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Objective:Given the aging population of people with HIV (PWH), along with increasing rates of binge drinking among both PWH and the general older adult population, this study examined the independent and interactive effects of HIV, binge drinking, and age on neurocognition.Method:Participants were 146 drinkers stratified by HIV and binge drinking status (i.e., ≥4 drinks for women and ≥5 drinks for men within approximately 2 h): HIV+/Binge+ (n = 30), HIV−/Binge+ (n = 23), HIV+/Binge− (n = 55), HIV−/Binge− (n = 38). All participants completed a comprehensive neuropsychological battery measuring demographically-corrected global and domain-specific neurocognitive T scores. ANCOVA models examined independent and interactive effects of HIV and binge drinking on neurocognitive outcomes, adjusting for overall alcohol consumption, lifetime substance use, sex, and age. Subsequent multiple linear regressions examined whether HIV/Binge group moderated the relationship between age and neurocognition.Results:HIV+/Binge+ participants had worse global neurocognition, processing speed, delayed recall, and working memory than HIV−/Binge− participants (p’s < .05). While there were significant main effects of HIV and binge drinking, their interaction did not predict any of those neurocognitive outcomes (p’s > .05). Significant interactions between age and HIV/Binge group showed that HIV+/Binge+ participants demonstrated steeper negative relationships between age and neurocognitive outcomes of learning, delayed recall, and motor skills compared to HIV−/Binge− participants (p’s < .05).Conclusions:Results showed adverse additive effects of HIV and binge drinking on neurocognitive functioning, with older adults demonstrating the most vulnerability to these effects. Findings support the need for interventions to reduce binge drinking, especially among older PWH.

We examined the joint effects of depressive symptoms (Beck Depression Inventory-II (BDI-II)) and systemic inflammation (plasma C-reactive protein (CRP)) on longitudinal profiles of neurocognition in a cohort of 143 people with HIV (PWH) on antiretroviral therapy. Global neurocognition, processing speed, motor skills, and attention/working memory all worsened as CRP increased but only among PWH who, on average, exhibited moderate to severe depressive symptoms (BDI-II>22). Findings suggest that some PWH with chronically elevated depressive symptoms may have an inflammatory subtype of depression and a particular vulnerability to neurocognitive changes that may respond to drugs targeting inflammation or its neural sequelae.

OBJECTIVE HIV disease and methamphetamine (METH) dependence share overlapping mechanisms of neurotoxicity that preferentially compromise monoamine-rich frontostriatal circuitry. However, norepinephrine (NE) function is poorly understood in HIV and METH dependence. We evaluated associations between cerebrospinal fluid (CSF) NE and HIV, METH dependence, and neurocognition. METHODS Participants included 125 adults, stratified by HIV serostatus (HIV+/HIV-) and recent METH dependence (METH+/METH-), who underwent comprehensive neurocognitive testing and lumbar puncture. CSF NE was assayed using high-performance liquid chromatography. Multivariable regression modelled NE as a function of HIV, METH, and their interaction, adjusting for demographic and clinical factors. Pearson correlations examined relationships between NE and demographically-adjusted neurocognitive domain scores. RESULTS HIV significantly interacted with METH (P < 0.001) such that compared with HIV-/METH-, CSF NE was markedly elevated in the single risk-groups (HIV+/METH-: d = 0.96; HIV-/METH+: d = 0.79) and modestly elevated in the dual-risk group (HIV+/METH+: d = 0.48). This interaction remained significant after adjustment for lifetime depression, antidepressant use, and race/ethnicity. In the full sample, higher NE levels significantly correlated with worse global function (r = -0.19), learning (r = -0.23), and delayed recall (r = -0.18). Similar relationships between higher NE and worse neurocognition were detected in the METH- groups (ie, HIV-/METH- and HIV+/METH-) and in the virally-suppressed persons HIV+ subgroup, but not in the METH+ groups (ie, HIV-/METH+, HIV+/METH+). DISCUSSION HIV and METH independently, but not additively, relate to noradrenergic excess in the central nervous system, and perturbations to noradrenergic function may represent a pathophysiological mechanism of HIV-related neurocognitive dysfunction. Consistent with prior reports that noradrenergic excess compromises hippocampal and prefrontal function, higher NE related to worse neurocognition, even among successfully treated persons with HIV. Pharmacological and psychosocial interventions that stabilize NE function may improve neurocognition in persons with HIV.

HIV infection and drug use intersect epidemiologically, and their combination can result in complex effects on brain and behavior. The extent to which drugs affect the health of persons with HIV (PWH) depends on many factors including drug characteristics, use patterns, stage of HIV disease and its treatment, comorbid factors, and age. To consider the range of drug effects, we have selected two that are in common use by PWH: methamphetamine and cannabis. We compare the effects of methamphetamine with those of cannabis, to illustrate how substances may potentiate, worsen, or even buffer the effects of HIV on the CNS. Data from human, animal, and ex vivo studies provide insights into how these drugs have differing effects on the persistent inflammatory state that characterizes HIV infection, including effects on viral replication, immune activation, mitochondrial function, gut permeability, blood brain barrier integrity, glia and neuronal signaling. Moving forward, we consider how these mechanistic insights may inform interventions to improve brain outcomes in PWH. This review summarizes literature from clinical and preclinical studies demonstrating the adverse effects of METH, as well as the potentially beneficial effects of cannabis, on the interacting systemic (e.g., gut barrier leakage/microbial translocation, immune activation, inflammation) and CNS-specific (e.g., glial activation/neuroinflammation, neural injury, mitochondrial toxicity/oxidative stress) mechanisms underlying HIV-associated neurocognitive disorders.

This study evaluated whether a history of lifetime methamphetamine (MA) use disorder increases risk for poor sleep quality in people with or without HIV infection (HIV+/HIV-). Participants (n = 313) were stratified into four groups based on HIV status and lifetime MA use disorder diagnosis [HIV+/MA+ (n = 84); HIV+/MA- (n = 141); HIV-/MA+ (n = 16); and HIV-/MA- (n = 72)] and compared on global sleep outcomes using the Pittsburgh Sleep Quality Index (PSQI). Significant differences on global sleep were observed between HIV+/MA+ and HIV+/MA- groups, but not between the HIV- groups. Follow-up multiple regression analyses within the HIV+ subgroups examined global sleep scores as a function of MA status and clinical covariates, including those related to HIV disease and demographics. HIV+ individuals with a history of MA use disorder evidenced significantly poorer sleep quality and were more likely to be classified as problematic sleepers than those without a lifetime disorder. This was independent of depressed mood, body mass index, and viral suppression while on treatment. Poorer reported sleep quality among HIV+/MA+ was associated also with multiple adverse functional outcomes, including greater objective cognitive impairment, unemployment, clinical ratings of functional impairment, and self-reported cognitive difficulties, decreased independence in activities of daily living, and poorer overall life quality. Interventions to avoid or curtail MA use in HIV+ individuals may help protect sleep quality and improve functioning.

Older people with HIV (PWH) experience heightened risk for the acquisition of cumulative, multisystem decline, that is, frailty syndrome. Frailty relates to poorer sleep quality in the general older adult population; however, this association has yet to be explored among PWH. A cross-sectional analysis of 285 PWH ≥50 years of age (mean age 60.5 ± 7.0) examined the relationship between frailty (Fried frailty phenotype) and self-reported sleep quality [Pittsburgh Sleep Quality Index (PSQI)]. Three separate multivariable linear regression models examined global PSQI as a function of (1) frailty phenotype, (2) total number of frailty symptoms, or (3) specific individual frailty symptoms. Models covaried for demographic and biopsychosocial risk factors, including age, sex, race/ethnicity, education, premorbid verbal IQ estimate, current depressive symptoms, and diagnosis of a substance abuse disorder. Compared to nonfrail (B = 0.151; p = .021) and prefrail (B = 0.144; p = .021), frail phenotype was related to poorer sleep quality (increased global PSQI; F(5,278) = 11.34, p

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

HIV and methamphetamine (MA) use disorder are commonly comorbid and individually associated with adverse health consequences, including frailty; however, less is known about the combined effects of both conditions. The current cross-sectional study examined how HIV and lifetime MA use disorder relate to frailty and explored associations between frailty and relevant clinical outcomes (i.e., neurocognitive and everyday functioning). Participants were categorized into three groups based on HIV status and lifetime MA diagnosis: HIV+/MA+ (n = 43), HIV+/MA− (n = 75), and HIV−/MA− (n = 92). A frailty index score (representing proportion of accumulated multisystem deficits) was calculated from 27 medical and psychiatric deficits. Multiple regression was used to examine frailty index score by HIV/MA group. Additional multiple regression models examined the interaction between frailty and HIV/MA group on cognitive and everyday functioning. Comorbid HIV+/MA+ participants had higher frailty index scores than both HIV−/MA− (b = −0.13, p

Objective:Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.Method:Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.Results:When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.Conclusions:The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.

Author(s): Saloner, Rowan; Heaton, Robert K; Campbell, Laura M; Chen, Anna; Franklin, Donald; Ellis, Ronald J; Collier, Ann C; Marra, Christina; Clifford, David B; Gelman, Benjamin; Sacktor, Ned; Morgello, Susan; McCutchan, J Allen; Letendre, Scott; Grant, Igor; Fennema-Notestine, Christine; CHARTER Study Group | Abstract: ObjectiveThe influence of confounding neurocognitive comorbidities in people living with HIV (PLWH) on neuroimaging has not been systematically evaluated. We determined associations between comorbidity burden and brain integrity and examined the moderating effect of age on these relationships.DesignObservational, cross-sectional substudy of the CNS HIV Antiretroviral Therapy Effects Research cohort.MethodsA total of 288 PLWH (mean age = 44.2) underwent structural MRI and magnetic resonance spectroscopy as well as neurocognitive and neuromedical assessments. Consistent with Frascati criteria for HIV-associated neurocognitive disorders (HAND), neuromedical and neuropsychiatric comorbidity burden was classified as incidental (mild), contributing (moderate), or confounding (severe-exclusionary) to a diagnosis of HAND. Multiple regression modeling predicted neuroimaging outcomes as a function of comorbidity classification, age, and their interaction.ResultsComorbidity classifications were 176 incidental, 77 contributing, and 35 confounded; groups did not differ in HIV disease characteristics. Relative to incidental and contributing participants, confounded participants had less cortical gray matter and more abnormal white matter and ventricular cerebrospinal fluid, alongside more neuroinflammation (choline, myo-inositol) and less neuronal integrity (N-acetylaspartate). Older age exacerbated the impact of comorbidity burden: to a greater extent in the confounded group, older age was associated with more abnormal white matter (P = 0.017), less total white matter (P = 0.015), and less subcortical gray matter (P = 0.014).ConclusionNeuroimaging in PLWH reveals signatures associated with confounding neurocognitive conditions, emphasizing the importance of evaluating these among individuals with suspected HAND. Older age amplifies subcortical and white matter tissue injury, especially in PLWH with severe comorbidity burden, warranting increased attention to this population as it ages.

Author(s): Saloner, Rowan; Campbell, Laura M; Serrano, Vanessa; Montoya, Jessica L; Pasipanodya, Elizabeth; Paolillo, Emily W; Franklin, Donald; Ellis, Ronald J; Letendre, Scott L; Collier, Ann C; Clifford, David B; Gelman, Benjamin B; Marra, Christina M; McCutchan, J Allen; Morgello, Susan; Sacktor, Ned; Jeste, Dilip V; Grant, Igor; Heaton, Robert K; Moore, David J; CHARTER and HNRP Groups | Abstract: OBJECTIVES:Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA. METHODS:734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status. RESULTS:Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA. CONCLUSIONS:Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. (JINS, 2019, 25, 507-519).

Author(s): Paolillo, Emily W; Inkelis, Sarah M; Heaton, Anne; Saloner, Rowan; Moore, Raeanne C; Moore, David J | Abstract: AimsOlder persons living with HIV (PLWH) and past alcohol use disorder (AUD) are at higher risk for neurocognitive deficits compared to those with either condition alone; however, factors underlying this relationship are unknown. Given that aging potentiates multi-system damage from alcohol misuse, the current study examined whether neurocognitive functioning among older adults relates to the age at which they last met criteria for AUD (i.e. 'age of last AUD'), and whether this relationship differed by HIV serostatus.MethodsAll participants (aged between 50 and 75 years) were grouped by HIV/AUD status: 345 HIV+/AUD+, 148 HIV-/AUD+, 273 HIV+/AUD-, and 206 HIV-/AUD-. Neurocognitive functioning was assessed globally and within seven domains. Among only the two AUD+ groups, multivariable linear regressions examined the interaction between age of last AUD and HIV status on neurocognitive functioning, controlling for demographics and clinical characteristics.ResultsOlder age of last AUD related to worse processing speed among PLWH (b = -0.03; P = 0.006); however, this relationship was not significant among persons without HIV (b = 0.01; P = 0.455). The interaction between age of last AUD and HIV status did not predict neurocognitive functioning in other domains. Processing speed appeared clinically important, as slower speed related to worse everyday functioning, including more reported cognitive difficulties (r = -0.26, P l 0.001) and higher rates of functional dependence (OR = 0.87, 95%CI = 0.80-0.95, P = 0.002).ConclusionsOur novel findings, demonstrating slower processing speed when a past AUD occurred at an older age in PLWH, highlight the value in assessing older PLWH for processing speed deficits, even if other cognitive domains appear to be intact.

Background Age-related comorbidities accumulate faster in people with HIV (PWH) than in those without HIV. We evaluated whether a validated multimorbidity scale, the Charlson index, predicted neurocognitive trajectories in PWH. Methods Scaled scores of a comprehensive neuropsychological battery were averaged across all visits. Multilevel modeling examined between- and within-person predictors of global neurocognition. At the between-person level, averaged Charlson scores were examined as a predictor of neurocognitive change rate, covarying for HIV disease characteristics. Within-persons, visit-specific Charlson index was used to predict fluctuations in global neurocognition at the same and next visit, covarying for disease measures. Results Participants were 1195 PWH (mean baseline age: 43.0; SD: 9.7 years) followed for a mean of 7.1 years (range: 0.5–20.5). At the between-person level, more rapid neurocognitive worsening correlated with higher (worse) average Charlson scores (standardized β: −0.062; SE: 0.015; P = .001) and lower CD4 nadir (standardized β: 0.055; SE: 0.021; P = .011), but not viral suppression or average CD4+ lymphocytes (P > .05). At the within-person level, poorer visit-specific neurocognition was related to worse concurrent, but not preceding, Charlson scores (standardized β: −0.046; SE: 0.015; P = .003), detectable HIV viral load (standardized β: 0.018; SE: 0.006; P = .001), and higher CD4+ (standardized β: 0.043; SE: 0.009; P < .001). Conclusions The impact of comorbidities on neurocognitive decline exceeded that of HIV disease factors. Although correlative, the temporal relationships suggested that treatment of comorbidities might improve neurocognitive prognosis for PWH.

This observational cross-sectional study of 152 people with HIV (PWH) examined the effects of age and estimated duration of HIV infection (EDI) on depressive and anxiety symptoms. All participants were cisgender men and completed the Profile of Moods State (POMS), a self-report inventory of current (i.e., past week) mood states. Overall, study results confirmed higher levels of anxiety and depression in PWH compared to individuals without HIV. Age group (

Background: Comorbidities linked to aging such as diabetes mellitus, pulmonary disease and renal insufficiency accumulate at a faster rate in people with HIV (PWH) than in the general population. We evaluated whether the Charlson Index, a multimorbidity scale comprising 17 variables that has been validated in previous studies, predicted neurocognitive trajectories in PWH. Methods: Neurocognition was measured by averaging scaled scores from all assessments in a comprehensive neuropsychological battery. Multilevel modeling was used to examine between- and within-person predictors of global neurocognition. At the between-person level, average Charlson Index (averaged within each person across all their visits) was examined as a predictor of neurocognitive change over time, covarying for the effect of HIV disease characteristics (proportion of visits virally suppressed, average CD4). At the within-person level, Charlson Index was used to predict fluctuations in global neurocognition at the same and next visit, covarying for visit-specific effects of viral load detectability and current CD4 count. Results: Participants were 1195 PWH (mean age at baseline = 43·0; SD 9·7) followed for an average of over 7·1 years (SD = 5·0; range = 0·5 to 20·5 years). Between persons, higher average Charlson index scores were associated with faster rates of global neurocognitive decline (standardized β = -0·050 [0·015], p = 0·001)· This global effect was driven by significant declines in the domains of executive functioning (p = 0·001) and working memory (p = 0·007). HIV disease characteristics did not predict trajectories of neurocognitive change (ps > 0·05). At the within-person level of the model, lower current CD4+ lymphocytes (β = 0·043 [0·009]; p < 0·001), detectable plasma HIV RNA (β = 0·018 [0·006]; p = 0·001), and higher Charlson Index score (β =-0·046 [0·015]; p = 0·003) independently predicted worse concurrent global neurocognitive performance. Time-lag analyses demonstrated that increasing comorbidities occurred concurrent with, not before, neurocognitive decline. Conclusion: The impact of comorbidities on trajectories of neurocognitive decline was greater than that of HIV disease factors and independent of chronological age. Although correlative, the temporal relationship between accumulating comorbidities and neurocognitive decline suggests that interventions to prevent or ameliorate a variety of comorbidities may improve neurocognitive prognosis for PWH. Funding Statement: This publication was made possible through funding by the NIMH and NINDS by the following grants: HIV Neurobehavioral Research Center (HNRC): P30 MH62512 Manhattan HIV Brain Bank (MHBB): U24MH100931 Texas NeuroAIDS Research Center (TNRC): U24MH100930 National Neurological AIDS Bank (NNAB): U24MH100929 California NeuroAIDS Tissue Network (CNTN): U24MH100928 Data Coordinating Center (DCC): U24MH100925 Translational Methamphetamine AIDS Research Center (TMARC): P50 DA026306 Declaration of Interests: None to declare. Ethics Approval Statement: UCSD's Human Research Protections Program (irb.ucsd.edu) approved all study procedures, and all participants provided written informed consent.

Author(s): Sundermann, Erin E; Fields, Adam; Saloner, Rowan; Gouaux, Ben; Bharti, Ajay; Murphy, Claire; Moore, David J | Abstract: ObjectivesGiven the rising number of older people with HIV (PWH) and the overlap in cognitive dysfunction profiles in HIV-associated neurocognitive disorders (HAND) and Alzheimer's disease and its precursor, amnestic mild cognitive impairment (aMCI), methods are needed to distinguish aMCI/Alzheimer's disease from HAND. As an early indicator of Alzheimer's disease, we examined whether olfactory dysfunction could help to distinguish between aMCI/Alzheimer's disease and HAND among PWH.DesignAn observational cohort study.MethodsEighty-one older (≥50 years) PWH (83% men, 65% white) from the California NeuroAIDS Tissue Consortium completed the University of Pennsylvania Smell Identification Test (UPSIT; higher scores = better smell identification) and a comprehensive seven-domain neuropsychological test battery and neuromedical evaluation. HAND was classified via Frascati criteria. High aMCI risk was defined as impairment (g1.0 SD below normative mean) on two of four delayed recall or recognition outcomes (at least one recognition impairment required) from the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised. We examined UPSIT scores in relation to aMCI risk and HAND status, and continuous memory scores considering adjustments for demographics and relevant clinical or HIV disease characteristics.ResultsFifty-seven participants were classified with HAND (70%) and 35 participants were classified as high aMCI risk (43%). UPSIT scores were lower (worse) in the high versus low aMCI risk group [F (1,76) = 10.04, P = 0.002], but did not differ by HAND status [F (1,76) = 0.62, P = 0.43]. UPSIT scores positively correlated with all memory outcomes (Ps l 0.05).ConclusionOlfactory assessments may help in detecting early aMCI/Alzheimer's disease among PWH and allow for appropriate and early disease intervention.

BackgroundHIV infection and methamphetamine dependence (METH) are each associated with inflammation and premature aging, but their impact on biological aging is difficult to measure. Here we examined the impact of HIV and METH on leukocyte telomere lengths (LTL), and the correlations between LTL and other aging biomarkers.MethodsThe study was a cross-sectional analysis of 161 individuals categorized by HIV and methamphetamine (METH) dependence status into four groups: HIV-METH- (n = 50), HIV-METH+ (n = 29), HIV + METH- (n = 40), and HIV + METH+ (n = 42). We analyzed the relationships of leukocyte telomere length (telomere to single copy gene [T/S] ratio) with demographic and clinical data as well as a panel of biomarkers of inflammation and endothelial activation measured in blood and cerebrospinal fluid (CSF).ResultsHIV and METH were independently associated with shorter T/S ratio, even after adjusting for demographics and leukocyte count (R2 = 0·59, p < 0·0001). Higher plasma C-reactive protein (p = 0·0036) and CSF VCAM-1 (p = 0·0080) were also associated with shorter T/S ratio. A shorter T/S ratio was associated with higher risk for cardiovascular disease (p < 0·0001) and stroke (p < 0·0001), worse motor functioning (p = 0·037) and processing speed (p = 0·023), more depressive symptoms (p = 0·013), and higher CSF neurofilament-light (p = 0·003).ConclusionsHIV and METH dependence were each associated with shorter telomeres. After adjusting for demographics, HIV, and METH, T/S ratio remained associated with aging-related outcomes including neurocognitive impairment, neurodegeneration, risks of cardiovascular disease and stroke. While not establishing causality, this study supports using the T/S ratio as a biomarker for estimating the impact of HIV and comorbidities on long-term health.

Background HIV-related neuroinflammation has been proposed as a catalyst for dopaminergic dysregulation in mesocortical pathways, which may contribute to the pathogenesis of depression. Abnormalities in dopaminergic neurotransmission and depression are common in people with HIV (PWH), however the link between dopamine (DA) and depression in PWH is poorly characterized. This study investigated CSF dopaminergic biomarkers, specifically DA and its metabolite, homovanillic acid (HVA), and examined their relationship with depressive symptoms and CSF neuroinflammatory markers in PWH and HIV-seronegative (HIV-) individuals. Methods Participants were 102 HIV- individuals and 123 PWH (mean age = 42) who underwent neuropsychiatric evaluations and lumbar puncture. Current depression severity was classified using the Beck Depression Inventory-II (BDI-II). CSF was assayed for DA and HVA using high performance liquid chromatography and neuroinflammatory markers using immunoassays. Linear regressions modelled BDI-II scores as a function of HIV, dopaminergic biomarker z-scores, and their interaction, controlling for psychosocial factors. Correlational analyses examined dopaminergic and neuroinflammatory relationships. Results PWH had significantly higher BDI-II scores than HIV- participants. DA and HVA were not associated with HIV status but both significantly moderated the effect of HIV on BDI-II scores, such that PWH exhibited higher depressive symptoms than HIV- participants only at lower concentrations of HVA (z ≤ 0.06) and DA (z ≤ 0.11). In PWH only, lower HVA significantly correlated with higher BDI-II scores and higher neuroinflammation, including higher MCP-1 and IP-10. Conclusions Results suggest that the pathophysiology of depression in PWH differs from that in HIV- individuals. Specifically, lower central dopaminergic activity was selectively associated with greater depressive symptoms and neuroinflammation in PWH. With the rise in consideration of DA agonists for the treatment of depression, these results suggest that PWH may show a greater response to these agents than their HIV- peers.

Author(s): Kohli, Maulika; Paolillo, Emily W; Saloner, Rowan; Umlauf, Anya; Ellis, Ronald; Moore, David J | Abstract: BackgroundHeavy alcohol use negatively impacts neurocognition, but some studies report neurocognitive benefits associated with light drinking among HIV-seronegative (HIV-) older persons, suggesting a nonlinear or an inverted "J-shaped" association of alcohol consumption on neurocognition. Alcohol use is common among people with HIV (PWH); however, the association between recent "low-risk" alcohol consumption and neurocognition among PWH is poorly understood.MethodsParticipants included 310 PWH and 89 HIV- older (≥50nyears) adults who reported alcohol abstinence or "low-risk" drinking, defined per the National Institute on Alcohol Abuse and Alcoholism criteria (i.e., ≥15 drinks/wk or ≥5 drinks/d for men; ≥8 drinks/wk or ≥4ndrinks/d for women). Neurocognition was measured using global and domain-specific demographically corrected T-scores. Multiple linear regressions examined the interaction between total drinks in the last 30ndays (linear and quadratic terms) and HIV serostatus on neurocognition, covarying for age, sex, lifetime major depressive disorder, lifetime nonalcohol substance use disorders, and lifetime alcohol use disorder.ResultsTotal drinks consumed in the last 30ndays did not differ by HIV serostatus (pn=n0.202). Among HIV- older adults, quadratic effects of total drinks on neurocognition occurred such that optimal neurocognition (i.e., global function, executive function, learning, delayed recall, and motor skills) was detected at intermediate levels of "low-risk" drinking (~20 to 40 drinks), with poorer performance at the lower and higher ranges of "low-risk" consumption. In PWH, total drinks did not exhibit linear or quadratic associations with neurocognition.ConclusionsIn HIV- "low-risk" drinkers, intermediate levels of recent alcohol use were associated with better neurocognition, consistent with the inverted J-shaped association. The same nonlinear effect of recent alcohol consumption on neurocognition was absent in PWH, indicating there may be no beneficial or deleterious effects of low-risk alcohol consumption on neurocognition among PWH. Future research is warranted to examine associations between alcohol consumption and HIV-related biopsychosocial disadvantages that may supersede the neurocognitive benefits of alcohol.

Although cognitive impairment has been well documented in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) mono-infections, research on neurocognitive effects is limited in the context of HIV/HCV co-infection. The aims of this study were to explore the interplay between HIV and HCV infections in the expression of neurocognitive impairment (NCI), and to examine the differences in test performance between HIV/HCV co-infected and HIV or HCV mono-infected patients. A total of 128 participants from Southern Brazil underwent a comprehensive neuropsychological (NP) battery comprising 18 tests. Participants were grouped according to their serological status: HCV mono-infected (n = 20), HIV mono-infected (n = 48), HIV/HCV co-infected (n = 12), and HIV-/HCV-uninfected controls (n = 48). The frequencies of HIV subtypes B and C between the HIV mono-infected and HIV/HCV co-infected groups were comparable. There was greater prevalence of neuropsychological impairment among all three infection groups compared with the uninfected control group, but no statistically significant differences among mono- and co-infected groups were found. HCV infection was associated with cognitive deficits, independently of liver dysfunction. HCV infection did not show an additive effect on neurocognitive function among HIV+. NCI was independent of HCV RNA on peripheral blood, CSF, and hepatic injury. While we did not find additive global effect, in the present study, there was some evidence of additive HIV/HCV co-infection effects in speed of information processing, executive function, and verbal fluency domains when comparing the co-infected group with the other three groups. NP impairment was not dependent on HCV subtypes.

The co-occurrence of HIV and alcohol use disorder (AUD) amplifies risk for neural injury and neurocognitive deficits. However, the substantial neurocognitive heterogeneity across HIV+/AUD+ individuals suggests inter-individual differences in vulnerability to the neurotoxicity of comorbid HIV/AUD. Genetic variation in alcohol dehydrogenase (ADH), which metabolizes ethanol, may contribute to inter-individual neurocognitive variability. We evaluated associations between five ADH single-nucleotide polymorphisms (SNPs) and neurocognition in men stratified by HIV and lifetime AUD status. Neurobehavioral assessments were administered to 153 men. Three-way ANOVAs examined the interaction of HIV, AUD, and ADH SNPs on global and domain-specific demographically corrected T scores. Follow-up ANCOVAs adjusted for age, estimated verbal IQ, depression, and remote non-alcohol substance use disorders. HIV/AUD groups differed globally and for verbal fluency, working memory, executive function, and processing speed T scores specifically, with HIV+/AUD+ exhibiting the poorest performance. ADH4 (rs1126671) was associated with large effects on working memory (d = - 1.16, p = .001) and executive function (d = - 0.77, p = .028) selectively in HIV+/AUD+, which remained significant in ANCOVA models. ADH1A (rs3819197) moderated the deleterious effects of HIV+/AUD+ on processing speed such that HIV+/AUD+ related to slower information processing in A allele carriers but not GG homozygotes (ps

There is increasing awareness that self-reported sleep abnormalities are negatively associated with brain structure and function in older adults. Less is known, however, about how objectively measured sleep associates with brain structure. We objectively measured at-home sleep to investigate how sleep architecture and sleep quality related to white matter microstructure in older adults. 43 cognitively normal, older adults underwent diffusion tensor imaging (DTI) and a sleep assessment within a six-month period. Participants completed the PSQI, a subjective measure of sleep quality, and used an at-home sleep recorder (Zeo, Inc.) to measure total sleep time (TST), sleep efficiency (SE), and percent time in light sleep (LS), deep sleep (DS), and REM sleep (RS). Multiple regressions predicted fractional anisotropy (FA) and mean diffusivity (MD) of the corpus callosum as a function of total PSQI score, TST, SE, and percent of time spent in each sleep stage, controlling for age and sex. Greater percent time spent in RS was significantly associated with higher FA (β = 0.41, p = 0.007) and lower MD (β = -0.30, p = 0.03). Total PSQI score, TST, SE, and time spent in LS or DS were not significantly associated with FA or MD (p>0.13). Percent time spent in REM sleep, but not quantity of light and deep sleep or subjective/objective measures of sleep quality, positively predicted white matter microstructure integrity. Our results highlight an important link between REM sleep and brain health that has the potential to improve sleep interventions in the elderly.

ObjectiveDespite potential for dependence and adverse neurological effects, long-term benzodiazepine (BZD) use is common among people living with HIV (PLWH). As PLWH are at risk for central nervous system dysfunction, we retrospectively examined the association between BZD use and HIV-associated neurocognitive impairment (NCI).MethodsThree hundred six PLWH underwent comprehensive neurobehavioral evaluations. Current BZD use (BZD+) was determined through self-report. Using propensity scores, 153 BZD- individuals were matched to 153 BZD+ participants on demographics and medical comorbidities. Multiple regression models examined NCI and demographically adjusted neurocognitive T-scores as a function of BZD status, adjusting for estimated premorbid ability, current affective symptoms, and nadir CD4 count. Secondary analyses explored neurocognitive correlates of positive BZD urine toxicology screens (TOX+) and specific BZD agents.ResultsMedian duration of BZD use was 24 months. Current BZD use related to higher likelihood of NCI (odds ratio = 2.13, P = 0.003) and poorer global (d = -0.28, P = 0.020), processing speed (d = -0.23, P = 0.047), and motor T-scores (d = -0.32, P = 0.008). Compared with BZD-/TOX-, BZD+/TOX+ exhibited additional decrements in executive function (d = -0.48, P = 0.013), working memory (d = -0.49, P = 0.011), and delayed recall (d = -0.41, P = 0.032). For individual agents, diazepam, lorazepam, and alprazolam were most strongly associated with NCI (odds ratios >2.31).DiscussionBZD use may elevate risk for NCI in PLWH, potentially through diffuse neurocognitive slowing and acute compromise of recall and higher-order capacities. These effects are robust to psychosocial and HIV-specific factors and occur in comparison with a tightly matched BZD- group. Prospective and interventional studies should evaluate causal associations between NCI and BZD use and explore treatment alternatives to BZDs in PLWH.

Author(s): Saloner, Rowan; Marquine, Maria J; Sundermann, Erin E; Hong, Suzi; McCutchan, John Allen; Ellis, Ronald J; Heaton, Robert K; Grant, Igor; Cherner, Mariana | Abstract: ObjectiveThe Val allele of the Val158Met single-nucleotide polymorphism of the catechol-o-methyltransferase gene (COMT) results in faster metabolism and reduced bioavailability of dopamine (DA). Among persons living with HIV, Val carriers display neurocognitive deficits relative to Met carriers, presumably due to exacerbation of HIV-related depletion of DA. COMT may also impact neurocognition by modulating cardiometabolic function, which is often dysregulated among persons living with HIV. We examined the interaction of COMT, cardiometabolic risk, and nadir CD4 on neurocognitive impairment (NCI) among HIV+ men.MethodsThree hundred twenty-nine HIV+ men underwent COMT genotyping and neurocognitive and neuromedical assessments. Cohort-standardized z scores for body mass index, systolic blood pressure, glucose, triglycerides, and high-density lipoprotein cholesterol were averaged to derive a cardiometabolic risk score (CMRS). NCI was defined as demographically adjusted global deficit score of ≥0.5. Logistic regression modeled NCI as a function of COMT, CMRS, and their interaction, covarying for estimated premorbid function, race/ethnicity, and HIV-specific characteristics. Follow-up analysis included the 3-way interaction of COMT, CMRS, and nadir CD4.ResultsGenotypes were 81 (24.6%) Met/Met, 147 (44.7%) Val/Met, and 101 (30.7%) Val/Val. COMT interacted with CMRS (P = 0.02) such that higher CMRS increased risk of NCI among Val/Val [odds ratio (OR) = 2.13, P l 0.01], but not Val/Met (OR = 0.93, P g 0.05) or Met/Met (OR = 0.92, P g 0.05) carriers. Among Val/Val, nadir CD4 moderated the effect of CMRS (P l 0.01) such that higher CMRS increased likelihood of NCI only when nadir CD4 l180.DiscussionResults suggest a tripartite model by which genetically driven low DA reserve, cardiometabolic dysfunction, and historical immunosuppression synergistically enhance risk of NCI among HIV+ men, possibly due to neuroinflammation and oxidative stress.

Objectives:Methamphetamine (MA) dependence contributes to neurotoxicity and neurocognitive deficits. Although combined alcohol and MA misuse is common, how alcohol consumption relates to neurocognitive performance among MA users remains unclear. We hypothesized that alcohol and MA use would synergistically diminish neurocognitive functioning, such that greater reported alcohol consumption would exert larger negative effects on neurocognition among MA-dependent individuals compared to MA-nonusing persons.Methods:Eighty-seven MA-dependent (MA+) and 114 MA-nonusing (MA−) adults underwent neuropsychological and substance use assessments. Linear and logistic regressions examined the interaction between MA status and lifetime average drinks per drinking day on demographically corrected global neurocognitive T scores and impairment rates, controlling for recent alcohol use, lifetime cannabis use, WRAT reading performance, and lifetime depression.Results:MA+ displayed moderately higher rates of impairment and lower T scores compared to MA−. Lifetime alcohol use significantly interacted with MA status to predict global impairment (ORR = 0.70, p = .003) such that greater lifetime alcohol use increased likelihood of impairment in MA−, but decreased likelihood of impairment in MA+. Greater lifetime alcohol use predicted poorer global T scores among MA− (b = −0.44, p = .030) but not MA+ (b = 0.08, p = .586).Conclusions:Contrary to expectations, greater lifetime alcohol use related to reduced risk of neurocognitive impairment among MA users. Findings are supported by prior research identifying neurobiological mechanisms by which alcohol may attenuate stimulant-driven vasoconstriction and brain thermotoxicity. Replication and examination of neurophysiologic mechanisms underlying alcohol use in the context of MA dependence are warranted to elucidate whether alcohol confers a degree of neuroprotection.

Objective: To determine the longitudinal relationship between monocyte chemotactic protein 1 (MCP-1)/CCL2 and memory function in older adults. Methods: We examined longitudinal plasma MCP-1/CCL2 levels and a longitudinal verbal memory measure (CVLT-II 20’ recall) in a sample of 399 asymptomatic older adults (mean age = 72.1). Total visits ranged from 1 to 8, with an average time of 2.1 years between each visit, yielding 932 total observations. In order to isolate change over time, we decomposed MCP-1/CCL2 into subject-specific means and longitudinal deviations from the mean. The decomposed MCP-1/CCL2 variables were entered as predictors in linear mixed effects models, with age at baseline, sex, and education entered as covariates and recall as the longitudinal outcome. In follow-up analyses, we controlled for global cognition and APOE genotype, as well as baseline vascular risk factors. We also examined the specificity of findings by examining the longitudinal association between the MCP-1/CCL2 variables and non-memory cognitive tests. Results: Within-subject increases in MCP-1/CCL2 levels were associated with decreases in delayed recall (t = −2.65; p = 0.01) over time. Results were independent of global cognitive function and APOE status (t = −2.30, p = 0.02), and effects remained when controlling for baseline vascular risk factors (t = −1.92, p = 0.05). No associations were noted between within-subject increases in MCP-1/CCL2 levels and other cognitive domains. Conclusions: In an asymptomatic aging adult cohort, longitudinal increases in MCP-1/CCL2 levels were associated with longitudinal decline in memory. Results suggest that “healthy aging” is typified by early remodeling of the immune system, and that the chemokine, MCP-1/CCL2, may be associated with negative memory outcomes.

The present review on HIV-associated neurocognitive disorders (HAND) provides a worldwide overview of studies that have investigated the rate and neuropsychological (NP) profile of HAND research since the inception of the 2007 HAND diagnostic nomenclature. In the first part, the review highlights some of the current controversies around HAND prevalence rates. In the second part, the review critically assesses some solutions to move the field forward. In the third part, we present the cross-sectional NP profile in non-Western HIV+ cohorts and in relation to Western cohorts’ findings. The adopted global perspective highlights the successful expansion of NP studies in HIV infection to culturally diverse low- to medium-income countries with high HIV burden. These studies have produced interestingly similar rates of HAND whether patients were naïve or treated and/or virally suppressed compared to the rich income countries where the NP research in NeuroHIV has originated. The perspective also demonstrates that globally, the group which is the most representative of the HIV epidemic, and thus at risk for HAND are persons with chronic HIV infection and survivors of past immunosuppression, while in relative terms, those who have been treated early with long-term viral suppression represent a minority. In the last part, we present a review of the naturalistic longitudinal NP global studies in HIV+cohorts, discuss the role of longitudinal design in solving issues around the question of asymptomatic neurocognitive impairment, and the question of biomarker discovery. Finally, we conclude by calling for greater methods and data harmonization at a global level. (JINS, 2017,23, 860–869)

Objective Despite potential for dependence and adverse neurological effects, long-term benzodiazepine (BDZ) use is common among persons living with HIV (PLWH). As PLWH are at risk for CNS dysfunction, we retrospectively examined the association between BDZ use and HIV-associated neurocognitive disorders (HAND). Methods 306 PLWH (mean age = 45.1 years) underwent comprehensive neurobehavioral evaluations. Current BDZ use (BDZ+) was determined via self-report. Using propensity scores, 153 BDZ- individuals were matched to 153 BDZ+ participants on demographics, HIV disease characteristics, and comorbidities. Multiple regression models examined HAND and demographically-adjusted neurocognitive T-scores as a function of BDZ group, adjusting for estimated premorbid ability, current affective symptoms, and nadir CD4 count. Secondary analyses explored neurocognitive correlates of positive BDZ urine toxicology screens (TOX+). Results Median BDZ use was 24 months. Compared to BDZ-, BDZ+ had higher likelihood of HAND (OR = 2.14; p = .003) and poorer global (d = -0.33, p = .005), processing speed (d = -0.29, p = .013), and motor T-scores (d = -0.35, p = 0.003). Compared to BDZ+/TOX-, BDZ+/TOX+ users exhibited additional decrements in global (p = .033), executive function (p = .019), and delayed recall T-scores (p = .006). Conclusions BDZ use may elevate risk for HAND, potentially through diffuse neurocognitive slowing and acute compromise of recall and higher-order capacities. These effects are robust to psychosocial and HIV-specific factors and occur in comparison to a tightly-matched BDZ- group. Indications for BDZs (e.g., insomnia) may also impact neurocognition and/or manifest from latent neuropathology. Longitudinal studies should evaluate potential causal associations between HAND and BDZs. Given the extent of BDZ use and possibility of neurocognitive recovery post-abstinence, interventional studies should explore treatment alternatives to BDZs in PLWH.