Social support moderates D-dimer and self-rated successful aging within people with HIV and older adults.

Many factors can influence perceptions of successful aging (SA), including social isolation and poor physical health. We hypothesized that social support attenuates the negative effect of plasma D-dimer, a correlate of HIV and aging, on SA. Participants included 230 adults (134 people with HIV; PWH, 96 HIV-), ages 36-65, segregated into age cohorts with up to 5 yearly visits. Multilevel modeling examined longitudinal within-person associations between D-dimer, social support, and SA. Social support moderated the relationship between D-dimer and SA and was significant among PWH and older individuals (ages 56-65), but not HIV- or younger cohorts. This association was significant only at extreme levels of social support, with significant decreases in social support potentiating the negative impact of D-dimer on SA and significant increases in social support facilitating increased SA. Despite declining health, high social support may improve SA in PWH and older adults, and low support may be especially problematic for older adults

Linked CSF reduction of phosphorylated tau and IL-8 in HIV associated neurocognitive disorder.

HIV-associated neurocognitive disorder (HAND) is a common condition in both developed and developing nations, but its cause is largely unknown. Previous research has inconsistently linked Alzheimer's disease (AD), viral burden, and inflammation to the onset of HAND in HIV-infected individuals. Here we simultaneously measured cerebrospinal fluid (CSF) levels of established amyloid and tau biomarkers for AD, viral copy numbers, and six key cytokines in 41 HIV-infected individuals off combination anti-retroviral therapy (14 with HAND) who underwent detailed clinical and neuropsychological characterization, and compared their CSF patterns with those from young healthy subjects, older healthy subjects with normal cognition, and older people with AD. HAND was associated with the lowest CSF levels of phosphorylated tau (p-Tau181) after accounting for age and race. We also found very high CSF levels of the pro-inflammatory interferon gamma-induced protein 10 (IP-10/CXCL10) in HIV regardless of cognition, but elevated CSF interleukin 8 (IL-8/CXCL8) only in HIV-NC but not HAND. Eleven HIV-infected subjects underwent repeat CSF collection six months later and showed strongly correlated longitudinal changes in p-Tau181 and IL-8 levels (R = 0.841). These data suggest reduced IL-8 relative to IP-10 and reduced p-Tau181 to characterize HAND

Fibroblast growth factors 1 and 2 in cerebrospinal fluid are associated with HIV disease, methamphetamine use, and neurocognitive functioning.

BackgroundHuman immunodeficiency virus (HIV) and methamphetamine use commonly affect neurocognitive (NC) functioning. We evaluated the relationships between NC functioning and two fibroblast growth factors (FGFs) in volunteers who differed in HIV serostatus and methamphetamine dependence (MAD).MethodsA total of 100 volunteers were categorized into four groups based on HIV serostatus and MAD in the prior year. FGF-1 and FGF-2 were measured in cerebrospinal fluid by enzyme-linked immunosorbent assays along with two reference biomarkers (monocyte chemotactic protein [MCP]-1 and neopterin). Comprehensive NC testing was summarized by global and domain impairment ratings.ResultsSixty-three volunteers were HIV+ and 59 had a history of MAD. FGF-1, FGF-2, and both reference biomarkers differed by HIV and MAD status. For example, FGF-1 levels were lower in subjects who had either HIV or MAD than in HIV- and MAD- controls (P=0.003). Multivariable regression identified that global NC impairment was associated with an interaction between FGF-1 and FGF-2 (model R(2)=0.09, P=0.01): higher FGF-2 levels were only associated with neurocognitive impairment among subjects who had lower FGF-1 levels. Including other covariates in the model (including antidepressant use) strengthened the model (model R(2)=0.18, P=0.004) but did not weaken the association with FGF-1 and FGF-2. Lower FGF-1 levels were associated with impairment in five of seven cognitive domains, more than FGF-2, MCP-1, or neopterin.ConclusionThese findings provide in vivo support that HIV and MAD alter expression of FGFs, which may contribute to the NC abnormalities associated with these conditions. These cross-sectional findings cannot establish causality and the therapeutic benefits of recombinant FGF-1 need to be investigated

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico, In Vitro, and In Vivo Investigation

Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to suppress viral replication, but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate the efavirenz distribution in the cerebrospinal fluid (CSF) and the brain by using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. The efavirenz CNS distribution was calculated using a permeability-limited model on a virtual cohort of 100 patients receiving efavirenz (600 mg once daily). Simulation data were then compared with human data from the literature and with rodent data. Wistar rats were administered efavirenz (10 mg kg of body weight(−1)) once daily over 5 weeks. Plasma and brain tissue were collected for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median maximum concentrations of drug (C(max)) were predicted to be 3,184 ng ml(−1) (interquartile range [IQR], 2,219 to 4,851 ng ml(−1)), 49.9 ng ml(−1) (IQR, 36.6 to 69.7 ng ml(−1)), and 50,343 ng ml(−1) (IQR, 38,351 to 65,799 ng ml(−1)) in plasma, CSF, and brain tissue, respectively, giving a tissue-to-plasma ratio of 15.8. Following 5 weeks of oral dosing of efavirenz (10 mg kg(−1)), the median plasma and brain tissue concentrations in rats were 69.7 ng ml(−1) (IQR, 44.9 to 130.6 ng ml(−1)) and 702.9 ng ml(−1) (IQR, 475.5 to 1,018.0 ng ml(−1)), respectively, and the median tissue-to-plasma ratio was 9.5 (IQR, 7.0 to 10.9). Although it is useful, measurement of CSF concentrations may give an underestimation of the penetration of antiretrovirals into the brain. The limitations associated with obtaining tissue biopsy specimens and paired plasma and CSF samples from patients make PBPK modeling an attractive tool for probing drug distribution

Impact on Diet Quality and Resilience in Urban Community Dwelling Obese Women with a Nutrition and Physical Activity Intervention

Objective: To examine the effect of a Tai Chi, resistance training, and behaviorally-based diet education intervention on dietary quality as well as resilience and physical resilience in obese older women. Design: Community health outreach with a quasi-experimental design. Setting: An urban senior center in Rhode Island. Participants: Thirty-three women, 85% were minorities, with mean age of 65±8.2 years and BMI of 37.3±4.6 kg/m2, were enrolled in the study at baseline however only 17 women in the intervention (EXD) group and 9 women in the wait-list control (CON) group completed the study. Measurement: Dietary quality and nutrition risk were measured using the Dietary Screening Tool (DST), resilience was measured by the Resilience Scale, and physical resilience was examined using the Physical Resilience Scale. Intervention: Participants in the EXD group engaged in 12 weeks of Tai Chi, resistance training, and behaviorally-based diet education. The diet education was based off of the modified Dietary Approaches to Stop Hypertension (DASH) diet and led by a Registered Dietitian. Results: There was no change in dietary quality by group or time. However the EXD group had significantly higher dietary quality compared to the control group (p=0.025) at post intervention, although there was no difference in nutrition risk category. There was no change seen in overall resilience, however the EXD group improved physical resilience (p=0.048). Conclusion: A community health outreach that involved Tai Chi, resistance training, and behaviorally-based diet education may promote higher dietary quality as well as improve physical resilience in obese older women

Cognitive health in persons with human immunodeficiency virus: the impact of early treatment, comorbidities, and aging

With the advent of virally suppressive antiretroviral therapy (ART), life expectancy for persons with human immunodeficiency virus (HIV) with access to ART now approaches that of the general population. As persons with HIV age, noninfectious comorbidities occur more frequently compared with persons without HIV. Such comorbidities are likely to affect cognitive health, which may also be affected by lifestyle factors that may differ in persons with HIV. At the National Institutes of Health–supported meeting on Biotypes of Central Nervous System (CNS) Complications in persons with HIV, a session was devoted to early HIV treatment, noninfectious comorbidities, and aging as each pertains to cognitive health. Areas of consideration included acute and early HIV infection (presentation by Phillip Chan), drugs of abuse (Scott Letendre), stroke and cerebrovascular disease (Felicia Chow), mental health (John Joska), and aging (Julian Falutz). These presentations were followed by a discussion session led by Woody Lin, Jose A. Muñoz-Moreno, Paola Cinque, and Jeff Taylor. Alan Winston and Bruce Brew chaired the meeting with Jasmini Alagaratnam and Htein Linn Aung acting as rapporteurs. Here we present the main topics covered in the presentations, and the associated discussions highlighting knowledge gaps and future directions

Successful cognitive aging in persons living with HIV infection

The number of older adults living with human immunodeficiency virus (HIV) infection is growing and this subpopulation of the epidemic is at heightened risk for a variety of poor health outcomes including HIV-associated neurocognitive disorders. The current study sought to examine the factors associated with freedom from neurocognitive impairment in older HIV-infected adults. Participants included 74 middle-aged and older (mean age 51 years), HIV-infected individuals with a mean estimated duration of infection of 17 years who underwent comprehensive neuropsychological, psychiatric, and medical evaluations. Successful cognitive aging (SCA) was operationally defined as the absence of neurocognitive deficits as determined by a battery of well-validated cognitive tests and self-endorsed cognitive complaints. Thirty-two percent of the cohort met these criteria. Compared to the group that did not meet these criteria, successful cognitive agers had significantly lower lifetime rates of major depressive disorder and current affective distress (e.g., depression, anxiety). Moreover, the SCA group evidenced better everyday functioning outcomes, including medication adherence, lower self-reported rates of declines in activities of daily living, and superior abilities related to medication management and dealing with healthcare providers. SCA was not related to demographic composition, HIV disease or treatment factors, medical comorbidities, or histories of substance use disorders. Findings from this preliminary study suggest that approximately one-third of older persons with HIV were free of cognitive impairments, which is associated with more favorable emotional, psychosocial, and everyday functioning

Chemokines in cerebrospinal fluid correlate with cerebral metabolite patterns in HIV-infected individuals

Chemokines influence HIV neuropathogenesis by affecting the HIV life cycle, trafficking of macrophages into the nervous system, glial activation, and neuronal signaling and repair processes; however, knowledge of their relationship to in vivo measures of cerebral injury is limited. The primary objective of this study was to determine the relationship between a panel of chemokines in cerebrospinal fluid (CSF) and cerebral metabolites measured by proton magnetic resonance spectroscopy (MRS) in a cohort of HIV-infected individuals. One hundred seventy-one stored CSF specimens were assayed from HIV-infected individuals who were enrolled in two ACTG studies that evaluated the relationship between neuropsychological performance and cerebral metabolites. Concentrations of six chemokines (fractalkine, IL-8, IP-10, MCP-1, MIP-1β, and SDF-1) were measured and compared with cerebral metabolites individually and as composite neuronal, basal ganglia, and inflammatory patterns. IP-10 and MCP-1 were the chemokines most strongly associated with individual cerebral metabolites. Specifically, (1) higher IP-10 levels correlated with lower N-acetyl aspartate (NAA)/creatine (Cr) ratios in the frontal white matter and higher MI/Cr ratios in all three brain regions considered and (2) higher MCP-1 levels correlated with lower NAA/Cr ratios in frontal white matter and the parietal cortex. IP-10, MCP-1, and IL-8 had the strongest associations with patterns of cerebral metabolites. In particular, higher levels of IP-10 correlated with lower neuronal pattern scores and higher basal ganglia and inflammatory pattern scores, the same pattern which has been associated with HIV-associated neurocognitive disorders (HAND). Subgroup analysis indicated that the effects of IP-10 and IL-8 were influenced by effective antiretroviral therapy and that memantine treatment may mitigate the neuronal effects of IP-10. This study supports the role of chemokines in HAND and the validity of MRS as an assessment tool. In particular, the findings identify relationships between the immune response—particularly an interferon-inducible chemokine, IP-10—and cerebral metabolites and suggest that antiretroviral therapy and memantine modify the impact of the immune response on neurons

Metabolic Risk Factors as Differential Predictors of Profiles of Neurocognitive Impairment Among Older HIV+ and HIV- Adults: An Observational Study.

ObjectiveNeurocognitive performance among older persons, including those living with HIV (people living with HIV [PLWH]), exhibits significant heterogeneity, suggesting subpopulations with differing profiles of neurocognitive impairment (NCI). Metabolic factors are associated with NCI, but their relationships to cluster-derived NCI profiles are unknown.MethodParticipants (144 PLWH and 102 HIV uninfected) aged 50+ years completed a neuropsychological battery assessing seven cognitive domains. Latent class analysis (LCA) identified NCI profiles separately by HIV serostatus and in a combined sample. Obtained classes were examined against the Montreal Cognitive Assessment (MoCA) and diagnoses of HIV-associated neurocognitive disorders (HAND). Multinomial regression identified metabolic predictors of classification.ResultsLCA identified three latent classes in each participant sample: Class1Multidomain NCI (high probability of impairment across multiple domains), Class 2Learning & Recall NCI (high probability of impairment in learning and recall), and Class 3NC Unimpaired (low probability of NCI across all domains). Severity of NCI implied by classes corresponded with MoCA scores and HAND diagnoses. In analyses on the combined sample, compared to HIV-uninfected individuals, PLWH were more likely to be in Class1Multidomain NCI. Among PLWH, those with dyslipidemia and hypertension had greater odds of classification in Class 1Multidomain NCI while those with central obesity had higher odds of classification in Class 2Learning & Recall NCI; metabolic syndrome approached significance as a differential predictor. Regardless of HIV status, individuals with diabetes were more likely to be in Class 1Multidomain NCI.ConclusionsMetabolic risk factors confer heightened risk of NCI in HIV infection. Interventions to reduce metabolic risk may improve neurocognitive outcomes among PLWH