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HIV-1 disrupts the host epigenetic landscape with consequences for disease pathogenesis, viral persistence, and HIV-associated comorbidities. Here, we examined how soon after infection HIV-associated epigenetic changes may occur in blood and whether early initiation of antiretroviral therapy (ART) impacts epigenetic modifications. We profiled longitudinal genome-wide DNA methylation in monocytes and CD4+ T lymphocytes from 22 participants in the RV254/SEARCH010 acute HIV infection (AHI) cohort that diagnoses infection within weeks after estimated exposure and immediately initiates ART. We identified monocytes harbored 22,697 differentially methylated CpGs associated with AHI compared to 294 in CD4+ T lymphocytes. ART minimally restored less than 1% of these changes in monocytes and had no effect upon T cells. Monocyte DNA methylation patterns associated with viral load, CD4 count, CD4/CD8 ratio, and longitudinal clinical phenotypes. Our findings suggest HIV-1 rapidly embeds an epigenetic memory not mitigated by ART and support determining epigenetic signatures in precision HIV medicine. Trial Registration: NCT00782808 and NCT00796146.
Assuntos
Terapia Antirretroviral de Alta Atividade/estatística & dados numéricos , Linfócitos T CD4-Positivos/virologia , Metilação de DNA , Infecções por HIV/virologia , HIV-1/imunologia , Monócitos/virologia , Carga Viral , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Estudos de Coortes , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Adulto JovemRESUMO
Background: Long-term neurocognitive outcomes following first-line suppressive anti-retroviral therapy (ART) remain uncertain for individuals with HIV and hepatitis C (HCV) co-infection. The study examined neurocognitive performance before and after 72 weeks of ART using repeated multivariate analyses and latent trajectory models. Methods: One hundred and sixty adults with chronic, untreated HIV infection (n = 80 with HCV co-infection and n = 80 HIV mono-infected) and 80 demographically similar healthy controls were recruited from the Hospital for Tropical Diseases in Ho Chi Minh City and the surrounding community, respectively. Neurocognitive measures (adapted for use in Vietnam) and liver enzyme tests were compared across groups at baseline. Repeated multivariate and group-based trajectory analyses (GBTA) examined neurocognitive subgroup profiles of the co-infected individuals after 72 weeks of de novo efavirenz- (n = 41) or raltegravir-based (n = 39) ART. Results: Baseline analyses revealed worse motor function in HIV-HCV co-infected individuals compared to both comparison groups. Longitudinal analyses revealed improved neurocognitive performance by week 48 for most participants regardless of treatment arm. GBTA identified a subgroup (35% of HIV-HCV sample) with persistent motor impairment despite otherwise successful ART. Higher HIV viral load and lower CD4+ T cell count at baseline predicted persistent motor dysfunction. Liver indices and ART regimen did not predict neurocognitive outcomes in HIV-HCV co-infected individuals. Conclusions: Most HIV-HCV co-infected individuals achieve normative neurocognitive performance after 48 weeks of de novo suppressive ART. However, individuals with more severe HIV disease prior to ART exhibited motor impairment at baseline and 72 weeks after otherwise successful treatment. Interventions aimed at improving motor symptoms at the time of HIV treatment onset may improve long-term clinical outcomes in HIV-HCV co-infected adults.
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BACKGROUND: Frailty is an important clinical concern for the aging population of people living with HIV (PLWH). The objective of this study was to identify the combination of risk features that distinguish frail from nonfrail individuals. SETTING: Machine learning analysis of highly dimensional risk features was performed on a clinical cohort of PLWH. METHODS: Participants included 105 older (average age = 55.6) PLWH, with at least a 3-month history of combination antiretroviral therapy (median CD4 = 546). Predictors included demographics, HIV clinical markers, comorbid health conditions, cognition, and neuroimaging (ie, volumetrics, resting-state functional connectivity, and cerebral blood flow). Gradient-boosted multivariate regressions were implemented to establish linear and interactive classification models. Model performance was determined by sensitivity/specificity (F1 score) with 5-fold cross validation. RESULTS: The linear gradient-boosted multivariate regression classifier included lower current CD4 count, lower psychomotor performance, and multiple neuroimaging indices (volumes, network connectivity, and blood flow) in visual and motor brain systems (F1 score = 71%; precision = 84%; and sensitivity = 66%). The interactive model identified novel synergies between neuroimaging features, female sex, symptoms of depression, and current CD4 count. CONCLUSIONS: Data-driven algorithms built from highly dimensional clinical and brain imaging features implicate disruption to the visuomotor system in older PLWH designated as frail individuals. Interactions between lower CD4 count, female sex, depressive symptoms, and neuroimaging features suggest potentiation of risk mechanisms. Longitudinal data-driven studies are needed to guide clinical strategies capable of preventing the development of frailty as PLWH reach advanced age.
Assuntos
Envelhecimento/fisiologia , Fragilidade/diagnóstico , Infecções por HIV/patologia , Aprendizado de Máquina , Neuroimagem , Desempenho Psicomotor/fisiologia , Algoritmos , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Feminino , Fragilidade/diagnóstico por imagem , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
OBJECTIVE: To develop a predictive model of neurocognitive trajectories in children with perinatal HIV (pHIV). DESIGN: Machine learning analysis of baseline and longitudinal predictors derived from clinical measures utilized in pediatric HIV. METHODS: Two hundred and eighty-five children (ages 2-14 years at baseline; Mageâ=â6.4 years) with pHIV in Southeast Asia underwent neurocognitive assessment at study enrollment and twice annually thereafter for an average of 5.4 years. Neurocognitive slopes were modeled to establish two subgroups [above (nâ=â145) and below average (nâ=â140) trajectories). Gradient-boosted multivariate regressions (GBM) with five-fold cross validation were conducted to examine baseline (pre-ART) and longitudinal predictive features derived from demographic, HIV disease, immune, mental health, and physical health indices (i.e. complete blood count [CBC]). RESULTS: The baseline GBM established a classifier of neurocognitive group designation with an average AUC of 79% built from HIV disease severity and immune markers. GBM analysis of longitudinal predictors with and without interactions improved the average AUC to 87 and 90%, respectively. Mental health problems and hematocrit levels also emerged as salient features in the longitudinal models, with novel interactions between mental health problems and both CD4 cell count and hematocrit levels. Average AUCs derived from each GBM model were higher than results obtained using logistic regression. CONCLUSION: Our findings support the feasibility of machine learning to identify children with pHIV at risk for suboptimal neurocognitive development. Results also suggest that interactions between HIV disease and mental health problems are early antecedents to neurocognitive difficulties in later childhood among youth with pHIV.
Assuntos
Cognição/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/psicologia , Transmissão Vertical de Doenças Infecciosas , Aprendizado de Máquina , Desempenho Psicomotor/efeitos dos fármacos , Algoritmos , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Função Executiva/efeitos dos fármacos , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Saúde Mental , Parto , GravidezRESUMO
Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within 4 hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9- to 14-year-olds; N = 120). Whole-brain regression analyses indicated that increasing genetic "risk" predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic "risk" and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Ansiedade/fisiopatologia , Emoções/fisiologia , Interação Gene-Ambiente , Sistema Hipotálamo-Hipofisário/fisiopatologia , Rede Nervosa/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Estresse Psicológico/fisiopatologia , Adolescente , Tonsila do Cerebelo/diagnóstico por imagem , Ansiedade/diagnóstico por imagem , Ansiedade/genética , Ansiedade/psicologia , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Rede Nervosa/diagnóstico por imagem , Neuroimagem , Polimorfismo de Nucleotídeo Único , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , Estresse Psicológico/diagnóstico por imagem , Estresse Psicológico/genética , Estresse Psicológico/psicologia , Proteínas de Ligação a Tacrolimo/genéticaRESUMO
OBJECTIVE: Despite research documenting the existence of depression and other psychiatric disorders in early childhood, little is known about the nature and consequences of suicidal cognitions and behaviors (SI) in young children ages 3 to 7 years. The identification of trajectories of SI across childhood is a critical step toward preventing childhood suicide. METHOD: Participants were 306 children enrolled in a prospective longitudinal investigation of young children and their families. Children and their families completed a baseline assessment between ages 3 and 7 years, and at least 1 follow-up assessment (ages 7-12 years). Child psychopathology, suicidal thoughts, plans, and behaviors were assessed via parent and trained interviewer report before age 9, and also with self-report after age 9. Data on maternal history of psychopathology, as well as maternal and family history of suicide attempts, were also obtained through parent report. RESULTS: Controlling for a range of clinical and demographic variables, early-childhood SI (as defined as suicidal thoughts, behavior, or any expression of plans/attempts occurring before age 7) and suicidal themes in play were concurrently associated with childhood attention-deficit/hyperactivity (ADHD) and oppositional defiant/conduct disorders (ODD/CD). Early-childhood SI also predicted school-age depression and ODD/CD; however, these findings were no longer significant after controlling for the same diagnoses at the childhood baseline. Longitudinal analysis indicated that early-childhood SI was a robust predictor of school-age SI, even after accounting for psychiatric disorders at both time points. CONCLUSION: Extending current research, these findings demonstrate that early-childhood SI confers significant risk for continuation into school-age SI and is concurrently associated with ADHD and ODD/CD. Although the meaning of early-childhood SI remains unclear, results suggest that it is a clinically important phenomenon that should be carefully assessed and taken seriously as a marker of risk for ongoing suicidal ideation/behavior. These findings suggest that early screening for SI in childhood is indicated in clinical settings, particularly in children less than 7 years of age with depression and externalizing disorders.
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Comportamento Infantil/psicologia , Cognição , Depressão/epidemiologia , Família/psicologia , Tentativa de Suicídio/estatística & dados numéricos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/diagnóstico , Escala de Avaliação Comportamental , Criança , Pré-Escolar , Transtorno da Conduta/diagnóstico , Feminino , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Fatores de Risco , Autorrelato , Tentativa de Suicídio/prevenção & controle , WashingtonRESUMO
Accumulating evidence suggests a role for stress exposure, particularly during early life, and for variation in genes involved in stress response pathways in neural responsivity to emotional stimuli. Understanding how individual differences in these factors predict differences in emotional responsivity may be important for understanding both normative emotional development and for understanding the mechanisms underlying internalizing disorders, like anxiety and depression, that have often been related to increased amygdala and hippocampus responses to negatively valenced emotional stimuli. The present study examined whether stress exposure and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predict individual differences in amygdala and hippocampus responses to fearful vs. neutral faces in school-age children (7-12 year olds; N = 107). Experience of more stressful and traumatic life events predicted greater left amygdala responses to negative emotional stimuli. Genetic profile scores interacted with sex and pubertal status to predict amygdala and hippocampus responses. Specifically, genetic profile scores were a stronger predictor of amygdala and hippocampus responses among pubertal vs. prepubertal children where they positively predicted responses to fearful faces among pubertal girls and positively predicted responses to neutral faces among pubertal boys. The current results suggest that genetic and environmental stress-related factors may be important in normative individual differences in responsivity to negative emotional stimuli, a potential mechanism underlying internalizing disorders. Further, sex and pubertal development may be key moderators of the effects of stress-system genetic variation on amygdala and hippocampus responsivity, potentially relating to sex differences in stress-related psychopathology.
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Tonsila do Cerebelo/fisiologia , Reconhecimento Facial/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Estresse Psicológico/fisiopatologia , Mapeamento Encefálico , Criança , Expressão Facial , Feminino , Humanos , Individualidade , Imageamento por Ressonância Magnética , Masculino , Polimorfismo de Nucleotídeo Único , Puberdade , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , Fatores Sexuais , Estresse Psicológico/genética , Proteínas de Ligação a Tacrolimo/genéticaRESUMO
Structural and functional alterations in a variety of brain regions have been associated with depression and risk for depression across the life span. A majority of these regions are associated with emotion reactivity and/or regulation. However, it is generally unclear what mechanistic role these alterations play in the etiology of depression. A first step toward understanding this is to characterize the relationships between variation in brain structure/function and individual differences in depression severity and related processes, particularly emotion regulation. To this end, the current study examines how brain structure and function predict concurrent and longitudinal measures of depression symptomology and emotion regulation skills in psychiatrically healthy school-age children (N = 60). Specifically, we found that smaller hippocampus volumes and greater responses to sad faces in emotion reactivity regions predict increased depressive symptoms at the time of scan, whereas larger amygdala volumes, smaller insula volumes, and greater responses in emotion reactivity regions predict decreased emotion regulation skills. In addition, larger insula volumes predict improvements in emotion regulation skills even after accounting for emotion regulation at the time of scan. Understanding brain-behavior relationships in psychiatrically healthy samples, especially early in development, will help inform normative developmental trajectories and neural alterations in depression and other affective pathology.
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Tonsila do Cerebelo/anatomia & histologia , Córtex Cerebral/anatomia & histologia , Depressão , Emoções/fisiologia , Expressão Facial , Adolescente , Criança , Depressão/patologia , Depressão/fisiopatologia , Feminino , Hipocampo/anatomia & histologia , Humanos , Imageamento por Ressonância Magnética , Masculino , RiscoRESUMO
Depression has been linked to increased cortisol reactivity and differences in limbic brain volumes, yet the mechanisms underlying these alterations are unclear. One main hypothesis is that stress causes these effects. This is supported by animal studies showing that chronic stress or glucocorticoid administration can lead to alterations in hippocampal and amygdala structures. Relatedly, life stress is cited as one of the major risk factors for depression and candidate gene studies have related variation in stress-system genes to increased prevalence and severity of depression. The present study tested the hypothesis that genetic profile scores combining variance across 10 single nucleotide polymorphisms from four stress-system genes (CRHR1, NR3C2, NR3C1, and FKBP5) and early life stress would predict increases in cortisol levels during laboratory stressors in 120 preschool-age children (3-5 years old), as well as hippocampal and amygdala volumes assessed with MRI in these same children at school age (7-12 years old). We found that stress-system genetic profile scores positively predicted cortisol levels while the number of stressful/traumatic life events experienced by 3-5 years old negatively predicted cortisol levels. The interaction of genetic profile scores and early life stress predicted left hippocampal and left amygdala volumes. Cortisol partially mediated the effects of genetic variation and life stress on limbic brain volumes, particularly on left amygdala volume. These results suggest that stress-related genetic and early environmental factors contribute to variation in stress cortisol reactivity and limbic brain volumes in children, phenotypes associated with depression in adulthood.
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Tonsila do Cerebelo/patologia , Hipocampo/patologia , Hidrocortisona/metabolismo , Saliva/metabolismo , Estresse Psicológico/genética , Estresse Psicológico/patologia , Criança , Pré-Escolar , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Processamento de Imagem Assistida por Computador , Entrevista Psicológica , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , Estresse Psicológico/metabolismo , Proteínas de Ligação a Tacrolimo/genéticaRESUMO
The amygdala is a key region in emotion processing. In particular, fMRI studies have demonstrated that the amygdala is active during the viewing of emotional faces. Previous research has consistently found greater amygdala responses to fearful than to neutral faces in adults, convergent with a focus in the animal literature on the amygdala's role in fear processing. Studies have shown that the amygdala also responds differentially to other facial emotion types in adults. Yet the literature regarding when this differential amygdala responsivity develops is limited and mixed. Thus, the goal of the present study was to examine amygdala responses to emotional and neutral faces in a relatively large sample of healthy school-age children (N = 52). Although the amygdala was active in response to emotional and neutral faces, the results did not support the hypothesis that the amygdala responds differentially to emotional faces in 7- to 12-year-old children. Nonetheless, amygdala activity was correlated with the severity of subclinical depression symptoms and with emotional regulation skills. Additionally, sex differences were observed in frontal, temporal, and visual regions, as well as effects of pubertal development in visual regions. These findings suggest important differences in amygdala reactivity in childhood.
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Tonsila do Cerebelo/irrigação sanguínea , Tonsila do Cerebelo/fisiologia , Emoções/fisiologia , Face , Reconhecimento Visual de Modelos/fisiologia , Análise de Variância , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Criança , Feminino , Lateralidade Funcional , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Movimento/fisiologia , Oxigênio/sangue , Estimulação Luminosa , Escalas de Graduação Psiquiátrica , Estatística como AssuntoRESUMO
BACKGROUND: Recent research has demonstrated that clinical depression can emerge as early as the preschool period. Here, we examine brain function in children with a history of preschool-onset depression (PO-MDD) in comparison with healthy children. METHODS: Participants were medication naïve school-aged children (ages 7-11) with PO-MDD (n = 22) or no psychiatric history (n = 16) followed longitudinally as part of the Preschool Depression Study. We used functional magnetic resonance imaging measures of blood oxygen level-dependent signal to examine functional brain activity in response to emotionally valenced faces (sad, fearful, angry, happy, neutral) following a negative mood induction provided to all children. RESULTS: In categorical group comparisons, children with PO-MDD demonstrated increased activity in parietal cortex in response to sad faces but no differences in brain activity in a priori regions of interest (e.g., amygdala). However, in dimensional analyses, the severity of depression symptoms at the baseline preschool assessment predicted increased responses to sad faces in amygdala, hippocampal, parietal, and orbital frontal regions. CONCLUSIONS: School-aged children with a history of PO-MDD showed patterns of functional brain responses to emotionally evocative stimuli similar to patterns found in adults and adolescents with major depression. These patterns were most strongly related to the severity of depression during the preschool period, suggesting that the magnitude of early symptoms may be particularly important for understanding altered brain function. These findings suggest that an early episode of depression before age 6 may be associated with enduring brain change or may represent a biomarker that was present even before the preschool episode.
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Encéfalo/fisiologia , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Emoções/fisiologia , Idade de Início , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Transtorno Depressivo Maior/diagnóstico , Face , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Estimulação LuminosaRESUMO
In 1940, the tidal Delaware River was "one of the most grossly polluted areas in the United States." During the 1950s, water quality was so poor along the river at Philadelphia that zero oxygen levels prevented migration of American shad leading to near extirpation of the species. Since then, water quality in the Delaware Basin has improved with implementation of the 1961 Delaware River Basin Compact and 1970s Federal Clean Water Act Amendments. At 15 gages along the Delaware River and major tributaries between 1980 and 2005, water quality for dissolved oxygen, phosphorus, nitrogen, and sediment improved at 39%, remained constant at 51%, and degraded at 10% of the stations. Since 1980, improved water-quality stations outnumbered degraded stations by a 4 to 1 margin. Water quality remains good in the nontidal river above Trenton and, while improved, remains fair to poor for phosphorus and nitrogen in the tidal estuary near Philadelphia and in the Lehigh and Schuylkill tributaries. Water quality is good in heavily forested watersheds (>50%) and poor in highly cultivated watersheds. Water quality recovery in the Delaware Basin is coincident with implementation of environmental laws enacted in the 1960s and 1970s and is congruent with return of striped bass, shad, blue crab, and bald eagle populations.