments. Founding members of clones were more often found in the draining CLNs. More mature clonal members derived from these founders were observed in the draining CLNs and also in the CNS, including lesions. These data provide new evidence that B cells traffic freely across the tissue barrier, with the majority of B cell maturation occurring outside of the CNS in the secondary lymphoid tissue. Our study may aid in further defining the mechanisms of immunomodulatory therapies that either deplete circulating B cells or affect the intrathecal B cell compartment by inhibiting lymphocyte transmigration into the CNS.

Multiple sclerosis.

Multiple sclerosis (MS) is a multifocal demyelinating disease with progressive neurodegeneration caused by an autoimmune response to self-antigens in a genetically susceptible individual. While the formation and persistence of meningeal lymphoid follicles suggest persistence of antigens to drive the continuing inflammatory and humoral response, the identity of an antigen or infectious agent leading to the oligoclonal expansion of B and T cells is unknown. In this review we examine new paradigms for understanding the immunopathology of MS, present recent data defining the common genetic variants underlying disease susceptibility, and explore how improved understanding of immune pathway disruption can inform MS prognosis and treatment decisions.

L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer's disease.

Alzheimer's disease (AD) is an age-related, progressive neurodegenerative disorder that occurs gradually and results in memory, behavior, and personality changes. L-3-n-butylphthalide (L-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), has been demonstrated to have neuroprotective effects on ischemic, vascular dementia, and amyloid-beta (Abeta)-infused animal models. In the current study, we examined the effects of L-NBP on learning and memory in a triple-transgenic AD mouse model (3xTg-AD) that develops both plaques and tangles with aging, as well as cognitive deficits. Ten-month-old 3xTg-AD mice were given 15 mg/kg L-NBP by oral gavage for 18 weeks. L-NBP treatment significantly improved learning deficits, as well as long-term spatial memory, compared with vehicle control treatment. L-NBP treatment significantly reduced total cerebral Abeta plaque deposition and lowered Abeta levels in brain homogenates but had no effect on fibrillar Abeta plaques, suggesting preferential removal of diffuse Abeta deposits. Furthermore, we found that L-NBP markedly enhanced soluble amyloid precursor protein secretion (alphaAPPs), alpha-secretase, and PKCalpha expression but had no effect on steady-state full-length APP. Thus, L-NBP may direct APP processing toward a non-amyloidogenic pathway and preclude Abeta formation in the 3xTg-AD mice. The effect of l-NBP on regulating APP processing was further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human APP(695) (SK-N-SH APPwt). L-NBP treatment in 3xTg-AD mice also reduced glial activation and oxidative stress compared with control treatment. L-NBP shows promising preclinical potential as a multitarget drug for the prevention and/or treatment of Alzheimer's disease.