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      New perspectives on central and peripheral immune responses to acute traumatic brain injury

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          Abstract

          Traumatic injury to the brain (TBI) results in a complex set of responses involving various symptoms and long-term consequences. TBI of any form can cause cognitive, behavioral and immunologic changes in later life, which underscores the problem of underdiagnosis of mild TBI that can cause long-term neurological deficits. TBI disrupts the blood–brain barrier (BBB) leading to infiltration of immune cells into the brain and subsequent inflammation and neurodegeneration. TBI-induced peripheral immune responses can also result in multiorgan damage. Despite worldwide research efforts, the methods of diagnosis, monitoring and treatment for TBI are still relatively ineffective. In this review, we delve into the mechanism of how TBI-induced central and peripheral immune responses affect the disease outcome and discuss recent developments in the continuing effort to combat the consequences of TBI and new ways to enhance repair of the damaged brain.

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          Most cited references146

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          The role of inflammation in CNS injury and disease.

          For many years, the central nervous system (CNS) was considered to be 'immune privileged', neither susceptible to nor contributing to inflammation. It is now appreciated that the CNS does exhibit features of inflammation, and in response to injury, infection or disease, resident CNS cells generate inflammatory mediators, including proinflammatory cytokines, prostaglandins, free radicals and complement, which in turn induce chemokines and adhesion molecules, recruit immune cells, and activate glial cells. Much of the key evidence demonstrating that inflammation and inflammatory mediators contribute to acute, chronic and psychiatric CNS disorders is summarised in this review. However, inflammatory mediators may have dual roles, with detrimental acute effects but beneficial effects in long-term repair and recovery, leading to complications in their application as novel therapies. These may be avoided in acute diseases in which treatment administration might be relatively short-term. Targeting interleukin (IL)-1 is a promising novel therapy for stroke and traumatic brain injury, the naturally occurring antagonist (IL-1ra) being well tolerated by rheumatoid arthritis patients. Chronic disorders represent a greater therapeutic challenge, a problem highlighted in Alzheimer's disease (AD); significant data suggested that anti-inflammatory agents might reduce the probability of developing AD, or slow its progression, but prospective clinical trials of nonsteroidal anti-inflammatory drugs or cyclooxygenase inhibitors have been disappointing. The complex interplay between inflammatory mediators, ageing, genetic background, and environmental factors may ultimately regulate the outcome of acute CNS injury and progression of chronic neurodegeneration, and be critical for development of effective therapies for CNS diseases.
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            Neuronal 'On' and 'Off' signals control microglia.

            Recent findings indicate that neurons are not merely passive targets of microglia but rather control microglial activity. The variety of different signals that neurons use to control microglia can be divided into two categories: 'Off' signals constitutively keep microglia in their resting state and antagonize proinflammatory activity. 'On' signals are inducible and include purines, chemokines, glutamate. They instruct microglia activation under pathological conditions towards a beneficial or detrimental phenotype. Various neuronal signaling molecules thus actively control microglia function, thereby contribute to the inflammatory milieu of the central nervous system. Thus, neurons should be envisaged as key immune modulators in the brain.
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              White matter integrity and cognition in chronic traumatic brain injury: a diffusion tensor imaging study.

              Traumatic brain injury (TBI) is a serious public health problem. Even injuries classified as mild, the most common, can result in persistent neurobehavioural impairment. Diffuse axonal injury is a common finding after TBI, and is presumed to contribute to outcomes, but may not always be apparent using standard neuroimaging. Diffusion tensor imaging (DTI) is a more recent method of assessing axonal integrity in vivo. The primary objective of the current investigation was to characterize white matter integrity utilizing DTI across the spectrum of chronic TBI of all severities. A secondary objective was to examine the relationship between white matter integrity and cognition. Twenty mild, 17 moderate to severe TBI and 18 controls underwent DTI and neuropsychological testing. Fractional anisotropy, axial diffusivity and radial diffusivity were calculated from the DTI data. Fractional anisotropy was the primary measure of white matter integrity. Region of interest analysis included anterior and posterior corona radiata, cortico-spinal tracts, cingulum fibre bundles, external capsule, forceps minor and major, genu, body and splenium of the corpus callosum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus and sagittal stratum. Cognitive domain scores were calculated from executive, attention and memory testing. Decreased fractional anisotropy was found in all 13 regions of interest for the moderate to severe TBI group, but only in the cortico-spinal tract, sagittal stratum and superior longitudinal fasciculus for the mild TBI group. White Matter Load (a measure of the total number of regions with reduced FA) was negatively correlated with all cognitive domains. Analysis of radial and axial diffusivity values suggested that all severities of TBI can result in a degree of axonal damage, while irreversible myelin damage was only apparent for moderate to severe TBI. The present data emphasize that white matter changes exist on a spectrum, including mild TBI. An index of global white matter neuropathology (White Matter Load) was related to cognitive function, such that greater white matter pathology predicted greater cognitive deficits. Mechanistically, mild TBI white matter changes may be primarily due to axonal damage as opposed to myelin damage. The more severe injuries impact both. DTI provides an objective means for determining the relationship of cognitive deficits to TBI, even in cases where the injury was sustained years prior to the evaluation.
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                Author and article information

                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central
                1742-2094
                2012
                12 October 2012
                : 9
                : 236
                Affiliations
                [1 ]Nanomedicine Research Center, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL, 33612, USA
                [2 ]Department of Internal Medicine, Division of Translational Medicine, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL, 33612, USA
                [3 ]Department of Molecular Medicine, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL, 33612, USA
                [4 ]James A. Haley Veteran’s Hospital and Medical Research Center, 13000 Bruce B. Downs Blvd., Tampa, FL, 33612, USA
                Article
                1742-2094-9-236
                10.1186/1742-2094-9-236
                3526406
                23061919
                af32ab68-382b-48c5-8633-6326b88d0cfa
                Copyright ©2012 Das et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 June 2012
                : 4 September 2012
                Categories
                Review

                Neurosciences
                chemokines,neuroinflammation,stem cells,blood–brain barrier,traumatic brain injury,cytokines

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