Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV.

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

"As I Grew Older, My Life Got Better": Conceptions of Successful Aging among Older Women Living with or at Risk of HIV.

Successful aging (SA) is an important target for HIV care. However, we have insufficient understanding of how older women living with HIV (OWLH) in the US define SA. We explored conceptions of SA by OWLH and older women at risk of HIV and examined whether SA conceptions differed by (1) HIV serostatus, and (2) participation in the Women's Interagency HIV Study (WIHS). These analyses were part of a larger mixed-methods study with a sequential design. Participants were recruited at two clinical WIHS sites. We enrolled both WIHS participants and non-WIHS clinic patients. Our sample was 84% Black and included 29 OWLH and 15 older women at risk of HIV. We conducted 21 semi-structured interviews and four focus groups. The dataset was analyzed using descriptive, comparative, and relational analysis. We found four interlinked themes: life course perspective, accepting and celebrating aging, taking care of yourself, and looking good. The life course perspective was a core theme: participants assessed their aging in comparison to their earlier life hardships. These themes were similarly present among OWLH and older women at risk of HIV, although OWLH emphasized taking care of HIV. SA conceptualizations by OWLH did not differ whether or not they participated in the WIHS. Women living with or at risk of HIV may experience severe hardships throughout their lives. Overcoming these hardships may be linked to SA. Assessing the needs and connecting women to resources and programs are critical for SA promotion.

Association of Gut Microbiota With Objective Sleep Measures in Women With and Without Human Immunodeficiency Virus Infection: The IDOze Study.

BACKGROUND: Poor sleep health is an underrecognized health challenge, especially for people with human immunodeficiency virus (HIV). Gut microbiota related to sleep are underinvestigated. METHODS: The IDOze microbiota substudy included 190 women (114 with HIV and 76 without HIV). Wrist actigraphy measured total sleep duration, sleep efficiency, number of wake bouts, wake after sleep onset, fragmentation index, and sleep timing. 16S rRNA gene sequencing identified gut microbial genera. Analysis of compositions of microbiomes with bias correction was used to investigate cross-sectional associations between gut microbiota and sleep. Abundances of sleep-related gut microbial genera were compared between women with and without HIV. RESULTS: Enrichment of 7 short-chain fatty acid-producing genera (eg, Butyricimonas, Roseburia, and Blautia) was associated with lower fragmentation index. Enrichment of 9 genera (eg, Dorea) was associated with lower sleep efficiency and/or more wake after sleep onset. Enrichment of proinflammatory Acidaminococcus was associated with late sleep midpoint and offset time. These associations were largely consistent regardless of HIV status. The abundance of Butyricimonas was lower among women with HIV compared to those without HIV. CONCLUSIONS: Seventeen genera were identified to be associated with sleep continuity or timing. Butyricimonas, a potentially beneficial genus associated with sleep continuity, was less abundant among women with HIV.

Human Immunodeficiency Virus and Cardiac End-Organ Damage in Women: Findings From an Echocardiographic Study Across the United States.

BACKGROUND: People with human immunodeficiency virus (HIV) have been reported to have increased risk of clinical and subclinical cardiovascular disease. Existing studies have focused on men and often have been uncontrolled or lacked adequate HIV-negative comparators. METHODS: We performed echocardiography in the Women's Interagency HIV Study to investigate associations of HIV and HIV-specific factors with cardiac phenotypes, including left ventricular systolic dysfunction (LVSD), isolated LV diastolic dysfunction (LVDD), left atrial enlargement (LAE), LV hypertrophy (LVH), and increased tricuspid regurgitation velocity (TRV). RESULTS: Of 1654 participants (age 51 ± 9 years), 70% had HIV. Sixty-three (5.4%) women with HIV (WWH) had LVSD; 71 (6.5%) had isolated LVDD. Compared with women without HIV (WWOH), WWH had a near-significantly increased risk of LVSD (adjusted relative risk = 1.69; 95% confidence interval = 1.00 to 2.86; P = .051). No significant association was noted for HIV seropositivity with other phenotypes, but there was a risk gradient for decreasing CD4+ count among WWH that approached or reached significance for isolated LVDD, LAE, and LVH. WWH with CD4+ count <200 cells/mm3 had significantly higher prevalence of LAE, LVH, and high TRV than WWOH. There were no consistent associations for viral suppression or antiretroviral drug exposure. CONCLUSIONS: This study suggests that WWH have a higher risk of LVSD compared with sociodemographically similar WWOH, but their risk for isolated LVDD, LAE, LVH, and high TRV is increased only with reduced CD4+ count. Although these findings warrant replication, they support the importance of cardiovascular risk-factor and HIV-disease control for heart disease prevention in this population.

Trauma Across the Life Span and Multisystem Morbidity in Women With HIV.

OBJECTIVE: Sexual and physical abuse are highly prevalent among women living with HIV (WLWH) and are risk factors for the development of mental health and substance use disorders (MHDs, SUDs), and cognitive and medical comorbidities. We examined empirically derived patterns of trauma, MHD, and SUD, and associations with later cognitive and health outcomes. METHODS: A total of 1027 WLWH (average age = 48.6 years) in the Women's Interagency HIV Study completed the World Mental Health Composite International Diagnostic Interview from 2010 to 2013 to identify MHDs, SUDs, and age at onset of sexual and physical abuse. Then, cognitive impairment, cardiovascular/metabolic conditions, and HIV disease outcomes were assessed for up to 8.8 years. Latent class analysis identified patterns of co-occurring trauma, MHDs, and/or SUDs. Generalized estimating equations determined associations between these patterns and midlife cognitive and medical outcomes. RESULTS: Six distinct profiles emerged: no/negligible sexual/physical trauma, MHD, or SUD (39%); preadolescent/adolescent sexual trauma with anxiety and SUD (22%); SUD only (16%); MHD + SUD only (12%); early childhood sexual/physical trauma only (6%); and early childhood sexual/physical trauma with later MHD + SUD (4%). Profiles including early childhood trauma had the largest number of midlife conditions (i.e., cognitive, cardiovascular, HIV-related). Preadolescent/adolescent sexual trauma with anxiety and SUD predicted both global and domain-specific cognitive declines. Only SUD without trauma predicted lower CD4, whereas childhood trauma with MHD + SUD predicted increased CD8. CONCLUSIONS: WLWH have complex multisystem profiles of abuse, MHD, and/or SUD that predict midlife cognitive, metabolic/cardiovascular, and HIV outcomes. Understanding the interplay between these factors over time can identify risks and personalize preventative and treatment interventions.

Gut Microbiota, Plasma Metabolomic Profiles, and Carotid Artery Atherosclerosis in HIV Infection.

BACKGROUND: Alterations in gut microbiota and blood metabolomic profiles have been implicated in HIV infection and cardiovascular disease. However, it remains unclear whether alterations in gut microbiota may contribute to disrupted host blood metabolomic profiles in relation to atherosclerosis, especially in the context of HIV infection. METHODS: We analyzed cross-sectional associations between gut microbiota features and carotid artery plaque in 361 women with or at high risk of HIV (67% HIV+), and further integrated plaque-associated microbial features with plasma lipidomic/metabolomic profiles. Furthermore, in 737 women and men, we examined prospective associations of baseline gut bacteria-associated lipidomic and metabolomic profiles with incident carotid artery plaque over 7-year follow-up. RESULTS: We found 2 potentially pathogenic bacteria, Fusobacterium and Proteus, were associated with carotid artery plaque; while the beneficial butyrate producer Odoribacter was inversely associated with plaque. Fusobacterium and Proteus were associated with multiple lipids/metabolites which were clustered into 8 modules in network. A module comprised of 9 lysophosphatidylcholines and lysophosphatidylethanolamines and a module comprised of 9 diglycerides were associated with increased risk of carotid artery plaque (risk ratio [95% CI], 1.34 [1.09-1.64] and 1.24 [1.02-1.51] per SD increment, respectively). Functional analyses identified bacterial enzymes in lipid metabolism associated with these plasma lipids. In particular, phospholipase A1 and A2 are the key enzymes in the reactions producing lysophosphatidylcholines and lysophosphatidylethanolamines. CONCLUSIONS: Among individuals with or at high risk of HIV infection, we identified altered gut microbiota and related functional capacities in the lipid metabolism associated with disrupted plasma lipidomic profiles and carotid artery atherosclerosis.

The IDOze Study: The Link Between Sleep Disruption and Tryptophan-Kynurenine Pathway Activation in Women With Human Immunodeficiency Virus.

BACKGROUND: Poor sleep is associated with human immunodeficiency virus (HIV), particularly among women with HIV (WWH), although mechanisms are unclear. We explored cross-sectional associations between sleep disruption and tryptophan-kynurenine (T/K) pathway activation, measured by the kynurenine-to-tryptophan ratio (K:T). METHODS: HIV-uninfected women (HIV-) and WWH aged 35-70 years and on stable antiretroviral therapy were included. Sleep metrics were measured using wrist actigraphy. Plasma T/K pathway metabolites were measured using liquid chromatography-tandem mass spectrometry. Multivariate linear regression models examined relationships between K:T and actigraphy-based sleep metrics by HIV status. RESULTS: WWH (n = 153) and HIV- women (n = 151) were demographically similar. Among WWH, median CD4 was 751 cells/µL; 92% had undetectable HIV RNA. Compared to HIV- women, WWH had higher K:T (P < .001) and kynurenine (P = .01) levels but similar tryptophan levels (P = .25). Higher K:T was associated with more wake bouts (P = .001), more time awake after sleep onset (P = .01), and lower sleep efficiency (P = .03) in WWH only. CONCLUSIONS: HIV infection was associated with T/K pathway activation; this activation was associated with poorer sleep efficiency and more fragmented sleep. While longitudinal studies are needed to elucidate the directionality of these associations, these findings may help identify treatments to reduce sleep disruption in WWH by targeting residual inflammation and T/K pathway activation.

Menopause Is Associated With Immune Activation in Women With HIV.

BACKGROUND: Persistent immune activation due to gut barrier dysfunction is a suspected cause of morbidity in HIV, but the impact of menopause on this pathway is unknown. METHODS: In 350 women with HIV from the Women's Interagency HIV Study, plasma biomarkers of gut barrier dysfunction (intestinal fatty acid binding protein; IFAB), innate immune activation (soluble CD14 and CD163; sCD14, sCD163), and systemic inflammation (interleukin-6 and tumor necrosis factor receptor 1; IL-6, TNFR1) were measured at 674 person-visits spanning ≤2 years. RESULTS: Menopause (post- vs premenopausal status) was associated with higher plasma sCD14 and sCD163 in linear mixed-effects regression adjusting for age and other covariates (ß = 161.89 ng/mL; 95% confidence interval [CI], 18.37-305.41 and 65.48 ng/mL, 95% CI, 6.64-124.33, respectively); but not with plasma IFAB, IL-6, or TNFR1. In piece-wise linear mixed-effects regression of biomarkers on years before/after the final menstrual period, sCD14 increased during the menopausal transition by 250.71 ng/mL per year (95% CI, 16.63-484.79; P = .04), but not in premenopausal or postmenopausal periods. CONCLUSIONS: In women with HIV, menopause may increase innate immune activation, but data did not support an influence on the gut barrier or inflammation. Clinical implications of immune activation during menopausal transition warrant further investigation.

Glucocorticoid Receptor Function and Cognitive Performance in Women With HIV.

OBJECTIVE: Alterations in glucocorticoid receptor (GCR) function may be a risk factor for cognitive complications among older people with human immunodeficiency virus (HIV). We evaluated whether HIV serostatus and age modify the GCR function-cognition association among women. METHODS: Eighty women with HIV ( n = 40, <40 years of age [younger]; n = 40, >50 years of age [older]) and 80 HIV-uninfected women ( n = 40 older, n = 40 younger) enrolled in the Women's Interagency HIV Study completed a comprehensive neuropsychological test battery. Peripheral blood mononuclear cells collected concurrent with neuropsychological testing were assessed for GCR function. Multivariable linear regression analyses were conducted to examine whether a) HIV serostatus and age were associated with GCR function, and b) GCR function-cognition associations are moderated by HIV serostatus and age adjusting for relevant covariates. RESULTS: Among older women, higher baseline FKBP5 expression level was associated with lower attention/working memory performance among women with HIV ( B = 6.4, standard error = 1.7, p = .0003) but not in women without HIV infection ( B = -1.7, standard error = 1.9, p = .37). There were no significant HIV serostatus by age interactions on dexamethasone (DEX)-stimulated expression of the genes regulated by the GCR or lipopolysaccharide-stimulated tumor necrosis factor α levels (with or without DEX stimulation; p values > .13). HIV serostatus was associated with GC target genes PER1 ( p = .006) and DUSP1 ( p = .02), but not TSC22D3 ( p = .32), after DEX stimulation. CONCLUSIONS: Collectively, these data suggest that HIV serostatus and age may modify the influence of the GCR, such that the receptor is likely engaged to a similar extent, but the downstream influence of the receptor is altered, potentially through epigenetic modification of target genes.

Jointly modeling of sleep variables that are objectively measured by wrist actigraphy.

Recently developed actigraphy devices have made it possible for continuous and objective monitoring of sleep over multiple nights. Sleep variables captured by wrist actigraphy devices include sleep onset, sleep end, total sleep time, wake time after sleep onset, number of awakenings, etc. Currently available statistical methods to analyze such actigraphy data have limitations. First, averages over multiple nights are used to summarize sleep activities, ignoring variability over multiple nights from the same subject. Second, sleep variables are often analyzed independently. However, sleep variables tend to be correlated with each other. For example, how long a subject sleeps at night can be correlated with how long and how frequent he/she wakes up during that night. It is important to understand these inter-relationships. We therefore propose a joint mixed effect model on total sleep time, number of awakenings, and wake time. We develop an estimating procedure based upon a sequence of generalized linear mixed effects models, which can be implemented using existing software. The use of these models not only avoids computational intensity and instability that may occur by directly applying a numerical algorithm on a complicated joint likelihood function, but also provides additional insights on sleep activities. We demonstrated in simulation studies that the proposed estimating procedure performed well in estimating both fixed and random effects' parameters. We applied the proposed model to data from the Women's Interagency HIV Sleep Study to examine the association of employment status and age with overall sleep quality assessed by several actigraphy measured sleep variables.

Psychosocial Mechanisms of Self-rated Successful Aging with HIV: A Structural Equation Model.

This study tested a conceptual psychosocial model of self-rated successful aging (SRSA) with HIV. Our sample (n = 356) included older women living with HIV (OWLH): average age 56.5 years, 73% Black. SRSA was assessed using a research-based 10-point scale (higher scores = better outcomes). We conducted adjusted structural equation modeling. The global model included two latent variables-protective attributes (composite of positive psychosocial factors: resilience, personal mastery, optimism, spirituality) and psychological distress (composite of negative psychosocial factors: anxiety, depression, loneliness, internalized HIV-related stigma). The model showed good fit (χ2(58) = 76, p = 0.06; RMSEA = 0.03; CFI = 0.99). Increased protective attributes were associated with improved SRSA both directly and mediated by improved coping with stress. While psychological distress did not have a direct effect on SRSA, it was indirectly associated with worsened SRSA via diminished protective attributes and via decreased coping with stress. Findings suggest the need for interventions enhancing positive and mitigating negative psychosocial factors in OWLH.

Starting or Switching to an Integrase Inhibitor-Based Regimen Affects PTSD Symptoms in Women with HIV.

As the use of Integrase inhibitor (INSTI)-class antiretroviral medications becomes more common to maintain long-term viral suppression, early reports suggest the potential for CNS side-effects when starting or switching to an INSTI-based regimen. In a population already at higher risk for developing mood and anxiety disorders, these drugs may have significant effects on PTSD scale symptom scores, particularly in women with HIV (WWH). A total of 551 participants were included after completing ≥ 1 WIHS study visits before and after starting/switching to an INSTI-based ART regimen. Of these, 14% were ART naïve, the remainder switched from primarily a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Using multivariable linear mixed effects models, we compared PTSD Civilian Checklist subscale scores before and after a "start/switch" to dolutegravir (DTG), raltegravir (RAL), or elvitegravir (EVG). Start/switch to EVG improved re-experiencing subscale symptoms (P's < 0.05). Switching to EVG improved symptoms of avoidance (P = 0.01). Starting RAL improved arousal subscale symptoms (P = 0.03); however, switching to RAL worsened re-experiencing subscale symptoms (P < 0.005). Starting DTG worsened avoidance subscale symptoms (P = 0.03), whereas switching to DTG did not change subscale or overall PTSD symptoms (P's > 0.08). In WWH, an EVG-based ART regimen is associated with improved PTSD symptoms, in both treatment naïve patients and those switching from other ART. While a RAL-based regimen was associated with better PTSD symptoms than in treatment naïve patients, switching onto a RAL-based regimen was associated with worse PTSD symptoms. DTG-based regimens either did not affect, or worsened symptoms, in both naïve and switch patients. Further studies are needed to determine mechanisms underlying differential effects of EVG, RAL and DTG on stress symptoms in WWH.

Associations of CKD risk factors and longitudinal changes in urine biomarkers of kidney tubules among women living with HIV.

BACKGROUND: Novel urine biomarkers have enabled the characterization of kidney tubular dysfunction and injury among persons living with HIV, a population at an increased risk of kidney disease. Even though several urine biomarkers predict progressive kidney function decline, antiretroviral toxicity, and mortality in the setting of HIV infection, the relationships among the risk factors for chronic kidney disease (CKD) and urine biomarkers are unclear. METHODS: We assessed traditional and infection-related CKD risk factors and measured 14 urine biomarkers at baseline and at follow-up among women living with HIV in the Women's Interagency Health Study (WIHS). We then used simultaneously adjusted multivariable linear regression models to evaluate the associations of CKD risk factors with longitudinal changes in biomarker levels. RESULTS: Of the 647 women living with HIV in this analysis, the majority (67%) were Black, the median age was 45 years and median follow-up time was 2.5 years. Each traditional and infection-related CKD risk factor was associated with a unique set of changes in urine biomarkers. For example, baseline hemoglobin a1c was associated with worse tubular injury (higher interleukin [IL]-18), proximal tubular reabsorptive dysfunction (higher α1-microglobulin), tubular reserve (lower uromodulin) and immune response to injury (higher chitinase-3-like protein-1 [YKL-40]). Furthermore, increasing hemoglobin a1c at follow-up was associated with further worsening of tubular injury (higher kidney injury molecule-1 [KIM-1] and IL-18), as well as higher YKL-40. HCV co-infection was associated with worsening proximal tubular reabsorptive dysfunction (higher ß2-microglobulin [ß2m]), and higher YKL-40, whereas HIV viremia was associated with worsening markers of tubular and glomerular injury (higher KIM-1 and albuminuria, respectively). CONCLUSIONS: CKD risk factors are associated with unique patterns of biomarker changes among women living with HIV, suggesting that serial measurements of multiple biomarkers may help in detecting and monitoring kidney disease in this setting.

Elevated Plasma Ceramides Are Associated With Antiretroviral Therapy Use and Progression of Carotid Artery Atherosclerosis in HIV Infection.

BACKGROUND: Ceramides have been implicated in the pathophysiology of HIV infection and cardiovascular disease. However, no study, to our knowledge, has evaluated circulating ceramide levels in association with subclinical cardiovascular disease risk among HIV-infected individuals. METHODS: Plasma levels of 4 ceramide species (C16:0, C22:0, C24:0, and C24:1) were measured among 398 women (73% HIV+) and 339 men (68% HIV+) without carotid artery plaques at baseline from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. We examined associations between baseline plasma ceramides and risk of carotid artery plaque formation, assessed by repeated B-mode carotid artery ultrasound imaging over a median 7-year follow-up. RESULTS: Plasma levels of C16:0, C22:0, and C24:1 ceramides were significantly higher in HIV-infected individuals compared with those without HIV infection (all P<0.001), and further analysis indicated that elevated ceramide levels were associated with antiretroviral therapy use, particularly protease inhibitor use, in HIV-infected individuals (all P<0.001). All 4 ceramides were highly correlated with each other ( r=0.70-0.94; all P<0.001) and significantly correlated with total-cholesterol ( r=0.42-0.58; all P<0.001) and low-density lipoprotein cholesterol ( r=0.24-0.42; all P<0.001) levels. Of note, C16:0 and C24:1 ceramides, rather than C22:0 and C24:0 ceramides, were more closely correlated with specific monocyte activation and inflammation markers (eg, r=0.30 between C16:0 ceramide and soluble CD14; P<0.001) and surface markers of CD4+ T-cell activation. A total of 112 participants developed carotid artery plaques over 7 years, and higher levels of C16:0 and C24:1 ceramides were significantly associated with increased risk of carotid artery plaques (relative risk [95% CI]=1.55 [1.29, 1.86] and 1.51 [1.26, 1.82] per standard deviation increment, respectively; both P<0.001), after adjusting for demographic and behavioral factors. After further adjustment for cardiovascular disease risk factors and immune activation markers, these associations were attenuated but remained significant. The results were consistent between men and women and between HIV-infected and HIV-uninfected participants. CONCLUSIONS: In 2 HIV cohorts, elevated plasma levels of C16:0 and C24:1 ceramides, correlating with immune activation and inflammation, were associated with antiretroviral therapy use and progression of carotid artery atherosclerosis.

Weight Gain Associated With Integrase Stand Transfer Inhibitor Use in Women.

BACKGROUND: Integrase strand-transfer inhibitor (INSTI)-based antiretroviral therapy (ART) is recommended for human immunodeficiency virus (HIV) management. Although studies have suggested associations between INSTIs and weight gain, women living with HIV (WLHIV) have been underrepresented in research. We evaluated the effect of switching or adding INSTIs among WLHIV. METHODS: Women enrolled in the Women's Interagency HIV Study (WIHS) from 2006-2017 who switched to or added an INSTI to ART (SWAD group) were compared to women on non-INSTI ART (STAY group). Body weight, body mass index (BMI), percentage body fat (PBF), and waist, hip, arm, and thigh circumferences were measured 6-12 months before and 6-18 months after the INSTI switch/add in SWAD participants, with comparable measurement time points in STAY participants. Linear regression models compared changes over time by SWAD/STAY group, adjusted for age, race, WIHS site, education, income, smoking status, and baseline ART regimen. RESULTS: We followed 1118 women (234 SWAD and 884 STAY) for a mean of 2.0 years (+/- 0.1 standard deviation [SD]; mean age 48.8 years, SD +/- 8.8); 61% were Black. On average, compared to the STAY group, the SWAD group experienced mean greater increases of 2.1 kg in body weight, 0.8 kg/m2 in BMI, 1.4% in PBF, and 2.0, 1.9, 0.6, and 1.0 cm in waist, hip, arm, and thigh circumference, respectively (all P values < .05). No differences in magnitudes of these changes were observed by INSTI type. CONCLUSIONS: In WLHIV, a switch to INSTI was associated with significant increases in body weight, body circumferences, and fat percentages, compared to non-INSTI ART. The metabolic and other health effects of these changes deserve further investigation.

African Mitochondrial DNA Haplogroup L2 Is Associated With Slower Decline of ß-cell Function and Lower Incidence of Diabetes Mellitus in Non-Hispanic, Black Women Living With Human Immunodeficiency Virus.

BACKGROUND: Susceptibility to metabolic diseases may be influenced by mitochondrial genetic variability among people living with human immunodeficiency virus (HIV; PLWH), but remains unexplored in populations with African ancestry. We investigated the association between mitochondrial DNA (mtDNA) haplogroups and the homeostatic model assessments of ß-cell function (HOMA-B) and insulin resistance (HOMA-IR), as well as incident diabetes mellitus (DM), among Black women living with or at risk for HIV. METHODS: Women without DM who had fasting glucose (FG) and insulin (FI) data for ≥2 visits were included. Haplogroups were inferred from genotyping data using HaploGrep. HOMA-B and HOMA-IR were calculated using FG and FI data. Incident DM was defined by a combination of FG ≥ 126 mg/dL, the use of DM medication, a DM diagnosis, or hemoglobin A1c ≥ 6.5%. We compared HOMA-B, HOMA-IR, and incident DM by haplogroups and assessed the associations between HOMA-B and HOMA-IR and DM by haplogroup. RESULTS: Of 1288 women (933 living with HIV and 355 living without HIV), PLWH had higher initial HOMA-B and HOMA-IR than people living without HIV. PLWH with haplogroup L2 had a slower decline in HOMA-B per year (Pinteraction = .02) and a lower risk of incident DM (hazard ratio [HR], 0.51; 95% confidence interval [CI], .32-.82) than PLWH with other haplogroups after adjustments for age, body mass index, combination antiretroviral therapy use, CD4 cell counts, and HIV RNA. The impact of HOMA-IR on incident DM was less significant in those with haplogroup L2, compared to non-L2 (HR, 1.28 [95% CI, .70-2.38] vs 4.13 [95% CI, 3.28-5.22], respectively; Pinteraction < .01), among PLWH. CONCLUSIONS: Mitochondrial genetic variation is associated with ß-cell functions and incident DM in non-Hispanic, Black women with HIV and alters the relationship between insulin resistance and DM.

Dietary fatty acids and risk of Alzheimer's disease and related dementias: Observations from the Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP).

INTRODUCTION: High dietary intake of long chain, polyunsaturated fatty acids is associated with lower Alzheimer's disease (AD) risk. METHODS: Washington Heights-Hamilton Heights-Inwood Columbia Aging Project is a multiethnic, prospective observational study of aging and dementia among elderly (≥ 65 years). Dietary intake was measured using a food frequency questionnaire. Dietary short-, medium-, and long-chain fatty acid intakes were categorized by number of carbons and double bonds. Consensus AD diagnoses were made. Associations between AD risk and dietary fatty acid and cholesterol intakes were estimated using multivariable Cox proportional hazards regression models. RESULTS: Of 2612 multiethnic women (67%) and men (baseline age 76.3 [6.4] years), 380 developed AD over an average 4.5 years follow-up. Lower risk of AD was associated with increasing intakes of docosahexaenoic acid (DHA; hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.57 to 0.95, P = 0.018) and eicosapentaenoic acid (EPA; HR = 0.74, 95% CI: 0.57 to 0.95, P = 0.021), and longer AD-free survival (P < 0.05). DISCUSSION: Higher intake of DHA and EPA are protective for AD.

Computerized cognitive performance assessments in the Brooklyn Cognitive Impairments in Health Disparities Pilot Study.

INTRODUCTION: Detecting cognitive impairment in diverse, health disparities communities is an urgent health care priority. METHODS: The Brooklyn Cognitive Impairments in Health Disparities Pilot Study investigated quantitative aspects and liking of a computerized cognitive performance assessment, Cognigram, among individuals ≥ 40 years in traditional and nontraditional primary care settings. RESULTS: Cognigram was piloted in the Emergency Department, Family Medicine, and Geriatric Psychiatry clinics: 58 adults (23 men, 35 women), 67.9 ± 9.8 years (range 43-91), completed the Cognigram and 5-item liking survey. The observed liking range was 2 to maximum score 5 (67% scored 4-5; no sex or age differences). DISCUSSION: The Cognigram was well liked in waiting rooms of primary care settings. Assistance from a trained adult and clinic endorsement were keys to success. How the Cognigram performs in a geographically compact, population-dense global setting, such as Brooklyn with high vascular disease risk and a plethora of health disparities, is being tested.

Vascular dysfunction-The disregarded partner of Alzheimer's disease.

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.

Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.