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Perceived and posttraumatic stress is associated with decreased learning, memory, and fluency in HIV-infected women

Rubin, Leah H.a,b; Cook, Judith A.a; Springer, Gaylec; Weber, Kathleen M.d; Cohen, Mardge H.e; Martin, Eileen M.f; Valcour, Victor G.g; Benning, Loriec; Alden, Christineb; Milam, Joelh; Anastos, Kathryni; Young, Mary A.j; Gustafson, Deborah R.k; Sundermann, Erin E.l; Maki, Pauline M.a,m

doi: 10.1097/QAD.0000000000001625
EPIDEMIOLOGY AND SOCIAL
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SDC

Objective: Psychological risk factors (PRFs) are associated with impaired learning and memory in HIV-infected (HIV+) women. We determined the dynamic nature of the effects of PRFs and HIV serostatus on learning and memory over time.

Design: Multicenter, prospective cohort study.

Methods: Every 2 years between 2009 and 2013 (three times), 646 HIV+ and 300 demographically similar HIV-uninfected (HIV−) women from the Women's Interagency HIV Study completed neuropsychological testing and questionnaires measuring PRFs [perceived stress, posttraumatic stress disorder (PTSD) symptoms, depressive symptoms]. Using mixed-effects regressions, we examined separate and interactive associations between HIV-serostatus and PRFs on performance over time.

Results: HIV+ and HIVwomen had similar rates of PRFs. Fluency was the only domain in which performance over time depended on the combined influence of HIV-serostatus and stress or PTSD (P < 0.05), not depression. In HIV, higher stress and PTSD were associated with a greater cognitive decline in performance (P < 0.05) vs. lower stress and PTSD. Irrespective of time, performance on learning and memory depended on the combined influence of HIV-serostatus and stress or PTSD (P ≤ 0.05). In the context of HIV, stress and PTSD were negatively associated with performance. Effects were pronounced on learning among HIV+ women without effective treatment or viral suppression. Regardless of time or HIV-serostatus, all PRFs were associated with lower speed, global neuropsychological, and executive function.

Conclusion: More than depression, perceived stress and PTSD symptoms are treatment targets to potentially improve fluency, learning, and memory in women living with HIV particularly when HIV treatment is not optimal.

Supplemental Digital Content is available in the text

aDepartment of Psychiatry, University of Illinois at Chicago, Chicago, Illinois

bDepartment of Neurology, Johns Hopkins University School of Medicine

cDepartment of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland

dCook County Health and Hospitals System/Hektoen Institute of Medicine

eDepartment of Medicine, Stroger Hospital and Rush University

fDepartment of Psychiatry, Rush University Medical Center, Chicago, Illinois

gDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco

hInstitute for Health Promotion & Disease Prevention Research, University of Southern California, Los Angeles, California

iDepartments of Medicine and Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York

jDepartment of Medicine, Georgetown University, Washington, District of Columbia

kDepartment of Neurology, SUNY-Downstate Medical Center, Brooklyn, New York

lUniversity of California San Diego School of Medicine, La Jolla, California

mDepartment of Psychology, University of Illinois at Chicago, Chicago, Illinois, USA.

Correspondence to Leah H. Rubin, PhD, MPH, Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street/Meyer 6-113, Baltimore, MD 21287-7613, USA. Tel: +1 443 287 0571; fax: +1 410 955 0672; e-mail: lrubin1@jhmi.edu

Received 5 June, 2017

Revised 5 August, 2017

Accepted 21 August, 2017

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

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Introduction

Negative life stressors such as childhood trauma and adult physical and sexual violence are prevalent among HIV-infected (HIV+) women [1–5]. These stressors increase susceptibility to mood and anxiety disorders [6–8] and contribute to perturbations in cognition and brain functioning [9,10]. Among HIV+ women, psychological risk factors (PRFs), including perceived stress, anxiety, posttraumatic stress, and depressive symptoms, are associated with deficits in verbal learning, memory, and attention [11–14]. Cross-sectional results from the Women's Interagency HIV Study (WIHS, n = 1505) showed an interaction between PRFs and HIV status, such that perceived stress and anxiety were more strongly associated with deficits in learning and memory among HIV+ compared with HIVwomen. By contrast, depressive symptoms were associated with a similarly lower level of cognitive performance in HIV+ and HIVwomen. This pattern of behavioral effects suggests that the neurobiological effects of PRFs on cognition differs between HIV+ and HIVwomen, potentially through differences in stress responsivity and immune function. Stress, posttraumatic stress disorder (PTSD), and depression influence the adaptive immune response in HIV+ women, but stress may have a stronger influence than depression because stress is more strongly associated with regulatory mechanisms necessary to maintain immune cell homeostasis [15] which may impact brain homeostasis [16]. Consistent with that view, our neuroimaging studies in the WIHS suggest that HIV, perceived stress and posttraumatic stress, individually and in combination, affect the structure and function of the prefrontal cortex, regions dense in receptors that bind to the stress hormone, glucocorticoids [17,18].

PRFs and cognitive performance may change over time in HIV+ individuals. Understanding the dynamic nature of these associations over time is important to determine the reliability of associations across successive time-points and to determine whether associations become weaker or stronger over time, or show the same magnitude over time. We sought to examine the interactive associations between HIV and PRFs on cognitive functioning over time in a large cohort of women. Here we present the first series of longitudinal analyses examining these interactions in the WIHS cohort across three cognitive assessments conducted over a 4-year period. Given our previous cross-sectional results [12,14], we hypothesized that the negative effect of PRFs on cognition would be greater in the context of HIV. Moreover, given our cross-sectional findings, we expected that perceived stress and posttraumatic stress would exacerbate HIV-associated cognitive compromise particularly for verbal memory and this relationship would become stronger over time [13,17,18].

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Methods

Participants

Participants were enrolled in the WIHS, a longitudinal, multisite cohort study of the natural and treated history of HIV+ and HIVwomen (http://wihshealth.org). Study enrollment occurred in two waves. The first wave occurred between October 1994 and November 1995 and the second between October 2001 and September 2002 from six sites (Brooklyn, Bronx, Chicago, District of Columbia, Los Angeles, and San Francisco). Detailed information regarding recruitment procedures and eligibility criteria have been previously published [19,20].

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Primary predictor variables

Concurrent with the neuropsychological test battery, questionnaires were administered measuring perceived stress, PTSD symptoms, and depressive symptoms. Stress was measured with the Perceived Stress Scale (PSS-10), a 10-item scale that assesses the degree to which life situations in the previous month are evaluated as unpredictable, uncontrollable, and overloaded (Likert scale, 0 = never, 4 = very often) [21,22]. Consistent with our previous work [14,17,18], the PSS-10 was dichotomized and considered to be higher when scores were in the top tertile (present sample ≥20 points) and lower when in the bottom two tertiles (<20 points). PTSD symptoms were measured with the PTSD Checklist-Civilian version (PCL-C), a 17-item measure of PTSD symptoms (re-experiencing, avoidance, hyperarousal) as defined by the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) [23]. As in our previous work [13], probable PTSD was defined as meeting DSM-IV symptom criteria in the previous month (≥1 B item – re-experiencing, ≥3 C items – avoidance, and ≥2 D items – arousal) and the total severity score more than 44. Depressive symptoms were measured with the Center for Epidemiological Studies Depression (CES-D) scale. Elevated depressive symptoms in the past 2 weeks was defined using a standard cutoff score of 16 [24,25] which we have also used in our previous work [12,17,26].

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Cognitive outcomes

Beginning in 2009, certified study personnel administered three longitudinal neuropsychological assessments to WIHS participants biennially over a 4-year period. The cognitive domains included learning and memory (primary outcomes of interest given previous cross-sectional studies [12–14,17,18]), attention, executive function, fluency, psychomotor speed, and motor skills. Table 1 provides the specific tests and outcomes used to assess each domain. Following methods used in other large HIV cohort studies [11–14], demographically adjusted T-scores were derived for each individual outcome adjusting for age, years of education, Wide Range Achievement-3 reading subtest (measure of premorbid intellect), race (African-American vs. not), ethnicity (Hispanic vs. not), and number of times the test had been administered in WIHS. Prior to the creation of T-scores, all timed outcomes were log transformed to normalize the distributions and then reverse scored so that higher scores equated to better performance across all domains. For each domain, a composite T-score was derived by averaging the T-scores for domains with at least two outcomes. If only one test in a domain was completed, the T-score for that test was used. A global neuropsychological composite T-score was derived for individuals who had T-scores for at least four out of six cognitive domains.

Table 1

Table 1

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Statistical analyses

A series of mixed-effects regression models (MRM) were used to examine whether PRFs altered the pattern of neuropsychological performance (domain-specific and global cognitive T-scores) for HIV+ and HIVwomen. Temporal ordering was structured into the analysis by the nature of the self-reported questionnaires used. For example, the PSS-10 and PCL-C assess stress and PTSD symptoms in the past month, whereas the CES-D assesses depressive symptom in the past 2 weeks. MRMs were selected to handle the repeated measurements of individuals over time and the nesting of individuals within site. Three primary sets of analyses were conducted – one for each of the three PRFs (PSS-10, PCL-C, and CES-D) which was done to avoid the issue of multicollinearity between measures (correlations ranged between 0.65 and 0.75). For each set of analyses, the primary predictor variables included the PRFs (time-varying predictor), HIV-serostatus, time, and all two-way and three-way interactions. Higher order interactions with nonsignificant P values (based on an alpha of P ≤ 0.05) were dropped one at a time in order of decreasing P value size. If there were no significant interactions with time, the average effects of the PRF and HIV-serostatus were also reported (Supplemental Tables 1, 2, and 3, http://links.lww.com/QAD/B151 for all final MRM models). All analyses included a standard set of covariates [11] including wave of enrollment (1994–1995, 2001–2002), self-reported annual household income (≤$12 000, >12 000, and missing), harmful alcohol use (>seven drinks/week or ≥four drinks in one sitting), smoking status (current refers to within the past week, former, never), marijuana use, and crack, cocaine, and/or heroin use (recent refers to within 6 months of the most recent WIHS visit, former, never), psychiatric antidepressant/antipsychotic medication (0, 1, or 2 medications), and positive hepatitis C (HCV) antibody. Observations were trimmed in which the studentized residuals were more than |4.5| to ensure effects were not driven by extreme values (<1% of observations for only motor skills and speed). When the interaction between HIV serostatus and a PRF were significant on a domain, planned analyses of HIV+ women only were conducted to examine interactions between PRFs and a standard set [11] of HIV-related characteristics including current HIV RNA (undetectable, <10 000 copies/ml, ≥10 000 copies/ml; determined using COBAS AmpliPrep/COBAS TaqMan HIV-1 Test; Roche Molecular Systems, Branchburg, New Jersey, USA; Oct 2008 through March 2011 sensitive to 48 copies/ml; April 2011 to present sensitive to 20 copies/ml), nadir and current CD4+ cell count (<200, 200–500, >500), reported clinical AIDS diagnosis, years on antiretroviral therapy, proportion of total WIHS visits with undetectable HIV RNA, cart refers to combination antiretroviral therapy (cART) use and adherence (cART use+≥95 adherence, cART use+<95% adherence, no cART), and current efavirenz (Bristol-Myers Squibb Company and Gilead Sciences LLC, Princeton NJ) use because of documented neuropsychological side effects. All analyses were conducted in SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, USA). Significance was set at P less than 0.05 two-tailed.

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Results

Measures of neuropsychological performance and concurrent PRFs were available for 946 WIHS participants (646 HIV+ and 300 HIVwomen) (Table 2). HIV+ women were significantly but slightly older, more likely to be HCV positive, and reported more antidepressants/antipsychotics use than HIVwomen (P < 0.05). HIV+ women were also less likely to engage in recent heavy alcohol use as well as recent marijuana use compared with HIVwomen (P < 0.05). All factors were included as covariates in the primary analyses except age which was accounted for in the creation of the T-score.

Table 2

Table 2

Longitudinal patterns of PSS-10, PCL-C, and CES-D were similar for HIV+ and HIVwomen (Fig. 1). Specifically, among HIV+ women, 55% had PSS-10 scores in the bottom two tertiles (<20 points) at all three NC visits, 36% had PSS-10 scores in the top tertile (≥20 points) at one or two visits, and 9% had PSS-10 in the top tertile at all three visits compared with 53, 37, and 9% among HIVwomen. For PCL-C, 27% of HIV+ and 27% of HIV− had probable PTSD at one or two visits; 5% of HIV+ and 5% of HIV− had probable PTSD at all three visits. Among HIV+ women, 32% had elevated CES-D at one or two visits and 12% at all three visits compared with 32 and 10% among HIVwomen.

Fig. 1

Fig. 1

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Separate and interactive effects of HIV-serostatus and psychological risk factors on neuropsychological performance

Verbal fluency was the only cognitive domain in which the magnitude of change in performance over time depended on the combined influence of HIV-serostatus and stress or PTSD (P < 0.05; Fig. 2). For both the PSS-10 and PCL-C, the PRF by time interaction was significant for HIV+ (P < 0.05) but not HIVwomen (P > 0.37). Restricting the follow-up to HIV+ women, higher PSS-10 [B (unstandardized beta) = −0.7, SE (standard error) = 0.3, P = 0.02] and PTSD (B = −0.9, SE = 0.4, P = 0.02) were associated with a greater decline in performance over time compared with lower PSS-10 (B = −0.3 SE = 0.2, P = 0.07) and no PTSD (B = −0.4, SE = 0.2, P = 0.40). Essentially, the effect of PSS-10 and PCL-C is not apparent until 4 years. There was no cognitive domain in which the magnitude of change in performance over time depended on the combined influence of HIV-serostatus and depressive symptoms.

Fig. 2

Fig. 2

Regardless of time, performance on the two primary domains of interest – verbal memory and learning – depended on the combined influence of HIV-serostatus and stress or PTSD (Fig. 3). Across time points, higher PSS-10 was associated with lower performance on memory among HIV+ (B = −1.3, SE = 0.5, P = 0.009) but not HIVwomen (B = 0.4, SE = 0.7, P = 0.59). Across time points, PTSD associated with lower performance on both learning (B = −2.7, SE = 0.6, P < 0.0001) and memory (B = −2.4, SE = 0.6, P < 0.0001) among HIV+ but not HIVwomen (P > 0.31). Although PTSD was associated negatively with executive function in both HIV+ (B = −1.1, SE = 0.4, P = 0.01) and HIVwomen (B = −2.8, SE = 0.6, P < 0.0001), the magnitude of the association was greater among HIV− compared with HIV+ women (P = 0.04). In addition, performance on attention/working memory depended on the combined influence of HIV-serostatus and CES-D (P = 0.01). On average, elevated depressive symptoms were associated with lower performance among HIV− (B = −2.4, SE = 0.7, P < 0.001) but not HIV+ women (B = −0.7, SE = 0.5, P = 0.12).

P

P

Regardless of time or HIV-serostatus, PRFs were associated with lower performance on a number of domains. On average, higher PSS-10 was associated with lower performance on global function (B = −0.9, SE = 0.02, P < 0.0001), verbal learning (B = −1.2, SE = 0.04, P = 0.004), attention/working memory (B = −1.1, SE = 0.04, P = 0.004), executive function (B = −1.1, SE = 0.03, P < 0.0001), and psychomotor speed (B = −1.4, SE = 0.3, P < 0.0001). On motor function, performance improved over time with lower PSS-10 (B = 0.7, SE = 0.3, P = 0.02) compared with higher PSS-10 (B = −0.8, SE = 0.5, P = 0.17). A similar, but slightly stronger, pattern was noted on the PCL-C. Across time points, PTSD was associated with lower performance on global function (B = −1.4, SE = 0.2, P < 0.0001), attention/working memory (B = −2.4, SE = 0.5, P < 0.0001), psychomotor speed (B = −1.8, SE = 0.3, P < 0.0001), and motor function (B = −1.2, SE = 0.5, P = 0.009). For the CES-D, elevated depressive symptoms were associated with lower performance on global function (B = −1.4, SE = 0.2, P < 0.0001), memory (B = −1.4, SE = 0.4, P = 0.001), executive function (B = −1.6, SE = 0.3, P < 0.0001), psychomotor speed (B = −1.4, SE = 0.3, P < 0.0001), verbal fluency (B = −1.0, SE = 0.3, P = 0.002), and motor function (B = −2.0, SE = 0.4, P < 0.0001) across time points.

In subanalyses among HIV+ women, HIV-related characteristics did not moderate the association of PSS-10 on verbal memory. However, current viral load moderated the effects of PTSD on both verbal learning (P = 0.04) and verbal memory (P = 0.03); the negative association of PTSD on verbal learning and verbal memory was only present when women had a detectable HIV RNA (Fig. 4). In addition, cART use/adherence (P = 0.005) and the proportion of virally suppressed visits in WIHS (P = 0.04) moderated the association between PTSD and verbal learning. Specifically, the negative association of PTSD with verbal learning was only present when women were not receiving cART or when women on cART reported non adherence (<95% adherence). Finally, a greater proportion of visits with viral suppression was associated with better verbal learning (P = 0.001) but only when women did not have PTSD.

P

P

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Discussion

In this longitudinal study, we provide evidence consistent with our cross-sectional findings [14] that elevated perceived stress and PTSD symptoms in the context of HIV are linked to alterations in verbal abilities (learning, memory, fluency) but not to other cognitive domains measured in this study. In individuals with HIV, the presence of perceived stress or PTSD symptoms compared with the absence of these factors are associated with a greater decline in verbal fluency over time and persistent negative effects on verbal learning and memory. Our results suggest that the effects of perceived and PTSD symptoms on fluency performance may be more delayed and require the occurrence of chronic periods of stress, whereas verbal learning and memory may be more impacted by acute periods of stress in the context of HIV. Our findings suggest that perceived stress and PTSD symptoms, more so than depressive symptoms, may contribute to different patterns of detrimental neuropsychological performance (stably declining or persistent impairment) among HIV+ individuals [27]. Moreover, our findings suggest that perceived stress and PTSD symptoms are a possible treatment target for improving verbal abilities among HIV+ women.

There are a number of possible mechanistic explanations for perceived stress and PTSD symptoms negatively influencing verbal abilities in the context of HIV. One possibility is that HIV and these PRFs may individually or in combination impair cognition in HIV+ women through effects on the hippocampus and prefrontal cortex. Neuroimaging and postmortem studies show that alterations in the hippocampus and prefrontal cortex contribute to memory deficits among HIV+ individuals [28–30] and stress may compound these effects on the prefrontal cortex [17,18]. In addition, alterations in the hypothalamic–pituitary–adrenal (HPA) axis, the key mediator of the stress response system, may mediate the relationship between these PRFs and memory in HIV+ individuals. Acute and chronic stressors alter the HPA axis, leading to neuronal atrophy in the prefrontal cortex [31,32]. In addition, HIV+ individuals show disruptions in the HPA axis including elevated basal cortisol levels [33–37]. Thus, both HIV and chronic stress are associated with disruption in HPA axis activation including elevated basal cortisol level, and the combination of both HIV and stress may have additive or multiplicative effects on HPA dysregulation.

Glucocorticoid receptor function may also play an important role in stress-related memory impairments in HIV+ women. Chronic stress reduces glucocorticoid receptor expression in the hippocampus and frontoparietal cortex, although these studies were in men [38,39]. Animal studies demonstrate the importance of glucocorticoid receptor function to memory. For example, intracellular trafficking of the glucocorticoid receptor is diminished in the hippocampus of aged rats [40], especially in those with hippocampal-related memory impairments [41]. Cumulative overexposure to glucocorticoids is also associated with age-related prefrontal impairments in rats [42]. Thus, glucocorticoid receptor dysfunction and altered cortisol levels combined could predispose HIV+ women to stress-associated psychiatric disorders and memory impairment linked to glucocorticoid resistance.

Although perceived stress, PTSD symptoms, and depressive symptoms were negatively associated with global neuropsychological function, unlike perceived stress and PTSD symptoms, depressive symptoms did not interact with HIV-serostatus on verbal abilities. Rather, HIV-serostatus moderated the effects of depressive symptoms in the domain of attention/working memory. However, on average, elevated depressive symptoms were associated with worse performance among HIV−, but not HIV+, women. Important to note is that, irrespective of depression symptoms, the attention/working memory performance of HIV+ women was worse than HIVwomen without depressive symptoms and similar to HIVwomen with depressive symptoms suggesting that the effects of HIV infection on performance overwhelm any negative effect of depressive symptoms. Although it is unclear what drives the pattern of effects, our findings give rise to the greater importance of targeting perceived stress and PTSD symptoms among HIV+ compared with HIV− individuals.

In HIV+ women, perceived stress and PTSD symptoms may have a stronger influence on HPA axis regulation and immune function compared with depressive symptoms. Although CD4+ cell count is associated with both higher self-reported perceived stress, worry, and depressive symptoms, regulatory T cells are associated with higher self-reported perceived stress and worry but not depressive symptoms [15]. Thus, although both stress, worry, and depression appear to be associated with the overall adaptive immune response in HIV+ women, stress and worry appear to be more strongly associated with regulatory mechanisms essential to maintain immune cell homeostasis [15] which may impact brain homeostasis [16].

Among HIV-related clinical characteristics, the strongest modifiers of the effect of PRFs on verbal learning and memory were current HIV RNA, cART use and adherence, and the proportion of time a woman achieves viral suppression over time. Specifically, the associations of PTSD symptoms with learning and memory were most pronounced among women with detectable HIV RNA and women who were not on cART nor adherent to their cART regimen. These findings are consistent with animal studies demonstrating that high levels of glucocorticoid exposure augment the negative effects of the neurotoxic viral protein, gp120, in the hippocampus through release of toxins by microglia [43,44].

The primary limitation is that we utilized self-report screeners of PTSD and depression rather than a structured diagnostic interview. Although studies indicate the CES-D and PCL-C are valid and reliable markers of mental health disorders, we have not validated scores in the WIHS. It is possible that the CES-D and PCL-C inventories may overestimate the number of individuals meeting criteria for a clinical diagnosis. Finally, our symptom-based measures may capture many mechanistic pathways linking mental health to cognition including inflammation and disordered sleep. Current and lifetime psychiatric diagnostic data are now available in the WIHS HIV+ women which will allow us to further examine whether associations we identified between mental health symptom based screening measures and NC performance are similar. Longer term follow-up is also needed to further determine the predictive nature of PRFs on cognition in HIV+ and HIVwomen. Finally, other cognitive domains including social cognition may be impacted by PRFs in HIV+ and HIVwomen; however, other domains such as visuospatial abilities and emotion processing were not part of the neurocognitive test battery administered in the WIHS.

In sum, HIV+ women are vulnerable to deficits in verbal abilities including verbal learning and memory. High perceived stress and PTSD symptoms, but not depressive symptoms, appear to be consistently linked to worse performance on these domains in the context of HIV. Stress reduction and posttraumatic stress prevention and treatment programs could help improve and maintain learning and memory function in women living with HIV and in turn may contribute to optimal HIV treatment adherence and viral suppression.

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Acknowledgements

L.H.R.'s effort was supported by Grant Number 1K01MH098798-01 and V.G.V.'s by K24MH098759, each from the National Institute of Mental Health (NIMH). Data in this article were collected by the Women's Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). WIHS (Principal Investigators): UAB-MS WIHS (Michael Saag, Mirjam-Colette Kempf, and Deborah Konkle-Parker), U01-AI-103401; Atlanta WIHS (Ighovwerha Ofotokun and Gina Wingood), U01-AI-103408; Bronx WIHS (Kathryn Anastos), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and Deborah Gustafson), U01-AI-031834; Chicago WIHS (Mardge Cohen and Audrey French), U01-AI-034993; Metropolitan Washington WIHS (Seble Kassaye), U01-AI-034994; Miami WIHS (Margaret Fischl and Lisa Metsch), U01-AI-103397; UNC WIHS (Adaora Adimora), U01-AI-103390; Connie Wofsy Women's HIV Study, Northern California (Ruth Greenblatt, Bradley Aouizerat, and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (Stephen Gange and Elizabeth Golub), U01-AI-042590; Southern California WIHS (Joel Milam), U01-HD-032632 (WIHS I–WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women's Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA).

Author contribution: L.H.R. and P.M.M. conceived the study idea. L.H.R. takes responsibility for the integrity of the statistical analyses and wrote the first draft of the article. All authors contributed to the writing of the manuscript and approved the final version of the article.

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Conflicts of interest

V.G.V. has served as a consultant to Merck and ViiV healthcare on topics related to HIV and aging.

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References

1. Brief DJ, Bollinger AR, Vielhauer MJ, Berger-Greenstein JA, Morgan EE, Brady SM, et al. Understanding the interface of HIV, trauma, posttraumatic stress disorder, and substance use and its implications for health outcomes. AIDS Care 2004; 16 (suppl 1):S97–120.
2. Spies G, Afifi TO, Archibald SL, Fennema-Notestine C, Sareen J, Seedat S. Mental health outcomes in HIV and childhood maltreatment: a systematic review. Syst Rev 2012; 1:30.
3. Machtinger EL, Wilson TC, Haberer JE, Weiss DS. Psychological trauma and PTSD in HIV-positive women: a meta-analysis. AIDS Behav 2012; 16:2091–2100.
4. Cohen M, Deamant C, Barkan S, Richardson J, Young M, Holman S, et al. Domestic violence and childhood sexual abuse in HIV-infected women and women at risk for HIV. Am J Public Health 2000; 90:560–565.
5. Decker MR, Benning L, Weber KM, Sherman SG, Adedimeji A, Wilson TE, et al. Physical and sexual violence predictors: 20 years of the Women's Interagency HIV Study Cohort. Am J Prev Med 2016; 51:731–742.
6. Neigh GN, Gillespie CF, Nemeroff CB. The neurobiological toll of child abuse and neglect. Trauma Violence Abuse 2009; 10:389–410.
7. Heim C, Shugart M, Craighead WE, Nemeroff CB. Neurobiological and psychiatric consequences of child abuse and neglect. Dev Psychobiol 2010; 52:671–690.
8. Penza KM, Heim C, Nemeroff CB. Neurobiological effects of childhood abuse: implications for the pathophysiology of depression and anxiety. Arch Womens Ment Health 2003; 6:15–22.
9. Masson M, East-Richard C, Cellard C. A meta-analysis on the impact of psychiatric disorders and maltreatment on cognition. Neuropsychology 2016; 30:143–156.
10. Goodkind M, Eickhoff SB, Oathes DJ, Jiang Y, Chang A, Jones-Hagata LB, et al. Identification of a common neurobiological substrate for mental illness. JAMA Psychiatry 2015; 72:305–315.
11. Maki PM, Rubin LH, Valcour V, Martin E, Crystal H, Young M, et al. Cognitive function in women with HIV: findings from the Women's Interagency HIV Study. Neurology 2015; 84:231–240.
12. Rubin LH, Sundermann EE, Cook JA, Martin EM, Golub ET, Weber KM, et al. Investigation of menopausal stage and symptoms on cognition in human immunodeficiency virus-infected women. Menopause 2014; 21:997–1006.
13. Rubin LH, Pyra M, Cook JA, Weber KM, Cohen MH, Martin E, et al. Posttraumatic stress is associated with verbal learning, memory, and psychomotor speed in HIV-infected and HIV-uninfected women. J Neurovirol 2016; 22:159–169.
14. Rubin LH, Cook JA, Weber KM, Cohen MH, Martin E, Valcour V, et al. The association of perceived stress and verbal memory is greater in HIV-infected versus HIV-uninfected women. J Neurovirol 2015; 21:422–432.
15. Rehm KE, Konkle-Parker D. Association of CD4+ T cell subpopulations and psychological stress measures in women living with HIV. AIDS Care 2017; 29:1–5.
16. de Groot NS, Burgas MT. Is membrane homeostasis the missing link between inflammation and neurodegenerative diseases?. Cell Mol Life Sci 2015; 72:4795–4805.
17. Rubin LH, Wu M, Sundermann EE, Meyer VJ, Smith R, Weber KM, et al. Elevated stress is associated with prefrontal cortex dysfunction during a verbal memory task in women with HIV. J Neurovirol 2016; 22:840–851.
18. Rubin LH, Meyer VJRJC, Sundermann EE, Wu M, Weber KM, et al. Prefrontal cortical volume loss is associated with stress-related deficits in verbal learning and memory in HIV-infected women. Neurobiol Dis 2016; 92 (Pt B):166–174.
19. Barkan SE, Melnick SL, Preston-Martin S, Weber K, Kalish LA, Miotti P, et al. The Women's Interagency HIV Study. WIHS Collaborative Study Group. Epidemiology 1998; 9:117–125.
20. Bacon MC, von Wyl V, Alden C, Sharp G, Robison E, Hessol N, et al. The Women's Interagency HIV Study: an observational cohort brings clinical sciences to the bench. Clin Diagn Lab Immunol 2005; 12:1013–1019.
21. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav 1983; 24:385–396.
22. Cohen S, Williamson G. Spacapan S, Oskamp S. Perceived stress in a probability sample of the United States. Sage, The social psychology of health: Claremont Symposium on applied social psychology. Newbury Park, CA: 1988.
23. Weathers FW, Huska JA, Keane TM. National Center for PTSD – Behavioral Science Division. PCL-C for DSM-IV. Boston: 1991.
24. Radloff LS. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977; 1:385–401.
25. Comstock GW, Helsing KJ. Symptoms of depression in two communities. Psychol Med 1976; 6:551–563.
26. Rubin LH, Cook JA, Grey DD, Weber K, Wells C, Golub ET, et al. Perinatal depressive symptoms in HIV-infected versus HIV-uninfected women: a prospective study from preconception to postpartum. J Womens Health (Larchmt) 2011; 20:1287–1295.
27. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69:1789–1799.
28. Maki PM, Cohen MH, Weber K, Little DM, Fornelli D, Rubin LH, et al. Impairments in memory and hippocampal function in HIV-positive vs HIV-negative women: a preliminary study. Neurology 2009; 72:1661–1668.
29. Castelo JM, Sherman SJ, Courtney MG, Melrose RJ, Stern CE. Altered hippocampal-prefrontal activation in HIV patients during episodic memory encoding. Neurology 2006; 66:1688–1695.
30. Levine AJ, Soontornniyomkij V, Achim CL, Masliah E, Gelman BB, Sinsheimer JS, et al. Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV. J Neurovirol 2016; 22:431–441.
31. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 2007; 87:873–904.
32. Wellman CL. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J Neurobiol 2001; 49:245–253.
33. Biglino A, Limone P, Forno B, Pollono A, Cariti G, Molinatti GM, et al. Altered adrenocorticotropin and cortisol response to corticotropin-releasing hormone in HIV-1 infection. Eur J Endocrinol 1995; 133:173–179.
34. Verges B, Chavanet P, Desgres J, Vaillant G, Waldner A, Brun JM, et al. Adrenal function in HIV infected patients. Acta Endocrinol (Copenh) 1989; 121:633–637.
35. Enwonwu CO, Meeks VI, Sawiris PG. Elevated cortisol levels in whole saliva in HIV infected individuals. Eur J Oral Sci 1996; 104:322–324.
36. Lortholary O, Christeff N, Casassus P, Thobie N, Veyssier P, Trogoff B, et al. Hypothalamo–pituitary–adrenal function in human immunodeficiency virus-infected men. J Clin Endocrinol Metab 1996; 81:791–796.
37. Christeff N, Gherbi N, Mammes O, Dalle MT, Gharakhanian S, Lortholary O, et al. Serum cortisol and DHEA concentrations during HIV infection. Psychoneuroendocrinology 1997; 22 (suppl 1):S11–18.
38. Herman JP, Adams D, Prewitt C. Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm. Neuroendocrinology 1995; 61:180–190.
39. Kitraki E, Karandrea D, Kittas C. Long-lasting effects of stress on glucocorticoid receptor gene expression in the rat brain. Neuroendocrinology 1999; 69:331–338.
40. Murphy EK, Spencer RL, Sipe KJ, Herman JP. Decrements in nuclear glucocorticoid receptor (GR) protein levels and DNA binding in aged rat hippocampus. Endocrinology 2002; 143:1362–1370.
41. Lee SY, Hwang YK, Yun HS, Han JS. Decreased levels of nuclear glucocorticoid receptor protein in the hippocampus of aged Long-Evans rats with cognitive impairment. Brain Res 2012; 1478:48–54.
42. Anderson RM, Birnie AK, Koblesky NK, Romig-Martin SA, Radley JJ. Adrenocortical status predicts the degree of age-related deficits in prefrontal structural plasticity and working memory. J Neurosci 2014; 34:8387–8397.
43. Yusim A, Franklin L, Brooke S, Ajilore O, Sapolsky R. Glucocorticoids exacerbate the deleterious effects of gp120 in hippocampal and cortical explants. J Neurochem 2000; 74:1000–1007.
44. Brooke SM, Sapolsky RM. Glucocorticoid exacerbation of gp120 neurotoxicity: role of microglia. Exp Neurol 2002; 177:151–158.
Keywords:

cognition; HIV; learning; memory; stress; women

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