Frailty in ageing persons with multiple sclerosis.

BACKGROUND: Recent progress in multiple sclerosis (MS) management has contributed to a greater life expectancy in persons with MS. Ageing with MS comes with unique challenges and bears the potential to greatly affect quality of life and socioeconomic burden. OBJECTIVES: To compare frailty in ageing persons with multiple sclerosis (pwMS) and controls; to correlate frailty with MS clinical characteristics. METHODS: PwMS and controls over 50 years old were recruited in a cross-sectional study. Two validated frailty measures were assessed: the frailty index and the Fried's phenotype. Several multiple linear regressions accounting for demographic and clinical characteristics were performed. RESULTS: Eighty pwMS (57 females, mean age 58.5 ± 6 years old) and 37 controls (24 females, mean age 61 ± 6.5 years old) were recruited. Multivariable analysis identified significantly higher frailty index in pwMS (0.21 ± 0.12 vs 0.11 ± 0.08, p < 0.0001). Similarly, according to Fried's phenotype, a significantly higher percentage of pwMS were frail compared to controls (28% vs 8%). In pwMS, frailty index was independently associated with expanded disability status scale (EDSS), comorbidities, education level and disease duration. CONCLUSION: Our results suggest that frailty can be routinely assessed in pwMS. Increased frailty in MS patients suggests that, along with MS therapeutics, a tailored multidisciplinary approach of ageing pwMS is needed.

Effectiveness of an Activity Tracker- and Internet-Based Adaptive Walking Program for Adults: A Randomized Controlled Trial.

BACKGROUND: The benefits of physical activity are well documented, but scalable programs to promote activity are needed. Interventions that assign tailored and dynamically adjusting goals could effect significant increases in physical activity but have not yet been implemented at scale. OBJECTIVE: Our aim was to examine the effectiveness of an open access, Internet-based walking program that assigns daily step goals tailored to each participant. METHODS: A two-arm, pragmatic randomized controlled trial compared the intervention to no treatment. Participants were recruited from a workplace setting and randomized to a no-treatment control (n=133) or to treatment (n=132). Treatment participants received a free wireless activity tracker and enrolled in the walking program, Walkadoo. Assessments were fully automated: activity tracker recorded primary outcomes (steps) without intervention by the participant or investigators. The two arms were compared on change in steps per day from baseline to follow-up (after 6 weeks of treatment) using a two-tailed independent samples t test. RESULTS: Participants (N=265) were 66.0% (175/265) female with an average age of 39.9 years. Over half of the participants (142/265, 53.6%) were sedentary (<5000 steps/day) and 44.9% (119/265) were low to somewhat active (5000-9999 steps/day). The intervention group significantly increased their steps by 970 steps/day over control (P<.001), with treatment effects observed in sedentary (P=.04) and low-to-somewhat active (P=.004) participants alike. CONCLUSIONS: The program is effective in increasing daily steps. Participants benefited from the program regardless of their initial activity level. A tailored, adaptive approach using wireless activity trackers is realistically implementable and scalable. TRIAL REGISTRATION: Clinicaltrials.gov NCT02229409, https://clinicaltrials.gov/ct2/show/NCT02229409 (Archived by WebCite at http://www.webcitation.org/6eiWCvBYe).

Melanoma cell adhesion molecule identifies encephalitogenic T lymphocytes and promotes their recruitment to the central nervous system.

In multiple sclerosis, encephalitogenic CD4(+) lymphocytes require adhesion molecules to accumulate into central nervous system inflammatory lesions. Using proteomic techniques, we identified expression of melanoma cell adhesion molecule (MCAM) on a subset of human effector memory CD4(+) lymphocytes and on human blood-brain barrier endothelium. Herein, we demonstrate that MCAM is a stable surface marker that refines the identification of interleukin 17(+), interleukin 22(+), RAR-related orphan receptor γ and interleukin 23 receptor(+) cells within the CD161(+)CCR6(+) subset of memory CD4(+) lymphocytes. We also show that MCAM(+) lymphocytes express significantly more granulocyte/macrophage colony stimulating factor and granzyme B than MCAM(-) lymphocytes. Furthermore, the proportion of MCAM(+) CD4(+) lymphocytes is significantly increased in the blood and in the central nervous system of patients with multiple sclerosis and experimental autoimmune encephalomyelitis animals compared with healthy controls or other neurological diseases, and MCAM expression is upregulated at the blood-brain barrier within inflammatory lesions. Moreover, blockade of MCAM or depletion of MCAM(+) CD4(+) T lymphocytes both restrict the migration of T(H)17 lymphocytes across blood-brain barrier endothelial cells and decrease the severity of experimental autoimmune encephalomyelitis. Our findings indicate that MCAM could serve as a potential biomarker for multiple sclerosis and represents a valuable target for the treatment of neuroinflammatory conditions.

Central nervous system recruitment of effector memory CD8+ T lymphocytes during neuroinflammation is dependent on α4 integrin.

Clonally expanded CD8(+) T lymphocytes are present in multiple sclerosis lesions, as well as in the cerebrospinal fluid of patients with multiple sclerosis. In experimental autoimmune encephalomyelitis, CD8(+) T lymphocytes are found in spinal cord and brainstem lesions. However, the exact phenotype of central nervous system-infiltrating CD8(+) T lymphocytes and the mechanism by which these cells cross the blood-brain barrier remain largely unknown. Using cerebrospinal fluid from patients with multiple sclerosis, spinal cord from experimental autoimmune encephalomyelitis and coronavirus-induced encephalitis, we demonstrate that central nervous system-infiltrating CD8(+) T lymphocytes are mostly of the effector memory phenotype (CD62L(-) CCR7(-) granzymeB(hi)). We further show that purified human effector memory CD8(+) T lymphocytes transmigrate more readily across blood-brain barrier-endothelial cells than non-effector memory CD8(+) T lymphocytes, and that blood-brain barrier endothelium promotes the selective recruitment of effector memory CD8(+) T lymphocytes. Furthermore, we provide evidence for the recruitment of interferon-γ- and interleukin-17-secreting CD8(+) T lymphocytes by human and mouse blood-brain barrier endothelium. Finally, we show that in vitro migration of CD8(+) T lymphocytes across blood-brain barrier-endothelial cells is dependent on α4 integrin, but independent of intercellular adhesion molecule-1/leucocyte function-associated antigen-1, activated leucocyte cell adhesion molecule/CD6 and the chemokine monocyte chemotactic protein-1/CCL2. We also demonstrate that in vivo neutralization of very late antigen-4 restricts central nervous system infiltration of CD8(+) T lymphocytes in active immunization and adoptive transfer experimental autoimmune encephalomyelitis, and in coronavirus-induced encephalitis. Our study thus demonstrates an active role of the blood-brain barrier in the recruitment of effector memory CD8(+) T lymphocytes to the CNS compartment and defines α4 integrin as a major contributor of CD8(+) T lymphocyte entry into the brain.

Social influence as a driver of engagement in a web-based health intervention.

BACKGROUND: Web-based health interventions can drive behavior change, but their effectiveness depends on participants' usage. A well-recognized challenge with these interventions is nonusage attrition or weak engagement that results in participants receiving low doses of the intervention, negatively affecting outcomes. We present an approach based on the theoretical concepts of social influence and complex contagion in an effort to address the engagement problem in a specific, commercial, online behavior change intervention. OBJECTIVE: To examine the relation between social ties and engagement within a specific online intervention. The aims were (1) to determine whether experiencing the intervention socially influences engagement, such that individuals with social ties show higher engagement than those without ties, and (2) to evaluate whether complex contagion increases engagement-that is, whether engagement increases as the number of ties an individual has in the intervention increases. METHODS: We analyzed observational data from 84,828 subscribed members of a specific Web-based intervention, Daily Challenge. We compiled three measures of engagement for every member: email opens, site visits, and challenge completions (response to action prompts). We compared members with and without social ties within the intervention on each measure separately using 2-tailed independent-sample t tests. Finally, we performed linear regressions with each simple engagement measure as the dependent variable and number of social ties as the independent variable. RESULTS: Compared with those without social ties, participants with social ties opened more emails (33.0% vs 27.2%, P < .001), visited the website more often (12.6 vs 6.7 visits, P < .001), and reported completing more of the actions they were prompted to perform (11.0 vs 6.1 actions, P < .001). Social ties were significant predictors of email opens (beta = 0.68, P < .001), site visits (beta = 1.52, P < .001), and reported action completions (beta = 1.32, P < .001). CONCLUSIONS: Our initial findings are higher engagement in participants with social ties in the program and are consistent with the view that social influence can drive engagement in a Web-based health intervention.

Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis.

OBJECTIVE: There is substantial evidence supporting the role of interferon (IFN)-gamma-producing T helper (T(H)) 1 and interleukin (IL)-17-expressing T(H)17 lymphocytes in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). However, to date little is known about the potential cooperative interplay between these 2 cytokines. In the current study, we sought to evaluate the frequency of IFN-gamma-expressing T(H)17 lymphocytes in MS and EAE, and study their recruitment into the central nervous system (CNS). METHODS: Human T(H)17 lymphocytes were expanded in vitro from the blood of healthy controls and relapsing MS patients using IL-23. Immune cell migration to the CNS was assessed in vitro with primary cultures of human blood-brain barrier (BBB)-derived endothelial cells, and in vivo in EAE mice. RESULTS: We demonstrate that in response to IL-23, human memory lymphocytes expand into a T(H)17 phenotype, with a subpopulation of cells simultaneously expressing IFN-gamma and IL-17. We note that lymphocytes obtained from the blood of relapsing MS patients have an increased propensity to expand into IFN-gamma-producing T(H)17 cells and identify numerous T lymphocytes coexpressing IL-17 and IFN-gamma in brain tissue of MS patients. We also find lymphocytes expressing both the T(H)1- and the T(H)17-associated transcription factors ROR gamma t and T-bet, in situ and in vitro. We further provide in vitro and in vivo evidence that IFN-gamma(+) T(H)17 lymphocytes preferentially cross the human BBB and accumulate in the CNS of mice during the effector phase of EAE. INTERPRETATION: Our data underscore the involvement of IFN-gamma(+) T(H)17 lymphocytes in the pathology of MS and EAE and their preferential recruitment into the CNS during inflammatory events.

The real-time processing of sluiced sentences.

Ellipsis refers to an element that is absent from the input but whose meaning can nonetheless be recovered from context. In this cross-modal priming study, we examined the online processing of Sluicing, an ellipsis whose antecedent is an entire clause: The handyman threw a book to the programmer but I don't know which book the handyman threw to the programmer(ellipsis.) To understand such an elliptical construction, the listener arguably must 'fill in' the missing material ("the handyman threw___ to the programmer") based on that which occurs in the antecedent clause. We aimed to determine the point in time in which reconstruction of the sluiced sentence is attempted and whether such a complex antecedent is re-accessed by the ellipsis. Out of the two antecedent constituents for which we probed, only the Object (programmer) was found active in the elliptical clause, confirming that an antecedent is attributed to the sluice in real time. Possible reasons for the non-observation of the Subject (handyman) are considered. We also suggest that ellipses are detected earlier in coordinated than subordinated sentences.

Interleukin-26, preferentially produced by TH17 lymphocytes, regulates CNS barrier function.

OBJECTIVE: To investigate the involvement of interleukin (IL)-26 in neuroinflammatory processes in multiple sclerosis (MS), in particular in blood-brain barrier (BBB) integrity. METHODS: Expression of IL-26 was measured in serum, CSF, in vitro differentiated T helper (TH) cell subsets, and postmortem brain tissue of patients with MS and controls by ELISA, quantitative PCR, and immunohistochemistry. Primary human and mouse BBB endothelial cells (ECs) were treated with IL-26 in vitro and assessed for BBB integrity. RNA sequencing was performed on IL-26-treated human BBB ECs. Myelin oligodendrocyte glycoprotein35-55 experimental autoimmune encephalomyelitis (EAE) mice were injected IP with IL-26. BBB leakage and immune cell infiltration were assessed in the CNS of these mice using immunohistochemistry and flow cytometry. RESULTS: IL-26 expression was induced in TH lymphocytes by TH17-inducing cytokines and was upregulated in the blood and CSF of patients with MS. CD4+IL-26+ T lymphocytes were found in perivascular infiltrates in MS brain lesions, and both receptor chains for IL-26 (IL-10R2 and IL-20R1) were detected on BBB ECs in vitro and in situ. In contrast to IL-17 and IL-22, IL-26 promoted integrity and reduced permeability of BBB ECs in vitro and in vivo. In EAE, IL-26 reduced disease severity and proinflammatory lymphocyte infiltration into the CNS, while increasing infiltration of Tregs. CONCLUSIONS: Our study demonstrates that although IL-26 is preferentially expressed by TH17 lymphocytes, it promotes BBB integrity in vitro and in vivo and is protective in chronic EAE, highlighting the functional diversity of cytokines produced by TH17 lymphocytes.

The on-line processing of verb-phrase ellipsis in aphasia.

We investigate the on-line processing of verb-phrase ellipsis (VPE) constructions in two brain injured populations: Broca's and Anomic aphasics. VPE constructions are built from two simple clauses; the first is the antecedent clause and the second is the ellipsis clause. The ellipsis clause is missing its verb and object (i.e., its verb phrase (VP)), which receives its reference from the fully specified VP in the antecedent clause. VPE constructions are unlike other sentence types that require displacement of an argument NP; these latter constructions (e.g., object-relatives, wh-questions) yield either on-time or delayed antecedent reactivation. Our results demonstrate that Anomics, like unimpaired individuals, evince reactivation of the direct object NP (within the VP) at the elided position. Broca's patients, on the other hand, do not show reactivation of the antecedent. We consider several interpretations for our data, including explanations focusing on the larger 'grain size' of the reconstructed material in the ellipsis clause, the properties of the auxiliary that carries tense and agreement features, and the possibility that the cost-free syntactic copy procedure claimed to underlie VPE may be modulated by the functional deficit in Broca's aphasia.

CD70 defines a subset of proinflammatory and CNS-pathogenic TH1/TH17 lymphocytes and is overexpressed in multiple sclerosis.

CD70 is the unique ligand of CD27 and is expressed on immune cells only upon activation. Therefore, engagement of the costimulatory CD27/CD70 pathway is solely dependent on upregulation of CD70. However, the T cell-intrinsic effect and function of human CD70 remain underexplored. Herein, we describe that CD70 expression distinguishes proinflammatory CD4+ T lymphocytes that display an increased potential to migrate into the central nervous system (CNS). Upregulation of CD70 on CD4+ T lymphocytes is induced by TGF-ß1 and TGF-ß3, which promote a pathogenic phenotype. In addition, CD70 is associated with a TH1 and TH17 profile of lymphocytes and is important for T-bet and IFN-γ expression by both T helper subtypes. Moreover, adoptive transfer of CD70-/-CD4+ T lymphocytes induced less severe experimental autoimmune encephalomyelitis (EAE) disease than transfer of WT CD4+ T lymphocytes. CD70+CD4+ T lymphocytes are found in the CNS during acute autoimmune inflammation in humans and mice, highlighting CD70 as both an immune marker and an important costimulator of highly pathogenic proinflammatory TH1/TH17 lymphocytes infiltrating the CNS.

A novel locus for idiopathic generalized epilepsy in French-Canadian families maps to 10p11.

Idiopathic generalized epilepsy (IGE) has evidence of a strong genetic etiology. We conducted genomewide linkage analysis for genes responsible for familial IGE in French-Canadian pedigrees. Twenty families segregating autosomal dominant epilepsy were collected. Four larger IGE families sufficiently powerful for independent linkage analysis were genome-scanned and follow-up fine mapping was performed over regions with LOD scores >3.0. The genotyping of 16 smaller families was carried out at significantly linked loci for supportive linkage analysis and haplotype comparisons. One of the four families provided a significant linkage result at marker D10S1426 on chromosome 10 (two-point LOD score = 3.05, theta = 0, multipoint LOD score = 3.18). Fine mapping revealed a segregating haplotype and key recombination breakpoints, suggesting a candidate gene interval of 6.5 Mb. Multipoint linkage analyses using the additional 16 families yielded a maximum LOD score under heterogeneity of 4.23 (alpha = 0.34) at this locus. Evaluation of recombination breakpoints in these families narrowed the candidate region to 1.7 Mb. Sequencing of the two known genes in this region, NRP1 and PARD3, was negative for mutation. Replication of linkage to this locus in other cohorts of IGE families is essential to characterize the underlying genetic mechanism for the disease.

Migration of multiple sclerosis lymphocytes through brain endothelium.

CONTEXT: T-lymphocyte migration through the blood-brain barrier is a central event in the process of lesion formation in multiple sclerosis (MS). OBJECTIVES: To assess the ability of lymphocytes derived from the peripheral blood of patients with clinically active and inactive MS to migrate across an artificial model of the blood-brain barrier and to elucidate the molecular mechanisms involved in such a process. DESIGN: We developed an in vitro model of lymphocyte migration using a Boyden chamber coated with a monolayer of human brain microvascular endothelial cells. RESULTS: The rates of migration of lymphocytes obtained from patients with acutely relapsing and active secondary progressive MS was significantly increased compared with those obtained from healthy controls and patients with inactive secondary progressive disease. Ribonuclease protection assays and enzyme-linked immunosorbent assays indicated that monocyte chemoattractant protein 1 and interleukin 8 were the major chemokines produced by brain endothelial cells grown under the culture conditions used for the migration assays. The rate of migration of the MS lymphocytes could be inhibited by 60% with an antimonocyte chemoattractant protein 1 monoclonal antibody, indicating a functional role for this chemokine in the migration process. In agreement with previous reports, we found that the tissue inhibitor of metalloproteinase 1, a matrix metalloproteinase inhibitor, also reduced migration of MS lymphocytes by 50%. CONCLUSIONS: The results demonstrate an increased migration rate of MS T lymphocytes across the brain endothelium barrier and that such migration is dependent on chemokine monocyte chemoattractant protein 1 and on matrix metalloproteinases.

Long-term treatment optimization in individuals with multiple sclerosis using disease-modifying therapies: a nursing approach.

The introduction of disease-modifying therapies (DMTs) for multiple sclerosis (MS) over the last 7 years has had a significant effect on the management of those living with this disease. Initially, the focus of improving treatment outcomes was on ensuring adherence to therapy by managing drug-related adverse events. However, treatment adherence is only one facet of ensuring optimal health outcomes for patients using DMTs. Therefore, a group of 80 nurses from Canada and the United States (The North American MS Nurses' Treatment Optimization Group) developed an evidence-based nursing approach to address the various factors involved in obtaining optimal patient outcomes. The goal of this nursing approach is to ensure the best possible clinical, subclinical, psychosocial, and quality-of-life outcomes for patients with MS using DMTs.

Effectiveness of a multimodal online well-being intervention: a randomized controlled trial.

BACKGROUND: Well-being encompasses physical, psychological, and social aspects of health and predicts healthcare utilization and expenditures. Despite their potential clinical impact, interventions that leverage social network effects to target well-being are uncommon. PURPOSE: Using a pragmatic design, to evaluate the effectiveness of an online well-being intervention as part of ongoing program development. DESIGN: Randomized, placebo-controlled, parallel-group trial with longitudinal outcome measurements at baseline, 30 days, and 90 days. PARTICIPANTS/SETTING: A total of 1503 U.S.-based adults were enrolled. Recruitment, eligibility verification, and baseline data collection were conducted entirely online; follow-up took place online or by phone. The study was conducted in 2012. INTERVENTION: A multimodal e-mail-, web-, and mobile-based intervention (Daily Challenge), in which participants receive daily suggestions of small health actions that they complete in a social environment. A traditional weekly health newsletter served as control. MAIN OUTCOME MEASURE: Overall well-being as measured by the Individual-level Well-Being Assessment and Scoring Method (scale: 0 to 100). RESULTS: Follow-up rates reached 68.7% (n=1032) at 30 days and 62.6% (n=940) at 90 days. Overall, 84.6% of treatment group participants visited the website, and 76.5% opened program e-mails (vs 51.1% in the control group). Daily Challenge improved well-being significantly more than control at 30 days (2.27 points, p=0.004) and at 90 days (2.35 points, p=0.004). A dose response for intensity of use was observed at 30 days (p=0.001) and 90 days (p=0.003). Well-being improvement was greater in participants with than without social ties in the program (at 30 days: p=0.02; at 90 days: p=0.003). CONCLUSIONS: A multimodal online intervention leveraging social network effects significantly improved well-being over control. Higher levels of participation as well as increasing levels of social integration were associated with greater improvement in well-being. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01586949).

Implementation of an online pragmatic randomized controlled trial: a methodological case study.

Rigorous evaluation of eHealth interventions is acutely needed but can be challenging to execute in a cost- and time-efficient way. The purpose of this study is to describe a randomized controlled trial carried out as part of an approach that evaluates and informs product development throughout an intervention's life cycle. We present the methodological case of a pragmatic randomized controlled trial evaluating the effectiveness of the web-based intervention "Daily Challenge." We conducted the trial entirely online and leveraged existing resources to implement it quickly and within budget. One thousand five hundred three participants were recruited in 49 days (17.1 % of candidates assessed for eligibility). Then, 68.7 % of participants were reached for follow-up at 30 days and 62.5 % at 90 days. Data collection (baseline to 90-day follow-up) was completed within 5 months. Rigorous trials can be conducted efficiently and in a timely manner, enabling evaluation on a continuous basis. Development should include ongoing empirical input to inform product iterations.

The role of parallelism in the real-time processing of anaphora.

Parallelism effects refer to the facilitated processing of a target structure when it follows a similar, parallel structure. In coordination, a parallelism-related conjunction triggers the expectation that a second conjunct with the same structure as the first conjunct should occur. It has been proposed that parallelism effects reflect the use of the first structure as a template that guides the processing of the second. In this study, we examined the role of parallelism in real-time anaphora resolution by charting activation patterns in coordinated constructions containing anaphora, Verb-Phrase Ellipsis (VPE) and Noun-Phrase Traces (NP-traces). Specifically, we hypothesised that an expectation of parallelism would incite the parser to assume a structure similar to the first conjunct in the second, anaphora-containing conjunct. The speculation of a similar structure would result in early postulation of covert anaphora. Experiment 1 confirms that following a parallelism-related conjunction, first-conjunct material is activated in the second conjunct. Experiment 2 reveals that an NP-trace in the second conjunct is posited immediately where licensed, which is earlier than previously reported in the literature. In light of our findings, we propose an intricate relation between structural expectations and anaphor resolution.