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  • Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex.

    20 November 2017

    OBJECTIVE: Neuronal loss, a key substrate of irreversible disability in multiple sclerosis (MS), is a recognized feature of MS cortical pathology of which the cause remains unknown. Fibrin(ogen) deposition is neurotoxic in animal models of MS, but has not been evaluated in human progressive MS cortex. The aim of this study was to investigate the extent and distribution of fibrin(ogen) in progressive MS cortex and elucidate its relationship with neurodegeneration. METHODS: A postmortem cohort of pathologically confirmed MS (n = 47) and control (n = 10) cases was used. The extent and distribution of fibrin(ogen) was assessed and related to measures of demyelination, inflammation, and neuronal density. In a subset of cases (MS, n = 20; control, n = 10), expression of plasminogen activator inhibitor 1 (PAI-1), a key enzyme in the fibrinolytic cascade, was assessed and related to the extent of fibrin(ogen). RESULTS: Motor cortical fibrin(ogen) deposition was significantly over-represented in MS compared to control cases in all compartments studied (ie, extracellular [p = 0.001], cell body [p = 0.003], and neuritic/glial-processes [p = 0.004]). MS cases with high levels of extracellular fibrin(ogen) had significantly upregulated PAI-1 expression in all cortical layers assessed (p < 0.05) and reduced neuronal density (p = 0.017), including in the functionally-relevant layer 5 (p = 0.001). INTERPRETATION: For the first time, we provide unequivocal evidence that fibrin(ogen) is extensively deposited in progressive MS motor cortex, where regulation of fibrinolysis appears perturbed. Progressive MS cases with severe fibrin(ogen) deposition have significantly reduced neuronal density. Future studies are needed to elucidate the provenance and putative neurotoxicity of fibrin(ogen), and its potential impact on clinical disability. Ann Neurol 2017;82:259-270.

  • Cultivating the multiple sclerosis workforce of the future

    27 October 2017

    © 2017 Consortium of Multiple Sclerosis Centers. Multiple sclerosis (MS) is a complex neurologic disorder that affects people with ever-changing needs. The MS health-care field has entered an era of exponential knowledge growth in which better understanding of the immunologic dysregulation of the disease has translated into an expanding array of treatment options. It is estimated that, if it has not already, within the next decade the demands of a growing MS patient population will outstrip the number of professionals dedicated to the management of this chronic, lifelong disease. Therefore, there is a pressing need to attract and retain clinicians in this dynamic field. In response to this need, the Foundation of the Consortium of Multiple Sclerosis Centers organized a 2-day colloquium, a Mentorship Forum, on January 23-24, 2015, bringing together talented internal medicine and neurology trainees from across North America with an interest in MS and neuroimmunology. This article highlights the rationale for the MS Mentorship Forum, its structure and content, and its outcomes. We believe that the stage has been set to interest young, promising clinicians in learning more about MS and to encourage them to consider a career in this field. In so doing, we hope to contribute to the development of the next generation of MS experts to make a palpable difference in the lives of those affected by MS.

  • Effects of dopamine on reinforcement learning and consolidation in Parkinson's disease.

    20 November 2017

    Emerging evidence suggests that dopamine may modulate learning and memory with important implications for understanding the neurobiology of memory and future therapeutic targeting. An influential hypothesis posits that dopamine biases reinforcement learning. More recent data also suggest an influence during both consolidation and retrieval. Eighteen Parkinson's disease patients learned through feedback ON or OFF medication, with memory tested 24 hr later ON or OFF medication (4 conditions, within-subjects design with matched healthy control group). Patients OFF medication during learning decreased in memory accuracy over the following 24 hr. In contrast to previous studies, however, dopaminergic medication during learning and testing did not affect expression of positive or negative reinforcement. Two further experiments were run without the 24 hr delay, but they too failed to reproduce effects of dopaminergic medication on reinforcement learning. While supportive of a dopaminergic role in consolidation, this study failed to replicate previous findings on reinforcement learning.

  • Changes in health-related quality of life (HRQoL) after discharge from intensive care unit: a protocol for a systematic review.

    27 October 2017

    INTRODUCTION: Treatment on an intensive care unit (ICU) imposes a high treatment burden on patients, as well as an economic burden for the healthcare provider. Many studies have recorded health-related quality of life (HRQoL) in patients after treatment on an ICU. We propose a systematic review of these studies. METHODS: We will search the National Library of Medicine's PubMed electronic database (PubMed), the Cochrane database, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science and Open Grey to identify papers reporting quality of life after discharge from ICU. We will include papers including validated quality of life measures. We will examine three categories: populations of patients treated on general ICUs, patients with severe infections and patients with respiratory dysfunction. We will extract HRQoL data. We will assess papers for risk of bias using the QUADAS-2 tool. The strength of our conclusions will depend on the quality and number of papers showing uniform results. ETHICS AND DISSEMINATION: This review will use published literature and contains no primary data; so we do not need ethical approval. We will submit the outcome of the systematic review to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015024700.