Proton magnetic resonance spectroscopy (1H MRS) has been applied to numerous clinical studies, especially for neurological disorders. This technique can non-invasively evaluate brain metabolites and neurochemicals in selected brain regions and is particularly useful for assessing neuroinflammatory disorders. Neurometabolites assessed with MRS include the neuronal markers N-acetylasparate (NAA) and glutamate (Glu), as well as the glial marker myoinositol (MI). Therefore, the concentrations of these metabolites typically correspond to disease severity and often correlate well with clinical variables in the various brain disorders. Neuroinflammation with activated astrocytes and microglia in brain disorders are often associated with elevated MI, and to a lesser extent elevated total creatine (tCr) and choline containing compounds (Cho), which are found in higher concentrations in glia than neurons, while neuronal injury is indicated by lower than normal levels of NAA and Glu. This review summarizes the neurometabolite abnormalities found in MRS studies performed in patients with neuroinflammatory disorders or neuropathic pain, which also may be associated with neuroinflammation. These brain disorders include multiple sclerosis, neuroviral infections (including Human Immunodeficiency virus and Hepatitis C), degenerative brain disorders (including Alzheimer’s disease and Parkinson’s disease), stimulant abuse (including methamphetamine and cocaine) as well as several chronic pain syndromes.
Objective: In this multicenter cohort study, we sought to identify prognostic and associative metabolic indicators for HIV-associated neurocognitive disorders (HAND).Methods: A quantitative lipidomic analysis was conducted on 524 longitudinal CSF samples collected from 7 different performance sites across the mainland United States, Hawaii, and Puerto Rico. Subjects included HIV-infected individuals with longitudinal clinical and cognitive testing data and cognitively normal HIV-negative healthy controls.Results: At baseline, HIV1 subjects could be differentiated from HIV2 controls by reductions in a single ceramide species and increases in multiple forms of cholesterol. Perturbations in cholesterol metabolism and ceramide were influenced by combined antiretroviral therapy (cART) use. There were no cross-sectional baseline differences in any lipid metabolite when HIV1 subjects were grouped according to cognitive status. However, a single sphingolipid metabolite and reduced levels of esterified cholesterols were prognostic indicators of incident cognitive decline. Longitudinal patterns of these disturbances in sphingolipid and sterol metabolism suggest that a progressive disorder of lipid metabolism that is similar to disorders of lipid storage may contribute to the pathogenesis of HAND.Conclusions: These findings suggest that HIV infection and cART are independently associated with a CNS metabolic disturbance, identify surrogate markers that are prognostic for cognitive decline, and implicate a lipid storage-like disorder in the progression of HAND. The widespread use of combined antiretroviral therapy (cART) in developed countries has dramatically decreased the death rates due to AIDS and decreased the incidence of dementia. 1,2However, cART has not reduced the prevalence rates for milder forms of HIV-associated neurocognitive disorders (HAND) that are associated with increased mortality.3-6 HAND frequently manifests in the domains of memory and executive functions, 7 and is associated with decreased adherence to pharmacotherapy, lower cognitive reserve, and increased incidence of psychiatric comorbidities. 8,9 Despite cART, there is evidence for ongoing neurologic damage that includes persistent astrocyte infection, brain volume loss, inflammation, synaptodendritic damage, and disruptions in white matter integrity. 5,[10][11][12] The mechanisms underlying these residual neuropathologic impairments remain obscure.Several studies have suggested that dysregulations in CNS lipid metabolism may be involved in the pathogenesis of HAND. [13][14][15] In particular, roles for ceramides, sphingomyelins, and cholesterol have been described, but the interrelationships of these bioactive lipids to the temporal progression *These authors contributed equally to this work.
Purpose of Review To systematically review recent findings on the role of immune cell activation in the pathogenesis of hypertension in people living with HIV (PLWH) and compare studies from Sub-Saharan Africa with what is reported in the USA and European literature according to guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Recent Findings PLWH have an increased risk for development of hypertension and cardiovascular disease. Chronic immune activation contributes to hypertension but the inflammatory milieu that predisposes PLWH to hypertension is poorly understood. We identified 45 relevant studies from 13 unique African countries. The prevalence of hypertension in PLWH on antiretroviral therapy (ART) and the ART-naive PLWH ranged from 6 to 50% and 2 to 41%, respectively. Interleukin (IL)-17A, interferon (IFN)-γ, and higher CD4 + T cell counts were associated with hypertension in ART-treated participants. Summary Targeting adaptive immune activation could provide improved care for hypertensive PLWH. Further research is needed to characterize the inflammatory milieu contributing to hypertension in PLWH especially in African populations where the global burden of HIV is the highest.
Purpose of Review With the advent of highly active antiretroviral therapy (ART), the life span of persons with HIV (PWH) has been nearly normalized. With aging, prevalence of the metabolic syndrome (MetS), including hypertension, has increased in the HIV population and exceeds that in the general population in some studies. This is due to a combination of traditional risk factors in addition to the effects attributable to the virus and ART. We review recent findings on the mechanisms contributing to MetS and hypertension in PWH, particularly those specific to the viral infection and to ART. Recent Findings Activation of the renin-angiotensin-aldosterone system (RAAS) and chronic immune activation contribute to the development of MetS and hypertension in PWH. HIV proteins and some ART agents alter adipocyte health contributing to dyslipidemias, weight gain, and insulin resistance. HIV infection also contributes to hypertension by direct effects on the RAAS that intertwine with inflammation by the RAAS also contributing to T cell activation. Summary Recent data suggest that in addition to current ART, therapeutic targeting of the MetS and hypertension in PWH, by interfering with the RAAS, treating insulin resistance directly or by use of immunomodulators that dampen inflammation, may be critical for preventing or treating these risk factors and to improve overall cardiovascular complications in the HIV-infected aging population.
The significance of the cerebrospinal fluid (CSF) Apolipoprotein E (APOE) level and whether it might have differential effects on brain function due to the presence of APOE ε4 allele(s) in HIV-infected patients are unknown. However, APOE ε4 allele has been associated with greater incidence of HIV-associated dementia and accelerated progression of HIV infection. Here, we show further evidence for the role of APOE ε4 in promoting cognitive impairment. We measured the APOE levels in the CSF of HIV-infected individuals. HIV+ subjects showed lower CSF APOE proteins than SN controls (−19%, p=0.03). While SN subjects with or without ε4 allele showed no difference in CSF APOE levels, ε4+ HIV+ subjects had similar levels to the SN subjects but higher levels than ε4− HIV+ subjects (+34%, p=0.01). Furthermore, while HIV+ subjects with ε2 or ε3 allele(s) showed a positive relationship between their CSF APOE levels and cognitive performance on the speed of processing domain (r=+0.35, p=0.05), ε4+ HIV+ subjects, in contrast, exhibited a negative relationship such that those with higher levels of CSF APOE(4) performed worse on the HIV Dementia Scale (r=−0.61, p=0.02), had lower Global Cognitive Scores (r=−0.57, p=0.03), and had poorer performance on tests involving learning (ε4 allele × [APOE] interaction, p=0.01). Our findings also suggest that the relatively higher levels of CSF APOE in ε4+ HIV+ (having primarily APOE4 isoforms) may negatively impact the brain and lead to poorer cognitive outcomes, while those individuals without the ε4 allele (with primarily APOE2 or APOE3 isoforms) may show compensatory responses that lead to better cognitive performance.
Background People living with HIV ( PLWH ) are at increased risk of cardiovascular disease, including hypertension, which persists despite effective plasma viral suppression on antiretroviral therapy. HIV infection is characterized by long‐term alterations in immune function, but the contribution of immune factors to hypertension in PLWH is not fully understood. Prior studies have found that both innate and adaptive immune cell activation contributes to hypertension. Methods and Results We hypothesized that chronic inflammation may contribute to hypertension in PLWH . To test this hypothesis, we enrolled a cohort of 70 PLWH (44% hypertensive) on a long‐term single antiretroviral therapy regimen for broad phenotyping of inflammation biomarkers. We found that hypertensive PLWH had higher levels of inflammatory cytokines, including tumor necrosis factor‐α receptor 1, interleukin‐6, interleukin‐17, interleukin‐5, intercellular adhesion molecule 1 and macrophage inflammatory protein‐1α. After adjustment for age, sex, and fat mass index, the circulating eosinophils remained significantly associated with hypertension. On the basis of these results, we assessed the relationship of eosinophils and hypertension in 2 cohorts of 50 and 81 039 similar HIV ‐negative people; although eosinophil count was associated with prevalent hypertension, this relationship was abrogated by body mass index. Conclusions These findings may represent a unique linkage between immune status and cardiovascular physiological characteristics in HIV infection, which should be evaluated further.
The Coronavirus disease 2019 (COVID-19) pandemic has killed over two hundred thousand people by end of April, 2020. America and Europe top in deaths from COVID-19 whereas the numbers are lower in Africa for unclear reasons. Emerging evidence suggests the role of hyperactive immune responses characterised by high pro-inflammatory cytokines in severe cases of COVID-19 and deaths. In this perspective, we explore the possible factors that may contribute to mild inflammatory responses in some cases of COVID-19 by focusing on immune education, parasites, sex hormones and chronic diseases, as well as genetic tolerance. To build our perspective, evidence is also extracted from wild rodents due to their multi-tasking immune responses as a result of constant exposure to pathogens.
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