Long term impact of systemic bacterial infection on the cerebral vasculature and microglia

Background: Systemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes. Repeated or chronic systemic inflammation leads to a state of innate immune tolerance: a protective mechanism against over-activity of the immune system. In this study we investigated the immune adaptation of microglia and brain vascular endothelial cells in response to systemic inflammation or bacterial infection. Methods: Mice were given repeated doses of lipopolysaccharide (LPS) or a single injection of live Salmonella typhimurium. Inflammatory cytokines were measured in serum, spleen and brain, and microglial phenotype studied by immunohistochemistry.mice were infected with Salmonella typhimurium and subsequently challenged with a focal unilateral, intracerebral injection of LPS. Results: Repeated systemic LPS challenges resulted in increased brain IL-1?, TNF? and IL-12 levels, despite attenuated systemic cytokine production. Each LPS challenge induced significant changes in burrowing behaviour. In contrast, brain IL-1? and IL-12 levels in Salmonella typhimurium infected mice increased over three weeks, with high interferon-? levels in the circulation. Behavioural changes were only observed during the acute phase of the infection. Microglia and cerebral vasculature display an activated phenotype, and focal intracerebral injection of LPS 4 weeks after infection results in an exaggerated local inflammatory response when compared to non-infected mice. Conclusions: These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have aprofound effect on the onset and/ or progression of pre-existing neurodegenerative disease.Humans and animals are regularly exposed to bacterial and viral pathogens that can have a considerable impact on our day-to-day living [1]. Upon infection, a set of immune, physiological, metabolic, and behavioural responses is initiated, representing a highly organized strategy of the organism to fight infection. Pro-inflammatory mediators generated in peripheral tissue communicate with the brain to modify behaviour [2], which aids our ability to fight and eliminate the pathogen. The communication pathways from the site of inflammation to the brain have been investigated in animal models and systemic challenge with lipopolysaccharide (LPS) or double stranded RNA (poly I:C) have been widely used to mimic aspects of bacterial and viral infection respectively [3, 4]. These studies have provided evidence that systemically generated inflammatory mediators signal to the brain via both neural and humoral routes, the latter signalling via the circumventricular organs or across the blood-brain barrier (BBB). Signalling into the brain via these routes evokes a response in the perivascular macrophages (PVMs) and microglia, which in turn synthesise diverse inflammatory mediators including cytokines, prostaglandins and nitric oxide [2, 5, 6]. Immune-to-brain communication also occurs in humans who show changes in mood and cognition following systemic inflammation or infection, which are associated with changes in activity in particular regions of the CNS [7-9]. While these changes are part of our normal homeostasis, it is increasingly evident that systemic inflammation has a detrimental effect in animals and also humans, that suffer from chronic neurodegeneration [10, 11]. We, and others, have shown that microglia become primed by on-going neuropathology in the brain, which increases their response towards subsequent inflammatory stimuli, including systemic inflammation [12, 13] Similar findings have been made in aged rodents [14, 15], where it has been shown that there is an exaggerated behavioural and innate immune response in the brainto systemic bacterial and viral infections, but the molecular mechanisms underlying the microglial priming under these conditions is far from understood.Humans and animals are rarely exposed to a single acute systemic inflammatory event: they rather encounter infectious pathogens that replicate in vivo or are exposed to low concentrations of LPS over a prolonged period of time. There is limited information on the impact of non-neurotrophic bacterial infections on the CNS and whether prolonged systemic inflammation will give rise to either a hyper-(priming) or hypo-(tolerance) innate immune response in the brain in response to a subsequent inflammatory stimulus.In this study we measured the levels of cytokines in the serum, spleen and brain as well as assessing sickness behaviour following a systemic bacterial infection using attenuated Salmonella typhimurium SL3261: we compared the effect to that of repeated LPS injections. We show that Salmonella typhimurium caused acute, transient behavioural changes and a robust peripheral immune response that peaks at day 7. Systemic inflammation resulted in a delayed increase in cytokine production in the brain and priming of microglia, which persisted up to four weeks post infection. These effects were not mimicked by repeated LPS challenges. It is well recognised that systemic bacterial and viral infections are significant contributors to morbidity in the elderly [16], and it has been suggested that primed microglia play a role in the increased clinical symptoms seen in patients with Alzheimer’s disease who have systemic inflammation or infections [11, 17]. We show here that systemic infection leads to prolonged cytokine synthesis in the brain and also priming of brain innate immune cells to a subsequent focal inflammatory challenge in the brain parenchyma

Biomarkers of Multiple Sclerosis

The search for an ideal multiple sclerosis biomarker with good diagnostic value, prognostic reference and an impact on clinical outcome has yet to be realized and is still ongoing. The aim of this review is to establish an overview of the frequent biomarkers for multiple sclerosis that exist to date. The review summarizes the results obtained from electronic databases, as well as thorough manual searches. In this review the sources and methods of biomarkers extraction are described; in addition to the description of each biomarker, determination of the prognostic, diagnostic, disease monitoring and treatment response values besides clinical impact they might possess. We divided the biomarkers into three categories according to the achievement method: laboratory markers, genetic-immunogenetic markers and imaging markers. We have found two biomarkers at the time being considered the gold standard for MS diagnostics. Unfortunately, there does not exist a single solitary marker being able to present reliable diagnostic value, prognostic value, high sensitivity and specificity as well as clinical impact. We need more studies to find the best biomarker for MS.publishersversionPeer reviewe

A model of internalized stigma in parents of individuals with disabilities

Background: Stigma has negative impacts on both individuals with disabilities and their caregivers, including poor mental health and social isolation. In the present study, we aimed to test a model of stigma internalization among parents of individuals with disabilities, as this process in not yet completely understood. Aim: Specifically, we explored effects of experienced stigma and neuroticism on affiliate stigma and examined whether perceived stigma and self-blame are mediators in a stigma internalization model. Methods: We recruited 82 parents of individuals with disabilities in Serbia over the course of six months. Parents were asked about perceived stigma, experienced stigma, affiliate stigma, self-blame, and they completed an assessment of personality traits. Results: Both experienced stigma and neuroticism were positively correlated with affiliate stigma. In addition, perceived stigma was a mediator between these variables: parents who experienced stigma more and had higher neuroticism scores reported higher degrees of perceived stigma, which in turn positively affected affiliate stigma. Self-blame was not a significant mediator in the tested model. Conclusion: We conclude stigma internalization among parents of individuals with disabilities is a complex process, involving experienced stigma, neuroticism, and perceived stigma. Interventions should include multiple paths to adequately support parents to combat stigma

Bacterial peptidoglycan and immune reactivity in the central nervous system in multiple sclerosis

Multiple sclerosis is believed to result from a CD4+ T-cell response against myelin antigens. Peptidoglycan, a major component of the Gram-

The reliability and validity of the PALOC-s: a post-acute level of consciousness scale for assessment of young patients with prolonged disturbed consciousness after brain injury

The objective of the study was the validation of the Post-Acute Level of Consciousness scale (PALOC-s) for use in assessing levels of consciousness of severe brain injured patients in a vegetative state or in a minimally conscious state. A cohort of 44 successively admitted patients (between 2 and 25 years of age), who were treated in an early intensive neurorehabilitation programme, were included in the study. Each patient was examined, using the Western Neuro Sensory Stimulation Profile (WNSSP) and the Disability Rating Scale (DRS), once every two weeks resulting in 327 examinations (all videotaped). To determine the reliability of the PALOC-s, six observers rated one videotape of each patient. One of the observers rated the same tapes a second time, 3-4 months later. Validity was determined by correlating 100 ratings of one observer with the scores on the WNSSP and the DRS. To determine the responsiveness of the PALOC-s, the size of change between the scores of the first and last examinations was calculated. The inter-observer correlations and agreement scores varied between .82 and .95. The intra-observer correlation and agreement scores varied between .94 and .96. Correlations with the WNSSP varied between .88 and .93, and with the DRS between .75 and .88. The responsiveness was significantly high (t=8.2), with a standardised effect size of 1.30. It is concluded that the PALOC-s is a reliable, valid, and responsive observation instrument provided it is administered after a structured assessment by an experienced and trained clinician. The PALOC-s is feasible for use in clinical management, as well as in outcome research