Central Nervous System Compartment Research Articles

Neuroinflammation During RNA Viral Infections.

Neurotropic RNA viruses continue to emerge and are increasingly linked to diseases of the central nervous system (CNS) despite viral clearance. Indeed, the overall mortality of viral encephalitis in immunocompetent individuals is low, suggesting efficient mechanisms of virologic control within the CNS. Both immune and neural cells participate in this process, which requires extensive innate immune signaling between resident and infiltrating cells, including microglia and monocytes, that regulate the effector functions of antiviral T and B cells as they gain access to CNS compartments. While these interactions promote viral clearance via mainly neuroprotective mechanisms, they may also promote neuropathology and, in some cases, induce persistent alterations in CNS physiology and function that manifest as neurologic and psychiatric diseases. This review discusses mechanisms of RNA virus clearance and neurotoxicity during viral encephalitis with a focus on the cytokines essential for immune and neural cell inflammatory responses and interactions. Understanding neuroimmune communications in the setting of viral infections is essential for the development of treatments that augment neuroprotective processes while limiting ongoing immunopathological processes that cause ongoing CNS disease.

Cross-sectional study of smoking exposure: no differential effect on OCT metrics in a cohort of MS patients

BackgroundOptical coherence tomography (OCT) provides quantitative measures of retinal layer thickness. Cigarette smoking is a risk factor for multiple sclerosis (MS) onset and disease severity: its effects on OCT metrics have not been assessed.ObjectiveThe objective of this study was to assess the effect of smoking history on retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform (GCIP) of MS patients by OCT.Methods112 MS patients were recruited from the Brigham and Women’s Hospital. Spectralis OCT scans were acquired to measure GCIP, peripapillary RNFL, and total macular volume. Multivariable linear mixed effects regression model assessed RNFL and GCIP change with fixed effects for smoking history while adjusting for optic neuritis eye status, age, disease duration, sex, baseline EDSS, and disease modifying therapies (DMTs).ResultsSmoking histories were available for 102 patients: 46 (45.10%) had a history of smoking cigarettes and 56 (54.90%) never smoked. No statistically significant differences were found between ever-smokers and never-smokers with respect to GCIP, RNFL, and macular volume.ConclusionOur study shows no significant difference in retinal thickness between ever-smokers and never-smokers. If confirmed, this result suggests mechanistic differences between the retina and other central nervous system (CNS) compartments in response to smoking and should be noted when considering OCT as a surrogate measure of CNS activity.

Spatial and molecular changes of mouse brain metabolism in response to immunomodulatory treatment with teriflunomide as visualized by MALDI-MSI.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS). One of the most promising recent medications for MS is teriflunomide. Its primary mechanism of action is linked to effects on the peripheral immune system by inhibiting dihydroorotate dehydrogenase (DHODH)-catalyzed de novo pyrimidine synthesis and reducing the expansion of lymphocytes in the peripheral immune system. Some in vitro studies suggested, however, that it can also have a direct effect on the CNS compartment. This potential alternative mode of action depends on the drug's capacity to traverse the blood-brain barrier (BBB) and to exert an effect on the complex network of brain biochemical pathways. In this paper, we demonstrate the application of high-resolution/high-accuracy matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry for molecular imaging of the mouse brain coronal sections from animals treated with teriflunomide. Specifically, in order to assess the effect of teriflunomide on the mouse CNS compartment, we investigated the feasibility of teriflunomide to traverse the BBB. Secondly, we systematically evaluated the spatial and semi-quantitative brain metabolic profiles of 24 different endogenous compounds after 4-day teriflunomide administration. Even though the drug was not detected in the examined cerebral sections (despite the high detection sensitivity of the developed method), in-depth study of the endogenous metabolic compartment revealed noticeable alterations as a result of teriflunomide administration compared to the control animals. The observed differences, particularly for purine and pyrimidine nucleotides as well as for glutathione and carbohydrate metabolism intermediates, shed some light on the potential impact of teriflunomide on the mouse brain metabolic networks. Graphical Abstract.

Myeloid-derived suppressor cells control B cell accumulation in the central nervous system during autoimmunity.

PMN-MDSCs (polymorphonuclear myeloid-derived suppressor cells) have been characterized in the context of malignancies. Here we found that PMN-MDSCs had the unique ability to restrain B cell accumulation during central nervous system (CNS) autoimmunity. Ly6G+ cells were recruited to the CNS during experimental autoimmune encephalomyelitis (EAE), interacted with B cells that produced the cytokines GM-CSF and IL-6, and acquired properties of PMN-MDSCs in the CNS in a manner dependent on the signal transducer STAT3. Depletion of Ly6G+ cells or dysfunction of Ly6G+ cells through conditional ablation of STAT3 resulted in the selective accumulation of GM-CSF-producing B cells in the CNS compartment, which in turn promoted an activated microglial phenotype and failure to recover from EAE. The frequency of CD138+ B cells in the cerebrospinal fluid (CSF) of human patients with multiple sclerosis negatively correlated with the frequency of PMN-MDSCs in the CSF. Thus, PMN-MDSCs might selectively control the accumulation and cytokine secretion of B cells within the inflamed CNS.

Impact of Glatiramer Acetate on B Cell-Mediated Pathogenesis of Multiple Sclerosis.

Growing evidence indicates that B cells play a key role in the pathogenesis of multiple sclerosis (MS). B cells occupy distinct central nervous system (CNS) compartments in MS, including the cerebrospinal fluid and white matter lesions. Also, it is now known that, in addition to entering the CNS, B cells can circulate into the periphery via a functional lymphatic system. Data suggest that the role of B cells in MS mainly involves their in situ activation in demyelinating lesions, leading to altered pro- and anti-inflammatory cytokine secretion, and a highly effective antigen-presenting cell function, resulting in activation of memory or naïve T cells. Clinically, B cell-depleting agents show significant efficacy in MS. In addition, many disease-modifying therapies (DMTs) traditionally understood to target T cells are now known to influence B cell number and function. One of the earliest DMTs to be developed, glatiramer acetate (GA), has been shown to reduce the total frequency of B cells, plasmablasts, and memory B cells. It also appears to promote a shift toward reduced inflammation by increasing anti-inflammatory cytokine release and/or reducing pro-inflammatory cytokine release by B cells. In the authors’ opinion, this may be mediated by cross-reactivity of B cell receptors for GA with antigen (possibly myelin basic protein) expressed in the MS lesion. More research is required to further characterize the role of B cells and their bidirectional trafficking in the pathogenesis of MS. This may uncover novel targets for MS treatments and facilitate the development of B cell biomarkers of drug response.

Central Nervous System Prophylaxis Strategies in Diffuse Large B Cell Lymphoma.

Central nervous system (CNS) relapse is an undesirable event in the course of patients with diffuse large B cell lymphoma (DLBCL) with a median survival of approximately 6months following CNS relapse. CNS prophylaxis for the prevention of CNS recurrence, in addition to the standard R-CHOP chemotherapy, is thus preferable. For an overall relapse risk of 2-5%, administration of CNS-directed therapies for all patients with DLBCL is unnecessary and prophylaxis should be targeted for the high-risk patients. CNS-International Prognostic Index (CNS-IPI) score has enabled risk stratification with risk ranging < 1% (low-risk group) compared to > 10% (high-risk group). The latter could be considered for CNS prophylaxis. CNS-IPI, however, is not perfect and may not capture patients with high-risk extra-nodal sites such as testicular DLBCL. Cell-of-origin and MYC/BCL2 expression can further build on CNS-IPI to narrow higher risk patients. CNS prophylaxis strategies are controversial. Common strategies include intrathecal (IT) chemotherapy and systemic CNS penetrants such as methotrexate. IT chemotherapy does not adequately penetrate the brain parenchyma and hence it is insufficient in preventing parenchymal CNS recurrences. Most experts promote systemic methotrexate for high-risk groups, which penetrates both the leptomeningeal and parenchymal CNS compartments. Even though systemic CNS prophylaxis is widely promoted over IT alone, its efficacy is unclear. Ongoing efforts in search for appropriate CNS prophylaxis strategies are warranted. My personal practice is to administer systemic high-dose methotrexate in conjunction with R-CHOP chemotherapy for eligible patients deemed at a high risk of CNS recurrence, especially those with high-risk CNS-IPI and extra-nodal involvement.

Challenges in the Treatment of Glioblastoma: Multisystem Mechanisms of Therapeutic Resistance

Glioblastoma is one of the most lethal human cancers, with poor survival despite surgery, radiation treatment, and chemotherapy. Advances in the treatment of this type of brain tumor are limited because of several resistance mechanisms. Such mechanisms involve limited drug entry into the central nervous system compartment by the blood-brain barrier and by actions of the normal brain to counteract tumor-targeting medications. In addition, the vast heterogeneity in glioblastoma contributes to significant therapeutic resistance by preventing adequate control of the entire tumor mass by a single drug and by facilitating escape mechanisms from targeted agents. The stem cell-like characteristics of glioblastoma promote resistance to chemotherapy, radiation, and immunotherapy through upregulation of efflux transporters, promotion of glioblastoma stem cell proliferation in neurogenic zones, and immune suppression, respectively. Metabolic cascades in glioblastoma prevent effective treatments through the optimization of glucose use, the use of alternative nutrient precursors for energy production, and the induction of hypoxia to enhance tumor growth. In the era of precision medicine, an assortment of molecular techniques is being developed to target an individual's unique tumor, with the hope that this personalized strategy will bypass therapeutic resistance. Although each resistance mechanism presents an array of challenges to effective treatment of glioblastoma, as the field recognizes and addresses these difficulties, future treatments may have more efficacy and promise for patients with glioblastoma.

MicroRNA signature of central nervous system-infiltrating dendritic cells in an animal model of multiple sclerosis.

Innate immune cells are integral to the pathogenesis of several diseases of the central nervous system (CNS), including multiple sclerosis (MS). Dendritic cells (DCs) are potent CD11c+ antigen-presenting cells that are critical regulators of adaptive immune responses, particularly in autoimmune diseases such as MS. The regulation of DC function in both the periphery and CNS compartment has not been fully elucidated. One limitation to studying the role of CD11c+ DCs in the CNS is that microglia can upregulate CD11c during inflammation, making it challenging to distinguish bone marrow-derived DCs (BMDCs) from microglia. Selective expression of microRNAs (miRNAs) has been shown to distinguish populations of innate cells and regulate their function within the CNS during neuro-inflammation. Using the experimental autoimmune encephalomyelitis (EAE) murine model of MS, we characterized the expression of miRNAs in CD11c+ cells using a non-biased murine array. Several miRNAs, including miR-31, were enriched in CD11c+ cells within the CNS during EAE, but not LysM+ microglia. Moreover, to distinguish CD11c+ DCs from microglia that upregulate CD11c, we generated bone marrow chimeras and found that miR-31 expression was specific to BMDCs. Interestingly, miR-31-binding sites were enriched in mRNAs downregulated in BMDCs that migrated into the CNS, and a subset was confirmed to be regulated by miR-31. Finally, miR-31 was elevated in DCs migrating through an invitro blood-brain barrier. Our findings suggest miRNAs, including miR-31, may regulate entry of DCs into the CNS during EAE, and could potentially represent therapeutic targets for CNS autoimmune diseases such as MS.

VLA4 expression by B cells enables B cell-restricted antigen presentation to support CD4 T cell driven central nervous system autoimmunity

Abstract Clonal expansion along with immunoglobulin (Ig) class-switching and secretion result from B cell antigen presentation to cognate CD4 T cells. The presence of oligoclonal Ig in the cerebrospinal fluid of most patients with multiple sclerosis raises the important question of where cognate B:T cell interactions occurs during disease. Previously we showed that increasing the frequency of MOG-specific B cells is sufficient to drive EAE in mice expressing MHCII solely by B cells. We have now established a system in which EAE reliably occurs upon expression of MHCII using Tamoxifen-induced temporal regulation in MOG-specific B cells. While B cells express MHCII in the central nervous system (CNS) in these models, whether or not B cells acquire and present antigen in the CNS compartment is unknown. Large clusters of B cells rapidly formed in the subarachnoid space of the spinal cord during EAE in our model, suggesting homing to the CNS is important for antigen presentation. Genetic regulation of B cell MOG-specificity and expression of MHCII and Very Late Antigen-4 (VLA-4) was used to determine the dependence of passive EAE susceptibility on B cell access to the CNS. Mice in which VLA-4 expression was abrogated simultaneously with MHCII expression by MOG-specific B cells were subjected to passive EAE. Disease exclusively mediated by B cell antigen presentation was dependent on VLA-4 expression by B cells. MOG-specific CD4 T cell hybridomas did not detect endogenous MOG presented by B cells harvested from the periphery of mice prior to the onset of disease. Taken together, our findings indicate that B cells require access to CNS myelin targets in order to propagate antigen-specific CD4 T cell-dependent neuro-inflammation.

The Multiple Roles of B Cells in Multiple Sclerosis and Their Implications in Multiple Sclerosis Therapies.

Increasing evidence has suggested that both antibody-dependent and antibody-independent functions of B cells are involved in multiple sclerosis (MS). The contrasting results of distinct B-cell targeting therapies in MS patients underscores the importance of elucidating these multiple B-cell functions. In this review, we discuss the generation of autoreactive B cells, migration of B cells into the central nervous system (CNS), and how different functions of B cells may contribute to MS disease activity and potentially mitigation in both the periphery and CNS compartments. In addition, we propose several future therapeutic strategies that may better target/shape B-cell responses for long-term treatment of MS.

Brain Quantitative MRI Metrics in Astronauts as a Unique Professional Group.

As part of its technological sophistication, the International Space Station (ISS) Program operates a robust medical surveillance schedule for its rotating 6-person crew to control the known health risks and to address knowledge gaps related to human health in space flight environment. Recent evidence on visual impairment in a subset of ISS crew has renewed the interest in the effects of long-duration space flight on the central nervous system (CNS). Through retrospective analysis in a sample of 10 healthy astronauts, we demonstrate the utility of multimodal quantitative magnetic resonance imaging (qMRI) with diffusion tensor imaging (DTI)-based customized brain templates to examine the structural attributes of various CNS compartments in this occupational group. The study included 10 healthy astronauts (45-55 years). All subjects had previous space flights with the median duration of 110 days. Multimodal quantitative structural imaging modalities performed and used in analyses. A host of CNS features are presented, which are largely commensurate with the available normative data. Remarkably, some of our findings demonstrate statistically significant positive features suggestive of structural neuroplasticity conceivably associated with the professional activities of astronauts, and compensatory neurogenesis that counterweighs the expected normative volume loss with age. The novelty of this exploratory report is in the demonstration of a qMRI toolset as a potential capability for characterization and surveillance of unique professional groups, and for future prospective examinations of the effects of various long-term exposures on CNS.

Pharmacokinetics and pharmacodynamics of antibiotics in central nervous system infections.

The barriers surrounding the central nervous system (CNS) together with the emergence of multiresistant pathogens pose a therapeutic challenge for the effective treatment of CNS infections. In addition to vancomycin, colistin and aminoglycosides, classically used for intrathecal injection, drug concentrations in cerebrospinal fluid after intrathecal injection of daptomycin and tigecyclin were recently studied. The entry of antiinfectives into the CNS compartments is determined by the physicochemical properties of the drug and by conditions in the host. The most important drug properties are lipophilicity at a neutral pH, molecular mass and drug binding to serum proteins. In clinical practice, active transport is of importance only for some drugs. In recent years, intrathecal injection of antiinfectives in addition to systemic therapy has regained attention as a means to achieve high cerebrospinal fluid concentrations. The classification of antibacterials and antifungals into time-dependent and concentration-dependent compounds is also valid for the CNS compartments.

Molecular Signatures of HIV-1 Envelope Associated with HIV-Associated Neurocognitive Disorders.

The HIV-1 envelope gene (env) has been an intense focus of investigation in the search for genetic determinants of viral entry and persistence in the central nervous system (CNS). Molecular signatures of CNS-derived HIV-1 env reflect the immune characteristics and cellular constraints of the CNS compartment. Although more readily found in those with advanced HIV-1 and HIV-associated neurocognitive disorders (HAND), molecular signatures distinguishing CNS-derived quasispecies can be identified early in HIV-1 infection, in the presence or absence of combination antiretroviral therapy (cART), and are dynamic. Amino acid signatures of CNS-compartmentalization and HAND have been identified across populations. While some significant overlap exists, none are universal. Detailed analyses of CNS-derived HIV-1 env have allowed researchers to identify a number of molecular determinants associated with neuroadaptation. Future investigations using comprehensive cohorts and longitudinal databases have the greatest potential for the identification of robust, validated signatures of HAND in the cART era.

Chapter 5 - Neuropharmacology

With virologically suppressive antiretroviral therapy, immune system recovery is now achievable for persons living with HIV (PLWH). This immune recovery is associated with dramatic reductions in acquired immune deficiency syndrome (AIDS) defining illnesses including HIV dementia. However, milder form of cognitive disturbances are widely reported in PLWH despite effective antiretroviral therapy. The underlying pathogenic mechanisms of these cognitive disturbances remain elusive, with many potential pathogenic mechanisms including residual brain damage prior to the initiation of antiretroviral therapy and neuroinflammation and ongoing immune system disturbances despite antiretroviral therapy. Lifestyle factors and concomitant infections and medical problems are also likely to be major contributing factors. The penetration of antiretroviral agents into the central nervous system compartment resulting in a lack of suppression of HIV viremia in the brain has generated much interest as well as potential neuro-toxicities from antiretroviral agents themselves. This chapter reviews the clinical pharmacology, both the pharmacokinetic and pharmacodynamic effects, of antiretroviral therapy in the central nervous system compartment.

Chapter 8 - NeuroAIDS in children

The human immunodeficiency virus-1 (HIV-1) enters the central nervous system compartment within the first few weeks of systemic HIV infection and may cause a spectrum of neurologic complications. Without combination antiretroviral therapy (cART), 50-90% of all HIV-infected infants and children develop some form of neuroAIDS. Of the estimated 2.3 million children less than 15 years of age who were living in sub-Saharan Africa at the end of 2014, only 30% were receiving cART, suggesting that there is a large burden of neuroAIDS among HIV-infected children in sub-Saharan Africa. There is complex interplay between the disease process itself, the child's immune reaction to the disease, the secondary complications, the side-effects of antiretroviral drugs, and inadequate antiretroviral drug uptake into the central nervous system. In addition there is the layering effect from the multiple socioeconomic challenges for children living in low- and middle-income countries. Adolescents may manifest with a range of neurocognitive sequelae from mild neurocognitive disorder through to severe neurocognitive impairment. Neuroimaging studies on white-matter tracts have identified dysfunction, especially in the frontostriatal networks needed for executive function. Psychiatric symptoms of depression, attention deficit hyperactivity disorder, and behavioral problems are also commonly reported in this age group. Antiretroviral drugs may cause treatment-limiting neurologic and neuropsychiatric adverse reactions. The following chapter addresses the neurologic complications known to be, and suspected of being, associated with HIV infection in children and adolescents.

Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach

Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human, and to predict drug concentration-time profiles in multiple CNS compartments on available human data of four drugs (acetaminophen, oxycodone, morphine and phenytoin).Values of the system-specific parameters in the rat CNS PBPK model were replaced by corresponding human values. The contribution of active transporters for the four selected drugs was scaled based on differences in expression of the pertinent transporters in both species. Model predictions were evaluated with available pharmacokinetic (PK) data in human brain extracellular fluid and/or cerebrospinal fluid, obtained under physiologically healthy CNS conditions (acetaminophen, oxycodone, and morphine) and under pathophysiological CNS conditions where CNS physiology could be affected (acetaminophen, morphine and phenytoin).The human CNS PBPK model could successfully predict their concentration-time profiles in multiple human CNS compartments in physiological CNS conditions within a 1.6-fold error. Furthermore, the model allowed investigation of the potential underlying mechanisms that can explain differences in CNS PK associated with pathophysiological changes. This analysis supports the relevance of the developed model to allow more effective selection of CNS drug candidates since it enables the prediction of CNS target-site concentrations in humans, which are essential for drug development and patient treatment.

Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.

Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System‐specific and drug‐specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration‐time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue. These drugs, all small molecules, were selected to cover a wide range of physicochemical properties. The concentration‐time profiles for these drugs were adequately predicted across the CNS compartments (symmetric mean absolute percentage error for the model prediction was <91%). In conclusion, the developed PBPK model can be used to predict temporal concentration profiles of drugs in multiple relevant CNS compartments, which we consider valuable information for efficient CNS drug development.

Congenital HIV

The human immunodeficiency virus (HIV) type 1 is highly neurotropic, entering the central nervous system compartment within the first few weeks of systemic infection and may cause a spectrum of neurological complications collectively known as neuroAIDS. In children infected through vertical transmission, the neurological manifestations may display a more complex phenotype as a consequence of the effects of HIV on the immature brain and contribute significantly to the morbidity of HIV infection. With the early initiation of combination antiretroviral therapy, there has been an improvement in the overall health of children with vertically transmitted HIV infection. HIV encephalopathy (HIVE) which previously presented with severe neurodisability and demise, now presents with a more insidious phenotype in association with prolonged survival. As these children survive into adolescence and adulthood, behavioural and psychiatric complications are becoming more relevant in clinical practice. This talk provides a general overview of neuroAIDS from congenital transmission in childhood and adolescence.

Dose-dependent effect and pharmacokinetics of fexinidazole and its metabolites in a mouse model of human African trypanosomiasis

Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 million at risk. Current treatment options are limited. In the search for new therapeutics, the repurposing of the broad-spectrum antiprotozoal drug fexinidazole has completed Phase III trials with the anticipation that it will be the first oral treatment for HAT.This study used the recently validated bioluminescence imaging model to assess the dose and rate of kill effect of fexinidazole in infected mice, and the dose-dependent effect of fexinidazole on trypanosome infection. Pharmacokinetics of fexinidazole in plasma and central nervous system (CNS) compartments were similar in both infected and uninfected mice. Drug distribution within the CNS was further examined by microdialysis, showing similar levels in the cortex and hippocampus. However, high variability in drug distribution and exposure was found between mice.

Microdialysis: the Key to Physiologically Based Model Prediction of Human CNS Target Site Concentrations

Despite the enormous research efforts that have been put into the development of central nervous system (CNS) drugs, the success rate in this area is still disappointing. To increase the successful rate in the clinical trials, first the problem of predicting human CNS drug distribution should be solved. As it is the unbound drug that equilibrates over membranes and is able to interact with targets, especially knowledge on unbound extracellular drug concentration-time profiles in different CNS compartments is important. The only technique able to provide such information in vivo is microdialysis. Also, obtaining CNS drug distribution data from human subjects is highly limited, and therefore, we have to rely on preclinical approaches combined with physiologically based pharmacokinetic (PBPK) modeling, taking unbound drug CNS concentrations into account. The next step is then to link local CNS pharmacokinetics to target interaction kinetics and CNS drug effects. In this review, system properties and small-molecule drug properties that together govern CNS drug distribution are summarized. Furthermore, the currently available approaches on prediction of CNS pharmacokinetics are discussed, including in vitro, in vivo, ex vivo, and in silico approaches, with special focus on the powerful combination of in vivo microdialysis and PBPK modeling. Also, sources of variability on drug kinetics in the CNS are discussed. Finally, remaining gaps and challenges are highlighted and future directions are suggested.