Childhood trauma interacts with ApoE to influence neurocognitive function in women living with HIV.
ABSTRACT: HIV-associated neurocognitive disorder (HAND) describes a spectrum of behavioural, motor and cognitive disturbances that can occur secondary to HIV infection. Less severe forms of the disorder persist despite advances in antiretroviral medication efficacy and availability. Childhood trauma (CT) may predispose individuals to developing HAND. As genetic variation in human apolipoprotein E (ApoE) has been implicated in cognitive decline and may mediate the development of long-term health outcomes following CT, we investigated the influence of ApoE and CT on cognitive function in the context of HIV. One hundred twenty-eight HIV-positive Xhosa women completed the Childhood Trauma Questionnaire-Short Form (CTQ-SF) as well as the HIV Neurobehavioural Research Center neurocognitive test battery. rs7412 and rs429358 were genotyped using KASP assays, and this data was used to determine the ApoE isoform. Baseline differences in demographic and clinical variables according to CT exposure were calculated. Analysis of covariance was used to assess the contributions of CT and ApoE variants, as well as their interaction, to cognitive function. Eighty-eight participants reported experiencing CT. The rs7412 C allele protected against the harmful effect of CT on motor scores using an additive model. The interaction of ApoE ?4 and CT was associated with worse attention/working memory scores. ApoE ?4, alone and in combination with CT, is associated with poorer cognitive function. Further research into this gene-environment interaction may assist in identifying at-risk individuals for targeted interventions.
Project description:Purpose:Previous studies have independently provided evidence for the effects of HIV infection, hypothalamic-pituitary-adrenal (HPA) axis dysfunction and early life trauma on neurocognitive impairment (NCI). This study examined the interaction between single-nucleotide polymorphisms (SNPs) of two HPA axis genes, corticotrophin-releasing hormone receptor 1 (CRHR1; rs110402, rs242924, rs7209436, and rs4792888) and corticotrophin-releasing hormone-binding protein (CRHBP; rs32897, rs10062367, and rs1053989), childhood trauma, and HIV-associated NCI. Patients and methods:The sample comprised 128 HIV-positive Xhosa females of whom 88 (69%) had a history of childhood trauma. NCI was assessed using a battery of 17 measures sensitive to the effects of HIV, and the history of childhood trauma was assessed using the validated retrospective Childhood Trauma Questionnaire-Short Form. Generalized linear regression models were used to compare allelic distribution by trauma status and global NCI. The association between genotype, childhood trauma, and cognitive scores was also evaluated using generalized linear regression models, assuming additive models for the SNPs, and ANOVA. Results:Of the seven polymorphisms assessed, only the rs10062367 variant of CRHBP was significantly associated with global NCI (P=0.034), independent of childhood trauma. This polymorphism was not significantly associated with z-scores on any specific cognitive domain. The interaction of childhood trauma and variants of CRHR1 was associated with poorer learning (rs110402) and/or recall (rs110402 and rs4792888). Conclusion:These findings suggest that CRHBP rs10062367 A allele is a possible risk variant for NCI in HIV, independent of childhood trauma. Furthermore, results show that the interaction of childhood trauma with variants of CRHR1, rs110402 and rs4792888, confer added vulnerability to NCI in HIV-infected individuals in cognitive domains that are known to be impacted by HIV. While these findings need independent replication in larger samples, it adds CRHBP and CRHR1 to the list of known genes linked to HIV- and childhood trauma-associated neurocognitive phenotypes.
Project description:OBJECTIVE:Gene-environment interactions contribute to the development of HIV-associated neurocognitive disorders. We examined whether childhood trauma, apolipoprotein E isoforms and viral protein R (Vpr) variants were associated with change in cognitive performance. Seventy-three seropositive women completed neuropsychological assessments at baseline and 1-year follow-up. We conducted genetic analyses using DNA obtained from blood and calculated risk scores based on Vpr amino acid 37, 41 and 55 variants that were previously associated with cognitive performance. RESULTS:Global cognitive scores declined significantly over the 1-year study period (p?=?0.029). A reduction in global cognitive scores was associated with childhood trauma experience (p?=?0.039).
Project description:Apolipoprotein E (APOE) and oxidative damage were correlated with the risk of Alzheimer's disease (AD). Glutathione S-transferase (GST) polymorphism was proved to be associated with body antioxidant capacity and involved in the oxidative damage related chronic diseases. To explore the combined effects of APOE rs429358, rs7412 and GSTM1/T1 polymorphism on antioxidant parameters and cognition in old Chinese adults, a community-based cross-sectional study was carried out in 477 Chinese adults aged from 55 to 75. Information on demography and lifestyle of the participants was collected with a questionnaire. Cognitive function was measured by using a Montreal Cognitive Assessment (MoCA) test. Fasting venous blood samples were collected for APOE rs429358, rs7412 and GSTM1/T1 genotyping, and parameter measurement. No association of APOE rs7412, rs429358 and GSTM1/T1 polymorphisms with cognition was detected in the old Chinese adults. APOE rs429358, rs7412 polymorphism was mainly associated with plasma ?-tocopherol, low density lipoprotein cholesterol (LDL-C) and plasma total antioxidant capacity (T-AOC) levels (p < 0.05). Interaction of APOE rs429358 and GSTT1 genotype on the plasma triglyceride (TG) level and erythrocyte catalase (CAT) and GST enzyme activities were detected (p < 0.05). The subjects with APOE rs429358 T/C + C/C and GSTT1- genotype were found to have the highest plasma TG level, erythrocyte CAT enzyme activity, and the lowest GST enzyme activity compared to subjects with other genotypes (p < 0.05). Lowest erythrocyte CAT enzyme activity and highest glutathione peroxidase (GSH-Px) enzyme activity were detected in the subjects with APOE rs7412 T/C + T/T and GSTM1+ genotype as compared with subjects with other genotypes. The levels of plasma and erythrocyte antioxidant parameters were APOE genotype associated. GSTM1 or GSTT1 genotype modified the influence of APOE rs7412, rs429358 polymorphism on antioxidant parameters.
Project description:OBJECTIVES:Recent research has linked psychological (personality) factors and specific genetic risk polymorphisms to performance on neurocognitive phenotypes. We examined whether episodic or semantic memory performance is associated with (a) three personality traits (i.e. neuroticism, extraversion, and openness to experience), (b) two neurodegenerative-related polymorphisms (i.e. Apolipoprotein E (APOE; rs7412; rs429358), Clusterin (CLU; rs11136000)), and (c) cross-domain risk interactions (magnification effects). METHODS:Linear growth models were examined to test independent associations between personality traits and declarative memory performance, and potential interaction effects with APOE and CLU genetic risk. Normal older adults (n = 282) with personality and genetic data from the Victoria Longitudinal Study were included at baseline and for up to 14 years of follow-up. RESULTS:First, we observed that higher openness to experience levels were associated with better episodic and semantic memory. Second, three significant gene × personality interactions were associated with poorer memory performance at baseline. These synergistic effects are: (a) APOE allelic risk (?4+) carriers with lower openness to experience levels, (b) CLU (no risk: T/T) homozygotes with higher extraversion levels, and (c) CLU (no risk: T/T) homozygotes with lower neuroticism levels. CONCLUSIONS:Specific neurodegenerative-related genetic polymorphisms (i.e. APOE and CLU) moderate and magnify the risk contributed by selected personality trait levels (i.e. openness to experience, extraversion) on declarative memory performance in non-demented aging. Future research could target interactions of other personality traits and genetic polymorphisms in different clinical populations to predict other neurocognitive deficits or transitions to cognitive impairment and dementia.
Project description:With aging of HIV populations, there is concern that Alzheimer's disease (AD) may become prevalent and difficult to distinguish from HIV-associated neurocognitive disorders. To date, there are no reports documenting histologically verified Alzheimer's neuropathology in individuals with HIV and dementia. Herein, we report two antiretroviral-treated, virally suppressed, HIV-infected individuals autopsied by the Manhattan HIV Brain Bank. Subject A presented to study at 52 years, already dependent in instrumental activities of daily living (ADLs), with severe cognitive impairment inclusive of learning and memory dysfunction. Her history was significant for educational disability and head trauma. She had rapid cognitive decline and, by death at age 59 years, was bed-bound, incontinent, and non-communicative. At autopsy, she exhibited severe AD neuropathologic change (NIA-AA score A3B3C3) and age-related tau astrogliopathy (ARTAG). She was homozygous for APOE ?3/?3. No HIV DNA was detected in frontal lobe by nested polymerase chain reaction. Subject B was a community dwelling 81-year-old woman who experienced sudden death by pulmonary embolus. Prior to death, she was fully functional, living independently, and managing all ADLs. At autopsy, she displayed moderate amyloid and severe tau AD neuropathologic changes (A2B3C2), ARTAG, and cerebral congophilic angiopathy. She was an APOE ?3/?4 heterozygote, and HIV DNA, but not RNA, was detected in frontal lobe, despite 20 years of therapy-induced viral suppression. We conclude that in the setting of HIV, AD neuropathology may occur with or without symptomatic cognitive dysfunction; as with seronegative individuals, there are likely to be complex factors in the generation of clinically relevant impairments.
Project description:BACKGROUND:Characterizing the link between childhood trauma and adult neurocognitive function in psychosis is crucial for improving the fields understanding of how early environmental risk factors impact the presentation of the disorder. To date, the literature has been inconsistent: meta-analytic synthesis is lacking, and it is unclear whether specific cognitive functions are affected. METHODS:A meta-analysis was performed on a total of 3315 subjects with a psychotic disorder. The links between childhood trauma, overall neurocognitive function, and four cognitive subdomains (working memory, executive function, verbal/visual memory, and attention/processing speed) were examined. Relevant sample characteristics and methodological moderators were tested. The strength of the association between trauma and overall neurocognition in individuals with psychotic disorders was also compared to that of healthy controls. RESULTS:Among individuals with psychotic disorders, there was a significant association between overall cognition and childhood trauma, r = -.055; 95% CI = -0.09, -0.02, P = .002. There was also a modest, negative relationship between childhood trauma and working memory, r = -.091; 95% CI = -0.15, -0.03, P = .002. Moderators did not have a significant effect on these analyses. Further, the association between childhood trauma and neurocognition was significantly stronger in healthy controls compared to patients with a psychotic disorder. CONCLUSION:A small negative association was found between overall cognition and childhood trauma in individuals with psychotic disorders. Results suggest the association is less strong for individuals with a psychotic disorder compared to healthy populations. Findings are informative for prominent etiological models of psychosis.
Project description:Apolipoprotein E (APOE) genotype (?2/?3/?4: rs429358 ?4 allele; rs7412 ?2 allele) is strongly associated with both lipid levels and Alzheimer's disease. Although there is also evidence of milder cognitive impairment in later life in carriers of the APOE ?4 allele, there have been few studies investigating the impact of APOE genotype on cognitive function in children.We determined APOE genotype in 5995 children from the Avon Longitudinal Study of Parents and Children and investigated associations between APOE genotype and plasma lipids (at age 9), IQ (at age 8), memory (at ages 8 and 10), and performance in school attainment tests (at ages 7, 11, and 14).Observed genotype group counts were consistent with Hardy-Weinberg equilibrium (?(2)p value = .84). There were strong relationships between APOE genotype and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, which follow the same patterns as in adults. There was no strong evidence to suggest that APOE genotype was associated with IQ (all p values ? .46), memory function (p ? .35), or school attainment test results (p ? .28).Although APOE genotype does have strong associations with lipid levels in childhood, there does not seem to be meaningful effects on cognitive performance, suggesting that any detrimental effects of the ?4 allele on cognitive function are not important until later life.
Project description:The ?4 allele of the APOE gene is associated with poorer cognition in later life. This study aimed to advance understanding of how environments potentially moderate this genetic risk by focusing on childhood socioeconomic status (SES). Previous research across diverse national contexts has found that older adults from higher-SES families in childhood demonstrate better cognitive functioning than their lower-SES counterparts. Nevertheless, few studies have examined whether higher childhood SES might also promote later life cognition by mitigating the effects of ?4 carrier status. To address this gap, we used data from 3017 participants in the Wisconsin Longitudinal Study, which has followed a random sample of people who graduated from Wisconsin high schools in 1957. Childhood SES included parents' educational attainment, father's occupational status, and household income in adolescence. We constructed measures of memory and of language/executive functioning using scores from neurocognitive tests administered when participants were approximately ages 65 and 72. APOE ?4 status was measured through saliva samples. Results from cross-controlled multilevel models indicated that APOE ?4 status-and not childhood SES-independently predicted memory, whereas childhood SES-and not APOE ?4 status-independently predicted language/executive functioning. Moreover, a statistical interaction between APOE ?4 status and childhood SES for memory indicated that at baseline, higher childhood SES protected against the risk of APOE ?4 status, whereas lower childhood SES exacerbated the risk of APOE ?4 status. However, by follow-up, these moderating effects dissipated, and APOE ?4 status alone was associated with memory. We interpret these results in light of theorizing on differential susceptibility for poorer cognition across the life course.
Project description:With the implementation of increasingly effective antiretroviral therapy (ART) over the past three decades, individuals infected with HIV live a much longer life. HIV infection is no longer a terminal but rather a chronic disease. However, the lifespan of infected individuals remains shorter than that of their uninfected peers. Even with ART, HIV infection may potentiate "premature" aging. Organ-associated disease and systemic syndromes that occur in treated HIV-infection are like that of older, uninfected individuals. Brain aging may manifest as structural changes or neurocognitive impairment that are beyond the chronological age. The spectrum of neurological, cognitive, and motor deficiencies, currently described as HIV-associated neurocognitive disorders (HAND), may reflect earlier onset of mechanisms common to HIV infection and aging (accelerated aging). HAND could also reflect the neurological impact of HIV infection superimposed on comorbidities linked to age and chronic inflammation, leading to a higher prevalence of neurocognitive impairment across the age span (accentuated aging). In addition, apolipoprotein E (ApoE), one of the most influential host risk factors for developing Alzheimer's disease, has been implicated in the development of HAND. But studies differ as to whether ApoE is relevant, and whether age and ApoE interact to impair brain function in the HIV-infected patient. What is clear is that HIV-infected individuals are living longer with HIV, and therefore factors related to aging and health need to be examined in the context of current, effective ART. This review addresses the recent evidence for the influence of aging and ApoE on HIV-associated neurocognitive impairment.
Project description:APOE is the biomarker with the greatest known influence on cognitive function; however, the effect of complex haplotypes involving polymorphisms rs449647, rs405509, rs440446, rs429358 and rs7412 has never been studied in older populations.We evaluated APOE polymorphisms using multiplex PCR for genotyping and Mini-Mental State Examination (MMSE) to evaluate cognitive function in 819 individuals from VA Normative Aging Study.Combinatorial analysis of all polymorphisms and individual analysis of polymorphisms rs449647, rs405509, rs440446 and rs7412 did not show any association with cognitive performance. Polymorphism rs429358 was associated with better cognitive performance (odds of MMSE???25 = 0.63, 95% CI 0.42-0.95; p = 0.03) in the oldest subsample (5th quintile of age) (odds of MMSE???25 = 0.34; 95% CI 0.13-0.86; p = 0.02). APOE allele ?4 was also associated with better cognitive performance (odds of MMSE???25 = 0.61, 95% CI 0.40-0.94; p = 0.02), also in the oldest subsample (odds of MMSE???25 = 0.35, 95% CI 0.14-0.90; p = 0.03).These results suggest a beneficial effect of polymorphism rs429358 in the oldest men.