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1.  Efavirenz concentrations in CSF exceed IC50 for wild-type HIV 
Objectives
HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF.
Methods
CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
Results
Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2–17] of therapy were 2145 ng/mL in plasma (IQR 1384–4423) and 13.9 ng/mL in CSF (IQR 4.1–21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026–0.0076; n = 69). The CSF/IC50 ratio was 26 (IQR 8–41) using the published IC50 for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC50 for wild-type HIV.
Conclusions
Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC50 in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
doi:10.1093/jac/dkq434
PMCID: PMC3019085  PMID: 21098541
CNS; pharmacology; non-nucleoside reverse transcriptase inhibitors
2.  Apathy is associated with white matter abnormalities in anterior, medial brain regions in persons with HIV infection 
Apathy is a relatively common psychiatric syndrome in HIV infection, but little is known about its neural correlates. In the present study, we examined the associations between apathy and diffusion tensor imaging (DTI) indices in key frontal white matter regions in the thalamocorticostriatal circuit that has been implicated in the expression of apathy. Nineteen participants with HIV infection and 19 demographically comparable seronegative comparison subjects completed the Apathy subscale of the Frontal Systems Behavioral Scale as a part of a comprehensive neuropsychiatric research evaluation. When compared to the seronegative participants, the HIV+ group had significantly more frontal white matter abnormalities. Within HIV+ persons, and as predicted, higher ratings of apathy were associated with greater white matter alterations in the anterior corona radiata, genu, and orbital medial prefrontal cortex. The associations between white matter alterations and apathy were independent of depression and were stronger among participants with lower current CD4 counts. All told, these findings indicate that apathy is independently associated with white matter abnormalities in anterior, medial brain regions in persons infected with HIV, particularly in the setting of lower current immune functioning, which may have implications for antiretroviral therapy.
doi:10.1080/13803395.2014.950636
PMCID: PMC4303236  PMID: 25275424
Diffusion tensor imaging; apathy; HIV/AIDS; Prefrontal cortex; depression
3.  Genetic Attributes of Blood-Derived Subtype-C HIV-1 tat and env in India and Neurocognitive Function 
Journal of medical virology  2013;86(1):10.1002/jmv.23816.
Genetic elements in HIV-1 subtype B tat and env are associated with neurotoxicity yet less is known about other subtypes. HIV-1 sub-type C tat and env sequences were analyzed to determine viral genetic elements associated with neurocognitive impairment in a large Indian cohort. Population-based sequences of HIV-1 tat (exon 1) and env (C2-V3 coding region) were generated from blood plasma of HIV-infected patients in Pune, India. Participants were classified as cognitively normal or impaired based on neuropsychological assessment. Tests for signature residues, positive and negative selection, entropy, and ambiguous bases were performed using tools available through Los Alamos National Laboratory (http://www.hiv.lanl.gov) and Datamonkey (http://www.datamonkey.org). HIV-1 subtype C tat and env sequences were analyzed for 155 and 160 participants, of which 34–36% were impaired. Two signature residues were unique to impaired participants in exon 1 of tat at codons 29 (arginine) and 68 (proline). Positive selection was noted at codon 29 among normal participants and at codon 68 in both groups. The signature at codon 29 was also a signature for low CD4+ (<200 cells/mm3) counts but remained associated with impairment after exclusion of those with low CD4+ counts. No unique genetic signatures were noted in env. In conclusion, two signature residues were identified in exon 1 of HIV-1 subtype C tat that were associated with neurocognitive impairment in India and not completely accounted for by HIV disease progression. These signatures support a linkage between diversifying selection in HIV-1 subtype C tat and neurocognitive impairment.
doi:10.1002/jmv.23816
PMCID: PMC3872113  PMID: 24150902
neuropsychological testing; impairment; sequence; signature; residue; clade C
4.  Cluster Analysis of the Klein Sexual Orientation Grid in Clinical and Nonclinical Samples: When Bisexuality Is Not Bisexuality 
Journal of bisexuality  2014;14(3-4):349-372.
We used a cluster analysis to empirically address whether sexual orientation is a continuum or can usefully be divided into categories such as heterosexual, homosexual, and bisexual using scores on the Klein Sexual Orientation Grid (KSOG) in three samples: groups of men and women recruited through bisexual groups and the Internet (Main Study men; Main Study women), and men recruited for a clinical study of HIV and the nervous system (HIV Study men). A five-cluster classification was chosen for the Main Study men (n = 212), a four-cluster classification for the Main Study women (n = 120), and a five-cluster classification for the HIV Study men (n = 620).
We calculated means and standard deviations of these 14 clusters on the 21 variables composing the KSOG. Generally, the KSOG’s overtly erotic items (Sexual Fantasies, Sexual Behavior, and Sexual Attraction), as well as the Self Identification items, tended to be more uniform within groups than the more social items were (Emotional Preference, Socialize with, and Lifestyle). The result is a set of objectively identified subgroups of bisexual men and women along with characterizations of the extent to which their KSOG scores describe and differentiate them.
The Bisexual group identified by the cluster analysis of the HIV sample was distinctly different from any of the bisexual groups identified by the clustering process in the Main Sample. Simply put, the HIV sample’s bisexuality is not like bisexuality in general, and attempts to generalize (even cautiously) from this clinical Bisexual group to a larger population would be doomed to failure. This underscores the importance of recruiting non-clinical samples if one wants insight into the nature of bisexuality in the population at large. Although the importance of non-clinical sampling in studies of sexual orientation has been widely and justly asserted, it has rarely been demonstrated by direct comparisons of the type conducted in the present study.
doi:10.1080/15299716.2014.938398
PMCID: PMC4267693  PMID: 25530727
sexual orientation; bisexuality; cluster analysis; Internet; Klein Sexual Orientation Grid
5.  Attention-Deficit/Hyperactivity Disorder Among Chronic Methamphetamine Users: Frequency, Persistence, and Adverse Effects on Everyday Functioning 
Addictive behaviors  2013;38(12):2874-2878.
Aims
Attention-Deficit/Hyperactivity Disorder (ADHD) is widely regarded as a common comorbidity of methamphetamine (MA) dependence, but the frequency, persistence, and real-world impact of ADHD among MA users is not known.
Methods
Four hundred individuals with MA use disorders within 18 months of evaluation and 355 non-MA using comparison subjects completed a comprehensive neuropsychiatric research battery, including self-report measures of everyday functioning.
Results
In logistic regression models adjusting for potential confounds, lifetime diagnoses of ADHD as determined by a structured clinical interview were significantly more prevalent among the MA participants (21%) versus comparison subjects (6%), particularly the hyperactive and combined subtypes. MA use was also associated with an increased persistence of combined subtype of ADHD into adulthood. Among the MA users, lifetime ADHD diagnoses were uniquely associated with greater concurrent risk of declines in instrumental activities of daily living, elevated cognitive symptoms in day-to-day life, and unemployment.
Conclusions
Findings indicate that ADHD is prevalent among chronic MA users, who are at increased risk for persistence of childhood diagnoses of ADHD into their adult years. ADHD also appears to play an important role in MA-associated disability, indicating that targeted ADHD screening and treatment may help to improve real-world outcomes for individuals with MA use disorders.
doi:10.1016/j.addbeh.2013.08.010
PMCID: PMC3805791  PMID: 24018233
Substance Abuse; Developmental Disorder; Comorbidity; Functioning; Disability; Neuropsychiatry
6.  Real-World Impact of Neurocognitive Deficits in Acute and Early HIV Infection 
Journal of neurovirology  2013;19(6):10.1007/s13365-013-0218-2.
The acute and early period of HIV-1 infection (AEH) is characterized by neuroinflammatory and immunopathogenic processes that can alter the integrity of neural systems and neurocognitive functions. However, the extent to which central nervous system changes in AEH confer increased risk of real-world functioning (RWF) problems is not known. In the present study, 34 individuals with AEH and 39 seronegative comparison participants completed standardized neuromedical, psychiatric, and neurocognitive research evaluations, alongside a comprehensive assessment of RWF that included cognitive symptoms in daily life, basic and instrumental activities of daily living, clinician-rated global functioning, and employment. Results showed that AEH was associated with a significantly increased risk of dependence in RWF, which was particularly elevated among AEH persons with global neurocognitive impairment (NCI). Among those with AEH, NCI (i.e., deficits in learning and information processing speed), mood disorders (i.e., Bipolar Disorder), and substance dependence (e.g., methamphetamine dependence) were all independently predictive of RWF dependence. Findings suggest that neurocognitively impaired individuals with AEH are at notably elevated risk of clinically significant challenges in normal daily functioning. Screening for neurocognitive, mood, and substance use disorders in AEH may facilitate identification of individuals at high risk of functional dependence who may benefit from psychological and medical strategies to manage their neuropsychiatric conditions.
doi:10.1007/s13365-013-0218-2
PMCID: PMC3865175  PMID: 24277439
Infectious disease; Disability; Substance use; Neuropsychology; AIDS-related Dementia
7.  A CONCISE PANEL OF BIOMARKERS IDENTIFIES NEUROCOGNITIVE FUNCTIONING CHANGES IN HIV-INFECTED INDIVIDUALS 
Background
Neurocognitive (NC) impairment (NCI) occurs commonly in people living with HIV. Despite substantial effort, no biomarkers have been sufficiently validated for diagnosis and prognosis of NCI in the clinic. The goal of this project was to identify diagnostic or prognostic biomarkers for NCI in a comprehensively characterized HIV cohort.
Methods
Multidisciplinary case review selected 98 HIV-infected individuals and categorized them into four NC groups using normative data: stably normal (SN), stably impaired (SI), worsening (Wo), or improving (Im). All subjects underwent comprehensive NC testing, phlebotomy, and lumbar puncture at two timepoints separated by a median of 6.2 months. Eight biomarkers were measured in CSF and blood by immunoassay. Results were analyzed using mixed model linear regression and staged recursive partitioning.
Results
At the first visit, subjects were mostly middle-aged (median 45) white (58%) men (84%) who had AIDS (70%). Of the 73% who took antiretroviral therapy (ART), 54% had HIV RNA levels below 50 c/mL in plasma. Mixed model linear regression identified that only MCP-1 in CSF was associated with neurocognitive change group. Recursive partitioning models aimed at diagnosis (i.e., correctly classifying neurocognitive status at the first visit) were complex and required most biomarkers to achieve misclassification limits. In contrast, prognostic models were more efficient. A combination of three biomarkers (sCD14, MCP-1, SDF-1α) correctly classified 82% of Wo and SN subjects, including 88% of SN subjects. A combination of two biomarkers (MCP-1, TNF-α) correctly classified 81% of Im and SI subjects, including 100% of SI subjects.
Conclusions
This analysis of well-characterized individuals identified concise panels of biomarkers associated with NC change. Across all analyses, the two most frequently identified biomarkers were sCD14 and MCP-1, indicators of monocyte/macrophage activation. While the panels differed depending on the outcome and on the degree of misclassification, nearly all stable patients were correctly classified.
doi:10.1007/s11481-013-9504-2
PMCID: PMC3874146  PMID: 24101401
HIV; Neurocognitive Disorders; Cerebrospinal Fluid; Biomarkers
8.  Visuospatial Temporal Order Memory Deficits in Older Adults with HIV Infection 
Objective
To compare temporal order memory in older adults with and without HIV infection.
Background
The frontal and temporal lobes play a key role in temporal order memory for items in a sequence. HIV-associated episodic memory deficits correlate with damage to neocortical interneurons in the fronto-striato-thalamo-cortical pathway and with atypical activation of the medial temporal lobes. Therefore, temporal order memory may be sensitive to neuropathological changes in individuals with HIV.
Methods
In this study, 50 HIV-seropositive individuals aged ≥ 50 years and 50 seronegative controls performed a computerized visuospatial temporal order memory task. During the sample phase of each trial, participants were shown circles presented 1 at a time in a random sequence at the end of each of the 8 arms of a radial maze. During the choice phase, they were shown the maze with a circle at the ends of 2 of the arms and asked which circle had appeared earlier than the other in the original sequence.
Results
Performance in both groups improved as a function of greater temporal separation between circle presentations. However, the HIV group had significantly worse memory impairment across all temporal separations, and the impairment was independently associated with clinical deficits in executive function and delayed retrospective memory.
Conclusions
Our results extend prior findings that HIV is associated with deficits in strategic aspects of memory encoding and retrieval. The neural mechanisms warrant further research, as do potential impacts on everyday function, eg, adherence to antiretroviral drug regimens.
doi:10.1097/WNN.0000000000000013
PMCID: PMC3893039  PMID: 24378603
HIV; temporal order; visuospatial; episodic memory; executive function
9.  Alterations in the levels of vesicular trafficking proteins involved in HIV replication in the brains and CSF of patients with HIV-associated neurocognitive disorders 
Human immunodeficiency virus (HIV) associated neurocognitive disorders (HAND) remain prevalent despite improved antiretroviral therapies. A HAND-specific biomarker indicative of neuropsychological impairment (NPI) would give insight into disease progression and aid clinicians in designing therapy. Endosomal sorting complex required for transport (ESCRT) proteins such as tumor susceptibility gene (TSG)-101, vacuolar protein sorting (VPS)-4 and LIP-5 are important for HIV replication and recently antiviral interferon stimulated gene (ISG)-15 was proposed as a biomarker for CNS injury. Here, we analyzed a well-characterized cohort of HIV+ cerebral spinal fluid (CSF) and postmortem brain specimens for multiple vesicular trafficking proteins and a related innate immune protein, ISG-15, TSG-101, VPS-4 and LIP-5. All protein levels trended higher with increased NPI and neuropathology. ISG-15 CSF levels were increased in HIV encephalitis (HIVE) compared to normal cases, and three quarters of HIVE samples had above average CSF ISG-15 levels. VPS-4 CSF levels were increased in NPI/NPI-O compared to normal patients. VPS-4 CSF levels in HIV-associated dementia were equivalent to that of normal patients. LIP-5 CSF levels positively correlate with ISG-15 levels, and higher than average ISG-15 levels indicate elevated viral load. Immunoblot and immunohistochemical analyses show increased expression of ISG-15, VPS-4 and LIP-5 in neuronal cell bodies and astroglial cells. ESCRT protein CSF levels analyzed in conjunction with viral load may be indicative of NPI stage, and may aid in the diagnosis and design of therapies for HIV patients. Further studies on the ESCRT protein expression during HIV infection may lead to a promising biomarker for predicting progression of NPI.
doi:10.1007/s11481-013-9511-3
PMCID: PMC3973444  PMID: 24292993
HIV; biomarker; ESCRT; ISG-15; VPS-4; LIP-5
10.  Association between Hospice Care and Psychological Outcomes in Alzheimer's Spousal Caregivers 
Journal of Palliative Medicine  2013;16(11):1450-1454.
Abstract
Context
Dementia care giving can lead to increased stress, physical and psychosocial morbidity, and mortality. Anecdotal evidence suggests that hospice care provided to people with dementia and their caregivers may buffer caregivers from some of the adverse outcomes associated with family caregiving in Alzheimer's Disease (AD).
Objectives
This pilot study examined psychological and physical outcomes among 32 spousal caregivers of patients with AD. It was hypothesized that caregivers who utilized hospice services would demonstrate better outcomes after the death of their spouse than caregivers who did not utilize hospice.
Methods
The charts of all spousal caregivers enrolled in a larger longitudinal study from 2001 to 2006 (N=120) were reviewed, and participants whose spouse had died were identified. Of these, those who received hospice care (n=10) were compared to those who did not (n=22) for various physiological and psychological measures of stress, both before and after the death of the care recipient. An Analysis of Covariance (ANCOVA), with postdeath scores as the dependent variable and pre-death scores as covariates, was used for all variables.
Results
Significant group differences were found in postdeath depressive symptoms (HAM-D; F(1,29)=6.10, p<0.05) and anxiety symptoms (HAM-A; F(1,29)=5.71, p<0.05). Most psychological outcome variables demonstrated moderate effect sizes with a Cohen's d of>0.5 between groups.
Conclusions
These data suggest that hospice enrollment may ameliorate the detrimental psychological effects in caregivers who have lost a spouse with Alzheimer's Disease. Based on these pilot data, further prospective investigation is warranted.
doi:10.1089/jpm.2013.0130
PMCID: PMC3822398  PMID: 24093721
11.  Dynamic Indices of Methamphetamine Dependence and HIV Infection Predict Fluctuations in Affective Distress: A Five-year Longitudinal Analysis 
Journal of affective disorders  2013;151(2):10.1016/j.jad.2013.07.036.
Background
Methamphetamine (METH) use and human immunodeficiency virus (HIV) infection are highly comorbid, and both are associated with increased prevalence of affective distress. Delineating the trajectory of affective distress in the context of METH dependence and HIV infection is important given the implications for everyday functional impairment, adverse health behaviors, and increased risk for adverse health outcomes.
Methods
We conducted a five-year longitudinal investigation involving 133 METH-dependent (74 HIV seropositive) and 163 non-METH-dependent (90 HIV seropositive) persons to examine both long-standing patterns and transient changes in affective distress. Mixed-effect regression models with random subject-specific slopes and intercepts evaluated the effect of METH dependence, HIV serostatus, and related variables on affective distress, as measured by the Profile of Mood States.
Results
Transient changes in affective distress were found to be greater among those with a diagnosis of current MDD, briefer durations of abstinence from METH, and higher quantity of METH consumed. Weak associations were observed among static (time-independent predictors) covariates and long-standing patterns in affective distress.
Limitations
Study lacked data pertaining to the participants’ involvement in METH treatment and relied on respondent-driven sampling.
Conclusions
Our longitudinal investigation of the trajectory of affective distress indicated that specific and dynamic indices of current METH use were associated with greater transient changes in mood. In the evaluation and treatment of affective distress, recency and quantity of current METH use are important to consider given their association with heightened affective distress and mood instability over time.
doi:10.1016/j.jad.2013.07.036
PMCID: PMC3845675  PMID: 24012068
Affective distress; Methamphetamine; Dependence; HIV; Longitudinal
12.  Altered Functional Response to Risky Choice in HIV Infection 
PLoS ONE  2014;9(10):e111583.
Background
Risky decision-making is commonly observed in persons at risk for and infected with HIV and is associated with executive dysfunction. Yet it is currently unknown whether HIV alters brain processing of risk-taking decision-making.
Methods
This study examined the neural substrate of a risky decision-making task in 21 HIV seropositive (HIV+) and 19 seronegative (HIV-) comparison participants. Functional magnetic resonance imaging was conducted while participants performed the risky-gains task, which involves choosing among safe (20 cents) and risky (40/80 cent win or loss) choices. Linear mixed effects analyses examining group and decision type were conducted. Robust regressions were performed to examine the relationship between nadir CD4 count and Kalichman sexual compulsivity and brain activation in the HIV+ group. The overlap between the task effects and robust regressions was explored.
Results
Although there were no serostatus effects in behavioral performance on the risky-gains task, HIV+ individuals exhibited greater activation for risky choices in the basal ganglia, i.e. the caudate nucleus, but also in the anterior cingulate, dorsolateral prefrontal cortex, and insula relative to the HIV- group. The HIV+ group also demonstrated reduced functional responses to safe choices in the anterior cingulate and dorsolateral prefrontal cortex relative to the HIV- group. HIV+ individuals with higher nadir CD4 count and greater sexual compulsivity displayed lower differential responses to safe versus risky choices in many of these regions.
Conclusions
This study demonstrated fronto-striatal loop dysfunction associated with HIV infection during risky decision-making. Combined with similar between-group task behavior, this suggests an adaptive functional response in regions critical to reward and behavioral control in the HIV+ group. HIV-infected individuals with higher CD4 nadirs demonstrated activation patterns more similar to seronegative individuals. This suggests that the severity of past immunosuppression (CD4 nadir) may exert a legacy effect on processing of risky choices in the HIV-infected brain.
doi:10.1371/journal.pone.0111583
PMCID: PMC4210250  PMID: 25347679
13.  Frontal White Matter Integrity Predictors of Adult Alcohol Treatment Outcome 
Biological psychiatry  2011;71(3):262-268.
Background
Previous research has associated abnormalities in frontal lobe functioning with alcohol relapse. In this study, we used diffusion tensor imaging to investigate whether frontal white matter integrity measured at the start of treatment differs between persons with alcohol use disorders (AUD) who sustain treatment gains and those who return to heavy use after treatment.
Methods
Forty-five treatment-seeking AUD inpatients and 30 healthy control subjects were included in the study. Six months after completing treatment, 16 of the AUD participants had resumed heavy use (RHU) and 29 others remained abstinent or drank minimally (treatment sustainers [TS]). Voxel-wise group comparisons (TS vs. RHU) were performed on fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity maps generated from each subject’s diffusion tensor imaging scan at the start of treatment.
Results
We found significantly lower FA and significantly higher RD in the frontal lobes of the RHU group, relative to the TS group. The RHU group data are consistent with previous reports of abnormal frontal white matter tract abnormalities in persons with AUD.
Conclusions
It is possible that the lower FA and higher RD in the RHU group reflect microstructural injury to frontal circuitries, and these may underlie the reduced cognitive control amid heightened reward sensitivity associated with resumption of heavy drinking.
doi:10.1016/j.biopsych.2011.09.022
PMCID: PMC4208753  PMID: 22047719
Alcohol; diffusion tensor imaging; frontal lobe; relapse; TBSS; white matter
14.  A lipid storage–like disorder contributes to cognitive decline in HIV-infected subjects 
Neurology  2013;81(17):1492-1499.
Objective:
In this multicenter cohort study, we sought to identify prognostic and associative metabolic indicators for HIV-associated neurocognitive disorders (HAND).
Methods:
A quantitative lipidomic analysis was conducted on 524 longitudinal CSF samples collected from 7 different performance sites across the mainland United States, Hawaii, and Puerto Rico. Subjects included HIV-infected individuals with longitudinal clinical and cognitive testing data and cognitively normal HIV-negative healthy controls.
Results:
At baseline, HIV+ subjects could be differentiated from HIV− controls by reductions in a single ceramide species and increases in multiple forms of cholesterol. Perturbations in cholesterol metabolism and ceramide were influenced by combined antiretroviral therapy (cART) use. There were no cross-sectional baseline differences in any lipid metabolite when HIV+ subjects were grouped according to cognitive status. However, a single sphingolipid metabolite and reduced levels of esterified cholesterols were prognostic indicators of incident cognitive decline. Longitudinal patterns of these disturbances in sphingolipid and sterol metabolism suggest that a progressive disorder of lipid metabolism that is similar to disorders of lipid storage may contribute to the pathogenesis of HAND.
Conclusions:
These findings suggest that HIV infection and cART are independently associated with a CNS metabolic disturbance, identify surrogate markers that are prognostic for cognitive decline, and implicate a lipid storage–like disorder in the progression of HAND.
doi:10.1212/WNL.0b013e3182a9565e
PMCID: PMC3888167  PMID: 24027056
15.  Physical Exercise is Associated with Less Neurocognitive Impairment Among HIV-Infected Adults 
Journal of neurovirology  2013;19(5):410-417.
Neurocognitive impairment (NCI) remains prevalent in HIV-infection. Randomized trials have shown that physical exercise improves NCI in non HIV-infected adults, but data on HIV-infected populations is limited. Community-dwelling HIV-infected participants (n=335) completed a comprehensive neurocognitive battery that was utilized to define both global and domain-specific NCI. Participants were divided into “Exercise” (n=83) and “No Exercise” (n=252) groups based on whether they self-reported engaging in any activity that increased heart rate in the last 72 hours or not. We also measured and evaluated a series of potential confounding factors, including demographics, HIV-disease characteristics, substance use and psychiatric comorbidities, and physical functioning. Lower rates of global NCI were observed among the Exercise group (15.7%) as compared to those in the No Exercise group (31.0%; p<.01). A multivariable logistic regression controlling for potential confounds (i.e., education, AIDS status, current CD4+ lymphocyte count, self-reported physical function, current depression) showed that being in the Exercise group remained significantly associated with lower global NCI (OR=2.63, p<.05). Similar models of domain-specific NCI showed that Exercise was associated with reduced impairment in working memory (p<.05) and speed of information processing (p<.05). The present findings suggest that HIV-infected adults who exercise are approximately half as likely to show NCI as compared to those who do not. Future longitudinal studies might be best suited to address causality and intervention trials in HIV-infected individuals will determine whether exercise can prevent or ameliorate NCI in this population.
doi:10.1007/s13365-013-0184-8
PMCID: PMC3795938  PMID: 23934585
HIV/AIDS; Mild Neurocognitive Impairment; Physical Exercise; Cognition; Lifestyle; Neuropsychology
16.  A Randomized Clinical Trial of Behavioral Activation (BA) Therapy for Improving Psychological and Physical Health in Dementia Caregivers: Results of the Pleasant Events Program (PEP) 
Behaviour research and therapy  2013;51(10):623-632.
Dementia caregiving is associated with elevations in depressive symptoms and increased risk for cardiovascular diseases (CVD). This study evaluated the efficacy of the Pleasant Events Program (PEP), a 6-week Behavioral Activation intervention designed to reduce CVD risk and depressive symptoms in caregivers. One hundred dementia family caregivers were randomized to either the 6-week PEP intervention (N=49) or a time-equivalent Information-Support (IS) control condition (N=51). Assessments were completed pre- and post-intervention and at 1-year follow-up. Biological assessments included CVD risk markers Interleukin-6 (IL-6) and D-dimer. Psychosocial outcomes included depressive symptoms, positive affect, and negative affect. Participants receiving the PEP intervention had significantly greater reductions in IL-6 (p=.040), depressive symptoms (p=.039), and negative affect (p=.021) from pre- to post-treatment. For IL-6, clinically significant improvement was observed in 20.0% of PEP participants and 6.5% of IS participants. For depressive symptoms, clinically significant improvement was found for 32.7% of PEP vs 11.8% of IS participants. Group differences in change from baseline to 1-year follow-up were non-significant for all outcomes. The PEP program decreased depression and improved a measure of physiological health in older dementia caregivers. Future research should examine the efficacy of PEP for improving other CVD biomarkers and seek to sustain the intervention’s effects.
doi:10.1016/j.brat.2013.07.005
PMCID: PMC3774137  PMID: 23916631
Depression; Cardiovascular Disease; Alzheimer’s Disease; Intervention; Treatment
17.  Dual-mixed HIV-1 Coreceptor Tropism and HIV-Associated Neurocognitive Deficits 
Journal of neurovirology  2013;19(5):488-494.
Background
HIV coreceptor usage of CXCR4 (X4) is associated with decreased CD4+ T-cell counts and accelerated disease progression, but the role of X4 tropism in HIV-associated neurocognitive disorders (HAND) has not previously been described.
Methods
This longitudinal study evaluated data on 197 visits from 72 recently HIV-infected persons who had undergone up to 4 sequential neurocognitive assessments over a median of 160 days (IQR 138–192). Phenotypic tropism testing (Trofile ES, Monogram, Biosciences) was performed on stored blood samples. Multivariable mixed model repeated measures regression was used to determine the association between HAND and dual-mixed (DM) viral tropism, estimated duration of infection (EDI), HIV RNA, CD4 count and problematic methamphetamine use.
Results
Six subjects (8.3%) had dual mixed tropism (DM) at their first neurocognitive assessment and four converted to DM in subsequent sampling (for total of 10 DM) at a median EDI of 10.1 months (IQR 7.2–12.2). There were 44 (61.1%) subjects who demonstrated HAND on at least one study visit. HAND was associated with DM tropism (odds ratio 4.4, 95% CI 0.9–20.5) and shorter EDI (odds ratio 1.1 per month earlier, 95% CI 1.0–1.2).
Conclusion
This study found that recency of HIV-1 infection and the development of DM tropism may be associated with HAND in the relatively early stage of infection. Together these data suggest that viral interaction with cellular receptors may play an important role in the early manifestation of HAND.
doi:10.1007/s13365-013-0203-9
PMCID: PMC3921071  PMID: 24078557
HIV-associated neurocognitive disorders; coreceptor tropism; methamphetamine
18.  Genetic Variation in Iron Metabolism Is Associated with Neuropathic Pain and Pain Severity in HIV-Infected Patients on Antiretroviral Therapy 
PLoS ONE  2014;9(8):e103123.
HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP.
doi:10.1371/journal.pone.0103123
PMCID: PMC4140681  PMID: 25144566
19.  Increases in brain white matter abnormalities and subcortical gray matter are linked to CD4 recovery in HIV infection 
Journal of neurovirology  2013;19(4):393-401.
MRI alterations in the cerebral white (WM) and gray matter (GM) are common in HIV infection, even during successful combination antiretroviral therapy (CART), and their pathophysiology and clinical significance are unclear. We evaluated the association of these alterations with recovery of CD4+ T-cells. Seventy-five HIV-infected (HIV+) volunteers in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study underwent brain MRI at two visits. Multi-channel morphometry yielded volumes of total cerebral WM, abnormal WM, cortical and subcortical GM, and ventricular and sulcal CSF. Multivariable linear regressions were used to predict volumetric changes with change in current CD4 and detectable HIV RNA. On average, the cohort (79% initially on CART) demonstrated loss of total cerebral WM alongside increases in abnormal WM and ventricular volumes. A greater extent of CD4 recovery was associated with increases in abnormal WM and subcortical GM volumes. Virologic suppression was associated with increased subcortical GM volume, independent of CD4 recovery. These findings suggest a possible link between brain alterations and immune recovery, distinct from the influence of virologic suppression. The association of increasing abnormal WM and subcortical GM volumes with CD4+ T-cell recovery suggests that neuroinflammation may be one mechanism in CNS pathogenesis.
doi:10.1007/s13365-013-0185-7
PMCID: PMC3776609  PMID: 23838849
Antiretroviral therapy; brain; CD4+ T-cell; immune recovery/reconstitution; inflammation; MRI
20.  Epigenetic Alterations in the Brain Associated with HIV-1 Infection and Methamphetamine Dependence 
PLoS ONE  2014;9(7):e102555.
HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has reached epidemic proportions and is associated with high-risk sexual behavior, increased HIV transmission, and development of drug resistance. HIV infection and METH dependence can have synergistic pathological effects, with preferential involvement of frontostriatal circuits. At the molecular level, epigenetic alterations have been reported for both HIV-1 infection and drug abuse, but the neuropathological pathways triggered by their combined effects are less known. We investigated epigenetic changes in the brain associated with HIV and METH. We analyzed postmortem frontal cortex tissue from 27 HIV seropositive individuals, 13 of which had a history of METH dependence, in comparison to 14 cases who never used METH. We detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Genome-wide profiling of DNA methylation in a subset of cases, showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation. We provide evidence for the synergy of HIV and METH dependence on the patterns of DNA methylation on the host brain, which results in a distinctive landscape for the comorbid condition. Importantly, we identified new epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions.
doi:10.1371/journal.pone.0102555
PMCID: PMC4108358  PMID: 25054922
21.  Relations between personal mastery, chronic caregiving stress, and multiple dimensions of fatigue 
Objective
A substantial proportion of chronically stressed informal caregivers of Alzheimer’s disease patients report experiencing fatigue. The objective of this study was to examine whether personal mastery moderates the relationship between caregiving status (caregiver/non-caregiver) and multiple dimensions of fatigue.
Methods
Seventy-three elderly Alzheimer’s caregivers and 41 elderly non-caregivers completed the short form of the Multidimensional Fatigue Symptom Inventory (MFSI-SF) and questionnaires assessing mastery.
Results
Regression analyses indicate that global fatigue scores were significantly higher for caregivers (M = 38.0 ± 21.0) compared to non-caregivers (M = 18.2 ± 10.4). However, personal mastery moderated the relations between caregiving status and global fatigue (t = −2.03, df = 107, p = .045), such that for those with low mastery, caregivers’ fatigue scores were 18.1 points higher than non-caregivers, and for those with high mastery, this difference was only 7.5 points. For specific dimensions of fatigue, mastery moderated the relations between caregiving status and both Emotional (t = −2.01, df = 107, p = .047) and Physical (t = −2.51, df = 107, p = .014) fatigue. Specifically, association between caregiving status and emotional fatigue was greater when mastery was low than when mastery was high. In regards to physical fatigue, caregiving status was significantly associated with physical fatigue when mastery was low, but was not when mastery was high. Significant main effects were found between mastery and general fatigue and vigor.
Conclusion
Given the high proportion of caregivers who experience fatigue and the impact that fatigue can have on health; these findings provide important information regarding mastery’s relationship with fatigue and may potentially inform interventions aiming to alleviate fatigue in caregivers.
doi:10.1002/gps.2286
PMCID: PMC4091958  PMID: 19548267
Alzheimer’s Disease; Caregiving; Fatigue; Control; Coping; Exhaustion
22.  Pleasant Events, Activity Restriction, and Blood Pressure in Dementia Caregivers 
Objective
A combination of high engagement in pleasurable activities and low perceived activity restriction is potentially protective for a number of health and quality of life outcomes. This study tests the newly proposed Pleasant Events and Activity Restriction (PEAR) model to explain level of blood pressure (BP) in a sample of elderly dementia caregivers.
Methods
This cross-sectional study included 66 caregivers, ≥ 55 years of age, providing in-home care to a relative with dementia. Planned comparisons were made to assess group differences in BP between caregivers reporting high engagement in pleasant events plus low perceived activity restriction (HPLR; N = 22) to those with low pleasure plus high restriction (LPHR; N = 23) or those with either high pleasure plus high restriction or low pleasure plus low restriction (HPHR/LPLR; N = 21).
Results
After adjustments for age, sex, body mass index, use of anti-hypertensive medication, physical activity, and number of health problems, HPLR participants (86.78 mm Hg) had significantly lower mean arterial pressure compared to LPHR participants (94.70 mm Hg) (p = .01, Cohen’s d=0.89) and HPHR/LPLR participants (94.84 mm Hg) (p = .023, d=0.91). Similar results were found in post-hoc comparisons of both systolic and diastolic BP.
Conclusions
This study extends support for the PEAR model to physical health outcomes. Differences in BP between the HPLR group and other groups were of large magnitude and thus clinically meaningful. The findings may inform intervention studies aimed at investigating whether increasing pleasant events and lowering perceived activity restriction may lower BP.
doi:10.1037/a0029412
PMCID: PMC3572271  PMID: 22888824
Alzheimer’s disease; dementia caregiving; behavioral activation; coping; elderly
23.  Sleep, Type 2 Diabetes, Dyslipidemia, and Hypertension in Elderly Alzheimer’s Caregivers 
Research indicates that very short or long durations of sleep and inefficient sleep, are associated with higher total cholesterol and risk of type 2 diabetes and hypertension. This study tested the hypothesis that inefficient sleep or short/long sleep durations are associated with an elevated prevalence of type 2 diabetes, dyslipidemia, and hypertension in a community-dwelling sample of elderly Alzheimer’s caregivers. Participants were 126 caregivers for spouses with Alzheimer’s disease who underwent in-home sleep assessment by wrist actigraphy for 72 consecutive hours. Sleep data were averaged across the 3 days/nights; nighttime sleep and daytime napping were computed. Morning fasting blood samples were collected to determine measures of blood lipids and glucose. The average of three resting blood pressure measurements was used to estimate mean resting blood pressure. Logistic regression models including covariates related to sleep and metabolic regulation indicated that nighttime sleep duration, percent sleep at night, and daytime naps were not significantly associated with odds of having diabetes (OR, 0.92; 95%CI, 0.56–1.53; OR, 0.93; 95%CI, 0.83–1.03; OR, 1.75; 95%CI, 0.74–4.11, respectively), dyslipidemia (OR, 0.83; 95%CI, 0.57–1.20; OR, 0.99; 95%CI, 0.92–1.07; OR, 0.64; 95%CI: 0.33–1.24, respectively), or hypertension (OR, 0.97; 95%CI, 0.62–1.52; OR, 1.02; 95%CI, 0.93–1.11; OR, 1.10; 95%CI, 0.44–2.74, respectively). When categorical and combined sleep parameters were examined, there were no significant associations with any of the metabolic conditions (all p>0.05). The current study suggests that in an elderly sample of Alzheimer’s caregivers, nighttime sleep duration, nighttime sleep efficiency and daytime naps are not significantly associated with prevalent type 2 diabetes, dyslipidemia, or hypertension. As several of the associations demonstrated clinically relevant magnitudes of the associations, larger studies to more fully test these hypotheses are warranted.
doi:10.1016/j.archger.2013.02.008
PMCID: PMC3696346  PMID: 23522093
Sleep; type 2 diabetes; hypertension; dyslipidemia; caregivers
24.  Etravirine in CSF is highly protein bound 
Objectives
Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).
Methods
Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL.
Results
Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.
Conclusions
Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
doi:10.1093/jac/dks517
PMCID: PMC3625433  PMID: 23335197
HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF
25.  A Case-Controlled Study of Successful Aging in Older Adults with HIV 
The Journal of clinical psychiatry  2013;74(5):e417-e423.
OBJECTIVES
There is a growing public health interest in the aging HIV-infected (HIV+) population, although there is a dearth of research on successful aging with HIV. This study aimed to understand the risk and protective factors associated with self-rated successful aging (SRSA) with HIV.
DESIGN
Cross-sectional, case-controlled.
SETTING
HIV Neurobehavioral Research Program and the Stein Institute for Research on Aging at University of California, San Diego.
PARTICIPANTS
Eighty-three community-dwelling HIV+ and 83 demographically matched HIV-uninfected (HIV−) individuals, enrolled between 12/1/11 and 5/10/12, mean age of 59 years, primarily Caucasian males, 69% with AIDS, who had been living with an HIV diagnosis for 16 years. Diagnostic criteria for HIV/AIDS was obtained through a blood draw.
MEASUREMENTS
Participants provided ratings of SRSA as part of a comprehensive survey which included measures of physical and emotional functioning and positive psychological traits. Relationships between how the different variables related to SRSA were explored.
RESULTS
While SRSA was lower in the HIV+ individuals than their HIV− counterparts, 66% of adults with HIV reported scores of 5 or higher on a 10-point scale of SRSA. Despite worse physical and mental functioning and greater psychosocial stress among the HIV+ participants, the two groups had comparable levels of optimism, personal mastery, and social support. SRSA in HIV+ individuals was associated with better physical and emotional functioning and positive psychological factors, but not HIV disease status or negative life events.
CONCLUSION
Successful psychosocial aging is possible in older HIV+ individuals. Positive psychological traits such as resilience, optimism, and sense of personal mastery have stronger relationship with SRSA than duration or severity of HIV disease. Research on interventions to enhance these positive traits in HIV+ adults is warranted.
doi:10.4088/JCP.12m08100
PMCID: PMC3683870  PMID: 23759460
HIV/AIDS; successful aging; physical function; emotional function; positive psychological factors; depression

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