Ghrelin, Amylin, Gastric Inhibitory Peptide and Cognition in Middle-Aged HIV-Infected and Uninfected Women: The Women's Interagency HIV Study.

OBJECTIVE: To explore the gut-brain axis by examining gut hormone levels and cognitive test scores in women with (HIV+) and without (HIV-) HIV infection. DESIGN/METHODS: Participants included 356 women (248 HIV+, 108 at risk HIV-) in the Brooklyn Women's Interagency HIV Study (WIHS) with measured levels of ghrelin, amylin and gastric inhibitory peptide (GIP), also known as glucose-dependent insulinotropic polypeptide. Cross-sectional analyses using linear regression models estimated the relationship between gut hormones and Trails A, Trails B, Stroop interference time, Stroop word recall, Stroop color naming and reading, and Symbol Digit Modalities Test (SDMT) with consideration for age, HIV infection status, Wide Range Achievement Test score (WRAT), CD4 count, insulin resistance, drug use, and race/ethnicity. RESULTS: Among women at mid-life with chronic (at least 10 years) HIV infection or among those at risk, ghrelin, amylin and GIP were differentially related to cognitive test performance by cognitive domain. Better performance on cognitive tests was generally associated with higher ghrelin, amylin and GIP levels. However, the strength of association varied, as did significance level by HIV status. CONCLUSION: Previous analyses in WIHS participants have suggested that higher BMI, waist, and WHR are associated with better cognitive function among women at mid-life with HIV infection. This study indicates that higher gut hormone levels are also associated with better cognition. Gut hormones may provide additional mechanistic insights regarding the association between obesity and Type 2 diabetes and cognition in middle-aged HIV+ and at risk HIV- women. In addition, measuring these hormones longitudinally would add to the understanding of mechanisms of actions of these hormones and their use as potential clinical tools for early identification and intervention on cognitive decline in this vulnerable population.

Association of the Fractal Dimension of Retinal Arteries and Veins with Quantitative Brain MRI Measures in HIV-Infected and Uninfected Women.

OBJECTIVE: The fractal dimension of retinal arteries and veins is a measure of the complexity of the vascular tree. We hypothesized that retinal fractal dimension would be associated with brain volume and white matter integrity in HIV-infected women. DESIGN: Nested case-control within longitudinal cohort study. METHODS: Women were recruited from the Brooklyn site of the Women's Interagency HIV study (WIHS); 34 HIV-infected and 21 HIV-uninfected women with analyzable MRIs and retinal photographs were included. Fractal dimension was determined using the SIVA software program on skeletonized retinal images. The relationship between predictors (retinal vascular measures) and outcomes (quantitative MRI measures) were analyzed with linear regression models. All models included age, intracranial volume, and both arterial and venous fractal dimension. Some models were adjusted for blood pressure, race/ethnicity, and HIV-infection. RESULTS: The women were 45.6 ± 7.3 years of age. Higher arterial dimension was associated with larger cortical volumes, but higher venous dimension was associated with smaller cortical volumes. In fully adjusted models, venous dimension was significantly associated with fractional anisotropy (standardized ß = -0.41, p = 0.009) and total gray matter volume (ß = -0.24, p = 0.03), and arterial dimension with mean diffusivity (ß = -0.33,.p = 0.04) and fractional anisotropy (ß = 0.34, p = 0.03). HIV-infection was not associated with any retinal or MRI measure. CONCLUSIONS: Higher venous fractal dimension was associated with smaller cortical volumes and lower fractional anisotropy, whereas higher arterial fractal dimension was associated with the opposite patterns. Longitudinal studies are needed to validate this finding.

Liver Fibrosis Linked to Cognitive Performance in HIV and Hepatitis C.

OBJECTIVE: Because HIV impairs gut barriers to pathogens, HIV-infected adults may be vulnerable to minimal hepatic encephalopathy in the absence of cirrhosis. BACKGROUND: Cognitive disorders persist in up to one-half of people living with HIV despite access to combination antiretroviral therapy. Minimal hepatic encephalopathy occurs in cirrhotic patients with or without HIV infection and may be associated with inflammation. DESIGN/METHODS: A cross-sectional investigation of liver fibrosis severity using the aspartate aminotransferase to platelet ratio index (APRI) and neuropsychological testing performance among women from the Women's Interagency HIV Study. A subset underwent liver transient elastography (FibroScan, n = 303). RESULTS: We evaluated 1479 women [mean (SD) age of 46 (9.3) years]: 770 (52%) only HIV infected, 73 (5%) only hepatitis C virus (HCV) infected, 235 (16%) HIV/HCV coinfected, and 401 (27%) uninfected. Of these, 1221 (83%) exhibited APRI ≤0.5 (no or only mild fibrosis), 206 (14%) exhibited APRI >0.5 and ≤1.5 (moderate fibrosis), and 52 (3%) exhibited APRI >1.5 (severe fibrosis). Having moderate or severe fibrosis (APRI >0.5) was associated with worse performance in learning, executive function, memory, psychomotor speed, fluency, and fine motor skills. In these models that adjusted for fibrosis, smaller associations were found for HIV (learning and memory) and HCV (executive functioning and attention). The severity of fibrosis, measured by FibroScan, was associated with worse performance in attention, executive functioning, and fluency. CONCLUSIONS: Liver fibrosis had a contribution to cognitive performance independent of HCV and HIV; however, the pattern of neuropsychological deficit associated with fibrosis was not typical of minimal hepatic encephalopathy.

First translational 'Think Tank' on cerebrovascular disease, cognitive impairment and dementia.

As the human population continues to age, an increasing number of people will exhibit significant deficits in cognitive function and dementia. It is now recognized that cerebrovascular, metabolic and neurodegenerative diseases all play major roles in the evolution of cognitive impairment and dementia. Thus with our more recent recognition of these relationships and our need to understand and more positively impact on this world health problem, "The Leo and Anne Albert Charitable Trust" (Gene Pranzo, Trustee with significant support from Susan Brogan, Meeting Planner) provided generous support for this inaugural international workshop that was held from April 13-16, 2015 at the beautiful Ritz Carlton Golf Resort in North Naples, Florida. Researchers from SUNY Downstate Medical Center, Brooklyn, NY organized the event by selecting the present group of translationally inclined preclinical, clinical and population scientists focused on cerebrovascular disease (CVD) risk and its progression to vascular cognitive impairment (VCI) and dementia. Participants at the workshop addressed important issues related to aging, cognition and dementia by: (1) sharing new data, information and perspectives that intersect vascular, metabolic and neurodegenerative diseases, (2) discussing gaps in translating population risk, clinical and preclinical information to the progression of cognitive loss, and (3) debating new approaches and methods to fill these gaps that can translate into future therapeutic interventions. Participants agreed on topics for group discussion prior to the meeting and focused on specific translational goals that included promoting better understanding of dementia mechanisms, the identification of potential therapeutic targets for intervention, and discussed/debated the potential utility of diagnostic/prognostic markers. Below summarizes the new data-presentations, concepts, novel directions and specific discussion topics addressed by this international translational team at our "First Leo and Anne Albert Charitable Trust 'Think Tank' VCI workshop".

Leptin, Adiponectin and Cognition in Middle-aged HIV-infected and Uninfected Women. The Brooklyn Women's Interagency HIV Study.

CONTEXT: Case-control study of women with and without HIV infection. OBJECTIVE: To explore the association of cognition and the adipokines, leptin and adiponectin (total; high molecular weight, HMW), in women with (HIV+) and without HIV (HIV-) infection. DESIGN: Cross-sectional analyses of adipokines and cognition using linear regression models of log-transformed adipokines, and Trails A, Trails B, Stroop interference time, Stroop word recall, Stroop color naming and reading, and Symbol Digit Modalities Test (SDMT) with consideration for age, HIV infection status, education, CD4 count, diabetes, body mass index (BMI), waist circumference (WC) and race/ethnicity. SETTING: Brooklyn, NY. PARTICIPANTS: 354 participants (247 HIV+, 107 HIV-), in the Brooklyn Women's Interagency HIV Study (WIHS), average age 38.9 years, with measured levels of leptin and adiponectin (total and high molecular weight, HMW). MAIN OUTCOME MEASURE: Cognition. RESULTS: Higher levels of leptin were positively associated with worse cognition on the basis of Trails A completion time and SDMT score. Among at risk HIV- women, leptin was associated with worse performance on Trails B. No associations were observed for total or HMW adiponectin. CONCLUSION: Blood adipokine levels were measured to provide mechanistic insights regarding the association of adipose with cognitive function. These data suggest that higher levels of leptin, consistent with more adipose tissue, are associated with worse cognitive function in middle age. Monitoring leptin over time and with increasing age in relation to cognition and dementia, may lend insights to the role of adipose tissue in successful body and brain aging among women with HIV infection.

Associations of cerebrovascular and Alzheimer's disease pathology with brain atrophy.

Cortical atrophy and brain vascular disease are both associated with dementia, but there are only limited pathological data on the association of brain vascular disease with cortical atrophy. We studied pathological material from the Rush Memory and Aging Project (MAP, N = 445). Cortical and hippocampal atrophy, and atherosclerosis at the circle of Willis (large vessel disease, LVD) and arteriolosclerosis (small vessel disease, SVD) were rated by neuropathologists unaware of this study's hypothesis. Quantitative measures of Alzheimer's disease (AD) pathology, specifically neuronal neurofibrillary tangles (NFT) and amyloid-beta (Aß) burden, were also obtained. Chronic micro and macroscopic infarcts were noted. In ordinal logistic regression models that included age at death, sex, apoE genotype, statin-use, Aß and NFT, more severe LVD was significantly associated with more severe cortical and hippocampal atrophy. The odds ratio for the association of the most severe LVD (compared to the least) with cortical atrophy was 2.7 (CI: 1.5-4.7) p = 0.001; for hippocampal atrophy the odds ratio was 2.8 (CI: 1.5-5.2), p = 0.001. The association of SVD with atrophy did not follow a consistent pattern. Neither macroscopic infarcts nor microscopic infarcts were associated with cortical or hippocampal atrophy (p's > 0.15). Tangle density was associated with cortical (p = 0.014) and hippocampal atrophy (p < 0.001). In contrast, amyloid burden was associated with less cortical (p = 0.02) or hippocampal (p = 0.002) atrophy. In this large autopsy study LVD was associated with cortical and hippocampal atrophy. The relationship between SVD and atrophy requires further study.

Anthropometric measures and cognition in middle-aged HIV-infected and uninfected women. The Women's Interagency HIV Study.

This study aimed to explore the relationship of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with cognition in women with (HIV+) and without HIV (HIV-) infection. One thousand six hundred ninety participants (1,196 HIV+, 494 HIV-) in the Women's Interagency HIV Study (WIHS) with data available on anthropometric measures comprise the analytical sample. Cross-sectional analyses using linear regression models estimated the relationship between anthropometric variables and Trails A, Trails B, Stroop interference time, Stroop word recall, Stroop color naming and reading, and Symbol Digit Modalities Test (SDMT) with consideration for age, HIV infection status, Wide Range Achievement Test score, CD4 count, insulin resistance, drug use, and race/ethnicity. Among HIV+ women, BMI < 18.5 kg/m(2) was associated with poorer cognitive performance evidenced by longer Trails A and Trails B and shorter SDMT completion times. An obese BMI (30 kg/m(2) or higher) was related to better performance on Trails B and worse performance on the Stroop interference test. Among HIV- women, an obese BMI was related to worse performance on the Stroop color naming test. Few and inconsistent associations were observed between WC, WHR, and cognition. Among women at mid-life with chronic (at least 10 years) HIV infection, common anthropometric measures, primarily BMI, were differentially related to cognitive test performance by cognitive domain. Higher levels of BMI were associated with better cognitive function. In this era of antiretroviral therapies, restoration of health evidenced as higher BMI due to effective antiretroviral therapies, may improve cognitive function in middle-aged HIV-infected women.

A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African American women.

Previous studies of the association of the C17T polymorphism of the mu opiate receptor gene with substance dependence compared cases with substance dependence to controls and usually found no significant association. However, the studies were limited by small sample size-no study had more than 12 subjects with the TT genotype, a genotype that is rare in white and Asian subjects. Moreover, drug use is not dichotomous but follows a spectrum from non-use to modest, intermittent use, to use several times daily. We asked whether the Kreek-McHugh-Schluger-Kellogg (KMSK) scales for alcohol, cocaine, opiates and tobacco that quantify substance use during the time of a subject's maximal use might be more sensitive measures than dichotomous outcomes. We administered the KMSK scales and completed C17T genotyping on 1009 human immunodeficiency virus (HIV)-infected and 469 HIV-uninfected women in The Women's Interagency HIV Study, an ongoing study of HIV in women. Forty-two of the 697 African American, 1 of the 182 Hispanic and none of the 161 white women had the TT genotype. KMSK cocaine, alcohol and tobacco scores were significantly higher in the African American women with the TT genotype (P = 0.008, 0.0001, and 0.006, respectively), but opiate scores were not. Ordinal regression models controlling for HIV serostatus, age, education, and income had odds ratios for the TT genotype for predicting alcohol, tobacco, cocaine and opiates scores of 2.1 (P = 0.02), 2.4 (P = 0.0004), 2.0 (P = 0.03) and 1.9 (P = 0.07). We conclude that the TT genotype of OPRM1 may increase the risk of substance use and abuse.

Associations of cardiovascular variables and HAART with cognition in middle-aged HIV-infected and uninfected women.

Despite the use of highly active anti-retroviral treatment (HAART), cognitive impairment remains prevalent in HIV. Indeed a recent study suggested that in certain instances, stopping HAART was associated with improved cognitive function (Robertson et al. Neurology 74(16):1260-1266 2010). HAART is occasionally associated with cardiovascular pathology and such pathology may be associated with cognitive impairment. To explore these associations, we assessed the relative contributions of cardiovascular variables such as hypertension and atherosclerosis, of HIV and HAART to cognition. The participants were members of the Women's Interagency HIV Study. In the analysis of cross-sectional data using general linear models, we assessed the relationship between each cardiovascular variable and Stroop interference time and symbol digit modalities test while adjusting for age, HIV, education, depression, and race/ethnicity. We also analyzed the association of summary measures of HAART use with cognition. In multivariate models, significance was limited to carotid lesions and carotid intima-medial thickness quintile (CIMT) with Stroop interference time (for carotid lesions, coefficient = 10.5, CI 3.5 to 17.5, p = 0.003, N = 1,130; for CIMT quintile, coefficient = 8.6, CI = 1.7 to 15.4, p = 0.025, N = 1,130). The summary measures of protease inhibitor use and other HAART measures were in most cases not associated with cognitive score in multivariate models. We conclude that in the HAART era among middle-aged women with HIV, carotid disease may be significantly associated with some measures of cognitive impairment. In this cross-sectional study, we could detect neither positive nor negative effects of HAART on cognition.

Relationship of ethnicity, age, education, and reading level to speed and executive function among HIV+ and HIV- women: the Women's Interagency HIV Study (WIHS) Neurocognitive Substudy.

Use of neuropsychological tests to identify HIV-associated neurocognitive dysfunction must involve normative standards that are well suited to the population of interest. Norms should be based on a population of HIV-uninfected individuals as closely matched to the HIV-infected group as possible and must include examination of the potential effects of demographic factors on test performance. This is the first study to determine the normal range of scores on measures of psychomotor speed and executive function among a large group of ethnically and educationally diverse HIV-uninfected, high-risk women, as well as their HIV-infected counterparts. Participants (n = 1,653) were administered the Trail Making Test Parts A and B (Trails A and Trails B), the Symbol Digit Modalities Test (SDMT), and the Wide Range Achievement Test-3 (WRAT-3). Among HIV-uninfected women, race/ethnicity accounted for almost 5% of the variance in cognitive test performance. The proportions ofvariance in cognitive test performance accounted for by age (13.8%), years of school (4.1%), and WRAT-3 score (11.5%) were each significant, but did not completely account for the effect of race (3%). HIV-infected women obtained lower scores than HIV-uninfected women on time to complete Trails A and B, SDMT total correct, and SDMT incidental recall score, but after adjustment for age, years of education, racial/ethnic classification, and reading level, only the difference on SDMT total correct remained significant. Results highlight the need to adjust for demographic variables when diagnosing cognitive impairment in HIV-infected women. Advantages of demographically adjusted regression equations developed using data from HIV-uninfected women are discussed.

Computerized cognitive assessment of mild cognitive impairment in urban African Americans.

Few objective cognitive assessment tools have been validated for mild cognitive impairment (MCI) in African Americans despite higher prevalence of disease. This preliminary study evaluated discriminant validity of a computerized cognitive assessment battery for MCI in an urban African American cohort. Twenty-seven participants with MCI and 22 cognitively healthy individuals completed a multidomain battery (Mindstreams, NeuroTrax Corp, New Jersey). Mild cognitive impairment participants performed more poorly than cognitively healthy participants in all domains, with significant differences in memory (P = .003; d = 0.96), executive function (P = .046; d = 0.64), and overall battery performance (P = .041; d = 0.63). Adjustment for intelligence quotient (IQ) yielded significant differences in memory (P < .001; d = 1.34), executive function (P = .007; d = 0.86), attention (P = .014; d = .80), and overall performance (P = .001; d = 1.09). Such a validated battery may help to address an important clinical need in this population.

Screening for dementia by telephone using the memory impairment screen.

OBJECTIVES: : To develop and assess telephone-based screening tests for dementia, especially Alzheimer's disease (AD). DESIGN: : A cross-sectional validation study nested within a longitudinal study of aging and dementia. SETTING: : The Einstein Aging Study of the Albert Einstein College of Medicine, Bronx, New York. PARTICIPANTS: : Three hundred elderly community volunteers living in Bronx County, 27 of whom were diagnosed with dementia based on in-person clinical evaluation. Of the 27 individuals with dementia, 18 had AD. MEASUREMENTS: : A telephone battery was administered that included the Memory Impairment Screen by telephone (MIS-T, a test of semantic memory), the Category Fluency Test (CF-T), and the Telephone Instrument for Cognitive Status (TICS). An in-person evaluation then followed that included a neurological examination, a neuropsychological battery, demographics, and medical history. RESULTS: : The telephone battery was well accepted. The MIS-T required 4 minutes; the CF-T, 3 minutes; and the TICS, 10 minutes. The MIS-T had excellent sensitivity and specificity when compared with the CF-T and the TICS. Using cutscores on all three tests that provide a sensitivity of 78%, specificity was significantly higher for the MIS-T (93%) than for the CF-T (78%, P<.05) or the TICS (80%, P<.05). Combining the MIS-T and CF-T improved discriminative validity but increased screening time and the complexity of scoring. Normative data for the MIS-T, the CF-T, and the TICS for use in settings with different base rates (prevalence) of dementia are presented in this study. CONCLUSION: : The MIS-T outperforms the CF-T and the TICS as a valid and time-efficient telephone screen for dementia. For applications that require optimal efficiency and accuracy, the MIS-T is recommended.