Central Nervous System Neuropathology Research Articles

The Role of Ca2+ Permeable AMPA Receptors in Neurodegeneration, Neurotoxicity, and Neuroinflammation.

It is believed that degenerative conditions that give rise to neurological diseases may share an abnormal influx of Ca2+, mainly through glutamate receptors. Current research on the glutamatergic system indicates that the N-methyl-D-aspartate receptor (NMDAR) is not the only receptor permeable to Ca2+. Under certain conditions, α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are able to rapidly and potently mediate a neurotoxic Ca2+ influx. AMPARs are encoded by four genes designated GluR 1-4. The presence of the edited GluA2 subunit makes the heteromeric AMPAR impermeable to Ca2+ (CI-AMPAR's). On the other hand, the lack of GluA2 or disruptions in its post-translational editing result in Ca2+-permeable AMPA receptors (CP-AMPARs). In addition to triggering behavioral changes, the increase in CP-AMPARs is documented in several neurodegenerative, neuroinflammatory and neurotoxic conditions, demonstrating that AMPAR changes may play a role in the emergence and evolution of pathological conditions of the central nervous system (CNS). Seeking to better understand how CP-AMPARs influence CNS neuropathology, and how it may serve as a pharmacological target for future molecules, in this article, we summarize and discuss studies investigating changes in the composition of AMPARs and their cellular and molecular effects, to improve the understanding of the therapeutic potential of the CP-AMPAR in neurodegenerative, neurotoxic and neuroinflammatory diseases.

Inflammatory bowel disease and risk of Parkinson's disease in Medicare beneficiaries

IntroductionGastrointestinal (GI) dysfunction precedes the motor symptoms of Parkinson's disease (PD) by several years. PD patients have abnormal aggregation of intestinal α-synuclein, the accumulation of which may be promoted by inflammation. The relationship between intestinal α-synuclein aggregates and central nervous system neuropathology is unknown. Recently, we observed a possible inverse association between inflammatory bowel disease (IBD) and PD as part of a predictive model of PD. Therefore, the objective of this study was to examine the relationship between PD risk and IBD and IBD-associated conditions and treatment. MethodsUsing a case-control design, we identified 89,790 newly diagnosed PD cases and 118,095 population-based controls >65 years of age using comprehensive Medicare data from 2004-2009 including detailed claims data. We classified IBD using International Classification of Diseases version 9 (ICD-9) diagnosis codes. We used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between PD and IBD. Covariates included age, sex, race/ethnicity, smoking, Elixhauser comorbidities, and health care use. ResultsPD was inversely associated with IBD overall (OR = 0.85, 95% CI 0.80–0.91) and with both Crohn's disease (OR = 0.83, 95% CI 0.74–0.93) and ulcerative colitis (OR = 0.88, 95% CI 0.82–0.96). Among beneficiaries with ≥2 ICD-9 codes for IBD, there was an inverse dose-response association between number of IBD ICD-9 codes, as a potential proxy for IBD severity, and PD (p-for-trend = 0.006). ConclusionIBD is associated with a lower risk of developing PD.

Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia.

ABSTRACTFriedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with progressive ataxia that affects both the peripheral and central nervous system (CNS). While later CNS neuropathology involves loss of large principal neurons and glutamatergic and GABAergic synaptic terminals in the cerebellar dentate nucleus, early pathological changes in FRDA cerebellum remain largely uncharacterized. Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model. At asymptomatic ages, VGLUT1 levels in cerebellar homogenates are significantly decreased, whereas VGLUT2 (SLC17A6) levels are significantly increased, in KIKO mice compared with age-matched controls. Additionally, GAD65 (GAD2) levels are significantly increased, while GAD67 (GAD1) levels remain unaltered. This suggests early VGLUT1-specific synaptic input deficits, and dysregulation of VGLUT2 and GAD65 synaptic inputs, in the cerebellum of asymptomatic KIKO mice. Immunohistochemistry and electron microscopy further show specific reductions of VGLUT1-containing PF presynaptic terminals in the cerebellar molecular layer, demonstrating PF synaptic input deficiency in asymptomatic and symptomatic KIKO mice. Moreover, the parvalbumin levels in cerebellar homogenates and Purkinje neurons are significantly reduced, but preserved in other interneurons of the cerebellar molecular layer, suggesting specific parvalbumin dysregulation in Purkinje neurons of these mice. Furthermore, a moderate loss of large principal neurons is observed in the dentate nucleus of asymptomatic KIKO mice, mimicking that of FRDA patients. Our findings thus identify early VGLUT1-specific PF synaptic input deficits and dysregulated cerebellar circuit as potential mediators of cerebellar dysfunction in KIKO mice, reflecting developmental features of FRDA in this mouse model.

P.1.h.015 - Optogenetic activation of prefrontal afferents in distinct hypothalamic regions facilitates aggressive behavior

Gastrointestinal (GI) dysfunction precedes the motor symptoms of Parkinson's disease (PD) by several years. PD patients have abnormal aggregation of intestinal α-synuclein, the accumulation of which may be promoted by inflammation. The relationship between intestinal α-synuclein aggregates and central nervous system neuropathology is unknown. Recently, we observed a possible inverse association between inflammatory bowel disease (IBD) and PD as part of a predictive model of PD. Therefore, the objective of this study was to examine the relationship between PD risk and IBD and IBD-associated conditions and treatment.Using a case-control design, we identified 89,790 newly diagnosed PD cases and 118,095 population-based controls >65 years of age using comprehensive Medicare data from 2004-2009 including detailed claims data. We classified IBD using International Classification of Diseases version 9 (ICD-9) diagnosis codes. We used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between PD and IBD. Covariates included age, sex, race/ethnicity, smoking, Elixhauser comorbidities, and health care use.PD was inversely associated with IBD overall (OR = 0.85, 95% CI 0.80–0.91) and with both Crohn's disease (OR = 0.83, 95% CI 0.74–0.93) and ulcerative colitis (OR = 0.88, 95% CI 0.82–0.96). Among beneficiaries with ≥2 ICD-9 codes for IBD, there was an inverse dose-response association between number of IBD ICD-9 codes, as a potential proxy for IBD severity, and PD (p-for-trend = 0.006).IBD is associated with a lower risk of developing PD.

A rodent model of human organophosphate exposure producing status epilepticus and neuropathology

Exposure to organophosphates (OPs) often results in seizures and/or status epilepticus (SE) that produce neural damage within the central nervous system (CNS). Early control of SE is imperative for minimizing seizure-related CNS neuropathology. Although standard therapies exist, more effective agents are needed to reduce OP-induced SE and neuronal loss, particularly therapies with efficacy when administered 10’s of minutes after the onset of SE. To evaluate novel antiseizure compounds, animal models should simulate the CNS effects of OP exposure observed in humans. We characterized in rats the effects of the OP, diisopropyl flourophosphate (DFP) as a function of dose and route of administration of supporting agents (pyridostigmine, 2-PAM, atropine); outcome measures were mortality, electrographic seizure activity during SE, and subsequent CNS neuropathology. Doses of DFP between 3 and 7mg/kg consistently caused SE, and the latency to behavioral tremors and to subsequent initiation of SE were dose related. In distinction, all doses of DFP that resulted in electrographic SE (3–7mg/kg) produced seizures of similar intensity and duration, and similar CNS neuropathology (i.e., the effects were all-or-none). Although SE was similar across doses, mortality progressively increased with higher doses of DFP. Mortality was significantly lower when the route of administration of therapeutic agents was intramuscular compared to intraperitoneal. This rodent model of OP poisoning demonstrates pathological characteristics similar to those observed in humans, and thus begins to validate this model for investigating potential new therapeutic approaches.

Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis

The emergence of a distinct subpopulation of human or simian immunodeficiency virus (HIV/SIV) sequences within the brain (compartmentalization) during infection is hypothesized to be linked to AIDS-related central nervous system (CNS) neuropathology. However, the exact evolutionary mechanism responsible for HIV/SIV brain compartmentalization has not been thoroughly investigated. Using extensive viral sampling from several different peripheral tissues and cell types and from three distinct regions within the brain from two well-characterized rhesus macaque models of the neurological complications of HIV infection (neuroAIDS), we have been able to perform in-depth evolutionary analyses that have been unattainable in HIV-infected subjects. The results indicate that, despite multiple introductions of virus into the brain over the course of infection, brain sequence compartmentalization in macaques with SIV-associated CNS neuropathology likely results from late viral entry of virus that has acquired through evolution in the periphery sufficient adaptation for the distinct microenvironment of the CNS. HIV-associated neurocognitive disorders remain prevalent among HIV type 1-infected individuals, whereas our understanding of the critical components of disease pathogenesis, such as virus evolution and adaptation, remains limited. Building upon earlier findings of specific viral subpopulations in the brain, we present novel yet fundamental results concerning the evolutionary patterns driving this phenomenon in two well-characterized animal models of neuroAIDS and provide insight into the timing of entry of virus into the brain and selective pressure associated with viral adaptation to this particular microenvironment. Such knowledge is invaluable for therapeutic strategies designed to slow or even prevent neurocognitive impairment associated with AIDS.

Low Dose Naltrexone Treatment of Established Relapsing-Remitting Experimental Autoimmune Encephalomyelitis

Background: Relapse-remitting multiple sclerosis is a chronic disorder that affects more than 400,000 individuals in the United States, often reducing their quality of life, increasing medical expenses, and limiting mobility. This study examines modulation of the opioid growth factor (OGF) – OGF receptor (OGFr) axis by low dosages of naltrexone (LDN) as a disease modifying therapy using a mouse model of relapse-remitting experimental autoimmune encephalomyelitis (RR-EAE). Methods: RR-EAE was induced by immunization of SJL/J mice with proteolipid protein 139-151. After two days of clinical disease, mice were injected intraperitoneally with 0.1 mg/kg naltrexone (LDN) or saline for 40 days. Behavior was observed daily, and periodically, mice were euthanized and spinal cords collected for neuropathological evaluation of glia, T lymphocyte infiltration, and demyelination. Results: LDN treatment significantly reduced behavioral scores across the 40 day observation period. LDN therapy increased the length of remission, as well as the duration of mild disease. A bimodal distribution of behavioral response to LDN was noted that distinguished “responders” from “non-responders”. Pathological analyses of spinal cord tissue from all LDN-treated mice revealed reductions in the number of inflammatory cells (microglia/macrophages), activated astrocytes, and proliferating cells, as well as decreases in areas of demyelination relative to saline-treated mice with RR-EAE. Conclusions: These data are the first to demonstrate that modulation of the OGF-OGFr axis by LDN in mice with established RR-EAE is effective at reducing clinical behavior and central nervous system neuropathology.

Quantitative MRI Measures in SIV-Infected Macaque Brains

Multiple MRI modalities including Diffusion Tensor Imaging (DTI), perfusion MRI, in vivo MR Spectroscopy (MRS), volumetric MRI, contrast-enhanced MRI, and functional MRI have demonstrated abnormalities of the structural and functional integrity as well as neurochemical alterations of the HIV-infected central nervous system (CNS). MRI has been proposed as a robust imaging approach for the characterization of the stage of progression in HIV infection. However, the interpretation of the MRI findings of HIV patients is complicated by the fact that these clinical studies cannot readily be controlled. Simian immunodeficiency virus (SIV) infected macaques exhibit neuropathological symptoms similar to those of HIV patients, and are an important model for studying the course of CNS infection, cognitive impairment, and neuropathology of HIV disease as well as treatment efficacy. MRI of non-human primates (NHPs) is of limited benefit on most clinical scanners operating at or below 1.5 Tesla because this low field strength does not produce high-quality images of the relatively small NHP brain. Contemporary high field MRI (3T or more) for clinical use provides impressive sensitivity for magnetic resonance signal detection and is now accessible in many imaging centers and hospitals, facilitating the use of various MRI techniques in NHP studies. In this article, several high field MRI techniques and applications in macaque models of neuroAIDS are reviewed and the relation between quantitative MRI measures and blood T-cell alterations is discussed.

P01.43. The calm mouse: an animal model of stress reduction

Purpose Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, suppressed immunity, and central nervous system neuropathology. While human studies have illustrated the benefits of stress reduction, mechanistic understanding of how decreasing stress affects health and disease progression remains unclear. Furthermore, prior animal studies have focused primarily on increasing stress, and few animal models of stress reduction have been fully developed.

Alpha-synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits

While studying transgenic mice that overexpress human wildtype alpha-synuclein (Thy1-ASO, ASO) for typical brain alpha-synucleinopathy and central nervous system neuropathology, we observed progressive functional changes in the gastrointestinal and other peripheral organs. A more systematic study revealed that the gastrointestinal tract in ASO mice showed severe distension and blockage of the large intestine by 9–12months of age. Functional assessments demonstrated a reduction in fecal water content and fecal pellet output, and increased whole gut transit time, in ASO mice compared to wildtype littermates, indicative of constipation, a symptom commonly reported by Parkinson's disease (PD) patients. Food intake was increased and body weight was decreased in 12month old ASO mice, suggestive of metabolic abnormalities. Post-mortem histological analyses showed that human alpha-synuclein protein was robustly expressed in axonal fibers and in occasional cell bodies of the enteric nervous system, and in the heart of ASO mice. Accumulation of proteinase-K insoluble alpha-synuclein, reminiscent of neurodegenerative processes in PD was also observed. The functional and pathological changes we document here in ASO mice could relate to the autonomic deficits also seen in idiopathic and alpha-synuclein-mediated genetic forms of PD. These experimental data provide a foundation for therapeutic modeling of autonomic changes in PD and related alpha-synucleinopathies.

The Calm Mouse: An Animal Model of Stress Reduction

Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, deleterious effects on innate and adaptive immunity, and central nervous system neuropathology. Although stress management is commonly advocated clinically, there is insufficient mechanistic understanding of how decreasing stress affects disease pathogenesis. Therefore, we have developed a "calm mouse model" with caging enhancements designed to reduce murine stress. Male BALB/c mice were divided into four groups: control (Cntl), standard caging; calm (Calm), large caging to reduce animal density, a cardboard nest box for shelter, paper nesting material to promote innate nesting behavior, and a polycarbonate tube to mimic tunneling; control exercise (Cntl Ex), standard caging with a running wheel, known to reduce stress; and calm exercise (Calm Ex), calm caging with a running wheel. Calm, Cntl Ex and Calm Ex animals exhibited significantly less corticosterone production than Cntl animals. We also observed changes in spleen mass, and in vitro splenocyte studies demonstrated that Calm Ex animals had innate and adaptive immune responses that were more sensitive to acute handling stress than those in Cntl. Calm animals gained greater body mass than Cntl, although they had similar food intake, and we also observed changes in body composition, using magnetic resonance imaging. Together, our results suggest that the Calm mouse model represents a promising approach to studying the biological effects of stress reduction in the context of health and in conjunction with existing disease models.

Relationship between diffusion tensor imaging and brain morphology in patients with myotonic dystrophy

Myotonic dystrophy type 1 (MyD) is a common inherited neuromuscular disorder. In addition to neuromuscular symptoms, many MyD patients show central nervous system neuropathology. This study evaluated whether MyD patients display diffusion tensor (DT) abnormalities associated with regional cortical atrophy and clinical features. Three-dimensional T1-weighted and DT magnetic resonance images of the brain were obtained in 11 MyD patients and 13 age- and sex-matched healthy subjects. Fractional anisotropy (FA) and mean diffusivity (MD) values were calculated in corpus callosum subregions with DT imaging (DTI) along with volumetric changes, and correlations with clinical features were examined. Differences between MyD patients and healthy subjects were analyzed statistically. Significantly lower FA and higher MD values were found in the genu, rostral body, anterior midbody, posterior midbody and splenium in MyD patients than in control subjects ( p < 0.05, corrected; lower FA in the splenium was at a trend level). These corpus callosum subregions were the areas connected to cortical areas where significantly lower volumes were found in MyD patients. No significant decrease in volumes was noted in the parietal cortex, where connecting fibers pass through the isthmus in which DTI abnormalities were not detected in MyD patients. Significant negative correlations to volumes of frontal areas were noted, particularly bilateral motor areas, with cytosine thymine guanidine (CTG) triplet expansion. DTI results in corpus callosum may reflect morphological changes in the connecting cortical areas of MyD patients.

Escherichia coli Shiga toxin 1 and TNF-α induce cytokine release by human cerebral microvascular endothelial cells

Infection with Shiga toxin (Stx)-producing Escherichia coli can lead to development of hemolytic uremic syndrome (HUS). Patients with severe HUS often exhibit central nervous system (CNS) pathology, which is thought to involve damage to brain endothelium, a component of the blood–brain barrier. We hypothesized that this neuropathology occurs when cerebral endothelial cells of the blood–brain barrier, sensitized by exogenous TNF-α and stimulated by Stx1, produce and release proinflammatory cytokines. This was tested by measuring changes in cytokine mRNA and protein expression in human brain endothelial cells (hBEC) in vitro when challenged by TNF-α and/or Stx. High doses of Stx1 alone were somewhat cytotoxic to hBEC; Stx1-treated cells produced increased amounts of IL-6 mRNA and secreted this cytokine. IL-1β and TNF-α mRNA, but not protein, were increased, and IL-8 secretion increased without an observed increase in mRNA. Cells pretreated with TNF-α were more sensitive to Stx1, displaying greater Stx1-induction of mRNA for TNF-α, IL-1β, and IL-6, and secretion of IL-6 and IL-8. These observations suggest that in the pathogenesis of HUS, Stx can induce cytokine release from hBEC, which may contribute toward the characteristic CNS neuropathology.

Neuronal survival strategies in the face of RNA viral infection.

Neurons of the mammalian central nervous system (CNS) are an essential and largely nonrenewable cell population. Thus, viral infections that result in neuronal depletion, either by viral lysis or by induction of the cytolytic immune response, would likely lead to profound neurologic impairment. However, many viral infections that result in tissue destruction elsewhere in the host produce few overt symptoms in the CNS, despite readily detectable virus expression. This observation has lead to the speculation that neurons possess strategies to limit the replication and spread of otherwise cytopathic viruses. These strategies either favor the clearance of virus in the absence of appreciable neuronal loss or promote the establishment of noncytolytic persistent infections. This review discusses some of these strategies, with an emphasis on how such survival techniques lessen the potential for CNS neuropathology

Cognitive functioning in schizophrenia: implications for psychiatric rehabilitation.

Research in psychopathology and the cognitive neurosciences suggests new applications in psychiatric rehabilitation. Analysis of performance deficits on laboratory tasks can contribute to treatment planning, individual and family counseling, and staff consultation, much like it does in cases of brain injury and other types of central nervous system neuropathology. Recognition of the nature of cognitive impairments in schizophrenia can inform design of psychosocial techniques such as social and living skills training. Cognitive impairments are increasingly seen as potential targets for pharmacological and psychosocial treatment and rehabilitation. In this article, three key issues for application of cognitive technology in psychiatric rehabilitation of schizophrenia and related disorders are formulated as straightforward, clinically relevant questions: (1) What is the prognostic significance of cognitive impairment in acute psychosis? (2) Can cognitive functioning improve in the chronic, residual course? (3) How does cognitive improvement benefit other aspects of recovery and rehabilitation? These questions are addressed through review of previous findings and new multivariate analyses of cognitive functioning in the acute, post-acute, and chronic residual phases of schizophrenia.

T cell lines derived from the spinal cords of mice with experimental allergic encephalomyelitis are self reactive.

Abstract Experimental allergic encephalomyelitis (EAE) is an animal model of T cell-mediated, central nervous system neuropathology that may be a relevant animal model for multiple sclerosis. EAE is usually induced by sensitization of animals with a xenogeneic myelin basic protein (MBP). Recently, MBP-reactive T cell lines and clones derived from lymphoid tissue of animals with EAE have proved very useful in elucidating certain aspects of the pathogenesis in EAE. However, questions relating to how T cells actually mediate the pathologic changes seen in EAE remain unresolved. We now report for the first time the derivation of long-term, interleukin 2-dependent T cell lines and sublines from a site of pathology in murine EAE--the spinal cord. All of the spinal cord-derived T cell lines and sublines were found to be "autoreactive" in that they responded to self (murine) MBP as well as to the xenogeneic immunogen, porcine MBP. The ability to derive T cell lines and sublines from the spinal cords of mice with EAE should now aid in the elucidation of pathogenetic mechanisms in EAE by allowing for a characterization of those T cells found at the site of pathology.