Albumin induces excitatory synaptogenesis through astrocytic TGF-ß/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction.

Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-ß) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-ß-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-ß inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-ß-pathway as a potential strategy for the prevention of PIE.

Exposure to vehicle emissions results in altered blood brain barrier permeability and expression of matrix metalloproteinases and tight junction proteins in mice.

BACKGROUND: Traffic-generated air pollution-exposure is associated with adverse effects in the central nervous system (CNS) in both human exposures and animal models, including neuroinflammation and neurodegeneration. While alterations in the blood brain barrier (BBB) have been implicated as a potential mechanism of air pollution-induced CNS pathologies, pathways involved have not been elucidated. OBJECTIVES: To determine whether inhalation exposure to mixed vehicle exhaust (MVE) mediates alterations in BBB permeability, activation of matrix metalloproteinases (MMP) -2 and -9, and altered tight junction (TJ) protein expression. METHODS: Apolipoprotein (Apo) E(-/-) and C57Bl6 mice were exposed to either MVE (100 µg/m(3) PM) or filtered air (FA) for 6 hr/day for 30 days and resulting BBB permeability, expression of ROS, TJ proteins, markers of neuroinflammation, and MMP activity were assessed. Serum from study mice was applied to an in vitro BBB co-culture model and resulting alterations in transport and permeability were quantified. RESULTS: MVE-exposed Apo E(-/-) mice showed increased BBB permeability, elevated ROS and increased MMP-2 and -9 activity, compared to FA controls. Additionally, cerebral vessels from MVE-exposed mice expressed decreased levels of TJ proteins, occludin and claudin-5, and increased levels of inducible nitric oxide synthase (iNOS) and interleukin (IL)-1ß in the parenchyma. Serum from MVE-exposed animals also resulted in increased in vitro BBB permeability and altered P-glycoprotein transport activity. CONCLUSIONS: These data indicate that inhalation exposure to traffic-generated air pollutants promotes increased MMP activity and degradation of TJ proteins in the cerebral vasculature, resulting in altered BBB permeability and expression of neuroinflammatory markers.

Neurocognitive functioning predicts frailty index in HIV.

OBJECTIVE: To evaluate the association between a frailty index (i.e., scale of accumulated deficits) and neurocognitive functioning among persons living with HIV/AIDS (PLWHA). METHODS: Observational, cross-sectional data were gathered from the University of California, San Diego, HIV Neurobehavioral Research Program from 2002 to 2016. Eight hundred eleven PLWHA aged 18 to 79 years completed comprehensive physical, neuropsychological, and neuromedical evaluations. The frailty index was composed of 26 general and HIV-specific health maintenance measures, and reflects the proportion of accumulated deficits from 0 (no deficits) to 1 (all 26 deficits). Multiple linear regression was used to examine the association between continuous frailty index scores and neurocognitive functioning. RESULTS: Participants had a mean age of 44.6 years (11.2), and were mostly male (86.9%) and white (60.2%) with a mean frailty index of 0.26 (0.11). Over the study period, prevalence of HIV-related components (e.g., low CD4) decreased, while non-HIV comorbidities (e.g., diabetes) increased. There were no changes in the frailty index by study year. Higher frailty index was associated with worse global neurocognitive functioning, even after adjusting for covariates (age, employment, and premorbid intellectual functioning; b = -0.007; 95% confidence interval [CI] = -0.0112 to -0.003; p < 0.001). The cognitive domains of verbal fluency (b = -0.004; 95% CI = -0.006 to -0.002), executive functioning (b = -0.004; 95% CI = -0.006 to -0.002), processing speed (b = -0.005; 95% CI = -0.007 to -0.003), and motor skills (b = -0.006; 95% CI = -0.007 to -0.005) also significantly predicted worse frailty index score (p values <0.001). CONCLUSION: A frailty index can standardize how clinicians identify PLWHA who may be at higher risk of neurocognitive impairment.

Coagulation imbalance and neurocognitive functioning in older HIV-positive adults on suppressive antiretroviral therapy.

OBJECTIVES: The aim of this study was to compare plasma biomarkers of coagulation between HIV-infected individuals and HIV-uninfected controls and to assess the impact of disturbances in coagulation on neurocognitive functioning in HIV. DESIGN: A cross-sectional study of 66 antiretroviral therapy treated, virally suppressed, HIV-infected and 34 HIV-uninfected older (≥50 years of age) adults. METHODS: Participants completed standardized neurobehavioral and neuromedical assessments. Neurocognitive functioning was evaluated using a well validated comprehensive neuropsychological battery. Plasma biomarkers associated with procoagulation (fibrinogen, p-selectin, tissue factor and von Willebrand factor), anticoagulation (antithrombin, protein C and thrombomodulin), fibrinolysis (d-dimer, plasminogen activator inhibitor-1 and plasminogen) were collected. Multivariable linear regression was used to test the interaction of HIV and coagulation on neurocognitive functioning. RESULTS: Most participants were male (78.0%) and non-Hispanic white (73.0%) with a mean age of 57.8 years. Among HIV-infected participants, mean estimated duration of HIV infection was 19.4 years and median current CD4 cell count was 654 cells/µl. Levels of soluble biomarkers of procoagulation, anticoagulation and fibrinolysis were comparable between the HIV serostatus groups. Coagulation and HIV had an interacting effect on neurocognitive functioning, such that greater coagulation imbalance was associated with poorer neurocognitive functioning among the HIV-infected participants. The moderating effect of coagulation on neurocognition was driven by procoagulant but not anticoagulant or fibrinolytic biomarkers. CONCLUSIONS: Elevated levels of procoagulants may exert a particularly detrimental effect on neurocognitive functioning among older HIV-infected persons. A better understanding of the specific role of coagulation in the cause of HIV-associated neurocognitive disorders may lead to treatments aimed at reducing coagulopathy, thereby improving neurocognitive outcomes.