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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.  The Cerebrospinal Fluid HIV Risk Score for Assessing Central Nervous System Activity in Persons With HIV 
American Journal of Epidemiology  2014;180(3):297-307.
Detectable human immunodeficiency virus (HIV) RNA in the cerebrospinal fluid (CSF) is associated with central nervous system (CNS) complications. We developed the CSF HIV risk score through prediction modeling to estimate the risk of detectable CSF HIV RNA (threshold >50 copies/mL) to help identify persons who might benefit most from CSF monitoring. We used baseline data from 1,053 participants receiving combination antiretroviral therapy who were enrolled in the 6-center, US-based CNS HIV Antiretroviral Therapy Effects Research (CHARTER) prospective cohort in 2004–2007. Plasma HIV RNA, CNS penetration effectiveness, duration of combination antiretroviral therapy, medication adherence, race, and depression status were retained correlates of CSF HIV RNA, displaying good discrimination (C statistic = 0.90, 95% confidence interval (CI): 0.87, 0.93) and calibration (Hosmer-Lemeshow P = 0.85). The CSF HIV risk score ranges from 0 to 42 points, with a mean of 15.4 (standard deviation, 7.3) points. At risk scores greater than 25, the probability of detecting CSF HIV RNA was at least 42.9% (95% CI: 36.6, 49.6). For each 1-point increase, the odds of detecting CSF HIV RNA increased by 26% (odds ratio = 1.26, 95% CI: 1.21, 1.31; P < 0.01). The risk score correlates with detection of CSF HIV RNA. It represents an advance in HIV management and monitoring of CNS effects, providing a potentially useful tool for clinicians.
doi:10.1093/aje/kwu098
PMCID: PMC4108039  PMID: 24966216
central nervous system; cerebrospinal fluid; cerebrospinal fluid human immunodeficiency virus risk score; human immunodeficiency virus; prediction model
3.  Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline 
Neurology  2014;82(23):2055-2062.
Objective:
While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline).
Methods:
A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7–63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood.
Results:
The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1–3.6; p = 0.02) for SR, 5.8 (CI 3.2–10.7; p < 0.0001) for PB, and 3.2 (CI 2.0–5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not.
Conclusions:
This longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression.
doi:10.1212/WNL.0000000000000492
PMCID: PMC4118496  PMID: 24814848
4.  An Active Lifestyle is Associated with Better Neurocognitive Functioning in Adults Living with HIV-infection 
Journal of neurovirology  2014;20(3):233-242.
Studies of healthy adults show that engagement in physical, social, and mental activities is associated with better cognitive outcomes, suggesting these activities may increase cognitive reserve. Given the prevalence and real-world impact of HIV-associated neurocognitive disorders (HAND), the present study examined the association between neurocognitive outcomes and self-reported proxies for physical exercise, social activity, and mental activity (employment was used as a proxy for mental activity) among 139 HIV-infected adults (Mage = 48.7; 48% age 50+). Participants completed a neuromedical and neuropsychological battery and were classified based on the number of self-reported active lifestyle factors (ALFs; 0 to 3), including physical exercise, social activity, and current employment. The association between ALFs and both demographically-adjusted average neuropsychological T-scores and HAND diagnoses were examined. Results revealed that an increased number of ALFs was associated with better global neurocognitive performance as well as a lower prevalence of HAND. These cross-sectional findings suggest that an active engagement in life may bolster neurocognitive functioning, perhaps by enhancing cognitive and/or brain reserve. However, an alternative explanation might be that persons with better neurocognitive functioning are more inclined and able to engage in these life activities. Future studies should utilize neuroimaging methodology, longitudinal data, and interventional approaches to establish cause-effect relationships and uncover the neural mechanisms whereby physical, social, and mental stimulation may protect neurocognition via cognitive reserve among those living with HIV.
doi:10.1007/s13365-014-0240-z
PMCID: PMC4040153  PMID: 24554483
cognitive reserve; neuroAIDS; cognitive impairment; protective factors
5.  HIV-Associated Distal Neuropathic Pain is Associated with Smaller Total Cerebral Cortical Gray Matter 
Journal of neurovirology  2014;20(3):209-218.
Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50% of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging (MRI) volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (R = −0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.
doi:10.1007/s13365-014-0236-8
PMCID: PMC4040150  PMID: 24549970
HIV Distal Neuropathic Pain; Structural MRI; Cortical Volume
6.  HIV protease inhibitor exposure predicts cerebral small vessel disease 
AIDS (London, England)  2014;28(9):1297-1306.
Objective
HIV-associated neurocognitive disorders (HAND) remain prevalent in patients who receive highly active antiretroviral therapy (HAART) and may be associated with cumulative exposure to antiretroviral medications and other factors. We proposed that chronic toxic effects of antiretroviral drugs could contribute to cerebral small vessel disease (CSVD), which might be one of the key underpinnings of HAND.
Design
Clinicopathological cross-sectional study of HIV-infected adults in the California NeuroAIDS Tissue Network.
Methods
We employed multivariable logistic regression methods to determine associations between HAART exposure (protease inhibitor [PI]-based, non-PI-based, or no HAART) and CSVD occurrence (standard histopathology: moderate/severe, mild, or absent). We also associated HAND (relative to normal cognition) with CSVD, HIV-related neuropathologic changes, older age at death (≥50 years), sex, or hepatitis C virus infection.
Results
We found that both mild and moderate/severe CSVD were associated with PI-based HAART exposure after adjusting for diabetes mellitus [odds ratio (OR) 2.8 [95% confidence interval (CI) 1.03, 7.9] and 2.6 [95% CI 1.03, 6.7], respectively, n=134]. Moderate/severe CSVD was associated with diabetes after adjusting for HAART exposure (OR 7.4 [95% CI 1.6, 70.7], n=134). Notably, HAND was associated with mild CSVD (OR 4.8 [95% CI 1.1, 21.2], n=63), which remained statistically significant after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age.
Conclusion
PI-based HAART exposure may increase the risk of CSVD and thereby neurocognitive impairment in HIV-infected adults. Besides the possible direct toxicity to cerebral small vessels, PI-based HAART may contribute indirectly to CSVD by inducing metabolic abnormalities.
doi:10.1097/QAD.0000000000000262
PMCID: PMC4071161  PMID: 24637542
aging; antiretroviral; cognition; HIV dementia; protease inhibitor; small vessel disease
7.  Successful Cognitive Aging and Health-Related Quality of Life in Younger and Older Adults Infected with HIV 
AIDS and behavior  2014;18(6):1186-1197.
OBJECTIVE
Neurocognitive impairments commonly occur and adversely impact everyday functioning in older adults infected with HIV, but little is known about successful cognitive aging (SCA) and its health-related quality of life (HRQoL) correlates.
METHOD
Seventy younger (≤ 40 years) and 107 older (≥ 50 years) HIV+ adults, as well as age-matched seronegative comparison groups of younger (N=48) and older (N=77) subjects completed a comprehensive battery of neuropsychological, psychiatric, medical, and HRQoL assessments. SCA was operationalized as the absence of both performance-based neurocognitive deficits and self-reported symptoms (SCA-ANDS) as determined by published normative standards.
RESULTS
A stair-step decline in SCA-ANDS was observed in accordance with increasing age and HIV serostatus, with the lowest rates of SCA-ANDS found in the older HIV+ group (19%). In both younger and older HIV+ adults, SCA-ANDS was strongly related to better mental HRQoL.
CONCLUSION
HIV infection has additive adverse effects on SCA, which may play a unique role in mental well-being among HIV-infected persons across the lifespan.
doi:10.1007/s10461-014-0743-x
PMCID: PMC4020963  PMID: 24633788
Successful aging; well-being; neuropsychological assessment; AIDS-related dementia
8.  Longitudinal Relationship of Low Leisure Satisfaction but not Depressive Symptoms With Systemic Low-Grade Inflammation in Dementia Caregivers 
Objectives.
This study aimed to further elucidate the biobehavioral mechanisms linking dementia caregiving with an increased cardiovascular disease risk. We hypothesized that both elevated depressive symptoms and a behavioral correlate of depression, low leisure satisfaction, are associated with systemic inflammation.
Method.
We studied 121 elderly Alzheimer’s disease caregivers who underwent 4 annual assessments for depressive symptoms, leisure satisfaction, and circulating levels of inflammatory markers. We used mixed-regression analyses controlling for sociodemographic and health-relevant covariates to examine longitudinal relationships between constructs of interest.
Results.
There were inverse relationships between total leisure satisfaction and tumor necrosis factor-α (TNF-α; p = .047), interleukin-8 (IL-8; p < .001), and interferon-γ (IFG; p = .020) but not with IL-6 (p = .21) and C-reactive protein (p = .65). Lower enjoyment from leisure activities was related to higher levels of TNF-α (p = .045), IL-8 (p < .001), and IFG (p = .002), whereas lower frequency of leisure activities was related only to higher IL-8 levels (p = .023). Depressive symptoms were not associated with any inflammatory marker (all p values > .17). Depressive symptoms did not mediate the relationship between leisure satisfaction and inflammation.
Discussion.
Lower satisfaction with leisure activities is related to higher low-grade systemic inflammation. This knowledge may provide a promising way of improving cardiovascular health in dementia caregivers through behavioral activation treatments targeting low leisure satisfaction.
doi:10.1093/geronb/gbt020
PMCID: PMC3983912  PMID: 23650246
Biomarkers; Blood coagulation; Cardiovascular disease; Depression; Inflammation; Psychological stress.
9.  Reduced Activity Restriction Buffers the Relations Between Chronic Stress and Sympathetic Nervous System Activation 
Objectives.
Caregivers of dementia patients are at risk for developing cardiovascular disease (CVD), and this risk increases the longer they provide care. Greater perceptions that caregiving restricts social/recreational activities (i.e., activity restriction [AR]) has been associated with poorer health, and AR may exacerbate the relations between stress and health outcomes. The current study examined the interactive role of greater exposure to stress and increased AR on plasma catecholamine (CAT) levels: norepinephrine (NE) and epinephrine (EPI).
Method.
A total of 84 dementia caregivers completed a standard assessment battery, and a nurse collected blood, which was assayed for NE and EPI. Separate regressions for NE and EPI were used to determine whether the relations between years caregiving and CATs were greater in those with high versus low AR.
Results.
A significant interaction was found between years caregiving and AR in predicting resting EPI (p = .032) but not resting NE (p = .103). Post hoc analyses indicated that years caregiving was significantly associated with EPI when AR was high (p = .008) but not when AR was low (p = .799). Additionally, years caregiving was not significantly associated with NE when AR was high or low.
Discussion.
The subjective experience of AR can play an important role in determining risk for detrimental physical health outcomes, particularly CVD risk.
doi:10.1093/geronb/gbt028
PMCID: PMC3983913  PMID: 23685924
Activity restriction; Catecholamines; SNS; Stress.
10.  Shallow Encoding and Forgetting Are Associated with Dependence in Instrumental Activities of Daily Living Among Older Adults Living with HIV Infection 
Aging and HIV are both risk factors for memory deficits and declines in real-world functioning. However, we know little about the profile of memory deficits driving instrumental activities of daily living (IADL) declines across the lifespan in HIV. This study examined 145 younger (<50 years) and 119 older (≥50 years) adults with HIV who completed the California Verbal Learning Test-Second Edition (CVLT-II), the Wechsler Memory Scale-Third Edition Logical Memory subtest (WMS-III LM), and a modified Lawton and Brody ADL questionnaire. No memory predictors of IADL dependence emerged in the younger cohort. In the older group, IADL dependence was uniquely associated with worse performance on all primary CVLT-II variables, as well as elevated recency effects. Poorer immediate and delayed recall of the WMS-III LM was also associated with IADL dependence, although recognition was intact. Findings suggest older HIV-infected adults with shallow encoding and forgetting are at risk for IADL dependence.
doi:10.1093/arclin/acu009
PMCID: PMC4000232  PMID: 24695591
Aging; Disability; Everyday functioning; Learning and memory
11.  HIV infection is associated with attenuated frontostriatal intrinsic connectivity 
Objective
HIV-associated cognitive impairments are prevalent, and are consistent with injury to both frontal cortical and subcortical regions of the brain. The current study aimed to assess the impact of HIV infection on functional connections within the frontostriatal network, circuitry hypothesized to be highly vulnerable to HIV infection.
Method
Fifteen HIV-positive and 15 demographically matched control participants underwent 6 minutes of resting-state functional magnetic resonance imaging (RS-fMRI). Multivariate group comparisons of age-adjusted estimates of connectivity within the frontostriatal network were derived from BOLD data for dorsolateral prefrontal cortex (DLPFC), dorsal caudate and mediodorsal thalamic regions of interest. Whole-brain comparisons of group differences in frontostriatal connectivity were conducted, as were pairwise tests of connectivity associations with measures of global cognitive functioning and clinical and immunological characteristics (nadir and current CD4 count, duration of HIV infection, plasma HIV RNA).
Results
HIV – associated reductions in connectivity were observed between the DLPFC and the dorsal caudate, particularly in younger participants (< 50 years, N = 9). Seropositive participants also demonstrated reductions in dorsal caudate connectivity to frontal and parietal brain regions previously demonstrated to be functionally connected to the DLPFC. Cognitive impairment, but none of the assessed clinical/immunological variables, was associated with reduced frontostriatal connectivity.
Conclusions
In conclusion, our data indicate that a diagnosis of HIV is associated with attenuated intrinsic frontostriatal connectivity. Intrinsic connectivity of this network may therefore serve as a marker of the deleterious effects of HIV infection on the brain, possibly via HIV-associated dopaminergic abnormalities. These findings warrant independent replication in larger studies.
doi:10.1017/S1355617715000156
PMCID: PMC4400233  PMID: 25824201
Magnetic Resonance Imaging; Resting-state; Dorsolateral Prefrontal Cortex; Caudate Nucleus; Thalamus; Dopamine
12.  Corrigendum 
Journal of neurovirology  2010;16(2):185-188.
doi:10.3109/13550284.2010.481820
PMCID: PMC4386597  PMID: 20443740
13.  Absence of neurocognitive impairment in a large Chinese sample of HCV-infected injection drug users receiving methadone treatment 
Drug and alcohol dependence  2014;137:29-35.
Background
Prior research has demonstrated neuropsychological (NP) impairment in persons with histories of injection drug use (IDU), hepatitis C virus (HCV) infection, and methadone maintenance treatment (MMT), individually, but little is known about the NP effects of these three risk factors in combination. This issue is particularly important in China, which is addressing its highly HCV-comorbid IDU epidemic with widespread government sponsored MMT, especially in light of recent evidence suggesting that methadone may be neuroprotective in some circumstances.
Methods
We administered a comprehensive NP test battery to 195 Chinese heroin IDU individuals taking MMT (IDU+ group), the majority of whom were also HCV+ (87%; n = 169), and compared their NP performance to that of 198 demographically comparable, non-IDU Chinese controls (IDU− group). All participants in both groups tested negative for HIV infection, which is also a common comorbidity in the Chinese IDU population.
Results
The IDU+ group did not have an increased rate of global NP impairment, or perform significantly worse on any individual NP test measure. Within the IDU+ group, liver disease characteristics and reported details of heroin use were not significantly associated with NP performance.
Conclusion
Failure to detect NP impairment in IDU+ subjects with or without HCV infection was surprising, particularly considering the previously demonstrated sensitivity of our NP battery to neurocognitive disorders associated with HIV infection in China. One possible explanation, which should be explored in future research, is the potential neuroprotective effect of methadone in the context of HCV infection and/or heroin withdrawal.
doi:10.1016/j.drugalcdep.2013.12.021
PMCID: PMC3961522  PMID: 24508003
HCV; Neurocognitive impairment; China; Injection drugs
14.  Second-Language Fluency Predicts Native Language Stroop Effects: Evidence from Spanish–English Bilinguals 
Studies have shown reduced Stroop interference in bilinguals compared to monolinguals defined dichotomously, but no study has explored how varying degrees of second language fluency, might affect linguistic inhibitory control in the first language. We examined effects of relative English fluency on the ability to inhibit the automatic reading response on the Golden version of the Stroop Test administered in Spanish. Participants were 141 (49% male) adult native Spanish speakers from the U.S.–Mexico border region (education range =8–20 and age range =20–63). A language dominance index was calculated as the ratio of English words to total words produced in both languages using the Controlled Oral Word Association Test with letters PMR in Spanish and FAS in English. Greater degree of English fluency as measured by the dominance index predicted better speed on the Stroop incongruent trial independent of education effects. On the other hand, neither the dominance index nor education predicted performance on the word reading and color-naming trials. These results suggest an advantage in inhibitory control among those with greater second-language ability.
doi:10.1017/S1355617714000058
PMCID: PMC4296729  PMID: 24622502
Bilingualism; Hispanic Americans/psychology; Executive function; Verbal fluency; Regression analysis; Educational status; Spanish speaker
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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