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Supercooled water droplets are widely used to study supercooled water1,2, ice nucleation3-5 and droplet freezing6-11. Their freezing in the atmosphere affects the dynamics and climate feedback of clouds12,13 and can accelerate cloud freezing through secondary ice production14-17. Droplet freezing occurs at several timescales and length scales14,18 and is sufficiently stochastic to make it unlikely that two frozen drops are identical. Here we use optical microscopy and X-ray laser diffraction to investigate the freezing of tens of thousands of water microdrops in vacuum after homogeneous ice nucleation around 234-235 K. On the basis of drop images, we developed a seven-stage model of freezing and used it to time the diffraction data. Diffraction from ice crystals showed that long-range crystalline order formed in less than 1 ms after freezing, whereas diffraction from the remaining liquid became similar to that from quasi-liquid layers on premelted ice19,20. The ice had a strained hexagonal crystal structure just after freezing, which is an early metastable state that probably precedes the formation of ice with stacking defects8,9,18. The techniques reported here could help determine the dynamics of freezing in other conditions, such as drop freezing in clouds, or help understand rapid solidification in other materials.
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OBJECTIVE: This epigenomics sub-study embedded within a randomized controlled trial examined whether an evidenced-based behavioral intervention model that decreased stimulant use altered leukocyte DNA methylation (DNAm). METHODS: Sexual minority men with HIV who use methamphetamine were randomized to a five-session positive affect intervention (n = 32) or an attention-control condition (n = 21), both delivered during three months of contingency management for stimulant abstinence. All participants exhibited sustained HIV virologic control - an HIV viral load less than 40 copies/mL at baseline and six months post-randomization. The Illumina EPIC BeadChip measured leukocyte methylation of cytosine-phosphate-guanosine (CpG) sites mapping onto five a priori candidate genes of interest (i.e., ADRB2, BDNF, FKBP5, NR3C1, OXTR). Functional DNAm pathways and soluble markers of immune dysfunction were secondary outcomes. RESULTS: Compared to the attention-control condition, the positive affect intervention significantly decreased methylation of CpG sites on genes that regulate ß2 adrenergic and oxytocin receptors. There was an inconsistent pattern for the direction of the intervention effects on methylation of CpG sites on genes for glucocorticoid receptors and brain-derived neurotrophic factor. Pathway analyses adjusting for the false discovery rate (padj < 0.05) revealed significant intervention-related alterations in DNAm of Reactome pathways corresponding to neural function as well as dopamine, glutamate, and serotonin release. Positive affect intervention effects on DNAm were accompanied by significant reductions in the self-reported frequency of stimulant use. CONCLUSIONS: There is an epigenetic signature of an evidence-based behavioral intervention model that reduced stimulant use, which will guide the identification of biomarkers for treatment responses.
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Metilación de ADN , Infecciones por VIH , Leucocitos , Metanfetamina , Minorías Sexuales y de Género , Humanos , Masculino , Adulto , Infecciones por VIH/genética , Infecciones por VIH/tratamiento farmacológico , Leucocitos/metabolismo , Leucocitos/efectos de los fármacos , Persona de Mediana Edad , Epigénesis Genética , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteínas de Unión a Tacrolimus/genética , Afecto/efectos de los fármacos , Trastornos Relacionados con Anfetaminas/genética , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Terapia Conductista/métodos , Receptores de Oxitocina/genéticaRESUMEN
Cognitive disorders are prevalent in people with HIV (PWH) despite antiretroviral therapy. Given the heterogeneity of cognitive disorders in PWH in the current era and evidence that these disorders have different etiologies and risk factors, scientific rationale is growing for using data-driven models to identify biologically defined subtypes (biotypes) of these disorders. Here, we discuss the state of science using machine learning to understand cognitive phenotypes in PWH and their associated comorbidities, biological mechanisms, and risk factors. We also discuss methods, example applications, challenges, and what will be required from the field to successfully incorporate machine learning in research on cognitive disorders in PWH. These topics were discussed at the National Institute of Mental Health meeting on "Biotypes of CNS Complications in People Living with HIV" held in October 2021. These ongoing research initiatives seek to explain the heterogeneity of cognitive phenotypes in PWH and their associated biological mechanisms to facilitate clinical management and tailored interventions.
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Trastornos del Conocimiento , Disfunción Cognitiva , Infecciones por VIH , Humanos , Disfunción Cognitiva/etiología , Aprendizaje Automático , Fenotipo , Cognición , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológicoRESUMEN
PURPOSE OF REVIEW: In the era of HIV treatment as prevention (TasP), more clarity is needed regarding whether people with HIV who use stimulants (i.e., methamphetamine, powder cocaine, and crack cocaine) display elevated HIV viral load and greater immune dysregulation. RECENT FINDINGS: Although rates of viral suppression have improved in the TasP era, stimulant use was independently associated with elevated viral load in 23 of 28 studies included in our review. In the 12 studies examining other HIV disease markers, there was preliminary evidence for stimulant-associated alterations in gut-immune dysfunction and cellular immunity despite effective HIV treatment. Studies generally focused on documenting the direct associations of stimulant use with biomarkers of HIV pathogenesis without placing these in the context of social determinants of health. Stimulant use is a key barrier to optimizing the effectiveness of TasP. Elucidating the microbiome-gut-brain axis pathways whereby stimulants alter neuroimmune functioning could identify viable targets for pharmacotherapies for stimulant use disorders. Examining interpersonal, neighborhood, and structural determinants that could modify the associations of stimulant use with biomarkers of HIV pathogenesis is critical to guiding the development of comprehensive, multi-level interventions.
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Estimulantes del Sistema Nervioso Central , Infecciones por VIH , Humanos , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Biomarcadores , Estimulantes del Sistema Nervioso Central/efectos adversos , Cocaína Crack/efectos adversos , Infecciones por VIH/patología , Metanfetamina/efectos adversosRESUMEN
Variation and differential selection pressures on Tat genes have been shown to alter the biological function of the protein, resulting in pathological consequences in a number of organs including the brain. We evaluated the impact of genetic variation and selection pressure on 147 HIV-1 subtype C Tat exon 1 sequences from monocyte-depleted peripheral lymphocytes on clinical diagnosis of neurocognitive impairment. Genetic analyses identified two signature amino acid residues, lysine at codon 24 (24K) with a frequency of 43.4% and arginine at codon 29 (29R) with a frequency of 34.0% in individuals with HIV-associated neurocognitive impairment. The analyses also revealed two signature residues, asparagine, 24 N (31.9%), and histidine, 29H (21.3%), in individuals without neurocognitive impairment. Both codons, 24 and 29, were associated with high entropy but only codon 29 was under positive selection. The presence of signature K24 increased by 2.08 times the risk of neurocognitive impairment, 3.15 times higher proviral load, and 69% lower absolute CD4 T-cell count compared to those without the signature. The results support a linkage between HIV-1 C Tat N24K polymorphism, proviral load, immunosuppression, and neurocognitive impairment. The signature may induce more neurotoxic effects, which contributes to establishment and severity of HIV-associated neurocognitive impairment.
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Disfunción Cognitiva , Infecciones por VIH , VIH-1 , Productos del Gen tat del Virus de la Inmunodeficiencia Humana , Aminoácidos/genética , Codón , Disfunción Cognitiva/virología , Exones , Infecciones por VIH/complicaciones , VIH-1/genética , Humanos , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
ABSTRACT: People with HIV (PWH) receiving effective antiretroviral therapy (ART) continue to display residual immune dysregulation that amplifies the risk for neuropsychiatric comorbidities. At the same time, PWH commonly experience intersectional stigma and other psychosocial stressors that are linked to neuroendocrine stress responses, potentiate residual immune dysregulation, and alter other biobehavioral processes relevant to health outcomes. This special issue of Psychosomatic Medicine seeks to advance our understanding of the intersection of HIV with mental health in the modern ART era. Several articles cover topics related to the prevalence and treatment of psychiatric comorbidities among PWH such as depression, suicidality, and substance use disorders. Other articles delineate biobehavioral mechanisms relevant to mental health in PWH such as inflammation, immune activation, neuroendocrine signaling, cellular aging, the microbiome-gut-brain axis, and neurobehavioral processes. Collectively, the articles in this special issue highlight the continued importance of biobehavioral and neurobehavioral mental health research in the modern ART era.
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Infecciones por VIH , Trastornos Relacionados con Sustancias , Comorbilidad , Progresión de la Enfermedad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Inflamación/epidemiología , Salud Mental , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
OBJECTIVE: Depression, substance use disorders, and other neuropsychiatric comorbidities are common in people with HIV (PWH), but the underlying mechanisms are not sufficiently understood. HIV-induced damage to the gastrointestinal tract potentiates residual immune dysregulation in PWH receiving effective antiretroviral therapy. However, few studies among PWH have examined the relevance of microbiome-gut-brain axis: bidirectional crosstalk between the gastrointestinal tract, immune system, and central nervous system. METHODS: A narrative review was conducted to integrate findings from 159 articles relevant to psychoneuroimmunology (PNI) and microbiome-gut-brain axis research in PWH. RESULTS: Early PNI studies demonstrated that neuroendocrine signaling via the hypothalamic-pituitary-adrenal axis and autonomic nervous system could partially account for the associations of psychological factors with clinical HIV progression. This review highlights the need for PNI studies examining the mechanistic relevance of the gut microbiota for residual immune dysregulation, tryptophan catabolism, and oxytocin release as key biological determinants of neuropsychiatric comorbidities in PWH (i.e., body-to-mind pathways). It also underscores the continued relevance of neuroendocrine signaling via the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and oxytocin release in modifying microbiome-gut-brain axis functioning (i.e., mind-to-body pathways). CONCLUSIONS: Advancing our understanding of PNI and microbiome-gut-brain axis pathways relevant to depression, substance use disorders, and other neuropsychiatric comorbidities in PWH can guide the development of novel biobehavioral interventions to optimize health outcomes. Recommendations are provided for biobehavioral and neurobehavioral research investigating bidirectional PNI and microbiome-gut-brain axis pathways among PWH in the modern antiretroviral therapy era.
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Microbioma Gastrointestinal , Infecciones por VIH , Encéfalo/fisiología , Eje Cerebro-Intestino , Microbioma Gastrointestinal/fisiología , Infecciones por VIH/tratamiento farmacológico , Humanos , Sistema Hipotálamo-Hipofisario , Oxitocina/metabolismo , Sistema Hipófiso-Suprarrenal , Psiconeuroinmunología , TriptófanoRESUMEN
There is wide variation in the reported prevalence of cognitive impairment in people with HIV (PWH). Part of this variation may be attributable to different studies using different methods of combining neuropsychological test scores to classify participants as either cognitively impaired or unimpaired. Our aim was to determine, in a South African cohort of PWH (N = 148), (a) how much variation in reported rates was due to method used to define cognitive impairment and (b) which method correlated best with MRI biomarkers of HIV-related brain pathology. Participants completed detailed neuropsychological assessment and underwent 3 T structural MRI and diffusion tensor imaging (DTI). We used the neuropsychological data to investigate 20 different methods of determining HIV-associated cognitive impairment. We used the neuroimaging data to obtain volumes for cortical and subcortical grey matter and total white matter and DTI metrics for several white matter tracts. Applying each of the 20 methods to the cognitive dataset resulted in a wide variation (20-97%) in estimated rates of impairment. Logistic regression models showed no method was associated with HIV-related neuroimaging abnormalities as measured by structural volumes or DTI metrics. We conclude that for the population from which this sample was drawn, much of the variation in reported rates of cognitive impairment in PWH is due to the method of classification used, and that none of these methods accurately reflects biological effects of HIV in the brain. We suggest that defining HIV-associated cognitive impairment using neuropsychological test performance only is insufficient; pre-morbid functioning, co-morbidities, cognitive symptoms, and functional impairment should always be considered.
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Complejo SIDA Demencia/clasificación , Complejo SIDA Demencia/diagnóstico , Adulto , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Neuroimagen , SudáfricaRESUMEN
Although combination antiretroviral therapy (cART) has simplified over the past decade, polypharmacy is increasing for older people living with HIV (PLWH) due to the emergence of multiple health comorbidities. This study examined predictors of, and relationships between, objective (Medication Management Test-Revised (MMT-R)) and self-reported medication management ability in older (≥ 50 years) PLWH (n = 146) compared with HIV-uninfected (HIV-) individuals (n = 60). PLWH scored worse on the MMT-R and had a higher pill burden compared with HIV- individuals. MMT-R failure was predicted by HIV status, race, reading level, and worse executive functioning, as well as history of Hepatitis C and detectable viral load in PLWH. Self-reported ability to manage medications did not relate to MMT-R score. Older PLWH may not self-describe concerns regarding their ability to manage complex medication regimens. Our results emphasize the need for objective measurements of medication management ability.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación , Autoadministración , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , PolifarmaciaRESUMEN
A spectrum of cognitive impairments known as HIV-associated neurocognitive disorders (HAND) are consequences of the effects of HIV-1 within the central nervous system. Regardless of treatment status, an aberrant chronic neuro-immune regulation is a crucial contributor to the development of HAND. However, the extent to which inflammation affects brain structures critical for cognitive status remains unclear. The present study aimed to determine associations of peripheral immune markers with cortical thickness and surface area. Participants included 65 treatment-naïve HIV-positive individuals and 26 HIV-negative controls. Thickness and surface area of all cortical regions were derived using automated parcellation of T1-weighted images acquired at 3 T. Peripheral immune markers included C-C motif ligand 2 (CCL2), matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), thymidine phosphorylase (TYMP), transforming growth factor (TGF)-ß1, and vascular endothelial growth factor (VEGF), which were measured using enzyme-linked immunosorbent assays. Associations of these markers with thickness and surface area of cortical regions were evaluated. A mediation analysis examined whether associations of inflammatory markers with cognitive functioning were mediated by brain cortical thickness and surface area. After controlling for multiple comparisons, higher NGAL was associated with reduced thickness of the bilateral orbitofrontal cortex in HIV-positive participants. The association of NGAL with worse motor function was mediated by cortical thickness of the bilateral orbitofrontal region. Taken together, this study suggests that NGAL plays a potential role in the neuropathophysiology of neurocognitive impairments of HIV.
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Cognición , Disfunción Cognitiva/inmunología , Infecciones por VIH/inmunología , VIH-1/patogenicidad , Lipocalina 2/genética , Corteza Prefrontal/inmunología , Adulto , Biomarcadores/sangre , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Estudios de Casos y Controles , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Femenino , Expresión Génica , Infecciones por VIH/diagnóstico por imagen , Infecciones por VIH/genética , Infecciones por VIH/psicología , VIH-1/inmunología , Humanos , Lipocalina 2/inmunología , Imagen por Resonancia Magnética , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/inmunología , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/virología , Sudáfrica , Timidina Fosforilasa/genética , Timidina Fosforilasa/inmunología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/inmunología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/inmunologíaRESUMEN
It is not known if proviral DNA in the periphery corresponds to cognitive status in clade C as it does in clade B and recombinant forms. A cross-sectional study was conducted on participants investigated for HIV-associated neurocognitive impairment in South Africa. HIV-1 proviral DNA was quantified using a PCR assay targeting a highly conserved HIV-1 LTR-gag region. Fifty-four (36.7%) participants were cognitively impaired and 93 (63.3%) were not impaired. Forty-three (79.6%) of the cognitively impaired participants were female and 11 (20.4%) were male. There was no significant age difference between cognitively impaired and unimpaired participants (p = 0.42). HIV-1 DNA in cognitively impaired PLWH was significantly higher than in cognitively normal individuals (p = .016). Considering impaired participants, lymphocyte HIV-1 DNA was significantly higher in males than females (p = 0.02). There was a modest positive correlation between lymphocyte HIV-1 DNA and global deficit scores (GDS) r = 0.176; p = 0.03). The two measures of viral load, lymphocyte HIV-1 DNA copies/million and plasma RNA copies/ml, were positively correlated (r = 0.39; p < .001). After adjusting for other covariates, age, sex, treatment status, and the interactions between impairment and treatment, the multivariate regression showed association between proviral load and neurocognitive impairment; omega effect size was 0.04, p value = 0.010. The burden of HIV-1 peripheral blood lymphocyte proviral DNA corresponds to neurocognitive impairment among individuals infected with clade C disease. Therefore, therapeutic strategies to reduce the HIV-1 proviral DNA reservoir in lymphocytes may improve neurocognitive outcomes in PLWH.
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Linfocitos T CD4-Positivos/virología , Cognición , Disfunción Cognitiva/inmunología , ADN Viral/genética , Infecciones por VIH/inmunología , VIH-1/genética , Provirus/genética , Adulto , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Estudios Transversales , ADN Viral/inmunología , Femenino , Expresión Génica , Infecciones por VIH/diagnóstico , Infecciones por VIH/genética , Infecciones por VIH/psicología , VIH-1/clasificación , VIH-1/patogenicidad , Humanos , Masculino , Pruebas Neuropsicológicas , Provirus/inmunología , Receptores CCR5/genética , Receptores CCR5/inmunología , Factores Sexuales , Sudáfrica , Carga ViralRESUMEN
Background: Human immunodeficiency virus (HIV)-infected (HIV+) young adults often engage in risk-taking behavior. However, the disruptive effects of HIV on the neurobiological underpinnings of risky decision making are not well understood. Methods: Risky decision making, measured via the Iowa Gambling Task (IGT), was compared voxel-wise to resting cerebral blood flow (rCBF) acquired via arterial spin labeling. Separate topographical maps were obtained for HIV-uninfected (HIV-; n = 62) and HIV+ (n = 41) young adults (18-24 years old) and were compared to the full cohort of participants. For the HIV+ group, rCBF was compared to recent and nadir CD4. Results: IGT performance was supported by rCBF in 3 distinct brain regions: regions I, II, and III. The relationship between IGT performance and rCBF in HIV+ individuals was most robust in region I, the ventromedial prefrontal and insular cortices. Region II contained strong relationships for both HIV- and HIV+. Region III, dorsolateral prefrontal and posterior cingulate cortices, contained relationships that were strongest for HIV- controls. IGT performance was intact among HIV+ participants with higher rCBF in either region I or region III. By contrast, performance was worse among HIV+ individuals with lower rCBF in both regions I and III when compared to HIV- controls (P = .01). rCBF in region III was reduced in HIV+ compared with HIV- individuals (P = .04), and positively associated with nadir CD4 cell count (P = .02). Conclusions: Recruitment of executive systems (region III) mitigates risk-taking behavior in HIV+ and HIV- individuals. Recruitment of reward systems (region I) mitigates risk-taking behavior when region III is disrupted due to immunological compromise. Identifying individual recruitment patterns may aid anatomically directed therapeutics or psychosocial interventions.
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Toma de Decisiones/fisiología , Infecciones por VIH , Corteza Prefrontal/fisiología , Fármacos Anti-VIH , Terapia Antirretroviral Altamente Activa , Femenino , Juego de Azar , VIH , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Pruebas Neuropsicológicas , Asunción de Riesgos , Adulto JovenRESUMEN
Neuroimaging abnormalities are common in chronically infected HIV-positive individuals. The majority of studies have focused on structural or functional brain outcomes in samples infected with clade B HIV. While preliminary work reveals a similar structural imaging phenotype in patients infected with clade C HIV, no study has examined functional connectivity (FC) using resting-state functional magnetic resonance imaging (rs-fMRI) in clade C HIV. In particular, we were interested to explore HIV-only effects on neurocognitive function using associations with rs-fMRI. In the present study, 56 treatment-naïve, clade C HIV-infected participants (age 32.27 ± 5.53 years, education 10.02 ± 1.72 years, 46 female) underwent rs-fMRI and cognitive testing. Individual resting-state networks were correlated with global deficit scores (GDS) in order to explore associations between them within an HIV-positive sample. Results revealed ten regions in six resting-state networks where FC inversely correlated with GDS scores (worse performance). The networks affected included three independent attention networks: the default mode network (DMN), sensorimotor network, and basal ganglia. Connectivity in these regions did not correlate with plasma viral load or CD4 cell count. The design of this study is unique and has not been previously reported in clade B. The abnormalities related to neurocognitive performance reported in this study of clade C may reflect late disease stage and/or unique host/viral dynamics. Longitudinal studies will help to clarify the clinical significance of resting-state alterations in clade C HIV.
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Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Infecciones por VIH/diagnóstico por imagen , VIH-1/genética , Red Nerviosa/diagnóstico por imagen , Vías Nerviosas/diagnóstico por imagen , Adolescente , Adulto , Encéfalo/fisiopatología , Encéfalo/virología , Recuento de Linfocito CD4 , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/virología , Conectoma , Femenino , Genotipo , Infecciones por VIH/complicaciones , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/patogenicidad , Humanos , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/fisiopatología , Red Nerviosa/virología , Vías Nerviosas/fisiopatología , Vías Nerviosas/virología , Neuroimagen , Pruebas Neuropsicológicas , Carga ViralRESUMEN
Controversy remains regarding the neurotoxicity of clade C human immunodeficiency virus (HIV-C). When examined in preclinical studies, a cysteine to serine substitution in the C31 dicysteine motif of the HIV-C Tat protein (C31S) results in less severe brain injury compared to other viral clades. By contrast, patient cohort studies identify significant neuropsychological impairment among HIV-C individuals independent of Tat variability. The present study clarified this discrepancy by examining neuroimaging markers of brain integrity among HIV-C individuals with and without the Tat substitution. Thirty-seven HIV-C individuals with the Tat C31S substitution, 109 HIV-C individuals without the Tat substitution (C31C), and 34 HIV- controls underwent 3T structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Volumes were determined for the caudate, putamen, thalamus, corpus callosum, total gray matter, and total white matter. DTI metrics included fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). Tracts of interest included the anterior thalamic radiation (ATR), cingulum bundle (CING), uncinate fasciculus (UNC), and corpus callosum (CC). HIV+ individuals exhibited smaller volumes in subcortical gray matter, total gray matter and total white matter compared to HIV- controls. HIV+ individuals also exhibited DTI abnormalities across multiple tracts compared to HIV- controls. By contrast, neither volumetric nor diffusion indices differed significantly between the Tat C31S and C31C groups. Tat C31S status is not a sufficient biomarker of HIV-related brain integrity in patient populations. Clinical attention directed at brain health is warranted for all HIV+ individuals, independent of Tat C31S or clade C status.
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Sustitución de Aminoácidos , Imagen de Difusión Tensora/métodos , Infecciones por VIH/diagnóstico por imagen , VIH/genética , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética , Adulto , Mapeo Encefálico , Estudios de Casos y Controles , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/patología , Núcleo Caudado/virología , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Cuerpo Calloso/virología , Imagen de Difusión Tensora/instrumentación , Femenino , Expresión Génica , Variación Genética , Genotipo , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Sustancia Gris/virología , VIH/patogenicidad , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Putamen/diagnóstico por imagen , Putamen/patología , Putamen/virología , Tálamo/diagnóstico por imagen , Tálamo/patología , Tálamo/virología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Sustancia Blanca/virologíaRESUMEN
Most studies that have examined neuropsychological impairments associated with human immunodeficiency virus (HIV) have focused on males, yet females represent one of the largest groups of newly infected patients. Further, few studies have examined neuropsychological performance and neuroimaging outcomes among females compared to males in the modern era of highly active anti-retroviral therapy (HAART). The present study investigated neuropsychological performance and brain volumetrics among HIV+ males (n = 93) and females (n = 44) on stable HAART compared to HIV seronegative (HIV-) males (n = 42) and females (n = 49). Results revealed a significant effect of HIV on neuropsychological performance and neuroimaging measures. An effect of gender, independent of HIV status, was also observed for neuroimaging measures but not neuropsychological performance. Additionally, no significant differences in neuropsychological performance or brain volumetrics were seen between HIV+ males and females. No significant interaction was observed between HIV and gender on either neuropsychological or neuroimaging indices. Our results suggest that both HIV+ males and females treated with HAART experience similar outcomes in terms of brain integrity.
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Fármacos Anti-VIH/uso terapéutico , Encéfalo/fisiopatología , Trastornos del Conocimiento/fisiopatología , Infecciones por VIH/fisiopatología , ARN Viral/sangre , Anciano , Terapia Antirretroviral Altamente Activa , Encéfalo/virología , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Estudios de Casos y Controles , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/virología , Femenino , Neuroimagen Funcional , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , ARN Viral/antagonistas & inhibidores , Carga Viral/efectos de los fármacosRESUMEN
Previous neuroimaging studies suggest a negative relationship between the apolipoprotein (ApoE) ε4 allele and brain integrity in human immunodeficiency virus (HIV)-infected (HIV+) individuals, although the presence of this relationship across adulthood remains unclear. The purpose of this study is to clarify the discrepancies using a large, diverse group of HIV+ individuals and multiple imaging modalities sensitive to HIV. The association of ApoE ε4 with structural neuroimaging and magnetic resonance spectroscopy (MRS) was examined in 237 HIV+ individuals in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Cortical and subcortical gray matter, abnormal and total white matter, ventricles, sulcal cerebrospinal fluid (CSF), and cerebellar gray matter, white matter, and CSF volumes, and MRS concentrations of myo-inositol, creatine, N-acetyl-aspartate, and choline in the frontal white matter (FWM), frontal gray matter (FGM), and basal ganglia were examined. Secondary analyses explored this relationship separately in individuals ≥50 years old (n = 173) and <50 years old (n = 63). No significant differences were observed between ApoE ε4+ (ApoE ε3/ε4 and ApoE ε4/ε4) individuals (n = 69) and ApoE ε4- (ApoE ε2/ε3 and ApoE ε3/ε3) individuals (n = 167). When individuals were further divided by age, no significant genotype group differences were identified in individuals <50 or ≥50 years of age on any neuroimaging outcome. The ApoE ε4 allele did not affect brain integrity in this large, diverse sample of HIV+ individuals. The effects of ApoE ε4 may not be apparent until more advanced ages and may be more prominent when present along with other risk factors for neuronal damage.
Asunto(s)
Apolipoproteína E4/genética , Corteza Cerebral/diagnóstico por imagen , Genotipo , Infecciones por VIH/diagnóstico por imagen , Adulto , Alelos , Antineoplásicos/uso terapéutico , Apolipoproteína E4/sangre , Ganglios Basales/diagnóstico por imagen , Ganglios Basales/metabolismo , Cerebelo/diagnóstico por imagen , Cerebelo/metabolismo , Corteza Cerebral/metabolismo , Ventrículos Cerebrales/diagnóstico por imagen , Ventrículos Cerebrales/metabolismo , Estudios de Cohortes , Femenino , Expresión Génica , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/metabolismo , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Factores de Riesgo , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismoRESUMEN
Variations of the cholesteryl ester transfer protein polymorphism (CETP I405V/rs5882) have been associated with an increased risk for neurodegeneration, particularly when examined in conjunction with the epsilon 4 isoform of apolipoprotein E (ApoE4). Despite these identified relationships, the impact of I405V on gray matter microstructure remains unknown. The present study examined the impact of the CETP I405V polymorphism on gray matter integrity among 52 healthy adults between ages 51 and 85. Gray matter was measured bilaterally using diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Participants were grouped according to a dominant statistical model (II genotype vs. IV/VV genotypes) and secondary analyses were completed to examine the interactive effects of CETP and ApoE4 on DTI metrics. Compared to individuals with the IV/VV genotypes, II homozygotes demonstrated significantly higher MD in bilateral temporal, parietal, and occipital gray matter. Secondary analyses revealed higher FA and AD in the left temporal lobe of IV/VV genotypes with an ApoE4 allele. Our results provide preliminary evidence that CETP II homozygosity is a predisposing risk factor for gray matter abnormalities in posterior brain regions in healthy older adults, independent of an ApoE4 allele.
Asunto(s)
Transporte Biológico/genética , Encéfalo/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/genética , Colesterol/metabolismo , Sustancia Gris/metabolismo , Polimorfismo Genético , Anciano , Anciano de 80 o más Años , Anisotropía , Apolipoproteínas E/genética , Encéfalo/patología , Imagen de Difusión por Resonancia Magnética , Imagen de Difusión Tensora , Femenino , Genotipo , Técnicas de Genotipaje , Sustancia Gris/patología , Humanos , Masculino , Persona de Mediana Edad , Modelos Genéticos , Modelos EstadísticosRESUMEN
Normal aging involves a gradual breakdown of physiological processes that leads to a decline in cognitive functions and brain integrity, yet the onset and progression of decline are variable among older individuals. While many biological changes may contribute to this degree of variability, oxidative stress is a key mechanism of the aging process that can cause direct damage to cellular architecture within the brain. Oligodendrocytes are at a high risk for oxidative damage due to their role in myelin maintenance and production and limited repair mechanisms, suggesting that white matter may be particularly vulnerable to oxidative activity. Antioxidant defense enzymes within the brain, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione-S-transferase (GST), are crucial for breaking down the harmful end products of oxidative phosphorylation. Previous studies have revealed that allele variations of polymorphisms that encode these antioxidants are associated with abnormalities in SOD, CAT, GPx, and GST activity in the central nervous system. This review will focus on the role of oxidative stress in the aging brain and the impact of decreased antioxidant defense on brain integrity and cognitive function. Directions for future research investigations of antioxidant defense genes will also be discussed.
Asunto(s)
Envejecimiento/genética , Envejecimiento/metabolismo , Encefalopatías/fisiopatología , Trastornos del Conocimiento/fisiopatología , Marcadores Genéticos/fisiología , Estrés Oxidativo/genética , Animales , Antioxidantes/fisiología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Encefalopatías/genética , Encefalopatías/metabolismo , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/metabolismo , HumanosRESUMEN
Previous studies have identified cognitive impairments due to human immunodeficiency virus (HIV) in adults. However, few studies have examined the impact of HIV on cognition in young adults (18-24 years old). Yet, this group is one of the largest populations of individuals with new HIV infection. Young adulthood is also an important developmental window because the brain has not fully matured and individuals are prone to engage in risky behavior. The purpose of the present study was to examine the impact of HIV on neurocognition and risky behaviors. We hypothesized that HIV+ young adults (n = 23) would exhibit greater cognitive impairment and risky behaviors compared to seronegative controls (n = 21). In addition, we predicted that self-reported risky behavior as assessed by the Risk Assessment Battery (RAB) would covary with cognitive performances. Results revealed poorer executive function in HIV+ young adults compared to seronegative (HIV-) controls. HIV+ young adults exhibited significantly greater risk scores on the RAB (p < 0.01) compared to HIV- young adults. However, there were no relationships between risky behavior and cognitive performance. Overall, our results suggest that HIV is associated with poorer cognition and increased risky behaviors in young adults.