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1.  The paradox of overnutrition in aging and cognition 
Populations of many countries are becoming increasingly overweight and obese, driven largely by excessive calorie intake and reduced physical activity; greater body mass is accompanied by epidemic levels of comorbid metabolic diseases. At the same time individuals are living longer. The combination of aging and increased prevalence of metabolic disease is associated with increases in aging-related comorbid diseases such as Alzheimer’s disease, cerebrovascular dementia, and sarcopenia. Here, correlative and causal links between diseases of overnutrition and diseases of aging and cognition are explored.
doi:10.1111/nyas.12138
PMCID: PMC5166614  PMID: 23682739
overnutrition; obesity; cognitive decline; Alzheimer’s disease; sarcopenia
2.  Gender-related risk factors improve mortality predictive ability of VACS Index among HIV-infected women 
Background
Adding gender-related modifiable characteristics or behaviors to the Veterans Aging Cohort Study (VACS) Index might improve the accuracy of predicting mortality among HIV-infected women on treatment. We evaluated the VACS Index in women with HIV, determined whether additional variables would improve mortality prediction, and quantified the potential for improved survival associated with reduction in these additional risk factors.
Methods
The VACS Index (based on age, CD4 count, HIV-1 RNA, hemoglobin, AST, ALT, platelets, creatinine and Hepatitis C status) was validated in HIV-infected women in the Women’s Interagency HIV Study (WIHS) who initiated antiretroviral therapy (ART) between January 1996 and December 2007. Models were constructed adding race, depression, abuse, smoking, substance use, transactional sex, and comorbidities to determine whether predictability improved. Population attributable fractions were calculated.
Results
The VACS Index accurately predicted 5-year mortality in 1057 WIHS women with 1 year on HAART with c-index 0.83 (95% CI 0.79–0.87). In multivariate analysis, the VACS Index score (adjusted hazard ratio [aHR] for 5-point increment 1.30; 95% CI 1.25–1.35), depressive symptoms (aHR 1.73; 95% CI 1.17–2.56) and history of transactional sex (aHR 1.93; 95% CI 1.33–1.82) were independent statistically significant predictors of mortality.
Conclusions
Including depression and transactional sex significantly improved the performance of the VACS Index in predicting mortality among HIV-infected women. Providing treatment for depression and addressing economic and psychosocial instability in HIV infected women would improve health and perhaps point to a broader public health approach to reducing HIV mortality.
doi:10.1097/QAI.0000000000000795
PMCID: PMC4644433  PMID: 26284531
HIV; Women; Mortality; Depression; Transactional Sex
3.  Longitudinal associations between physical activity and depression scores in Swedish women followed 32 years 
Acta psychiatrica Scandinavica  2015;132(6):451-458.
Objective
Physical activity is negatively associated with depressive symptoms. However, few studies consider dynamic associations of changes in physical activity and reciprocal relationships. This study aimed to perform comprehensive evaluations of relationships between physical activity and depression scores in women followed from mid- to late-life.
Method
The Prospective Population Study of Women in Gothenburg, Sweden provided repeated measures of self-reported physical activity and depressive symptoms between 1974–2005 (baseline N=676, 84.5 % response rate). Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale and physical activity was evaluated by the Saltin-Grimby Physical Activity Level Scale. Latent growth curve analyses were used to evaluate associations of change and cross-lagged models were used to study the reciprocal relationship between physical activity and depression scores.
Results
At baseline, lower levels of physical activity were related to higher depression scores. Individuals with decreasing physical activity over time evidenced higher depression scores at 32 year follow-up. Higher average baseline depression score was related to declining levels of physical activity at subsequent examinations.
Conclusion
Reduced physical activity may be a long-term consequence of depression. It is important to address individual changes in physical activity and not merely absolute levels of physical activity in relationship to depression.
doi:10.1111/acps.12419
PMCID: PMC4600636  PMID: 25865488
Physical activity; depression scores; change; women
4.  Cognition, Depressive Symptoms and Vascular Factors among Southwest Tribal Elders 
Ethnicity & Disease  null;26(2):235-244.
Objective
Few data exist on cognitive and depressive symptoms and vascular factors in American Indian (AI) elders. Since vascular risk factors increase risk for cognitive impairments, depression and dementia, and since AI elders are at high vascular risk, it is timely to assess the interplay of these factors in comprehensive studies of aging in this population. To begin, pilot studies must be conducted to show these types of data can be collected successfully.
Design
A cross-sectional pilot study, the Southwest Heart Mind Study (SHMS).
Setting
Tribal community in the Southwest United States.
Participants
AI elders, aged ≥55 years.
Main Outcome Measures
Cross-cultural demographic, social network and risk factor surveys; tests of cognition, depression and anxiety; physical measurements; blood biochemistries; and APOE genotyping.
Results
SHMS elders were comparable to other rural elder populations on cognitive and depressive symptom scores. The average CogScore was 28.8 (out of 32), the average Geriatric Depression Scale (GDS) was 6.7 (of 30), and the average Hamilton Anxiety Scale was 1.2 (of 4). 32% possessed at least one APOEe4 allele. High vascular risk was evident: 76% were overweight or obese; 54% self-reported history of hypertension; 24% heart trouble; 32% type 2 diabetes; 35% depression; and 24% a family history of serious memory loss. More than 70% reported prescription medication use. 54% cared for someone besides self.
Conclusions
A better understanding of the burden of vascular risk in relation to cognition and depression among Southwest Tribes is needed.
doi:10.18865/ed.26.2.235
PMCID: PMC4836905  PMID: 27103775
Cognition; Vascular; Depression; American Indian
5.  Predicting episodic memory performance using different biomarkers: results from Argentina-Alzheimer’s Disease Neuroimaging Initiative 
Purpose
Argentina-Alzheimer’s Disease Neuroimaging Initiative (Arg-ADNI) is the first ADNI study to be performed in Latin America at a medical center with the appropriate infrastructure. Our objective was to describe baseline characteristics and to examine whether biomarkers related to Alzheimer’s disease (AD) physiopathology were associated with worse memory performance.
Patients and methods
Fifteen controls and 28 mild cognitive impairment and 13 AD dementia subjects were included. For Arg-ADNI, all biomarker parameters and neuropsychological tests of ADNI-II were adopted. Results of positron emission tomography (PET) with fluorodeoxyglucose and 11C-Pittsburgh compound-B (PIB-PET) were available from all participants. Cerebrospinal fluid biomarker results were available from 39 subjects.
Results
A total of 56 participants were included and underwent baseline evaluation. The three groups were similar with respect to years of education and sex, and they differed in age (F=5.10, P=0.01). Mean scores for the baseline measurements of the neuropsychological evaluation differed significantly among the three groups at P<0.001, showing a continuum in their neuropsychological performance. No significant correlations were found between the principal measures (long-delay recall, C-Pittsburgh compound-B scan, left hippocampal volume, and APOEε4) and either age, sex, or education (P>0.1). Baseline amyloid deposition and left hippocampal volume separated the three diagnostic groups and correlated with the memory performance (P<0.001).
Conclusion
Cross-sectional analysis of baseline data revealed links between cognition, structural changes, and biomarkers. Follow-up of a larger and more representative cohort, particularly analyzing cerebrospinal fluid and brain biomarkers, will allow better characterization of AD in our country.
doi:10.2147/NDT.S107051
PMCID: PMC5028172  PMID: 27695331
aging; Alzheimer’s disease; amyloid imaging; biomarkers; mild cognitive impairment
6.  Increased fracture incidence in middle-aged HIV-infected and uninfected women: updated results from the Women’s Interagency HIV Study 
Background
We previously reported that fracture incidence rates did not differ by HIV status among predominantly premenopausal Women's Interagency HIV Study (WIHS) participants. We now conduct a follow-up study with 5 additional observation years, to further characterize fracture risk associated with HIV infection in women as they age.
Methods
We measured time to first new fracture at any site in 2375 (1713 HIV-infected, 662 HIV-uninfected) WIHS participants, with median 10 years follow-up. Fractures were self-reported semiannually. Proportional Hazards models assessed predictors of incident fracture.
Results
At index visit, HIV-infected women were older (median age 40 yrs (IQR 34–46) vs. 35 (27–43), p<0.0001) and more likely to be postmenopausal, HCV-infected, and weigh less than HIV-uninfected women. Among HIV-infected women, mean CD4+ count was 480 cells/µL and 63% were taking HAART. Unadjusted incidence rates of any fracture were higher in HIV-infected than uninfected women (2.19/100 person-years (py) vs 1.54/100py, p=0.002). In multivariate models, HIV status, older age, white (vs. black) race, prior fracture, history of cocaine use, and history of injection drug use were significant predictors of incident fracture. Among HIV-infected women, age, white race, prior fracture, smoking, and prior AIDS were predictors of new fracture.
Conclusion
Middle-aged HIV-infected women had a higher adjusted fracture rate than uninfected women. Cocaine use and injection drug use were also associated with a greater risk of incident fracture. Further research is needed to understand whether the risk of fracture associated with cocaine use relates to increased rate of falls, or direct effects on bone metabolism.
doi:10.1097/QAI.0000000000000674
PMCID: PMC4557627  PMID: 26322667
HIV; women; bone; fracture; fragility fracture
7.  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.
doi:10.4172/2167-7182.1000240
PMCID: PMC4984413  PMID: 27536467
Cognition; Adipokine; Leptin; Adiponectin; HIV; Women; Overweight; Obesity
8.  Serum Adiponectin Levels, Neuroimaging, and Cognition in the Mayo Clinic Study of Aging 
BACKGROUND
Adiponectin, a protein involved in inflammatory pathways, may impact the development and progression of Alzheimer’s disease (AD). Adiponectin levels have been associated with mild cognitive impairment (MCI) and AD; however, its association with Alzheimer-associated neuroimaging and cognitive outcomes is unknown.
OBJECTIVE
Determine the cross-sectional association between plasma adiponectin and neuroimaging and cognitive outcomes in an older population-based sample.
METHODS
Multivariable adjusted regression models were used to investigate the association between plasma adiponectin and hippocampal volume (HVa), PiB-PET, FDG PET, cortical thickness, MCI diagnosis, and neuropsychological test performance. Analyses included 535 non-demented participants aged 70 and older enrolled in the Mayo Clinic Study of Aging.
RESULTS
Women had higher adiponectin than men (12,631 ng/mL vs. 8,908 ng/mL, P < .001). Among women, higher adiponectin was associated with smaller HVa (B=−0.595; 95% CI −1.19, −0.005), poorer performance in language (B−0.676; 95% CI −1.23, −0.121) and global cognition (B=−0.459; 95% CI −0.915, −0.002), and greater odds of a MCI diagnosis (OR=6.23; 95% CI 1.20, 32.43). In analyses stratified by sex and elevated amyloid (PiB-PET SUVR>1.4), among women with elevated amyloid, higher adiponectin was associated with smaller HVa (B=−0.723; 95% CI −1.43, −0.014), poorer performance in memory (B=−1.02; 95% CI −1.73, −0.312), language (B=−0.896; 95% CI −1.58, −0.212), and global (B=−0.650; 95% CI −1.18, −0.116) cognition, and greater odds of MCI (OR=19.34; 95% CI 2.72, 137.34).
CONCLUSION
Higher plasma adiponectin was associated with neuroimaging and cognitive outcomes among women. Longitudinal analyses are necessary to determine whether higher adiponectin predicts neurodegeneration and cognitive decline.
doi:10.3233/JAD-151201
PMCID: PMC4955718  PMID: 27163809
9.  Association of the Fractal Dimension of Retinal Arteries and Veins with Quantitative Brain MRI Measures in HIV-Infected and Uninfected Women 
PLoS ONE  2016;11(5):e0154858.
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 β = -0.41, p = 0.009) and total gray matter volume (β = -0.24, p = 0.03), and arterial dimension with mean diffusivity (β = -0.33,.p = 0.04) and fractional anisotropy (β = 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.
doi:10.1371/journal.pone.0154858
PMCID: PMC4861324  PMID: 27158911
10.  Post-traumatic stress is associated with verbal learning, memory, and psychomotor speed in HIV-infected and HIV-uninfected women 
Journal of neurovirology  2015;22(2):159-169.
The prevalence of post-traumatic stress disorder (PTSD) is higher among HIV-infected (HIV+) women compared with HIV-uninfected (HIV−) women, and deficits in episodic memory are a common feature of both PTSD and HIV infection. We investigated the association between a probable PTSD diagnosis using the PTSD Checklist-Civilian (PCL-C) version and verbal learning and memory using the Hopkins Verbal Learning Test in 1004 HIV+ and 496 at-risk HIV− women. HIV infection was not associated with a probable PTSD diagnosis (17 % HIV+, 16 % HIV−; p=0.49) but was associated with lower verbal learning (p<0.01) and memory scores (p<0.01). Irrespective of HIV status, a probable PTSD diagnosis was associated with poorer performance in verbal learning (p<0.01) and memory (p<0.01) and psychomotor speed (p<0.001). The particular pattern of cognitive correlates of probable PTSD varied depending on exposure to sexual abuse and/or violence, with exposure to either being associated with a greater number of cognitive domains and a worse cognitive profile. A statistical interaction between HIV serostatus and PTSD was observed on the fine motor skills domain (p= 0.03). Among women with probable PTSD, HIV− women performed worse than HIV+ women on fine motor skills (p=0.01), but among women without probable PTSD, there was no significant difference in performance between the groups (p= 0.59). These findings underscore the importance of considering mental health factors as correlates to cognitive deficits in women with HIV.
doi:10.1007/s13365-015-0380-9
PMCID: PMC4783199  PMID: 26404435
HIV; Post-traumatic stress disorder; Women; Cognition
11.  First translational ‘Think Tank’ on cerebrovascular disease, cognitive impairment and dementia 
Abstract and introduction to the workshop
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”.
doi:10.1186/s12967-016-0806-z
PMCID: PMC4752794  PMID: 26873444
12.  Relationship between Body Mass Index and Mortality in HIV-Infected HAART Users in the Women's Interagency HIV Study 
PLoS ONE  2015;10(12):e0143740.
Background
Early HIV studies suggested protective associations of overweight against mortality, yet data are lacking for the era of potent highly active antiretroviral therapy (HAART). We evaluated associations of pre-HAART initiation body mass index (BMI) with mortality among HAART-using women.
Methods
Prospective study of time to death after HAART initiation among continuous HAART users in the Women’s Interagency HIV Study. Unadjusted Kaplan–Meier and adjusted proportional hazards survival models assessed time to AIDS and non-AIDS death by last measured pre-HAART BMI.
Results
Of 1428 continuous HAART users 39 (2.7%) were underweight, 521 (36.5%) normal weight, 441 (30.9%) overweight, and 427 (29.9%) obese at time of HAART initiation. A total of 322 deaths occurred during median follow-up of 10.4 years (IQR 5.9–14.6). Censoring at non-AIDS death, the highest rate of AIDS death was observed among underweight women (p = 0.0003 for all 4 categories). In multivariate models, women underweight prior to HAART died from AIDS more than twice as rapidly vs. normal weight women (aHR 2.04, 95% CI 1.03, 4.04); but being overweight or obese (vs. normal weight) was not independently associated with AIDS death. Cumulative incidence of non-AIDS death was similar across all pre-HAART BMI categories.
Conclusions
Among continuous HAART-using women, being overweight prior to initiation was not associated with lower risk of AIDS or non-AIDS death. Being underweight prior to HAART was associated with over double the rate of AIDS death in adjusted analyses. Although overweight and obesity may be associated with many adverse health conditions, neither was predictive of mortality among the HAART-using women.
doi:10.1371/journal.pone.0143740
PMCID: PMC4689347  PMID: 26699870
13.  Obesity and dementia 
Obesity is a pandemic and a serious global health concern. Obesity is a risk factor for multiple conditions and contributes to multi-morbidities, resulting in increased health costs and millions of deaths each year. Obesity has been associated with changes in brain structure, cognitive deficits, and dementia and Alzheimer's disease. Adipokines, defined as hormones, cytokines and peptides secreted by adipose tissue, may have more widespread influence and functionality in the brain than previously thought. In this review, six adipokines, and their actions in the obese and non-obese condition will be discussed. Included are: plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factors alpha (TNF-α), angiotensinogen (AGT), adiponectin and leptin. Their functionality in the periphery, their ability to cross the blood brain barrier (BBB) and their influence on dementia processes within the brain will be discussed.
doi:10.1016/j.euroneuro.2014.03.002
PMCID: PMC4169761  PMID: 24704273
Obesity; adipokines; brain; leptin; Alzheimer; dementia
14.  The association of perceived stress and verbal memory is greater in HIV-infected versus HIV-uninfected women 
Journal of neurovirology  2015;21(4):422-432.
In contrast to findings from cohorts comprised primarily of HIV-infected men, verbal memory deficits are the largest cognitive deficit found in HIV-infected women from the Women’s Interagency HIV Study (WIHS), and this deficit is not explained by depressive symptoms or substance abuse. HIV-infected women may be at greater risk for verbal memory deficits due to a higher prevalence of cognitive risk factors such as high psychosocial stress and lower socioeconomic status. Here, we investigate the association between perceived stress using the Perceived Stress Scale (PSS-10) and verbal memory performance using the Hopkins Verbal Learning Test (HVLT) in 1009 HIV-infected and 496 at-risk HIV-uninfected WIHS participants. Participants completed a comprehensive neuropsychological test battery which yielded seven cognitive domain scores, including a primary outcome of verbal memory. HIV infection was not associated with a higher prevalence of high perceived stress (i.e., PSS-10 score in the top tertile) but was associated with worse performance on verbal learning (p<0.01) and memory (p<0.001), as well as attention (p=0.02). Regardless of HIV status, high stress was associated with poorer performance in those cognitive domains (p’s< 0.05) as well as processing speed (p=0.01) and executive function (p<0.01). A significant HIV by stress interaction was found only for the verbal memory domain (p=0.02); among HIV-infected women only, high stress was associated with lower performance (p’s<0.001). That association was driven by the delayed verbal memory measure in particular. These findings suggest that high levels of perceived stress contribute to the deficits in verbal memory observed in WIHS women.
doi:10.1007/s13365-015-0331-5
PMCID: PMC4562210  PMID: 25791344
HIV; Verbal memory; Stress; Women; Cognition
15.  Adipokines: a link between obesity and dementia? 
The Lancet. Neurology  2014;13(9):913-923.
Being overweight or obese, as measured with body mass index (BMI) or central adiposity (waist circumference), and evolving trajectory of BMI over the life course, have been associated with brain atrophy, white matter changes, blood brain barrier integrity and risk of all-cause late-onset dementia and Alzheimer’s Disease (AD). This observation leads us to question what it is about BMI that is associated with health of the brain and dementia risk. If high BMI and central adiposity represent an increase in adipose tissue, then the endocrine aspect of adipose tissue, mediated by adipose tissue hormones and adipokines, may be a clue to understanding the association with dementia and AD. Hundreds of adipokines have been identified, creating a complexity that is challenging to simplify. Nonetheless, adipokines are being investigated in association with clinical dementia outcomes, as well as imaging-based measures of brain volume, structure and function in preclinical and human models of clinical dementia.
doi:10.1016/S1474-4422(14)70085-7
PMCID: PMC4228955  PMID: 25142458
16.  Antiretroviral Therapy Modifies the Genetic Effect of Known Type 2 Diabetes-Associated Risk Variants in the Women’s Interagency HIV Study 
AIDS (London, England)  2014;28(12):1815-1823.
Objective
Type 2 diabetes (DM) incidence is increased in HIV-infected persons. We examined the associations of DM with known DM-risk alleles from the general population in the context of HIV infection and explored effect modification by combination antiretroviral treatment (cART).
Methods
The Women’s Interagency HIV Study (WIHS) is a prospective cohort of HIV-infected women. Seventeen European-derived DM-risk polymorphisms were genotyped in eligible WIHS participants. Analyses were run separately for non-African-Americans (Whites, Hispanics, Asians, and other; n=378, 49 with incident DM) and African-Americans (n=591, 49 with incident DM). Cox proportional hazards models were fit to estimate hazard ratios (HRs) for DM overall and within strata of cART.
Results
In non-African-Americans, heterogeneity across cART regimen was observed for 9 of 14 polymorphisms (phet<0.05). One polymorphism was statistically significantly inversely associated with DM risk among women taking 2 NRTIs+NNRTI. Five polymorphisms were statistically significantly associated with DM among women treated with ≥2 NRTIs + ≥1 PI and one polymorphism was associated with DM among those treated with ≥3 NRTIs ± NNRTI. The HR per risk allele for IGF2BP2 rs1470579 was 2.67 (95% CI 1.67–4.31) for women taking cART with ≥2 NRTIs+≥1 PI and 2.45 (95% CI 1.08–5.53) in women taking ≥3 NRTIs±NNRTI (phet=2.50×10−3). No such associations were observed in African-Americans.
Conclusions
Genetic susceptibility to DM, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/PI components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these DM-risk variants.
doi:10.1097/QAD.0000000000000366
PMCID: PMC4269472  PMID: 24932614
type 2 diabetes; genetics; HIV; women; antiretroviral therapy
17.  Changes in Body Mass Index Following HAART Initiation among HIV-Infected Women in the Women's Interagency HIV Study 
Objective
Examine changes in, and factors associated with changing body mass index (BMI) in women following highly active antiretroviral therapy (HAART) initiation.
Methods
1177 HIV-infected Women's Interagency HIV Study participants who contributed 10,754 years of follow-up following HAART initiation were studied. Changes in median BMI up to 15 years following HAART initiation, and the highest and lowest BMI reached following HAART initiation were summarized by pre-HAART BMI category (<18.5 [underweight], 18.5–<25.0 [normal weight], 25.0–<30.0 [overweight], 30.0–<40.0 [obese], and ≥ 40.0 [morbidly obese]). Multivariate mixed effects ordinal logistic regression estimated the degree of association of each exposure of interest with post-HAART BMI.
Results
Before HAART, 39% percent of women had normal BMI, 31% were overweight, 23% were obese, and 5% were morbidly obese. Following HAART initiation, median BMI change (per 5 years) was 0.21 kg/m2 (90% confidence interval [CI]: −1.33, 0.42) for those with normal pre-HAART BMI, 0.39 kg/m2 (90% CI: 0.15,0.66) for overweight, 0.31 kg/m2 (90% CI: −1.18,0.67) for obese, and −0.36kg/m2 for morbidly obese women. After initiating HAART, 40% with normal pre-HAART BMI became overweight at some point; of those overweight, 46% remained overweight and 47% became obese; 71% of obese women remained obese and 27% became morbidly obese. Each year of nucleoside analog reverse transcriptase inhibitor use was associated with a 3% decreased odds of reaching a higher BMI category (OR 0.97, 95% CI: 0.95, 0.99), while each year of protease inhibitor or non-nucleoside analog reverse transcriptase inhibitor use were associated with a 6% (OR 1.06, 95% CI: 1.04, 1.08) and 5%(OR 1.05, 95% CI: 1.01, 1.08) increased odds of having a higher BMI category, respectively.
Conclusions
Although overweight and obesity are highly prevalent in this large cohort of HIV-infected, minority women, HAART use was associated with only a modest increase in BMI over time.
doi:10.4172/2155-6113.1000323
PMCID: PMC4285631  PMID: 25580365
Obesity; Body mass index; HIV; Women; HAART; Women's interagency HIV study
18.  Body Mass Index, Weight Change, and Clinical Progression in Mild Cognitive Impairment and Alzheimer’s Disease 
The speed and severity of clinical progression after Alzheimer’s Disease (AD) diagnosis varies and depends on multiple factors, most not well elucidated. We assessed whether body mass index (BMI) and one-year weight change (WC) are associated with clinical progression in amnestic mild cognitive impairment (aMCI) and early-stage AD. Longitudinal data comprising 2,268 aMCI and 1,506 AD participants in the National Alzheimer’s Coordinating Center’s Uniform Data Set were used to examine nuances of clinical progression by BMI and WC, as well as potential variations in associations by age, sex, BMI (WC model), or apolipoprotein E (APOE) genotype. In aMCI, high BMI (versus moderate BMI) was associated with slower progression; weight loss (versus no WC) was associated with faster progression. In AD, no significant differences were observed in clinical progression by BMI or WC. The association between BMI and clinical progression varied significantly by APOE genotype in AD, and the association between WC and clinical progression varied significantly by sex and BMI in aMCI. Baseline BMI and one-year WC in late-life may serve as early prognostic indicators in aMCI and early-stage AD. If replicated, these results may help in counseling patients on anticipated clinical progression and suggest windows of opportunity for intervention.
doi:10.1097/WAD.0000000000000005
PMCID: PMC3945175  PMID: 24126214
Body Mass Index; Body Weight Changes; Weight Loss; Alzheimer Disease; Mild Cognitive Impairment; Disease Progression
19.  Anthropometric measures and cognition in middle-aged HIV-infected and uninfected women. The Women's Interagency HIV Study 
Journal of neurovirology  2013;19(6):574-585.
Objective
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.
Design/Methods
1690 participants (1196 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.
Results
Among HIV+ women, BMI < 18.5 kg/m2 was associated with poorer cognitive performance evidenced by longer Trails A and Trails B and shorter SDMT completion times. An obese BMI (30 kg/m2 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.
Conclusion
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.
doi:10.1007/s13365-013-0219-1
PMCID: PMC3957488  PMID: 24338243
Cognition; HIV; Women; Overweight; Obesity; Middle-Aged
20.  Serum biomarkers of immune activation and subsequent risk of non-Hodgkin B cell lymphoma among HIV-infected women 
Background
There is increasing evidence that chronic immune activation predisposes to non-Hodgkin’s lymphoma (NHL). Whether this association exists among women representative of the current HIV epidemic in the U.S. who are at high risk of HIV-associated NHL (AIDS-NHL), remains to be determined.
Methods
We conducted a nested case-control study within the Women’s Interagency HIV Study with longitudinally collected risk factor data and sera. Cases were HIV-infected women with stored sera collected at three time-windows 3–5 years, 1–3 years, and 0–1 year prior to AIDS-NHL diagnosis (n=22). Three to six HIV-infected controls, without AIDS-NHL, were matched to each case on age, race, CD4+ T cell count, and study follow-up time (n=78). Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between one unit increase in log-transformed biomarker levels and AIDS-NHL were computed using random effect multivariate logistic regression models.
Results
Elevated levels of sCD27 (OR=7.21, 95% CI=2.62–19.88), sCD30 (OR=2.64, 95% CI=1.24–5.64), and CXCL13 (OR=2.56, 95% CI=1.32–4.96) were associated with subsequent diagnosis of AIDS-NHL overall. Elevated sCD23 was associated with a 2-to 4-fold increased risk of AIDS-NHL in certain subgroups, while elevated IL6 was associated with a 2-fold increased risk in the 0–1 year time-window, only.
Conclusion
These findings support the hypothesis that chronic B cell activation contributes to the development of AIDS-NHL in women.
Impact
sCD23, sCD27, sCD30, and CXCL13 may serve as biomarkers for AIDS-NHL.
doi:10.1158/1055-9965.EPI-13-0614
PMCID: PMC3833437  PMID: 24045923
lymphoma; B cell; cytokines; AIDS; immune activation
21.  Host APOL1 genotype is independently associated with proteinuria in HIV infection 
Kidney international  2013;84(4):834-840.
Proteinuria is associated with adverse clinical outcomes in HIV infection. Here we evaluated whether APOL1 risk alleles, previously associated with advanced kidney disease, is independently associated with proteinuria in HIV infection in a cross-sectional study of HIV-infected women in the Women’s Interagency HIV Study. We estimated the percent difference in urine protein excretion and odds of proteinuria (200 mg/g and higher) associated with two versus one or no APOL1 risk allele using linear and logistic regression, respectively. Of 1285 women successfully genotyped, 379 carried one and 80 carried two risk alleles. Proteinuria was present in 124 women; 78 of whom had proteinuria confirmed on a second sample. In women without prior AIDS, two risk alleles were independently associated with a 69% higher urine protein excretion (95% CI: 36%, 108%) and 5-fold higher odds of proteinuria (95% CI: 2.45, 10.37) versus one or no risk allele. No association was found in women with prior AIDS. Analyses in which women with impaired kidney function were excluded and proteinuria was confirmed by a second urine sample yielded similar estimates. Thus, APOL1 risk alleles are associated with significant proteinuria in HIV-infected persons without prior clinical AIDS, independent of clinical factors traditionally associated with proteinuria. Trials are needed to determine whether APOL1 genotyping identifies individuals who could benefit from earlier intervention to prevent overt renal disease.
doi:10.1038/ki.2013.203
PMCID: PMC3788838  PMID: 23715117
22.  Sex differences in stroke 
Sex differences in stroke are observed across epidemiologic studies, pathophysiology, treatments, and outcomes. These sex differences have profound implications for effective prevention and treatment and are the focus of this review. Epidemiologic studies reveal a clear age-by-sex interaction in stroke prevalence, incidence, and mortality. While premenopausal women experience fewer strokes than men of comparable age, stroke rates increase among postmenopausal women compared with age-matched men. This postmenopausal phenomenon, in combination with living longer, are reasons for women being older at stroke onset and suffering more severe strokes. Thus, a primary focus of stroke prevention has been based on sex steroid hormone-dependent mechanisms. Sex hormones affect different (patho)physiologic functions of the cerebral circulation. Clarifying the impact of sex hormones on cerebral vasculature using suitable animal models is essential to elucidate male–female differences in stroke pathophysiology and development of sex-specific treatments. Much remains to be learned about sex differences in stroke as anatomic and genetic factors may also contribute, revealing its multifactorial nature. In addition, the aftermath of stroke appears to be more adverse in women than in men, again based on older age at stroke onset, longer prehospital delays, and potentially, differences in treatment.
doi:10.1038/jcbfm.2012.141
PMCID: PMC3519418  PMID: 23032484
epidemiology; gender; pathophysiology; risk factors; steroids; stroke
23.  High adiposity: risk factor for dementia and Alzheimer’s disease? 
Higher levels of total and central adiposity, measured as higher body mass index (BMI) (in kilograms per square meter), waist circumference, or waist-to-hip ratio, have been associated with late-onset Alzheimer’s disease (AD). However, some epidemiologic studies do not support this association, and potential underlying biological mechanisms that provide biological plausibility are not clear in terms of providing direct links to adipose tissue. Studies linking adiposity to AD have considered adiposity measures from mid-life and late-life. Given an evolving background trajectory of BMI that exists over the life course and the influence of dementia processes on BMI, results have been conflicting depending on when BMI is measured in relationship to clinical AD onset. This has made interpretation of the BMI-AD literature difficult. This debate will briefly review the epidemiologic evidence for and against an association between higher adiposity and AD, issues of timing of the adiposity measure in relation to AD onset, potential biological mechanisms for observed associations, and explanations for conflicting evidence.
doi:10.1186/alzrt221
PMCID: PMC4056613  PMID: 24932225
24.  Acupuncture and physical exercise for affective symptoms and health-related quality of life in polycystic ovary syndrome: secondary analysis from a randomized controlled trial 
Background
Women with polycystic ovary syndrome (PCOS) have symptoms of depression and anxiety and impaired health related quality of life (HRQoL). Here we test the post-hoc hypothesis that acupuncture and exercise improve depression and anxiety symptoms and HRQoL in PCOS women.
Methods
Seventy-two PCOS women were randomly assigned to 16 weeks of 1) acupuncture (n = 28); 2) exercise (n = 29); or 3) no intervention (control) (n = 15). Outcome measures included: change in Montgomery Åsberg Depression Rating Scale (MADRS-S), Brief Scale for Anxiety (BSA-S), Swedish Short-Form 36 (SF-36), and PCOS Questionnaire (PCOSQ) scores from baseline to after 16-week intervention, and to 16-week post-intervention follow-up.
Results
A reduction in MADRS-S and BSA-S from baseline to 16-weeks post-intervention follow-up was observed for the acupuncture group. The SF-36 domains role physical, energy/vitality, general health perception and the mental component of summary scores improved in the acupuncture group after intervention and at follow-up. Within the exercise group the role physical decreased after treatment, while physical functioning and general health perception scores increased at follow-up. The emotion domain in the PCOSQ improved after 16-weeks of intervention within all three groups, and at follow-up in acupuncture and exercise groups. At follow-up, improvement in the infertility domain was observed within the exercise group.
Conclusion
There was a modest improvement in depression and anxiety scores in women treated with acupuncture, and improved HRQoL scores were noted in both intervention groups. While not a primary focus of the trial, these data suggest continued investigation of mental health outcomes in women treated for PCOS.
Trial registration number
ClinicalTrials.gov Identifier: NCT00484705
doi:10.1186/1472-6882-13-131
PMCID: PMC3684530  PMID: 23763822
Acupuncture; Anxiety; Depression; Exercise; Health-related quality of life; Polycystic ovary syndrome
25.  THE GENETIC ARCHITECTURE OF ALZHEIMER’S DISEASE: BEYOND APP, PSENs AND APOE 
Neurobiology of Aging  2010;33(3):437-456.
Alzheimer’s disease (AD) is a complex disorder with a clear genetic component. Three genes have been identified as the cause of early onset familial AD (EOAD). The most common form of the disease is, however, a sporadic one presenting itself in later stages of life (LOAD). The genetic component of this late onset form of AD has been the target of a large number of studies, since only one genetic risk factor (APOE4) has been consistently associated with the disease. However, technological advances allow new approaches in the study of complex disorders. In this review, we discuss the new results produced by genome wide association studies, in light of the current knowledge of the complexity of AD genetics.
doi:10.1016/j.neurobiolaging.2010.03.025
PMCID: PMC2980860  PMID: 20594621

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