Immunomodulatory therapy with glatiramer acetate reduces endoplasmic reticulum stress and mitochondrial dysfunction in experimental autoimmune encephalomyelitis.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are found in lesions of multiple sclerosis (MS) and animal models of MS such as experimental autoimmune encephalomyelitis (EAE), and may contribute to the neuronal loss that underlies permanent impairment. We investigated whether glatiramer acetate (GA) can reduce these changes in the spinal cords of chronic EAE mice by using routine histology, immunostaining, and electron microscopy. EAE spinal cord tissue exhibited increased inflammation, demyelination, mitochondrial dysfunction, ER stress, downregulation of NAD+ dependent pathways, and increased neuronal death. GA reversed these pathological changes, suggesting that immunomodulating therapy can indirectly induce neuroprotective effects in the CNS by mediating ER stress.

Novel use of existing technology: A preliminary study of patient portal use for telerehabilitation.

CLINICALTRIALS.GOV IDENTIFIER: NCT02665052. Registered 27 January 2016. https://clinicaltrials.gov/ct2/show/NCT02665052.

7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder.

The combined antiretroviral therapy era has significantly increased the lifespan of people with HIV (PWH), turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In PWH, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile. Therefore, we investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. In these brain regions, we observed astrogliosis, increased expression of chemokine HIV-1 coreceptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Moreover, our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB-Akt-NFkB signaling pathway in mediating these pathological hallmarks. These findings guide future research as DHF shows promise as a TrkB agonist treatment for HAND patients in adjunction to the current antiviral therapies.

Comparing Home Upper Extremity Activity with Clinical Evaluations of Arm Function in Chronic Stroke.

OBJECTIVE: To determine if clinical evaluations of post-stroke arm function correspond to everyday motor performance indexed by arm accelerometers. DESIGN: Cross-sectional study analyzing baseline data from a larger trial (NCT02665052). SETTING: Outpatient research center. PARTICIPANTS: Twenty community-dwelling adults with chronic arm motor deficits (stroke≥6mo). INTERVENTION: 72-hours of home wrist-worn accelerometry during normal routine. MAIN OUTCOME MEASURES: Clinical evaluations included the Fugl-Meyer (FM), Action Research Arm Test (ARAT), Wolf Motor Function Test (WMFT), and two self-assessments: the Motor Activity Log (MAL) and hand motor subscale of the Stroke Impact Scale (SIS). Accelerometer-derived variables included quantifications of movement intensity (magnitude) and duration of arm use. RESULTS: Participants had moderate arm impairment (FM 36.1 ± 9.4). The accelerometer-derived mean magnitude ratio correlated significantly with the FM (ρ = 0.60, p < 0.01), WMFT functional score (ρ = 0.59, p < 0.01), and ARAT (ρ = 0.50, p < 0.05). The hours of use ratio correlated with the MAL amount of use (ρ = 0.58, p < 0.01) and quality of movement (ρ = 0.61, p < 0.01). Total paretic hours did not correlate with the FM, WMFT or ARAT, and intensity variables did not correlate with the MAL or SIS. CONCLUSIONS: Participants with higher baseline function had greater intensity of paretic arm movement at home; similarly, those who perceived they had less disability used their paretic arm more relative to their non-paretic arm. However, some participants with higher clinical scores did not exhibit greater arm use in everyday life, possibly due to neglect and learned non-use. Therefore, individualized home accelerometry profiles could provide valuable insight to better tailor post-stroke rehabilitation.

Research Lifecycle to Increase the Substantial Real-world Impact of Research: Accelerating Innovations to Application.

BACKGROUND: US health care systems face a growing demand to incorporate innovations that improve patient outcomes at a lower cost. Funding agencies increasingly must demonstrate the impact of research investments on public health. The Learning Health System promotes continuous institutional innovation, yet specific processes to develop innovations for further research and implementation into real-world health care settings to maximize health impacts have not been specified. OBJECTIVE: We describe the Research Lifecycle and how it leverages institutional priorities to support the translation of research discoveries to clinical application, serving as a broader operational approach to enhance the Learning Health System. METHODS: Developed by the US Department of Veterans Affairs Office of Research and Development Research-to-Real-World Workgroup, the Research Lifecycle incorporates frameworks from product development, translational science, and implementation science methods. The Lifecycle is based on Workgroup recommendations to overcome barriers to more direct translation of innovations to clinical application and support practice implementation and sustainability. RESULTS: The Research Lifecycle posits 5 phases which support a seamless pathway from discovery to implementation: prioritization (leadership priority alignment), discovery (innovation development), validation (clinical, operational feasibility), scale-up and spread (implementation strategies, performance monitoring), and sustainability (business case, workforce training). An example of how the Research Lifecycle has been applied within a health system is provided. CONCLUSIONS: The Research Lifecycle aligns research and health system investments to maximize real-world practice impact via a feasible pathway, where priority-driven innovations are adapted for effective clinical use and supported through implementation strategies, leading to continuous improvement in real-world health care.

Robot-Assisted Arm Training in Chronic Stroke: Addition of Transition-to-Task Practice.

Background. Robot-assisted therapy provides high-intensity arm rehabilitation that can significantly reduce stroke-related upper extremity (UE) deficits. Motor improvement has been shown at the joints trained, but generalization to real-world function has not been profound. Objective. To investigate the efficacy of robot-assisted therapy combined with therapist-assisted task training versus robot-assisted therapy alone on motor outcomes and use in participants with moderate to severe chronic stroke-related arm disability. Methods. This was a single-blind randomized controlled trial of two 12-week robot-assisted interventions; 45 participants were stratified by Fugl-Meyer (FMA) impairment (mean 21 ± 1.36) to 60 minutes of robot therapy (RT; n = 22) or 45 minutes of RT combined with 15 minutes therapist-assisted transition-to-task training (TTT; n = 23). The primary outcome was the mean FMA change at week 12 using a linear mixed-model analysis. A subanalysis included the Wolf Motor Function Test (WMFT) and Stroke Impact Scale (SIS), with significance P <.05. Results. There was no significant 12-week difference in FMA change between groups, and mean FMA gains were 2.87 ± 0.70 and 4.81 ± 0.68 for RT and TTT, respectively. TTT had greater 12-week secondary outcome improvements in the log WMFT (-0.52 ± 0.06 vs -0.18 ± 0.06; P = .01) and SIS hand (20.52 ± 2.94 vs 8.27 ± 3.03; P = .03). Conclusion. Chronic UE motor deficits are responsive to intensive robot-assisted therapy of 45 or 60 minutes per session duration. The replacement of part of the robotic training with nonrobotic tasks did not reduce treatment effect and may benefit stroke-affected hand use and motor task performance.

Interplay between ER stress and autophagy: A possible mechanism in multiple sclerosis pathology.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system that results in demyelination, neurodegeneration, and axonal loss. During MS pathology, autoreactive T cells specific for self-antigens migrate the blood-brain-barrier and are responsible for the axonal and neuronal damage. ER stress, a disruption in cellular homeostasis due to the accumulation of misfolded proteins, is a hallmark of MS pathology. In response to the homeostatic imbalance, ER stress activates the unfolded protein response, an intricate system of signaling pathways that aims to restore cellular balance. During the UPR, various autophagy pathways are also activated. Autophagy is a diverse network of regulatory catabolic processes which direct the clearance of damaged and unnecessary organelles and proteins while recycling necessary cellular components. In respect to its role in the health of the immune system, autophagy is critical to the survival and proliferation of T cells. This review consolidates current knowledge and recent literature about ER stress, UPR, and autophagy in MS and implicate their crosstalk as a characteristic feature of MS, potentially aiding in the development of novel therapeutic strategies for MS research.

A multicenter randomized controlled trial of two group education programs for fatigue in multiple sclerosis: Short- and medium-term benefits.

BACKGROUND: Fatigue occurs in 75%-95% of people with multiple sclerosis (MS) and is frequently reported as the most disabling symptom. A multicomponent group program of six weekly 2-hour sessions, Fatigue: Take Control (FTC), was developed from an international MS fatigue management guideline. OBJECTIVE: To determine whether FTC is associated with greater improvements in fatigue than MS: Take Control (MSTC), a similarly structured general MS education program. METHODS: This four-site, parallel, single-blind, randomized controlled trial compared FTC and MSTC in 204 ambulatory participants with MS. The primary outcome, the Modified Fatigue Impact Scale (MFIS), and secondary outcomes of self-efficacy, physical activity, sleep, and medications were assessed at baseline, program completion, and 3 and 6 months later. RESULTS: Mean MFIS scores improved in both groups between baseline and program completion (FTC -4.4, p < 0.001; MSTC -3.8, p < 0.001), between baseline and 3 months after program completion (FTC -3.2, p = 0.01; MSTC -3.3, p = 0.01), and between baseline and 6 months after program completion (FTC -5.2, p < 0.001; MSTC -4.8, p < 0.001). These improvements were not statistically different between groups ( p = 0.64, 0.92, and 0.82, respectively). CONCLUSION: Participation in FTC modestly improved self-reported fatigue for up to 6 months. This improvement did not differ significantly from that occurring with the control program.

A subset of mobilized human hematopoietic stem cells express germ layer lineage genes which can be modulated by culture conditions.

BACKGROUND: Adult bone marrow contains stem cells that replenish the myeloid and lymphoid lineages. A subset of human and mouse CD34+ bone marrow stem cells can be propagated in culture to autonomously express embryonic stem cell genes and embryonic germ layer lineage genes. The current study was undertaken to determine whether these CD34+ stem cells could be obtained from human blood, whether gene expression could be modulated by culture conditions and whether the cells produce insulin. METHODS: Human peripheral blood buffy coat cells and mobilized CD34+ cells from human blood and from blood from C57Bl/6 J mice were cultured in hybridoma medium or neural stem cell induction medium supplemented with interleukin (IL)-3, IL-6, and stem cell factor (SCF). Changes in mRNA and protein expression were assessed by Western blot analysis and by immunohistochemistry. Mass spectrometry was used to assess insulin production. RESULTS: We were able to culture CD34+ cells expressing embryonic stem cell and embryonic germ layer lineage genes from adult human peripheral blood after standard mobilization procedures and from mouse peripheral blood. Gene expression could be modulated by culture conditions, and the cells produced insulin in culture. CONCLUSION: These results suggest a practical method for obtaining large numbers of CD34+ cells from humans to allow studies on their potential to differentiate into other cell types.

Salutary effects of glibenclamide during the chronic phase of murine experimental autoimmune encephalomyelitis.

BACKGROUND: In multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), inflammation is perpetuated by both infiltrating leukocytes and astrocytes. Recent work implicated SUR1-TRPM4 channels, expressed mostly by astrocytes, in murine EAE. We tested the hypothesis that pharmacological inhibition of SUR1 during the chronic phase of EAE would be beneficial. METHODS: EAE was induced in mice using myelin oligodendrocyte glycoprotein (MOG) 35-55. Glibenclamide (10 µg/day) was administered beginning 12 or 24 days later. The effects of treatment were determined by clinical scoring and tissue examination. Drug within EAE lesions was identified using bodipy-glibenclamide. The role of SUR1-TRPM4 in primary astrocytes was characterized using patch clamp and qPCR. Demyelinating lesions from MS patients were studied by immunolabeling and immunoFRET. RESULTS: Administering glibenclamide beginning 24 days after MOG35-55 immunization, well after clinical symptoms had plateaued, improved clinical scores, reduced myelin loss, inflammation (CD45, CD20, CD3, p65), and reactive astrocytosis, improved macrophage phenotype (CD163), and decreased expression of tumor necrosis factor (TNF), B-cell activating factor (BAFF), chemokine (C-C motif) ligand 2 (CCL2) and nitric oxide synthase 2 (NOS2) in lumbar spinal cord white matter. Glibenclamide accumulated within EAE lesions, and had no effect on leukocyte sequestration. In primary astrocyte cultures, activation by TNF plus IFNγ induced de novo expression of SUR1-TRPM4 channels and upregulated Tnf, Baff, Ccl2, and Nos2 mRNA, with glibenclamide blockade of SUR1-TRPM4 reducing these mRNA increases. In demyelinating lesions from MS patients, astrocytes co-expressed SUR1-TRPM4 and BAFF, CCL2, and NOS2. CONCLUSIONS: SUR1-TRPM4 may be a druggable target for disease modification in MS.

SIRT1 as a potential biomarker of response to treatment with glatiramer acetate in multiple sclerosis.

SIRT1, a NAD dependent histone and protein deacetylase, is a member of the histone deacetylase class III family. We previously showed that SIRT1 mRNA expression is significantly lower in peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients during relapses than in stable patients. We have now investigated SIRT1 as a possible biomarker to predict relapse as well as responsiveness to glatiramer acetate (GA) treatment in relapsing-remitting MS (RRMS) patients. Over the course of 2years, a cohort of 15 GA-treated RRMS patients were clinically monitored using the Expanded Disability Status Scale and assessed for MS relapses. Blood samples collected from MS patients were analyzed for levels of SIRT1 and histone H3 lysine 9 (H3K9) acetylation and dimethylation. During relapses, MS patients had a lower expression of SIRT1 mRNA than did stable MS patients. In addition, there was a significant decrease in H3K9 dimethylation (H3K9me2) during relapses in MS patients when compared to stable patients (p=0.01). Responders to GA treatment had significantly higher SIRT1 mRNA (p=0.01) and H3K9me2 levels than did non-responders (p=0.018). Receiver operating characteristic analysis was used to assess the predictive power of SIRT1 and H3K9me2 as putative biomarkers: for SIRT1 mRNA, the predictive value for responsiveness to GA treatment was 70% (p=0.04) and for H3K9me2 was 71% (p=0.03). Our data suggest that SIRT1 and H3K9me2 could serve as potential biomarkers for evaluating patients' responsiveness to GA therapy in order to help guide treatment decisions in MS.

SIRT1 and NAD+ precursors: Therapeutic targets in multiple sclerosis a review.

Neurodegeneration is an important determinant of disability in multiple sclerosis (MS) but while currently approved treatments reduce inflammation, they have not been shown to reduce neurodegeneration. SIRT1, a NAD dependent protein deacetylase, has been implicated in the pathogenesis of neurodegeneration in neurological diseases including MS. We have studied the role of SIRT1 in experimental autoimmune encephalomyelitis (EAE) and found evidence for a neuroprotective role. In this review we summarize the most recent findings from the use of SIRT1 activators and SIRT1 overexpression in transgenic mice. These data support provide a rational for the use of SIRT1 activators in MS.

Introducing the Axon Registry: An opportunity to improve quality of neurologic care.

Clinical quality data registries are increasingly popular tools used by providers to improve the quality of clinical care and satisfy growing numbers of regulatory and reporting requirements. Specialty societies use registries to provide value to their members and guide improvements in care at the population level. In this article, we outline the rationale, structure, function, and challenges related to the American Academy of Neurology's development of its own clinical quality data registry: the Axon Registry.

TrkB agonist, 7,8-dihydroxyflavone, reduces the clinical and pathological severity of a murine model of multiple sclerosis.

7,8-Dihydroxyflavone (DHF), is a recently described TrkB agonist that readily crosses the blood brain barrier. We treated C57Bl/6 mice with MOG--induced EAE daily with DHF starting on the day of disease induction. Clinical severity of impairment was reduced throughout the course of disease. Pathological examination of brains and spinal cords on day 28 showed that DHF treatment increased the phosphorylation of TrkB and activated downstream signaling pathways including AKT and STAT3 and reduced inflammation, demyelination and axonal loss compared to EAE controls. DHF treatment duplicated the central nervous system effects of brain derived neurotrophic factor in the EAE.

A Clinically Relevant Method of Analyzing Continuous Change in Robotic Upper Extremity Chronic Stroke Rehabilitation.

BACKGROUND: Robots designed for rehabilitation of the upper extremity after stroke facilitate high rates of repetition during practice of movements and record precise kinematic data, providing a method to investigate motor recovery profiles over time. OBJECTIVE: To determine how motor recovery profiles during robotic interventions provide insight into improving clinical gains. METHODS: A convenience sample (n = 22), from a larger randomized control trial, was taken of chronic stroke participants completing 12 sessions of arm therapy. One group received 60 minutes of robotic therapy (Robot only) and the other group received 45 minutes on the robot plus 15 minutes of translation-to-task practice (Robot + TTT). Movement time was assessed using the robot without powered assistance. Analyses (ANOVA, random coefficient modeling [RCM] with 2-term exponential function) were completed to investigate changes across the intervention, between sessions, and within a session. RESULTS: Significant improvement (P < .05) in movement time across the intervention (pre vs post) was similar between the groups but there were group differences for changes between and within sessions (P < .05). The 2-term exponential function revealed a fast and slow component of learning that described performance across consecutive blocks. The RCM identified individuals who were above or below the marginal model. CONCLUSIONS: The expanded analyses indicated that changes across time can occur in different ways but achieve similar goals and may be influenced by individual factors such as initial movement time. These findings will guide decisions regarding treatment planning based on rates of motor relearning during upper extremity stroke robotic interventions.