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Abstract Blood pressure (BP) is a dynamic measure that is frequently discussed in static terms. There exist many limitations in current documentation systems whereby documented BP values may not be reflective of the dynamic variability of BP. This study used an observational, prospective, non-randomized study design to examine the variability in BP response during intravenous vasoactive medication administration in an intensive care unit setting. Subjects admitted to a neuroscience intensive care unit were monitored continuously during a 12-hour period. The BP values include systolic BP, diastolic BP, and mean arterial pressure. Intermittent values from an intra-arterial figurecatheter (a-line) and continuously sampled values from an a-line obtained using continuous data acquisition (CDA) software, were compared to intermittently sampling of cuff-based BP measurements documented in the medical record. The 30 patients provided 1,220,511 BP observations from CDA, 944 from a-line documentation, and 416 from cuff-based BP documentation. The systolic BP was used as a goal parameter for 23 (77%) of the patients. Repeated measures models demonstrated that on average cuff-based differed from intermittent a-line and from CDA (p

Abstract Objective Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2‐item scale polygenic score with anxiety in MS. Methods Using a case–control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview‐diagnosed, and lifetime self‐report physician‐diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome‐wide association study and was tested using regression. Results A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta‐analyses identified that in MS, each 1‐SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09–1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. Interpretation Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Background: Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation. Cladribine tablets act as a synthetic adenosine analog, disrupting DNA synthesis and repair, thereby reducing the number of lymphocytes. The generation of prospective, rigorous safety, and efficacy data in transitioning from natalizumab to cladribine is an unmet clinical need. Objectives: To test the feasibility of transitioning patients with relapsing forms of MS natalizumab to cladribine tablets. Design: Cladribine tablets after treatment with natalizumab (CLADRINA) is an open-label, single-arm, multicenter, collaborative phase IV, research study that will generate hypothesis regarding the safety, efficacy, and immunological impact of transition from natalizumab to cladribine tablets in patients with relapsing forms of MS. Methods and analysis: Participants will be recruited from three different sites. The primary endpoint is the absolute and percent change from baseline of lymphocytes and myeloid cell subsets, as well as blood neurofilament light levels. The secondary endpoint is the annualized relapse rate over the 12- and 24-month trial periods. Exploratory endpoints include the expanded disability status scale, and magnetic resonance imaging outcomes. Discussion: The CLADRINA trial will generate data regarding the safety, efficacy, and immunological impact of the transition from natalizumab to cladribine. As the pace of immunological knowledge of MS continues, insight into disease modifying therapy transition strategies is needed.

Background: Treatment guidelines recommend early disease-modifying therapy (DMT) initiation after diagnosis of multiple sclerosis (MS). Multinational comparative studies that assess time to DMT initiation in MS may allow detection of barriers inherent to healthcare systems to explain potential adverse systematic delays in commencing DMTs. Objectives: To investigate and compare the time to first DMT and its association with sociodemographic and clinical variables after MS diagnosis in three large MS registries. Design: This observational study was conducted using data from the German MS Registry (GMSR), the North American Research Committee on MS Registry (NARCOMS, US data only), and the United Kingdom MS Registry (UKMSR, both self- and clinician-reported). Methods: Data from relapsing people with MS (PwMS), with a diagnosis of MS between 2014 and 2019, and available DMT and disability status were pooled using a meta-analytic approach. Results: A total of 5395 PwMS were included in the analysis (GMSR: n = 2658; NARCOMS: n = 447; UKMSR: n = 2290). Kaplan–Meier estimates for the time to first DMT [median months (95% CI)] were 2.0 (1.9–2.0), 3.0 (2–4), and 9.0 (7.7–10.6) for GMSR, NARCOMS, and UKMSR, respectively. Pooled multivariable Cox regression demonstrated shorter time to first DMT for PwMS diagnosed after 2017 [1.65 (1.42–1.92), p

BackgroundA scoping review found that most studies on women’s health in multiple sclerosis (MS) focused on pregnancy, fetal/neonatal outcomes and sexual dysfunction. Few studies addressed menopause, contraception, gynecologic cancers/cancer screening. However, the perceived relative importance of these knowledge gaps to people living with MS and other partners is unknown. We engaged a range of partners, including people living with MS, health care providers, researchers, and patient advocacy groups, to set priorities for future research in women’s health in MS.MethodsWe employed a three-step global engagement process. First, we identified which broad research topics relevant to women’s health in MS were of highest priority using two surveys. Second, we developed specific research questions within these topics using focus groups. Finally, we prioritized the research questions with a third survey.ResultsOverall, 5,266 individuals responded to the initial surveys [n = 1,430 global survey, mean (SD) age 50.0 (12.6), all continents; n = 3,836 North American Research Committee on Multiple Sclerosis survey, mean (SD) age 64.8 (9.6), United States]. Menopause, sexual dysfunction, pregnancy, gynecologic cancer/cancer screening, hormones and parenthood were identified as the most important topics. Focus groups generated 80 potential research questions related to these topics. In the final survey 712 individuals prioritized these questions. The highest priority questions in each research topic were: (i) How do perimenopause and menopause affect disease activity, course, response to disease-modifying treatment and quality of life in MS; (ii) What are the most effective strategies for managing issues around sexual intimacy, including related to low sexual desire, changes in physical function, and MS symptoms; (iii) Are there long-term effects of disease-modifying therapies on the children of persons with MS; (iv) What are the short and long-term effects of disease-modifying drugs on gynecologic cancer risk, particularly for high efficacy disease-modifying drugs and hematopoietic stem cell transplantation; (v) Are there hormone related treatments that can stabilize fluctuations in MS symptoms; and (vi) How does MS fatigue impact parenting strategies.ConclusionPriorities for research relating to women’s health issues for persons with MS have been delineated using a collaborative process with key partners. Alignment of future research with these priorities should be monitored.

Multiple sclerosis (MS) is the most common non-traumatic cause of disability in young people, with vision loss in the disease representing the second largest contributor to disability. In particular, African-American patients with MS are noted to have lower vision than their Caucasian counterparts. In this review, we examine the disparities in eye diseases in the MS population with our gaps in knowledge and discuss the underlying nature of pathological disparities.

Comorbid conditions commonly affect people with multiple sclerosis (MS). Population-based studies indicate that people with MS have an increased incidence of ischemic heart disease, cerebrovascular disease, peripheral vascular disease, and psychiatric disorders as compared to people without MS. People with MS from underrepresented minority and immigrant groups have higher comorbidity burdens. Comorbidities exert effects throughout the disease course, from symptom onset through diagnosis to the end of life. At the individual level, comorbidity is associated with higher relapse rates, greater physical and cognitive impairments, lower health-related quality of life, and increased mortality. At the level of the health system and society, comorbidity is associated with increased health care utilization, costs and work impairment. A nascent literature suggests that MS affects outcomes from comorbidities. Comorbidity management needs to be integrated into MS care, and this would be facilitated by determining optimal models of care.

ObjectiveResearch directly examining brain tissue has played an important role in understanding the pathology and pathogenesis of multiple sclerosis (MS) and other diseases of the central nervous system. Such research relies heavily on donations of post-mortem brain tissue yet little is known about the attitudes of people with multiple sclerosis (MS) about brain donation. We aimed to assess the attitudes of people with MS toward brain donation, their preferences related to discussions of brain donation, and factors associated with attitudes toward brain donation including sociodemographic and clinical characteristics, health literacy and religiosity.MethodsIn a cross-sectional study, we surveyed participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry regarding their attitudes toward brain donation, reasons for participating or not participating in brain donation, and related communication preferences. We used multivariable logistic regression analyses to test factors associated with attitudes regarding brain donation.ResultsMost of the 4,520 participants were women (80.8%), self-identified as white (88.1%), with a post-secondary education, functional health literacy and moderate-severe disability. Sixty-two percent of participants would consider brain donation. Factors associated with considering brain donation included female gender, having a post-secondary education, being physically active, having moderate-severe disability and more comorbidities, and alcohol intake. Seventy-five percent of participants indicated that they preferred to receive information regarding brain donations from physicians.ConclusionTwo-thirds of people with MS would consider brain donation. People with MS desire to hear about brain donation from their health care providers rather than other sources.

BACKGROUND There is currently limited literature addressing the reporting of alopecia in multiple sclerosis (MS) patients treated with disease-modifying therapies (DMTs). Anecdotal reports of hair thinning from patients on various DMTs prompted further investigation of a large database. OBJECTIVE To analyze total reports, source of reporting, age distribution, and sex distribution of alopecia associated with DMTs. METHODS FDA Adverse Event Reporting System (FAERS) public dashboard and OpenFDA database were analyzed for alopecia reports between January 1, 2009, and June 30, 2020, attributed to usage in MS of FDA approved DMTs. The main outcomes included total reports for each drug, age, sex distribution, and reporting source. OpenFDA data was used for statistical analyses including reporting odds ratios (ROR) and information components. RESULTS 8759 alopecia reports were identified among 44 114 adverse events in skin and subcutaneous tissue disorders (19.9%). 3701 (42.3%) with teriflunomide, 1675 (19.1%) with dimethyl fumarate, 985 (11.2%) with natalizumab, 926 (10.6%) with fingolimod, 659 (7.5%) with interferon beta-1a, 257 (2.9%) with glatiramer acetate, 243 (2.8%) with ocrelizumab, 124 (1.4%) with interferon beta-1b, 117 (1.3%) with alemtuzumab, 36 (.4%) with siponimod, 24 (.3%) with cladribine, and 12 (.1%) with rituximab. Reports were mostly made by patients (78.3%) and highest in fifth and sixth decades of life. OpenFDA analyses showed increased ROR (ROR 95% confidence interval) of alopecia in females with teriflunomide (18.00, 17.12-18.93), alemtuzumab (1.43, 1.16-1.76), dimethyl fumarate (1.26, 1.18-1.34), and ocrelizumab (1.28, 1.11-1.49). Increased ROR in males was associated with teriflunomide (24.65, 20.72-29.31). CONCLUSION We identified many reports of alopecia for DMTs in addition to teriflunomide. Within the limitations of the database, increased RORs of alopecia were observed for females treated with alemtuzumab, dimethyl fumarate, and ocrelizumab. The source of reporting was largely driven by female patients. Possible alopecia, even if transient, should be considered during patient education when starting DMTs.

Abstract Background Cognitive dysfunction affects up to 70% of people with progressive MS (PMS). It can exert a deleterious effect on activities of daily living, employment and relationships. Preliminary evidence suggests that performance can improve with cognitive rehabilitation (CR) and aerobic exercise (EX), but existing data are predominantly from people with relapsing-remitting MS without cognitive impairment. There is therefore a need to investigate whether this is also the case in people with progressive forms of the disease who have objectively identified cognitive impairment. It is hypothesized that CR and EX are effective treatments for people with PMS who have cognitive impairment, in particular processing speed (PS) deficits, and that a combination of these two treatments is more effective than each individual treatment given alone. We further hypothesize that improvements in PS will be associated with modifications of functional and/or structural plasticity within specific brain networks/regions involved in PS measured with advanced MRI techniques. Methods This study is a multisite, randomized, double-blinded, sham controlled clinical trial of CR and aerobic exercise. Three hundred and sixty subjects from 11 sites will be randomly assigned into one of four groups: CR plus aerobic exercise; CR plus sham exercise; CR sham plus aerobic exercise and CR sham plus sham exercise. Subjects will participate in the assigned treatments for 12 weeks, twice a week. All subjects will have a cognitive and physical assessment at baseline, 12 weeks and 24 weeks. In an embedded sub-study, approximately 30% of subjects will undergo structural and functional MRI to investigate the neural mechanisms underlying the behavioral response. The primary outcome is the Symbol Digit Modalities Test (SDMT) measuring PS. Secondary outcome measures include: indices of verbal and non-verbal memory, depression, walking speed and a dual cognitive-motor task and MRI. Discussion The study is being undertaken in 6 countries (11 centres) in multiple languages (English, Italian, Danish, Dutch); with testing material validated and standardized in these languages. The rationale for this approach is to obtain a robustly powered sample size and to demonstrate that these two interventions can be given effectively in multiple countries and in different languages. Trial registration The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468 . Registration was performed before recruitment was initiated.

Background Multiple sclerosis (MS) lesions typically form around a central vein that can be visualized with FLAIR* MRI, creating the central vein sign (CVS) which may reflect lesion pathophysiology. Herein we used gradient echo plural contrast imaging (GEPCI) MRI to simultaneously visualize CVS and measure tissue damage in MS lesions. We examined CVS in relation to tissue integrity in white matter (WM) lesions and among MS subtypes. Objective We aimed to determine if CVS positive lesions were specific to MS subtype, if CVS can be detected consistently among readers using the GEPCI method, and if there were differences in tissue damage in lesions with vs without CVS. Subjects and Methods Thirty relapsing-remitting MS (RRMS) subjects and 38 primary and secondary progressive MS (PMS) subjects were scanned with GEPCI protocol at 3T. GEPCI T2*-SWI images were generated to visualize CVS. Two investigators independently evaluated WM lesions for CVS and measured lesion volumes. To estimate tissue damage severity, total lesion volume, and mean lesion volume, R2t*-based tissue damage score (TDS) of individual lesions and tissue damage load (TDL) were measured for CVS+, CVS-, and confluent lesions. Spearman correlations were made between MRI and clinical data. One-way ANCOVA with age and sex as covariates was used to compare measurements of CVS+ vs CVS- lesions in each individual. Results 398 of 548 lesions meeting inclusion criteria showed CVS. Most patients had ≥40% CVS+ lesions. CVS+ lesions were present in similar proportion among MS subtypes. Interobserver agreement was high for CVS detection. CVS+ and confluent lesions had higher average and total volumes vs CVS- lesions. CVS+ and confluent lesions had more tissue damage than CVS- lesions based on TDL and mean TDS. Conclusion CVS occurred in RRMS and PMS in similar proportions. CVS+ lesions had greater tissue damage and larger size than CVS- lesions.

Summary: Background: Multiple sclerosis (MS) has a complex genetic, immune and metabolic pathophysiology. Recent studies implicated the gut microbiome in MS pathogenesis. However, interactions between the microbiome and host immune system, metabolism and diet have not been studied over time in this disorder. Methods: We performed a six-month longitudinal multi-omics study of 49 participants (24 untreated relapse remitting MS patients and 25 age, sex, race matched healthy control individuals. Gut microbiome composition and function were characterized using 16S and metagenomic shotgun sequencing. Flow cytometry was used to characterize blood immune cell populations and cytokine profiles. Circulating metabolites were profiled by untargeted UPLC-MS. A four-day food diary was recorded to capture the habitual dietary pattern of study participants. Findings: Together with changes in blood immune cells, metagenomic analysis identified a number of gut microbiota decreased in MS patients compared to healthy controls, and microbiota positively or negatively correlated with degree of disability in MS patients. MS patients demonstrated perturbations of their blood metabolome, such as linoleate metabolic pathway, fatty acid biosynthesis, chalcone, dihydrochalcone, 4-nitrocatechol and methionine. Global correlations between multi-omics demonstrated a disrupted immune-microbiome relationship and a positive blood metabolome-microbiome correlation in MS. Specific feature association analysis identified a potential correlation network linking meat servings with decreased gut microbe B. thetaiotaomicron, increased Th17 cell and greater abundance of meat-associated blood metabolites. The microbiome and metabolome profiles remained stable over six months in MS and control individuals. Interpretation: Our study identified multi-system alterations in gut microbiota, immune and blood metabolome of MS patients at global and individual feature level. Multi-OMICS data integration deciphered a potential important biological network that links meat intakes with increased meat-associated blood metabolite, decreased polysaccharides digesting bacteria, and increased circulating proinflammatory marker. Funding: This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS10263304 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-180531003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG-190734474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Objective: Since the properties of health-related quality of life measures vary across samples, studies directly comparing the properties of different measures can be useful in understanding their relative strengths and limitations. We aimed to compare the psychometric properties of the Health Utilities Index Mark III (HUI3) and the Multiple Sclerosis Impact Scale-29 (MSIS-29).Methods: In Spring 2020, North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants completed the HUI3, MSIS-29, Patient Determined Disease Steps (PDDS) and SymptoMScreen. For the HUI3 and MSIS-29 we assessed floor and ceiling effects, construct validity, and internal consistency reliability. We used relative efficiency to compare the discriminating ability of the two measures with respect to disability.Results: We included 5,664 participants in the analysis, with mean (SD) age 63 (10.1) years; 4,579 (80.8%) were women. For the HUI3 the mean (SD) score was 0.44 (0.32), for the MSIS-29 physical it was 34.0 (24.2) and for the MSIS-29 psychological it was 25.9 (20.4). Neither of the measures had floor or ceiling effects, and internal consistency reliability was > 0.70 for both. The HUI3 and MSIS-29 physical were strongly correlated (r = −0.78; 95%CI:−0.79,−0.77). The correlation between the HUI3 and MSIS-29 psychological was weaker but remained moderately strong (r = −0.64; 95%CI:−0.66,−0.63). After adjusting for sociodemographic and clinical factors, relative efficiency to discriminate between disability (PDDS) groups was highest for the MSIS-29 physical scale, followed by the HUI3.Conclusion: Both measures had adequate validity and reliability. The MSIS-29 physical discriminated between disability groups better than the HUI3.

Introduction: Intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) are both standard of care treatments for acute ischemic stroke patients with large vessel occlusion (LVO) who are eligible for one or both treatments. IVT may result in early recanalization in some patients with LVO. The objective of this study is to analyze whether IVT influences pre‐thrombectomy clot lysis in LVO acute ischemic strokes. Methods: We reviewed prospectively collected data for all patients with LVO ischemic strokes who were transferred to the angiography suite with intention to perform EVT at a single comprehensive stroke center between January 2016 to December 2018. We identified subjects who showed partial or complete clot lysis vs no lysis based on the first angiographic picture of the occluded territory at the time of the initial vessel selection. Descriptive statistics were used to summarize demographic and clinical characteristics. We compared key predictor variables between lysis and no lysis groups including baseline variables, effect of IVT, time from IVT to groin puncture, LVO location, final modified treatment in cerebral ischemia (mTICI) score and discharge Modified Rankin Scale (mRS). t‐test or Kruskal‐Wallis test for continuous variables and chi square test or Fisher’s Exact test for categorical variables. Results: Two hundred and fifty‐nine patients were included. Among these patients, 10.8% (28/259) showed partial or complete lysis of the clot vs 89.2% (231/259) with no lysis. Among these patients who showed clot lysis, 16/28 (57.1%) received IVT. The use of IVT did not show differences between both groups (p = 0.18). There were no differences in the baseline characteristics except for gender, which was the only variable significantly associated with clot lysis. Men had 2‐fold higher odds of spontaneous lysis compared to females (OR [95%CI]: 2.39 [1.01, 5.65], p = 0.04). There was significant difference in the final mTICI between both groups (p

Background: The mycobiome is the fungal component of the gut microbiome and is implicated in several autoimmune diseases. However, its role in MS has not been studied. Methods: In this case-control observational study, we performed ITS sequencing and characterised the gut mycobiome in people with MS (pwMS) and healthy controls at baseline and after six months. Findings: The mycobiome had significantly higher alpha diversity and inter-subject variation in pwMS than controls. Saccharomyces and Aspergillus were over-represented in pwMS. Saccharomyces was positively correlated with circulating basophils and negatively correlated with regulatory B cells, while Aspergillus was positively correlated with activated CD16+ dendritic cells in pwMS. Different mycobiome profiles, defined as mycotypes, were associated with different bacterial microbiome and immune cell subsets in the blood. Initial treatment with dimethyl fumarate, a common immunomodulatory therapy which also has fungicidal activity, did not cause uniform gut mycobiome changes across all pwMS. Interpretation: There is an alteration of the gut mycobiome in pwMS, compared to healthy controls. Further study is required to assess any causal association of the mycobiome with MS and its direct or indirect interactions with bacteria and autoimmunity. Funding: This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS102633-04 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-1805-31003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG- 1907-34474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Background: Although the aggregate of data among patients with multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY), most studies have not assessed long-term worsening of disability. We compared long-term disability worsening over 5 years, as assessed by the Patient-Determined Disease Steps (PDDS), among participants with MS treated with DMF or FTY. Methods: We identified individuals in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry who had relapsing-remitting MS (RRMS), residing in the United States (Spring 2011 to Spring 2018), who initiated treatment with DMF ( n = 689) or FTY ( n = 565) and had ⩾1 year follow-up on index treatment. Participants receiving DMF who were previously treated with FTY and those on FTY previously treated with DMF were excluded. Propensity score matching at baseline was used to match FTY-treated to DMF-treated participants. Time to 6-month confirmed disability worsening (⩾1-point increase on PDDS, sustained for ⩾6 months) was estimated using Cox regression. A sensitivity analysis was conducted to account for differences in the duration of index exposure between DMF and FTY groups. Results: After propensity score matching, 468 DMF-treated participants were matched with 468 FTY-treated participants. Median treatment duration was 3.0 years for DMF and 4.0 years for FTY. At 5 years, 68.3% [95% confidence interval (CI): 62.4–73.5] of DMF-treated participants and 63.3% (95% CI: 59.6–70.1) treated with FTY were free from 6-month confirmed PDDS worsening [hazard ratio (HR) 1.01 (95% CI: 0.79–1.28); p = 0.95]. Results were similar in the sensitivity analysis: 70.5% (95% CI: 61.8–77.6) of DMF-treated participants and 72.7% (95% CI: 65.4–78.6) of FTY-treated participants were free from 6-month confirmed PDDS worsening [HR: 1.04 (95% CI: 0.71–1.51); p = 0.84]. Conclusions: In participants with MS from the NARCOMS registry, there was no significant difference in confirmed disability (PDDS) worsening over 5 years between those treated with DMF versus FTY.

Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for their ability to reduce disease activity, namely clinical relapses and signal changes on magnetic resonance imaging (MRI). Disease activity appears age dependent. Thus, the greatest benefit would be expected in younger people with MS (PwMS) whereas benefits in the elderly are uncertain. Methods: Real-world data were obtained from PwMS from the North American Research Committee on Multiple Sclerosis (NARCOMS) registry and the US Department of Veterans Affairs Multiple Sclerosis Surveillance Registry (MSSR). Results: 6948 PwMS were surveyed from NARCOMS, and the MSSR had 1719 participants. In younger adult PwMS 40-years old or less, 183 (61.4%) in NARCOMS and 179 (70.5%) in the MSSR were prescribed DMTs. Among PwMS over age 60, 1575 (40.1%) in NARCOMS and 239 (36.3%) in the MSSR were prescribed DMTs. More PwMS in the age group of 31–40 ( p = 0.035) and 41–50 ( p = 0.001) in the MSSR were using DMTs compared with PwMS of the same age groups in NARCOMS. Conclusion: These findings suggest that DMTs are under-utilized in the younger population and continue to be commonly prescribed in the elderly. Broader access may explain the higher prescription rate of DMTs in US veterans.

Most patients with glioblastoma (GBM) die within 2 years. A major therapeutic goal is to target GBM stem cells (GSCs), a subpopulation of cells that contribute to treatment resistance and recurrence. Since their discovery in 2003, GSCs have been isolated using single-surface markers, such as CD15, CD44, CD133, and α6 integrin. It remains unknown how these single-surface marker–defined GSC populations compare with each other in terms of signaling and function and whether expression of different combinations of these markers is associated with different functional capacity. Using mass cytometry and fresh operating room specimens, we found 15 distinct GSC subpopulations in patients, and they differed in their MEK/ERK, WNT, and AKT pathway activation status. Once in culture, some subpopulations were lost and previously undetectable ones materialized. GSCs that highly expressed all 4 surface markers had the greatest self-renewal capacity, WNT inhibitor sensitivity, and in vivo tumorigenicity. This work highlights the potential signaling and phenotypic diversity of GSCs. Larger patient sample sizes and antibody panels are required to confirm these findings.

Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for the treatment of disease activity and are effective in reducing relapses and new magnetic resonance imaging (MRI) lesions. However, disease activity generally subsides with time, and age-dependent changes in DMT efficacy are not well-established. We aimed to investigate whether age impacts the efficacy of DMTs in treating disease activity in patients with relapsing–remitting MS (RRMS). Methods: DMT efficacy related to age was assessed through a meta-analysis of clinical trials that evaluated the efficacy of DMTs in RRMS patients as measured by reductions in the annualized relapse rate (ARR), new T2 lesions, and gadolinium-enhanced lesions on MRI. Using the mean baseline patient age from each trial, a weighted linear regression was fitted to determine whether age was associated with treatment efficacy on a group level. Results: Group-level data from a total of 28,082 patients from 26 trials of 14 different DMTs were included in the meta-analysis. There were no statistically significant associations between age and reductions in ARR, new T2 lesions, and gadolinium-enhanced lesions of the treatment group compared with placebo. Conclusion: DMTs for RRMS show efficacy in treating disease activity independent of age as demonstrated by group-level data from DMT clinical trials. Nevertheless, clinical trials select for patients with baseline disease activity regardless of age, thereby not representing real-world patients with RRMS, where disease activity declines with age.

Background: Radiomics analyses has been proposed to interrogate the biology of tumour as well as to predict/assess response to therapy in vivo. The objective of this work was to assess the sensitivity of radiomics features to noise, resolution, and tumour volume in the context of a co-clinical trial. Methods: Triple negative breast cancer (TNBC) patients were recruited into an ongoing co-clinical imaging trial. Sub-typed matched TNBC patient-derived tumour xenografts (PDX) were generated to investigate optimal co-clinical MR radiomic features. The MR imaging protocol included T1-weighed and T2-weighted imaging. To test the sensitivity of radiomics to resolution, PDX were imaged at three different resolutions. Multiple sets of images with varying signal-to-noise ratio (SNR) were generated, and an image independent patch-based method was implemented to measure the noise levels. Forty-eight radiomic features were extracted from manually segmented 2D and 3D segmented tumours and normal tissues of T1- and T2- weighted co-clinical MR images. Findings: Sixteen radiomics features were identified as volume dependent and corrected for volume-dependency following normalization. Features from grey-level run-length matrix (GLRLM), grey-level size zone matrix (GLSZM) were identified as most sensitive to noise. Radiomic features Kurtosis and Run-length variance (RLV) from GLSZM were most sensitive to changes in resolution in both T1w and T2w MRI. In general, 3D radiomic features were more robust compared to 2D (single slice) measures, although the former exhibited higher variability between subjects. Interpretation: Tumour volume, noise characteristics, and image resolution significantly impact radiomic analysis in co-clinical studies.

PURPOSE:We aimed to evaluate weight changes after left gastric artery (LGA) embolization in a retrospective cancer-naive cohort.METHODS:A retrospective study was conducted to identify patients who underwent LGA embolization for gastrointestinal bleeding (GI). Patients with known cancer diagnoses at the time of LGA embolization were excluded. Pre- and postprocedure weights were assessed. Statistical analysis was performed using paired t-test and Wilcoxon signed-rank test.RESULTS:A total of 39 patients were identified. In 21 patients who had documented pre- and postprocedural weights, a median of 16.3 kg weight loss (P = 0.045) was observed over a median time of 12 months (range, 2–72). In patients who had pre- and postprocedure endoscopies (n=6), 2 had worsening ulcers following LGA embolization and 4 had stable or no abnormal findings.CONCLUSION:Our preliminary observation suggests that LGA embolization is well tolerated and results in unintended weight loss. Larger studies are needed to confirm these preliminary findings.

Introduction: Volumetric biomarkers for Alzheimer disease (AD) are attractive due to their wide availability and ease of administration, but have traditionally shown lower diagnostic accuracy than measures of neuropathological contributors to AD. Our purpose was to optimize the diagnostic specificity of structural MRIs for AD using quantitative, data-driven techniques. Methods: This retrospective study assembled several non-overlapping cohorts (total n = 1287) with publicly available data and clinical patients from Barnes–Jewish Hospital (data gathered 1990–2018). The Normal Aging Cohort (n = 383) contained amyloid biomarker negative, cognitively normal (CN) participants, and provided a basis for determining age-related atrophy in other cohorts. The Training (n = 216) and Test (n = 109) Cohorts contained participants with symptomatic AD and CN controls. Classification models were developed in the Training Cohort and compared in the Test Cohort using the receiver operating characteristics areas under curve (AUCs). Additional model comparisons were done in the Clinical Cohort (n = 579), which contained patients who were diagnosed with dementia due to various etiologies in a tertiary care outpatient memory clinic. Results: While the Normal Aging Cohort showed regional age-related atrophy, classification models were not improved by including age as a predictor or by using volumetrics adjusted for age-related atrophy. The optimal model used multiple regions (hippocampal volume, inferior lateral ventricle volume, amygdala volume, entorhinal thickness, and inferior parietal thickness) and was able to separate AD and CN controls in the Test Cohort with an AUC of 0.961. In the Clinical Cohort, this model separated AD from non-AD diagnoses with an AUC 0.820, an incrementally greater separation of the cohort than by hippocampal volume alone (AUC of 0.801, p = 0.06). Greatest separation was seen for AD vs. frontotemporal dementia and for AD vs. non-neurodegenerative diagnoses. Conclusions: Volumetric biomarkers distinguished individuals with symptomatic AD from CN controls and other dementia types but were not improved by controlling for normal aging.

Clinical trials of new treatments in multiple sclerosis (MS) currently require large sample sizes and long durations in order to yield reliable results. The differential responses of an already heterogeneous population of MS patients to individual disease-modifying therapies (DMTs) will further complicate future trials. MS trials with smaller samples and faster outcomes are conceivable through the substitution of current clinical and MRI outcomes with objectively measureable genomic and proteomic biomarkers. Currently, biomarkers that could be utilized for diagnosis and monitoring of MS disease activity are in the early validation phase. The power of single biomarkers or multiple correlated biomarkers to predict prognosis and response to treatment could initially be compared with currently accepted methods. These prospectively validated disease biomarkers could then be used to subcategorize the spectrum of MS patients into a finite number of endophenotypes with demonstrable different molecular pathogeneses and DMT response profiles. Newly developed DMT could potentially be assessed within specific endophenotypes and compared with pharmacogenomically relevant active comparator DMT. This approach may increase the efficiency of MS trials through homogenization of patient population and minimization of nonresponders in study groups, providing the potential for the development of targeted therapies.

Clinical trials have advanced the treatment of multiple sclerosis (MS) by demonstrating the safety and efficacy of disease-modifying therapies (DMTs). This review discusses major changes to MS clinical trials in the era of DMTs. As treatment options for MS continue to increase, patients in modern MS trials present earlier and with milder disease compared with historic MS populations. While placebo-controlled trials for some questions may still be relevant, DMT trials in relapsing–remitting MS (RRMS) are no longer ethical. The replacement of the placebo arm by an active comparator arm in trials have raised the cost of trials by requiring larger sample sizes to detect on-study changes in treatment effects. Efforts to improve trial efficiency in RRMS have focused on exploring adaptive designs and relying on sensitive magnetic resonance imaging measures of disease activity. In trials for progressive forms of MS (PMS), the lack of sensitive outcome measures that can be used in shorter-term trials have delayed the development of effective treatments. Recent shifting of the focus to advancing trials in PMS has identified paraclinical outcome measurements with improved potential, and the testing of agents for neuroprotection and remyelination is in progress.

BackgroundCancer patients undergoing Doxorubicin (DOX) treatment are susceptible to acute and chronic cardiac anomalies, including aberrant arrhythmias, ventricular dysfunction, and heart failure. To stratify patients at high risk for DOX -related heart failure (CHF), diagnostic techniques have been sought. While echocardiography is used for monitoring LVEF and LV volumes due to its wide-availability and cost-efficiency, it may not identify early stages of the initiation of DOX-induced systolic heart failure. To address these limitations, PET tracers could also provide noninvasive assessment of early and reversible metabolic changes of the myocardium.ObjectiveHerein, we report a preliminary investigation of 68Ga-Galmydar potential to monitor Dox-induced cardiomyopathy in vivo, ex vivo, and in cellulo employing both nuclear- and optical imaging.Methods and resultsTo assess 68Ga-Galmydar ability for monitoring DOX-induced cardiomyopathy, microPET imaging was performed 5 d post treatment of rats either with a single dose of DOX (15 mg/kg) or vehicle as a control (saline) and images were co-registered for anatomical reference using CT. Following tail-vein injection of the radiotracer in rats at 60 min, micro-PET/CT static scan (10 min acquisition), 68Ga-Galmydar demonstrated 1.91-fold lower uptake in hearts of DOX-treated (standard uptake value; SUV: 0.92, n = 3) rats compared with their vehicle treated (SUV: 1.76, n = 3) control counterparts. For correlation of PET imaging data, post-imaging quantitative biodistribution studies were also performed, wherein excised organs were counted for γ activity, and normalized to injected dose. The post imaging pharmacokinetic data also demonstrated heart uptake values of 2.0 fold lower for DOX treated rats(%ID/g; DOX: 0.44 ± 0.1, n = 3) compared to their vehicle-treated controls (%ID/g; Control: 0.89 ± 0.03, n = 3, p = 0.04). Employing the fluorescent traits of Galmydar, live cell fluorescence imaging indicated a gradual decrease in uptake and retention of Galmydar within mitochondria of H9c2 cells following DOX-treatment, while indicating dose-dependent and time-dependent uptake profiles. Following depolarization of electronegative transmembrane gradients at the mitochondrial membrane, the uptake of the probe was decreased in H9c2 cells, and the uptake profiles were found to be identical, using both fluorescence and radiotracer bioassays. Finally, the decreased uptake of the metalloprobe in H9c2 cells also correlated with caspase-3 expression resulting from DOX-induced cardiotoxicity and cell death.Conclusions68Ga-Galmydar could provide a noninvasive assessment of DOX-related and likely reversible metabolic changes at earliest stages. Further studies with other chemotherapeutics (potentially capable of inducing cardiomyopathy) are underway.

ObjectivesPrimary brain tumors are composed of tumor cells, neural/glial tissues, edema, and vasculature tissue. Conventional MRI has a limited ability to evaluate heterogeneous tumor pathologies. We developed a novel diffusion MRI-based method-Heterogeneity Diffusion Imaging (HDI)-to simultaneously detect and characterize multiple tumor pathologies and capillary blood perfusion using a single diffusion MRI scan.MethodsSeven adult patients with primary brain tumors underwent standard-of-care MRI protocols and HDI protocol before planned surgical resection and/or stereotactic biopsy. Twelve tumor sampling sites were identified using a neuronavigational system and recorded for imaging data quantification. Metrics from both protocols were compared between World Health Organization (WHO) II and III tumor groups. Cerebral blood volume (CBV) derived from dynamic susceptibility contrast (DSC) perfusion imaging was also compared with the HDI-derived perfusion fraction.ResultsThe conventional apparent diffusion coefficient did not identify differences between WHO II and III tumor groups. HDI-derived slow hindered diffusion fraction was significantly elevated in the WHO III group as compared with the WHO II group. There was a non-significantly increasing trend of HDI-derived tumor cellularity fraction in the WHO III group, and both HDI-derived perfusion fraction and DSC-derived CBV were found to be significantly higher in the WHO III group. Both HDI-derived perfusion fraction and slow hindered diffusion fraction strongly correlated with DSC-derived CBV. Neither HDI-derived cellularity fraction nor HDI-derived fast hindered diffusion fraction correlated with DSC-derived CBV.ConclusionsConventional apparent diffusion coefficient, which measures averaged pathology properties of brain tumors, has compromised accuracy and specificity. HDI holds great promise to accurately separate and quantify the tumor cell fraction, the tumor cell packing density, edema, and capillary blood perfusion, thereby leading to an improved microenvironment characterization of primary brain tumors. Larger studies will further establish HDI's clinical value and use for facilitating biopsy planning, treatment evaluation, and noninvasive tumor grading.

The achievements in multiple sclerosis (MS) therapeutics are founded on the outcomes of clinical trials that demonstrate quantifiable results in treating a disease with an unpredictable course. Much has changed since the early trials in MS from the mid-20th century that compared a potential therapeutic agent with a placebo and measured outcomes based on patients’ subjective reports. Advancements over the past decades have simplified diagnosis of the disease and allowed for more quantitative monitoring of its progression alongside support from paraclinical studies. Further collaborative efforts have led to pivotal meetings that steered the direction of future trials and the creation of patient databases that provided important epidemiologic information on trial subjects. These innovations and changes have improved MS clinical trials but challenge future trials to create more efficient designs lest the pace of progress necessarily slows because of the increased time to conduct such studies. As treatment options for MS broaden, clinical trials will continue to incorporate new strategies to identify novel therapies and pathways of intervention.

Volume loss in some limbic region structures has been observed in multiple sclerosis (MS) patients. However, in vivo evaluation of existing tissue cellular microstructure integrity has received less attention. The goal of studies reported here was to quantitatively assess loss of limbic system volumes and tissue integrity, and to evaluate associations of these measures with cognitive and physical dysfunction in MS patients. Thirty-one healthy controls (HC) and 80 MS patients, including 32 relapsing remitting (RRMS), 32 secondary progressive (SPMS) and 16 primary progressive (PPMS), participated in this study. Tissue cellular integrity was evaluated by means of recently introduced tissue-specific parameter R2t* that was calculated from multi-gradient-echo MRI signals using a recently developed method that separates R2t* from BOLD (blood oxygen level dependent) contributions to GRE signal decay rate constant (R2*), and accounting for physiological fluctuations and artifacts from background gradients. Volumes in limbic system regions, normalized to skull size (NV), were measured from standard MPRAGE images. MS patients had lower R2t* and smaller normalized volumes in the hippocampus, amygdala, and several other limbic system regions, compared to HC. Alterations in R2t* of several limbic system regions correlated with clinical and neurocognitive test scores in MS patients. In contrast, smaller normalized volumes in MS were only correlated with neurocognitive test scores in the hippocampus and amygdala. This study reports the novel finding that R2t*, a measure that estimates tissue integrity, is more sensitive to tissue damage in limbic system structures than is atrophy. R2t* measurements can serve as a biomarker that is distinct from and complementary to volume measurements.

Background: Mycophenolate mofetil (MMF) is an oral DNA base synthesis inhibitor with immunomodulatory effects on B cells, T cells, and macrophages. Objective: To conduct a safety and tolerability pilot study of interferon beta-1a (IFN-b1a) in combination with either placebo or oral MMF in multiple sclerosis (MS). Methods: Twenty-four treatment-naïve R—RMS patients participated in a one-year prospective, placebo-controlled, blinded, safety pilot clinical trial. Every patient injected weekly intramuscular interferon beta-1a. The cohort was then randomized (1 : 1) to either active oral MMF or identical-appearing placebo tablets. Clinical evaluations were assessed every 3 months, along with brain MRI scans performed at baseline and repeated every 60 days for one year. Comprehensive laboratory assessments were monitored for safety, along with adverse events. Results: In this small pilot investigation, no differences were identified between the two treatment groups with respect to patient-reported adverse events, MRI metrics, or laboratory abnormalities. Notwithstanding these observations, and the limited number of patients treated, trends appeared to favor the combination therapy regimen. Conclusions: The combination treatment regimen of interferon beta-1a and MMF appeared to be well tolerated in this pilot study. Despite the small sample size, therapeutic trends were observed in favor of combination therapy. An adequately powered controlled trial of MMF in MS appears warranted.

Background: Mycophenolate mofetil (MMF, CellCept ® ) has been utilized as an antirejection agent in transplant recipients and in patients with myriad autoimmune disorders including multiple sclerosis (MS). Objective: To investigate radiographic and clinical safety involving monotherapy use of daily oral MMF (1 g b.i.d.) versus weekly intramuscular interferon beta 1a (Avonex ® at 30 mcg) in relapsing-remitting MS (RRMS). Methods: We organized a randomized, serial, 6-monthly, MRI-blinded, parallel-group multicenter pilot study to determine the safety of MMF versus interferon beta monotherapy in 35 untreated patients with RRMS, all of whom exhibited evidence of gadolinium (Gd) enhancement on a screening MRI of the brain. The primary outcome was the reduction in the cumulative mean number of combined active lesions (CAL), new Gd-enhancing lesions, and new T2 lesions on MRI analyses. Results: Both interferon beta and MMF appeared safe and well tolerated in the majority of patients. There was no difference between MMF therapy and the standard regimen of interferon beta therapy on the primary safety MRI endpoints of the study. However, the MMF group showed a trend toward a lower accumulation of combined active lesions, CAL, Gd and T2 lesions when compared with interferon beta treated patients. Conclusions: The results from this pilot study suggest that the application of MMF monotherapy in MS deserves further exploration.