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Bruce J Brew - One of the best experts on this subject based on the ideXlab platform.
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Vascular cognitive impairment and HIV-associated Neurocognitive Disorder: a new paradigm
Journal of NeuroVirology, 2019Co-Authors: Lucette A. Cysique, Bruce J BrewAbstract:In this review, we propose that vascular cognitive impairment (VCI), with relevance for the global HIV population, is fundamentally and clinically linked to the persistence of mild forms of HIV-associated Neurocognitive Disorders (HAND) in ageing people living with HIV infection (PLWH). After placing our review within the context of the general literature on HIV and ageing, we review non-VCI risks for dementia in ageing PLWH. We then present the recently updated VCI nomenclature and show that the neuropsychological and neuroimaging phenotypes of VCI and HAND are largely overlapping, suggesting that further research is needed to accurately distinguish them. We further link VCI and HAND at the mechanistic level by advancing the innovative proposal that the neuro-vascular unit (NVU) may represent the primary target of HIV-related brain injury in treated HIV infection. To this, we add the fundamental impact of mild and major VCI on the NVU. Importantly, we show that the potential contribution of vascular damage to overall brain damage in ageing PLWH is probably much higher than currently estimated because of methodological limitations, and because this research is only emerging. Finally, because all VCI risk factors are more prevalent, premature, and sometimes accelerated in the HIV population at large, we conclude that the probable total burden of VCI in the global HIV population is higher than in the general population and would need to be compared to chronic conditions such as type I diabetes and multiple sclerosis to account for the disease chronicity and lifelong treatment effects. Therefore, this review is also a call to action. Indeed, it is fully established that this amount of VCI burden is a major risk factor for dementia at aged 60+.
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hiv brain latency as measured by csf bcl11b relates to disrupted brain cellular energy in virally suppressed hiv infection
AIDS, 2019Co-Authors: Lucette A. Cysique, Avindra Nath, Thomas M. Gates, Lauriane Juge, Matthew J Lennon, Simon Jones, Michael D Lovelace, Caroline Rae, Tory P Johnson, Bruce J BrewAbstract:Objective:We investigated whether HIV brain latency was associated with brain injury in virally suppressed HIV infection.Design:Observational cross-sectional and longitudinal study.Methods:The study included 26 virally suppressed HIV-infected men (61.5% with HIV-associated Neurocognitive Disorder) w
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HIV-associated Neurocognitive Disorder.
Handbook of clinical neurology, 2018Co-Authors: Ruaridh Cameron Smail, Bruce J BrewAbstract:Human immunodeficiency virus (HIV)-associated Neurocognitive Disorder (HAND) affects roughly half the HIV-positive population. The symptoms of cognitive slowing, poor concentration, and memory problems can impact on everyday life. Its diagnosis is validated where possible by identifying deficits in two cognitive domains on neuropsychologic testing in patients either with or without symptoms. Corroborating evidence may be found on imaging, blood tests, and cerebrospinal fluid analysis, though sensitive and specific biomarkers are currently lacking. The introduction of combined antiretroviral therapy in the 1990s has generated a therapeutic paradox whereby the number of severe cases of HAND has fallen, yet milder forms continue to rise in prevalence. New emphasis has been placed on identifying the cause of apparent ongoing HIV infection and inflammation of the central nervous system (CNS) in the face of durable systemic viral suppression, and how this equates to the neuronal dysfunction underlying HAND. The interaction with aging and comorbidities is becoming increasingly common as the HIV-positive population enters older adulthood, with neurodegenerative, metabolic, and vascular causes of cognitive impairment combining and probably accelerating in the context of chronic HIV infection. Therapies targeted to the CNS, but without neurotoxic side-effects, are being investigated to attempt to reduce the likelihood of developing, and improving, HAND.
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Functional Connectivity in Virally Suppressed Patients with HIV-associated Neurocognitive Disorder: A Resting-State Analysis.
AJNR. American journal of neuroradiology, 2017Co-Authors: Joga Chaganti, Armin Heinecke, Thomas M. Gates, Kirsten Moffat, Bruce J BrewAbstract:BACKGROUND AND PURPOSE: HIV-associated Neurocognitive Disorder still occurs despite virally suppressive combination antiretroviral therapy. In the pre-combination antiretroviral era and in patients without HIV suppression, HIV-associated Neurocognitive Disorder was caused by synaptodendritic injury resulting in impairment of neural networks, characterized by decreased attention, psychomotor slowing, and working memory deficits. Whether similar pathogenesis is true for HIV-associated Neurocognitive Disorder in the context of viral suppression is not clear. Resting-state fMRI has been shown to be efficient in detecting impaired neural networks in various neurologic illnesses. This pilot study aimed to assess resting-state functional connectivity of the brain in patients with active HIV-associated Neurocognitive Disorder in the context of HIV viral suppression in both blood and CSF. MATERIALS AND METHODS: Eighteen patients with active HIV-associated Neurocognitive Disorder (recent diagnosis with progressing symptoms) on combination antiretroviral therapy with viral suppression in both blood and CSF and 9 demographically matched control subjects underwent resting-state functional MR imaging. The connectivity in the 6 known neural networks was assessed. To localize significant ROIs within the HIV and control group, we performed a seed-based correlation for each known resting-state network. RESULTS: There were significant group differences between the control and HIV-associated Neurocognitive Disorder groups in the salience (0.26 versus 0.14, t = 2.6978, df = 25, P = .0123) and executive networks (0.52 versus 0.32, t = 2.2372, df = 25, P = .034). The covariate analysis with neuropsychological scores yielded statistically significant correlations in all 6 studied functional networks, with the most conspicuous correlation in salience networks. CONCLUSIONS: Active HIV-associated Neurocognitive Disorder in virally suppressed patients is associated with significantly decreased connectivity in the salience and executive networks, thereby making it potentially useful as a biomarker.
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Monitoring HIV-associated Neurocognitive Disorder Using Screenings: a Critical Review Including Guidelines for Clinical and Research Use
Current HIV AIDS Reports, 2017Co-Authors: Jody Kamminga, Bruce J Brew, Luxshimi Lal, Edwina J. Wright, Mark Bloch, Lucette A. CysiqueAbstract:Screening tools to identify HIV-associated Neurocognitive Disorder (HAND) are primarily devised to detect cognitive impairment on a single occasion. With the chronicity of HIV infection and the risk of HAND developing or progressing despite viral control, it may be pertinent to repeat HAND screening at more than one time point. Despite this, there are limited data on longitudinal use of such screening tools, particularly with regard to the role of practice effects. Additionally, no guidelines currently exist on the timeframe between testing intervals, or recommendation of the magnitude of baseline impairment that warrants follow-up testing. The aim of the current paper was to review existing evidence for longitudinal validity of HAND screening tools. Only those HAND screening tools previously found to have high cross-sectional criterion validity were included. Preliminary recommendations for clinical use and future research are proposed including in international settings.
Stuart A. Lipton - One of the best experts on this subject based on the ideXlab platform.
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Correction to: TCA cycle metabolic compromise due to an aberrant S‑nitrosoproteome in HIV‑associated Neurocognitive Disorder with methamphetamine use
Journal of NeuroVirology, 2021Co-Authors: Paschalis-thomas Doulias, Tomohiro Nakamura, Henry Scott, Abdullah Sultan, Scott R. Mckercher, Amanda Deal, Matthew Albertolle, Harry Ischiropoulos, Stuart A. LiptonAbstract:A correction to this paper has been published: https://doi.org/10.1007/s13365-021-00985-x
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TCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated Neurocognitive Disorder with methamphetamine use
Journal of NeuroVirology, 2021Co-Authors: Stuart A. Lipton, Paschalis-thomas Doulias, Tomohiro Nakamura, Henry Scott, Abdullah Sultan, Scott R. Mckercher, Amanda Deal, Matthew Albertolle, Harry IschiropoulosAbstract:In the brain, both HIV-1 and methamphetamine (meth) use result in increases in oxidative and nitrosative stress. This redox stress is thought to contribute to the pathogenesis of HIV-associated Neurocognitive Disorder (HAND) and further worsening cognitive activity in the setting of drug abuse. One consequence of such redox stress is aberrant protein S-nitrosylation, derived from nitric oxide, which may disrupt normal protein activity. Here, we report an improved, mass spectrometry-based technique to assess S-nitrosylated protein in human postmortem brains using selective enrichment of S-nitrosocysteine residues with an organomercury resin. The data show increasing S-nitrosylation of tricarboxylic acid (TCA) enzymes in the setting of HAND and HAND/meth use compared with HIV+ control brains without CNS pathology. The consequence is systematic inhibition of multiple TCA cycle enzymes, resulting in energy collapse that can contribute to the neuronal and synaptic damage observed in HAND and meth use.
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differential effects of pharmacologic and genetic modulation of nmda receptor activity on hiv gp120 induced neuronal damage in an in vivo mouse model
Journal of Molecular Neuroscience, 2016Co-Authors: Nobuki Nakanishi, Eliezer Masliah, Stuart A. Lipton, Scott R. Mckercher, Yeonjoo KangAbstract:HIV-associated Neurocognitive Disorder (HAND) consists of motor and cognitive dysfunction in a relatively large percentage of patients with AIDS. Prior work has suggested that at least part of the neuronal and synaptic damage observed in HAND may occur due to excessive stimulation of NMDA-type glutamate receptors (NMDARs). Here, we compared pharmacological and genetic manipulation of NMDAR activity using an improved derivative of the NMDAR antagonist memantine, termed NitroMemantine, and the modulatory NMDAR subunit GluN3A in the HIV/gp120 transgenic (tg) mouse model of HAND. Interestingly, we found that while both NitroMemantine and GluN3A have been shown to inhibit NMDAR activity, NitroMemantine protected synapses in gp120-tg mice, but overexpression of GluN3A augmented the damage. Given recent findings in the field, one explanation for this apparently paradoxical result is the location of the NMDARs primarily affected, with NitroMemantine inhibiting predominantly extrasynaptic pathologically activated NMDARs, but GluN3A disrupting normal NMDAR-mediated neuroprotective activity via inhibition of synaptic NMDARs.
Summer F Acevedo - One of the best experts on this subject based on the ideXlab platform.
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ywhae 14 3 3e a potential novel genetic risk factor and csf biomarker for hiv Neurocognitive impairment
Journal of NeuroVirology, 2013Co-Authors: Diana Morales, Rosa Hechavarria, Valerie Wojna, Summer F AcevedoAbstract:YWHAE (14-3-3e) protein levels are considered to be a reliable biomarker for neurodegeneration. The YWHAE protein interacts both directly and indirectly with human immunodeficiency virus (HIV) accessory proteins, leading to cell death. The purpose of this study was to examine the relationship between YWHAE polymorphisms and HIV-associated Neurocognitive Disorder (HAND) and the relationship between YWHAE protein levels and HAND. A cross-sectional study using random samples of HIV-seropositive (n = 20) and HIV-seronegative (controls) (n = 16) women from the Hispanic-Latino Longitudinal Cohort of Women was conducted. Individuals who are HIV-seropositive and heterozygous at the rs4790084/rs1204828 loci in the YWHAE gene were 3× more likely to display reduced cognitive functioning, to have received a HAND diagnosis, and to have less YHWAE protein expressed than homozygotes. Western blots from cerebral spinal fluid indicate that the HIV-seropositive women with HAND expressed 4.5× less YWHAE compared to HIV-seropositive cognitively normal women (94 % sensitivity, 84 % specificity; HIV-seropositive vs. controls). Therefore, polymorphism in YWHAE may be a genetic risk factor for HAND and levels of YWHAE protein are a likely biomarker for Neurocognitive status in HIV-seropositive women.
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YWHAE/14-3-3ε: a potential novel genetic risk factor and CSF biomarker for HIV Neurocognitive impairment
Journal of NeuroVirology, 2013Co-Authors: Diana Morales, Rosa Hechavarria, Valerie Wojna, Summer F AcevedoAbstract:YWHAE (14-3-3e) protein levels are considered to be a reliable biomarker for neurodegeneration. The YWHAE protein interacts both directly and indirectly with human immunodeficiency virus (HIV) accessory proteins, leading to cell death. The purpose of this study was to examine the relationship between YWHAE polymorphisms and HIV-associated Neurocognitive Disorder (HAND) and the relationship between YWHAE protein levels and HAND. A cross-sectional study using random samples of HIV-seropositive (n = 20) and HIV-seronegative (controls) (n = 16) women from the Hispanic-Latino Longitudinal Cohort of Women was conducted. Individuals who are HIV-seropositive and heterozygous at the rs4790084/rs1204828 loci in the YWHAE gene were 3× more likely to display reduced cognitive functioning, to have received a HAND diagnosis, and to have less YHWAE protein expressed than homozygotes. Western blots from cerebral spinal fluid indicate that the HIV-seropositive women with HAND expressed 4.5× less YWHAE compared to HIV-seropositive cognitively normal women (94 % sensitivity, 84 % specificity; HIV-seropositive vs. controls). Therefore, polymorphism in YWHAE may be a genetic risk factor for HAND and levels of YWHAE protein are a likely biomarker for Neurocognitive status in HIV-seropositive women.
Diana Morales - One of the best experts on this subject based on the ideXlab platform.
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ywhae 14 3 3e a potential novel genetic risk factor and csf biomarker for hiv Neurocognitive impairment
Journal of NeuroVirology, 2013Co-Authors: Diana Morales, Rosa Hechavarria, Valerie Wojna, Summer F AcevedoAbstract:YWHAE (14-3-3e) protein levels are considered to be a reliable biomarker for neurodegeneration. The YWHAE protein interacts both directly and indirectly with human immunodeficiency virus (HIV) accessory proteins, leading to cell death. The purpose of this study was to examine the relationship between YWHAE polymorphisms and HIV-associated Neurocognitive Disorder (HAND) and the relationship between YWHAE protein levels and HAND. A cross-sectional study using random samples of HIV-seropositive (n = 20) and HIV-seronegative (controls) (n = 16) women from the Hispanic-Latino Longitudinal Cohort of Women was conducted. Individuals who are HIV-seropositive and heterozygous at the rs4790084/rs1204828 loci in the YWHAE gene were 3× more likely to display reduced cognitive functioning, to have received a HAND diagnosis, and to have less YHWAE protein expressed than homozygotes. Western blots from cerebral spinal fluid indicate that the HIV-seropositive women with HAND expressed 4.5× less YWHAE compared to HIV-seropositive cognitively normal women (94 % sensitivity, 84 % specificity; HIV-seropositive vs. controls). Therefore, polymorphism in YWHAE may be a genetic risk factor for HAND and levels of YWHAE protein are a likely biomarker for Neurocognitive status in HIV-seropositive women.
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YWHAE/14-3-3ε: a potential novel genetic risk factor and CSF biomarker for HIV Neurocognitive impairment
Journal of NeuroVirology, 2013Co-Authors: Diana Morales, Rosa Hechavarria, Valerie Wojna, Summer F AcevedoAbstract:YWHAE (14-3-3e) protein levels are considered to be a reliable biomarker for neurodegeneration. The YWHAE protein interacts both directly and indirectly with human immunodeficiency virus (HIV) accessory proteins, leading to cell death. The purpose of this study was to examine the relationship between YWHAE polymorphisms and HIV-associated Neurocognitive Disorder (HAND) and the relationship between YWHAE protein levels and HAND. A cross-sectional study using random samples of HIV-seropositive (n = 20) and HIV-seronegative (controls) (n = 16) women from the Hispanic-Latino Longitudinal Cohort of Women was conducted. Individuals who are HIV-seropositive and heterozygous at the rs4790084/rs1204828 loci in the YWHAE gene were 3× more likely to display reduced cognitive functioning, to have received a HAND diagnosis, and to have less YHWAE protein expressed than homozygotes. Western blots from cerebral spinal fluid indicate that the HIV-seropositive women with HAND expressed 4.5× less YWHAE compared to HIV-seropositive cognitively normal women (94 % sensitivity, 84 % specificity; HIV-seropositive vs. controls). Therefore, polymorphism in YWHAE may be a genetic risk factor for HAND and levels of YWHAE protein are a likely biomarker for Neurocognitive status in HIV-seropositive women.
Valerie Wojna - One of the best experts on this subject based on the ideXlab platform.
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ywhae 14 3 3e a potential novel genetic risk factor and csf biomarker for hiv Neurocognitive impairment
Journal of NeuroVirology, 2013Co-Authors: Diana Morales, Rosa Hechavarria, Valerie Wojna, Summer F AcevedoAbstract:YWHAE (14-3-3e) protein levels are considered to be a reliable biomarker for neurodegeneration. The YWHAE protein interacts both directly and indirectly with human immunodeficiency virus (HIV) accessory proteins, leading to cell death. The purpose of this study was to examine the relationship between YWHAE polymorphisms and HIV-associated Neurocognitive Disorder (HAND) and the relationship between YWHAE protein levels and HAND. A cross-sectional study using random samples of HIV-seropositive (n = 20) and HIV-seronegative (controls) (n = 16) women from the Hispanic-Latino Longitudinal Cohort of Women was conducted. Individuals who are HIV-seropositive and heterozygous at the rs4790084/rs1204828 loci in the YWHAE gene were 3× more likely to display reduced cognitive functioning, to have received a HAND diagnosis, and to have less YHWAE protein expressed than homozygotes. Western blots from cerebral spinal fluid indicate that the HIV-seropositive women with HAND expressed 4.5× less YWHAE compared to HIV-seropositive cognitively normal women (94 % sensitivity, 84 % specificity; HIV-seropositive vs. controls). Therefore, polymorphism in YWHAE may be a genetic risk factor for HAND and levels of YWHAE protein are a likely biomarker for Neurocognitive status in HIV-seropositive women.
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YWHAE/14-3-3ε: a potential novel genetic risk factor and CSF biomarker for HIV Neurocognitive impairment
Journal of NeuroVirology, 2013Co-Authors: Diana Morales, Rosa Hechavarria, Valerie Wojna, Summer F AcevedoAbstract:YWHAE (14-3-3e) protein levels are considered to be a reliable biomarker for neurodegeneration. The YWHAE protein interacts both directly and indirectly with human immunodeficiency virus (HIV) accessory proteins, leading to cell death. The purpose of this study was to examine the relationship between YWHAE polymorphisms and HIV-associated Neurocognitive Disorder (HAND) and the relationship between YWHAE protein levels and HAND. A cross-sectional study using random samples of HIV-seropositive (n = 20) and HIV-seronegative (controls) (n = 16) women from the Hispanic-Latino Longitudinal Cohort of Women was conducted. Individuals who are HIV-seropositive and heterozygous at the rs4790084/rs1204828 loci in the YWHAE gene were 3× more likely to display reduced cognitive functioning, to have received a HAND diagnosis, and to have less YHWAE protein expressed than homozygotes. Western blots from cerebral spinal fluid indicate that the HIV-seropositive women with HAND expressed 4.5× less YWHAE compared to HIV-seropositive cognitively normal women (94 % sensitivity, 84 % specificity; HIV-seropositive vs. controls). Therefore, polymorphism in YWHAE may be a genetic risk factor for HAND and levels of YWHAE protein are a likely biomarker for Neurocognitive status in HIV-seropositive women.
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Proteomic analyses of monocytes obtained from Hispanic women with HIV-associated dementia show depressed antioxidants.
Proteomics. Clinical applications, 2010Co-Authors: Stephanie D. Kraft-terry, Valerie Wojna, Richard L. Skolasky, Yamil Gerena, Marines Plaud-valentin, Yolanda Rodriguez, Pawel Ciborowski, Raul Mayo, Howard E. Gendelman, Loyda M. MeléndezAbstract:Monocyte ingress into the brain during progressive human immunodeficiency virus (HIV-1) infection parallels the severity of cognitive impairments. Although activated monocyte phenotypes emerge during disease, the functional correlates of these cells remain unresolved. To this end, we studied the proteome of blood-derived monocytes obtained from Hispanic women with the most severe form of HIV-associated Neurocognitive Disorder, HIV-associated dementia (HAD). Monocytes isolated from peripheral blood mononuclear cells by CD14+ immunoaffinity column chromatography were >95% pure. Cells were recovered from five patients without evidence of cognitive impairment and four with HAD and analyzed by two-dimensional difference gel electrophoresis and tandem mass spectrometry. Importantly, ADP ribosylhydrolase, myeloperoxidase, thioredoxin, peroxiredoxin 3, NADPH, and GTPase activating protein were all downregulated in HAD. In regards to myeloperoxidase, thioredoxin, and peroxiredoxin 3 these changes were validated in an additional cohort of 30 patients by flow cytometry. We conclude that deficits in monocyte antioxidant proteins lead to neuronal damage through the loss of hydrogen peroxide scavenging capabilities, thus exposing neurons to apoptosis-inducing factors. Altered monocyte functions therefore may contribute to the development and progression of HAD.