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BackgroundPersons with HIV (PWH) have both more frequent depression and higher levels of plasma inflammatory biomarkers compared to persons without HIV (PWoH). Inflammation and depressive symptoms are linked, including in PWH; however, it is unclear whether these associations differ by HIV serostatus and biological sex.MethodsSix plasma inflammatory biomarkers were assessed using samples from PWH and PWoH who participated in six NIH-funded studies through the UCSD HIV Neurobehavioral Research Program (HNRP) from 2011 to 2019. Factor analysis was performed to identify intercorrelated groups of biomarkers. Factors and their components were then examined for relationships with Beck Depression Inventory-II (BDI-II) and modifying effects of sex or HIV serostatus using multivariable linear regression, adjusting for demographics, substance use diagnoses, and relevant co-morbidities.ResultsParticipants included 150 PWH (age = 48.3 ± 13.1 yr; 88% biologically male) and 138 PWoH (age = 46.3 ± 15.9; 56% male). Two inflammatory factors were identified: Factor 1 loaded on interleukin-6 (IL-6), C-reactive protein (CRP), and D-dimer; Factor 2 loaded on interleukin-8, chemokine C-C ligand 2 (CCL2), and chemokine C-X-C ligand 10 (CXCL10). Sex modified the effect of Factor 1 on BDI-II, with a more positive association for men than women (p = 0.04). No significant association between Factor 2 and BDI-II was found. Of the biomarkers in Factor 1, only IL-6 was significantly associated with BDI-II and was modified by sex (p = 0.003). In sex-stratified analysis, a positive association was found for men (β = 5.42; 95% confidence interval = [1.32, 9.52]) but not women (β = -3.88; 95% C.I. = [-11.02, 3.26]). No HIV-related interactions were detected.InterpretationWe identified a depression-associated inflammatory factor present in both PWH and PWoH, consistent with prior studies of PWH only. The association was driven by a correlation between IL-6 and depression exclusively in men, suggesting that the depression-inflammation link differs by sex. Future studies of depression etiology or treatment, including those on persons with HIV, should consider the impact of biological sex in both design and analysis.

BackgroundAnemia is linked to neurocognitive impairment (NCI) in people with HIV (PWH), but its impact within specific ability domains, and in diverse populations with HIV, is uncertain.MethodsParticipants included 1339 PWH enrolled in observational HIV cohort studies with a mean of 3 comprehensive neurocognitive assessments over 30 months. Global and domain-specific neurocognitive function were assessed by the global deficit score and domain deficit score (GDS and DDS, respectively) or as GDS-defined or DDS-defined NCI (GDS ≥ 0.5, DDS > 0.5). Time-dependent associations of anemia or red-cell indices with neurocognitive function were evaluated by multivariable regression.ResultsThe mean age at entry was 43.6 years (85% male, 23.9% Hispanic, 16.7% African ancestry by self-report, and 69.8% virally suppressed). Anemia occurred at entry in 297 (22.2%) and developed subsequently in another 129 (9.6%). Anemia (present in 26.8% of cognitively impaired PWH at entry) and lower hemoglobin were associated with higher (worse) GDS values; the association for anemia persisted after multivariable adjustment and in virally suppressed persons ( P < 0.0001). Anemia was also associated with reduced processing speed, motor function, learning, delayed recall, working memory (all P < 0.01), executive function ( P = 0.021), and verbal fluency ( P = 0.035), and these findings persisted in longitudinal analyses (adjusted P < 0.01 for all domains, except verbal fluency). Higher mean corpuscular volume and mean corpuscular hemoglobin were associated with less impairment in learning and recall (all P < 0.05).ConclusionsAnemia in diverse and virally suppressed PWH associates with reduced neurocognitive performance in multiple domains, cross-sectionally and over time. The impact of identifying and treating anemia to prevent or slow neurocognitive decline in PWH should be prospectively evaluated.

BackgroundNeurofilament light (NFL) chain concentrations, reflecting axonal damage, are seen in several polyneuropathies but have not been studied in human immunodeficiency virus (HIV) distal sensory polyneuropathy (DSP). We evaluated NFL in cerebrospinal fluid (CSF) and plasma in relation to DSP in people with HIV (PWH) from 2 independent cohorts and in people without HIV (PWoH).MethodsCohort 1 consisted of PWH from the CHARTER Study. Cohort 2 consisted of PWH and PWoH from the HIV Neurobehavioral Research Center (HNRC). We evaluated DSP signs and symptoms in both cohorts. Immunoassays measured NFL in CSF for all and for plasma as well in Cohort 2.ResultsCohort 1 consisted of 111 PWH, mean ± SD age 56.8 ± 8.32 years, 15.3% female, 38.7% Black, 49.6% White, current CD4+ T-cells (median, interquartile range [IQR]) 532/µL (295, 785), 83.5% with plasma HIV RNA ≤50 copies/mL. Cohort 2 consisted of 233 PWH of similar demographics to PWH in Cohort 1 but also 51 PWoH, together age 58.4 ± 6.68 years, 41.2% female, 18.0% Black, Hispanic, non-Hispanic White 52.0%, 6.00% White. In both cohorts of PWH, CSF and plasma NFL were significantly higher in both PWH with DSP signs. Findings were similar, albeit not significant, for PWoH. The observed relationships were not explained by confounds.ConclusionsBoth plasma and CSF NFL were elevated in PWH and PWoH with DSP. The convergence of our findings with others demonstrates that NFL is a reliable biomarker reflecting peripheral nerve injury. Biomarkers such as NFL might provide, validate, and optimize clinical trials of neuroregenerative strategies in HIV DSP.

Modern antiretroviral therapy (ART) has increased longevity of people with HIV and shifted the age distribution of the HIV pandemic upward toward that of the general population. This positive development has also led to concerns about premature and/or accelerated neurocognitive and physical ageing due to the combined effects of chronic HIV, accumulating comorbidities, adverse effects or possible toxicities of ART and biological ageing. Here we present results of comprehensive assessments over 12 years of 402 people with HIV in the CNS HIV ART Effects Research (CHARTER) programme, who at follow-up were composed of younger (

ObjectiveDistal sensory polyneuropathy (DSP) is a disabling consequence of human immunodeficiency virus (HIV), leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms; however, there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized.MethodsThis was a prospective longitudinal study of 265 people with HIV (PWH) enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates.ResultsMean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART), and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [95% CI 1.51, 2.58]).ConclusionsParesthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain.

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

Metabolic syndrome (MetS), a constellation of related metabolic risk factors, is a common comorbidity associated with cognitive difficulty in people living with HIV (PLWH). Neurobehavioral disturbances (e.g., behavioral manifestations of frontal-subcortical dysfunction) are also prevalent in HIV, yet the role MetS might play in HIV-associated neurobehavioral disturbances is unknown. Thus, we examined the link between MetS and neurobehavioral disturbances in PLWH. Participants included 215 adults (117 PLWH, 98 HIV-uninfected), aged 36 to 65 years, from a cohort study at the University of California San Diego. Using the Frontal Systems Behavior Scale, we captured neurobehavioral disturbances (apathy, disinhibition, and executive dysfunction). MetS was defined by the National Cholesterol Education Program's Adult Treatment Panel-III criteria. Covariates examined included demographic, neurocognitive impairment, and psychiatric characteristics. When controlling for relevant covariates, both HIV serostatus and MetS were independently associated with greater apathy and executive dysfunction. HIV, but not MetS, was associated with greater disinhibition. The present findings suggest an additive effect of HIV and MetS on specific neurobehavioral disturbances (apathy and executive dysfunction), underscoring the importance of identifying and treating both HIV and MetS to lessen central nervous system burden among PLWH.

Background and objectivesPeople with HIV (PWH) often suffer from depressive symptoms which have a deleterious impact on numerous domains including antiretroviral adherence and quality of life. In the general population, a treatment-resistant phenotype of depression is associated with systemic inflammation, which is of considerable importance as it responds favorably to anti-inflammatory medications. Aging PWH experience increasing inflammation. We sought to evaluate the impact of chronic inflammation in aging PWH on depressed mood.MethodsPWH were recruited at 6 U.S. academic medical centers. Depressed mood was assessed using the Beck Depression Inventory (BDI)-II. Inflammatory biomarkers measured at the 12-year follow-up visit in blood plasma using immunoassays were neopterin, sTNFRII, d-dimer, IL-6, CRP, MCP-1, sCD14 and sCD40L. Factor analyses with oblique Equamax rotation were employed to reduce the dimensionality of the biomarkers.ResultsParticipants were 78 PWH, 14 (17.9%) women, 40 (51.3%) non-White, mean age 55.3 (±SD 8.29), with a nadir and current CD4 of 134 (IQR 36, 204) and 567 (316, 797), respectively. 80.5% were virally suppressed. A factor analysis of the eight inflammatory biomarkers in plasma at the 12-year follow-up visit yielded 3 Factors, with Factor 1 loading on neopterin and sTNFRII, Factor 2 loading on d-dimer, IL-6 and CRP, and Factor 3 loading on sCD40L (MCP-1 and sCD14 did not appear in any of the factors). Univariate regressions of each factor vs BDI-II scores yielded significance only for Factor 2 (r ​= ​0.295; p ​= ​0.0083 (Bonferroni-adjusted p ​= ​0.0261). Of the Factor 2 component biomarkers, BDI-II scores correlated significantly with d-dimer and IL-6, but not CRP. Women had worse BDI-II scores (p ​= ​0.0127). In a logistic regression with sex and Factor 2, both variables were significant (sex p ​= ​0.0246, Factor 2 p ​= ​0.0168). The relationship between Factor 2 and BDI was significant for men (r ​= ​0.348 [95% CI 0.111, 0.547]; p ​= ​0.0049), but not women (r ​= ​0.0580 95% CI -0.488, 0.571]; p ​= ​0.844). Viral suppression was not significant in the multivariate model.ConclusionsSome PWH with depressed mood have elevated markers of inflammation in blood. Men showed this relationship, while women did not. Together with previous findings that an inflammatory depression phenotype responds to treatment with anti-inflammatory medications, our findings suggest that treatment with anti-inflammatory medications might benefit at least a subset of depressed PWH who have a high inflammatory biomarker profile, as well as poor response to antidepressant medications alone, and that the pathophysiology of depression in men and women with HIV may differ.

ObjectiveDistal sensory polyneuropathy (DSP) and neuropathic pain are important clinical concerns in virally suppressed people with HIV. We determined how these conditions evolved, what factors influenced their evolution, and their clinical impact.MethodsAmbulatory, community-dwelling HIV seropositive individuals were recruited at six research centers. Clinical evaluations at baseline and 12 years later determined neuropathy signs and distal neuropathic pain (DNP). Additional assessments measured activities of daily living and quality of life (QOL). Factors potentially associated with DSP and DNP progression included disease severity, treatment, demographics, and co-morbidities. Adjusted odds ratios were calculated for follow-up neuropathy outcomes.ResultsOf 254 participants, 21.3% were women, 57.5% were non-white. Mean baseline age was 43.5 years. Polyneuropathy prevalence increased from 25.7% to 43.7%. Of 173 participants initially pain-free, 42 (24.3%) had incident neuropathic pain. Baseline risk factors for incident pain included unemployment (OR [95% CI], 5.86 [1.97, 17.4]) and higher baseline body mass index (BMI) (1.78 [1.03, 3.19] per 10-units). Participants with neuropathic pain at follow-up had significantly worse QOL and greater dependence in activities of daily living than those who remained pain-free.InterpretationHIV DSP and neuropathic pain increased in prevalence and severity over 12 years despite high rates of viral suppression. The high burden of neuropathy included disability and poor life quality. However, substantial numbers remained pain-free despite clear evidence of neuropathy on exam. Protective factors included being employed and having a lower BMI. Implications for clinical practice include promotion of lifestyle changes affecting reversible risk factors.

ObjectiveFrascati 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.MethodTwo 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.ResultsWhen 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.ConclusionsThe 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.

BackgroundFew large projects have evaluated the factors that influence the HIV RNA concentrations (viral load) in cerebrospinal fluid (CSF) during antiretroviral therapy (ART) over time. We aimed to determine the correlates of HIV RNA in CSF in a large cohort.MethodsWe analysed longitudinal data from adults living with HIV in the US CHARTER cohort. Participants in the CHARTER study were recruited from six US academic medical centres-in Baltimore (MD), Galveston (TX), New York (NY), St Louis (MO), San Diego (C92A), and Seattle (WA). Participants in this study had been assessed at least three times between Sept 4, 2003, and Sept 14, 2010, and were taking ART and underwent venous and lumbar puncture with measurement of HIV RNA concentration at all assessments. The lower limit of quantification of the HIV RNA assays was 50 copies per mL. Data were analysed with longitudinal mixed effects logistic regression to identify correlates of HIV RNA concentration (as a binary [detectable or not] and as a continuous variable) in CSF over time. We tested demographic characteristics, plasma HIV RNA, nadir and current CD4 cell count in blood, current CD8 cell count in blood, estimated duration of HIV infection, AIDS diagnosis, duration of ART, adherence to ART, ART characteristics, and CSF characteristics as potential correlates.FindingsAt the time of analysis, 2207 assessments from 401 participants met the criteria for inclusion in this study. Mean duration of observation was 33·7 months (range 12-84). HIV RNA concentrations in 710 (32·2%) plasma specimens and in 255 (11·6%) CSF specimens were greater than the lower limit of quantification. The best multivariate model of HIV RNA concentration in CSF greater than the lower limit of quantification over time included increased plasma HIV RNA concentration (odds ratio 18·0 per 1 log10 copy per mL, 95% CI 11·3 to 28·8; p

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.

ObjectivesStudies 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.Methods734 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.ResultsNeurocognitive 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.ConclusionsDespite 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).

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection.

BackgroundHIV infection may result in neurocognitive deficits, but the effects of pulmonary tuberculosis (TB+), a common comorbid condition in HIV infection, on cognition in HIV infections are unknown. Accordingly, we examined the effects of TB+, on neurocognitive functioning in HIV-infected (HIV+) Zambian adults.SettingAll participants were drawn from HIV clinics in and around Lusaka, the capital of Zambia.MethodsParticipants were 275 HIV+, of whom 237 were HIV+ and TB-negative (HIV+/TB-), and 38 also had pulmonary TB+ (HIV+/TB+). Controls were 324 HIV- and TB-uninfected (HIV-) healthy controls. All HIV+ participants were prescribed combination antiretroviral treatment (cART). Published, demographically corrected Zambian neuropsychological norms were used to correct for effects of age, education, sex, and urban/rural residence.ResultsNeuropsychological deficits, assessed by global deficit scores, were more prevalent in this order: 14% (46 of 324) of HIV- controls, 34% (80 of 237) of HIV+/TB-, and 55% (21 of 38) of HIV+/TB+ group. Thus, both HIV-infected groups evidenced more impairment than HIV- controls, and the HIV+/TB+ group had a higher rate of neurocognitive impairment than the HIV+/TB- group. HIV+/TB+ patients were more likely to be male, younger, less-educated, and have lower CD4 counts and detectable HIV RNA in blood compared with the HIV+/TB- patients.ConclusionsIn HIV infection, TB may contribute to cognitive impairment, even after controlling for lower CD4 counts and viral load. Thus, systemic inflammation from HIV and TB and more advanced immune deficiency at diagnosis of HIV may contribute to impaired cognition in HIV+/TB+ patients.

ObjectivesHuman immunodeficiency virus (HIV) disproportionately affects Hispanics/Latinos in the United States, yet little is known about neurocognitive impairment (NCI) in this group. We compared the rates of NCI in large well-characterized samples of HIV-infected (HIV+) Latinos and (non-Latino) Whites, and examined HIV-associated NCI among subgroups of Latinos.MethodsParticipants included English-speaking HIV+ adults assessed at six U.S. medical centers (194 Latinos, 600 Whites). For overall group, age: M=42.65 years, SD=8.93; 86% male; education: M=13.17, SD=2.73; 54% had acquired immunodeficiency syndrome. NCI was assessed with a comprehensive test battery with normative corrections for age, education and gender. Covariates examined included HIV-disease characteristics, comorbidities, and genetic ancestry.ResultsCompared with Whites, Latinos had higher rates of global NCI (42% vs. 54%), and domain NCI in executive function, learning, recall, working memory, and processing speed. Latinos also fared worse than Whites on current and historical HIV-disease characteristics, and nadir CD4 partially mediated ethnic differences in NCI. Yet, Latinos continued to have more global NCI [odds ratio (OR)=1.59; 95% confidence interval (CI)=1.13-2.23; p

PurposeTo determine potential associations between histologic features of pediatric nonalcoholic fatty liver disease (NAFLD) and estimated quantitative magnetic resonance diffusion-weighted imaging (DWI) parameters.Materials and methodsThis prospective, cross-sectional study was performed as part of the Magnetic Resonance Assessment Guiding NAFLD Evaluation and Treatment (MAGNET) ancillary study to the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Sixty-four children underwent a 3T DWI scan (b-values: 0, 100, and 500 s/mm2 ) within 180 days of a clinical liver biopsy of the right hepatic lobe. Three parameters were estimated in the right hepatic lobe: apparent diffusion coefficient (ADC), diffusivity (D), and perfusion fraction (F); the first assuming exponential decay and the latter two assuming biexponential intravoxel incoherent motion. Grading and staging of liver histology were done using the NASH CRN scoring system. Associations between histologic scores and DWI-estimated parameters were tested using multivariate linear regression.ResultsEstimated means ± standard deviations were: ADC: 1.3 (0.94-1.8) × 10-3 mm2 /s; D: 0.82 (0.56-1.0) × 10-3 mm2 /s; and F: 17 (6.0-28)%. Multivariate analyses showed ADC and D decreased with steatosis and F decreased with fibrosis (P < 0.05). Associations between DWI-estimated parameters and other histologic features were not significant: ADC: fibrosis (P = 0.12), lobular inflammation (P = 0.20), portal inflammation (P = 0.27), hepatocellular inflammation (P = 0.29), NASH (P = 0.30); D: fibrosis (P = 0.34), lobular inflammation (P = 0.84), portal inflammation (P = 0.76), hepatocellular inflammation (P = 0.38), NASH (P = 0.81); F: steatosis (P = 0.57), lobular inflammation (P = 0.22), portal inflammation (P = 0.42), hepatocellular inflammation (P = 0.59), NASH (P = 0.07).ConclusionIn children with NAFLD, steatosis and fibrosis have independent effects on DWI-estimated parameters ADC, D, and F. Further research is needed to determine the underlying mechanisms and clinical implications of these effects.Level of evidence1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1149-1158.

HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive, and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded. Neurocognitive outcomes included GDS-defined neurocognitive impairment (NCI; binary GDS, 366 cases with GDS ≥ 0.5 and 684 controls with GDS

The criteria for differentiating symptomatic from asymptomatic HIV-associated neurocognitive disorder require evaluation of (1) cognitive impairment, (2) daily functioning declines, and (3) whether the functional declines are attributable to cognitive versus physical problems. Many providers rely only on self-report to evaluate these latter criteria. However, the accuracy of patient-provided information may be limited. This study evaluated the validity of self-assessment for HIV-associated neurocognitive disorder (HAND) diagnoses by comparing objective findings with self-report of criteria 2 and 3 above. Self-reports were used to stratify 277 cognitively impaired HIV+ individuals into functionally dependent (n = 159) and independent (n = 118) groups, followed by group comparisons of objective functional problems. The dependent group was then divided into those who self-attributed their functional dependence to only cognitive (n = 80) versus only physical (n = 79) causes, for further comparisons on objective findings. The functionally dependent group was significantly worse than the independent group on all objective disability characteristics except severity of cognitive impairment, while those who attributed their dependence to physical (versus cognitive) factors were similar on all objective physical, cognitive, and functioning variables. Of note, 28 % of physical attributors showed no physical abnormalities on neuromedical examinations. Results suggest that patient report is consistently associated with objective measures of functional loss; in contrast, patient identification of physical versus cognitive causes is poorly associated with objective criteria. These findings caution against relying solely on patient self-report to determine whether functional disability in cognitively impaired HIV+ individuals can be attributed to strictly physical causes.

Background Neurocognitive disorders remain common among human immunodeficiency virus (HIV)-positive adults, perhaps owing to persistent HIV-1 RNA in cerebrospinal fluid (CSF) during antiretroviral therapy (ART).Methods Using a single-copy assay, we measured HIV-1 RNA levels in CSF and plasma specimens from 220 HIV-positive adults who were taking suppressive ART. Fifty-five participants were tested twice.Results HIV-1 RNA was detected in 42.3% of CSF and 65.2% of plasma samples. Correlates of higher CSF HIV-1 RNA levels included higher nadir and current CD4+ T-cell counts, a plasma HIV-1 RNA level of ≥ 1 copy/mL, and a lower central nervous system penetration-effectiveness score (model P < .001). Worse neurocognitive performance was associated with discordance in HIV-1 RNA detection between plasma and CSF, lower overall CSF HIV-1 RNA level, and longer ART duration, among others (model P < .001). In the longitudinal subgroup, CSF HIV-1 RNA persisted in most participants (69%) over 7 months.Conclusions Low-level HIV-1 RNA in CSF is common during suppressive ART and is associated with low-level HIV-1 RNA in blood, better immune status, and lower ART drug distribution into CSF. The association between HIV-1 RNA discordance and HIV-associated neurocognitive disorder (HAND) may reflect compartmentalization. The relationship between HAND, lower HIV-1 RNA levels in CSF, and lower CD4+ T-cell counts may reflect disturbances in the immune response to HIV-1 in the CNS.

Previous neuroimaging studies suggest a negative relationship between the apolipoprotein (ApoE) ε4 allele and brain integrity in human immunodeficiency virus (HIV)-infected (HIV+) individuals, although the presence of this relationship across adulthood remains unclear. The purpose of this study is to clarify the discrepancies using a large, diverse group of HIV+ individuals and multiple imaging modalities sensitive to HIV. The association of ApoE ε4 with structural neuroimaging and magnetic resonance spectroscopy (MRS) was examined in 237 HIV+ individuals in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Cortical and subcortical gray matter, abnormal and total white matter, ventricles, sulcal cerebrospinal fluid (CSF), and cerebellar gray matter, white matter, and CSF volumes, and MRS concentrations of myo-inositol, creatine, N-acetyl-aspartate, and choline in the frontal white matter (FWM), frontal gray matter (FGM), and basal ganglia were examined. Secondary analyses explored this relationship separately in individuals ≥50 years old (n = 173) and

Prospective memory (PM) is associated with antiretroviral (ARV) adherence in HIV, but little is known about how pill burden and age might affect this association. One hundred seventeen older (≥50 years) and 82 younger (

BackgroundThe Veterans Aging Cohort Study (VACS) Index, a composite marker of disease severity among human immunodeficiency virus (HIV)-infected persons, has been associated with concurrent risk for neurocognitive impairment (NCI). The present study examined whether the VACS Index predicts longitudinal neurocognitive change.MethodsParticipants included 655 HIV-infected persons followed for up to 6 years in cohort studies at the University of California, San Diego, HIV Neurobehavioral Research Program (mean age at baseline, 42.5 years; 83% male; 60% white; AIDS in 67%; median current CD4(+) T-cell count, 346/μL; 61% receiving antiretroviral therapy). The VACS Index was calculated through standard methods. Participants completed a comprehensive neurocognitive battery. Neurocognitive status was plotted over time using demographically and practice-adjusted global and domain T scores. NCI was defined by global deficit scores derived from T scores.ResultsBaseline VACS Index scores were not predictive of changes in global T scores during the follow-up period (P = .14). However, in time-dependent analyses adjusting for covariates, higher VACS Index scores were significantly associated with worse global and domain neurocognitive performance (Ps < .01), as well as increased risk for developing NCI in a subgroup of persons who were neurocognitively normal at baseline (hazard ratio [HR], 1.17; P < .001). We categorized VACS Index scores by quartiles and found that the upper-quartile group was significantly more likely to develop NCI than the lower quartile (HR, 2.16; P < .01) and middle groups (HR, 1.76; P < .01).ConclusionsChanges in VACS Index scores correspond to changes in neurocognitive function. HIV-infected persons with high VACS Index scores are at increased risk for decline and incident NCI. The VACS Index shows promise as a tool for identifying HIV-infected persons at risk for NCI.

This study evaluated the effects of HIV-associated Neurocognitive Disorders (HAND) on 2 Internet-based tests of healthcare management. Study participants included 46 individuals with HIV infection, 19 of whom were diagnosed with HAND, and 21 seronegatives. Participants were administered Internet-based tests of online pharmacy and health records navigation skills in which they used mock credentials to log in to an experimenter-controlled website and independently perform a series of typical online health-related behaviors (e.g., refill a prescription, read and interpret an electronic chart note). HAND was associated with significantly lower accuracy on both the online pharmacy and health records navigation tasks. Among the HIV+ participants, poorer performance on the online healthcare navigation tasks was associated with fewer years of education, higher plasma viral load, less frequent Internet use, and lower health literacy. Findings indicate that individuals with HAND may have marked difficulties navigating the Internet to complete important health-related behaviors.

BackgroundHuman immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery.MethodsWe investigated the incidence and predictors of NC change over 16-72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change.ResultsNinety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001).ConclusionsNC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.

HIV-associated neurocognitive disorders (HAND) are associated with deficits in prospective memory (PM; "remembering to remember"), conferring risk of daily functioning declines. However, self-perceptions of PM functioning are not reliably associated with PM performance in HIV, suggesting a possible deficit in awareness of PM abilities (meta-PM). Our study examined meta-PM in HAND and its correlates using self-predictions of laboratory-based PM performance. Performance-based PM abilities, self-reported prediction of PM performance, and PM complaints in everyday life were assessed in 49 individuals with HAND, 93 HIV+ without HAND (HIV+ noHAND), and 121 seronegative adults (HIV-). After controlling for group-level differences, HAND was associated with a greater number of PM symptoms in everyday life and worse PM performance when compared with both HIV+ noHAND and HIV- samples. Although HAND individuals reported somewhat lower predictions regarding their laboratory PM performance relative to the other study groups, they nevertheless exhibited significantly greater inaccurate overconfidence in time-based PM abilities. Within the HAND group, overconfidence in time-based meta-PM was associated with executive dysfunction and antiretroviral (ARV) nonadherence. HAND individuals evidenced a moderate deficit in awareness of PM functioning characterized by overconfidence in time-based PM abilities. Overconfidence in PM may result in absence of compensatory strategy use, and lead to increased errors in daily functioning (e.g., ARV nonadherence).

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 volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral 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.

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 (

BackgroundAntiretroviral (ARV) medications differentially penetrate across the blood-brain barrier into central nervous system (CNS) tissues, potentially influencing their effectiveness in treating brain infection.MethodsThis randomized controlled clinical trial (RCT) called for 120 participants at 5 study sites to be randomized 1:1 to CNS-targeted (CNS-T) or non-CNS-T ART. Entry clinical factors such as ARV experience were balanced across arms using an adaptive randomization approach. The primary outcome, change in neurocognitive performance, was measured as the difference in global deficit score (GDS) from baseline to week 16.ResultsThe study was terminated early on the recommendation of its data safety monitoring board on the basis of slow accrual and a low likelihood of detecting a difference in the primary outcome. No safety concerns were identified. Of 326 participants screened, 59 met entry criteria and were randomized. The primary intent-to-treat analysis included 49 participants who completed week 16. These comprised 39 men and 10 women with a mean age of 44 years (SD, 10 years), and median nadir and current CD4(+) T-cell counts of 175 cells/µL and 242 cells/µL, respectively. The proportional improvement in GDS from baseline was nonsignificantly larger (7%; 95% confidence interval [CI], -31% to 62%) in the CNS-T arm than in the non-CNS-T arm, representing a treatment effect size of 0.09 (95% CI, -.48 to .65). Prespecified secondary analysis showed a trend interaction (P = .087), indicating that participants who had baseline plasma virologic suppression may have benefited from CNS-T.ConclusionsThis study found no evidence of neurocognitive benefit for a CNS-T strategy in HIV-associated neurocognitive disorders. A benefit for a subgroup or small overall benefits could not be excluded. Clinical Trials Registration NCT00624195.

HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p

MRI alterations in the cerebral white (WM) and gray matter (GM) are common in HIV infection, even during successful combination antiretroviral therapy (CART), and their pathophysiology and clinical significance are unclear. We evaluated the association of these alterations with recovery of CD4+ T cells. Seventy-five HIV-infected (HIV+) volunteers in the CNS HIV Anti-Retroviral Therapy Effects Research study underwent brain MRI at two visits. Multi-channel morphometry yielded volumes of total cerebral WM, abnormal WM, cortical and subcortical GM, and ventricular and sulcal CSF. Multivariable linear regressions were used to predict volumetric changes with change in current CD4 and detectable HIV RNA. On average, the cohort (79 % initially on CART) demonstrated loss of total cerebral WM alongside increases in abnormal WM and ventricular volumes. A greater extent of CD4 recovery was associated with increases in abnormal WM and subcortical GM volumes. Virologic suppression was associated with increased subcortical GM volume, independent of CD4 recovery. These findings suggest a possible link between brain alterations and immune recovery, distinct from the influence of virologic suppression. The association of increasing abnormal WM and subcortical GM volumes with CD4+ T cell recovery suggests that neuroinflammation may be one mechanism in CNS pathogenesis.

BackgroundEstimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART).MethodParticipants (n=1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n=981) were classified into five categories: 1) no thoughts of death or suicide (n=352); 2) thoughts of death (n=224); 3) thoughts of suicide (n=99); 4) made a suicide plan (n=102); and 5) attempted suicide (n=204).ResultsTwenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p

HIV-negative individuals with a family history of dementia (FHD) are more likely to develop dementia than those without FHD. Whether FHD increases risk for neuropsychological (NP) impairment in HIV+ persons is unknown. As part of a multisite study into HIV-associated neurocognitive disorders (HAND), the authors captured FHD with a free-response, self-report question, and assessed NP performance with a comprehensive battery of tests. The authors examined HIV+ persons with (N=190) and without (N=916) self-reported FHD. Despite the fact that the FHD group had factors typically associated with better NP performance (e.g., higher CD4 counts and estimated verbal IQ), persons with FHD had significantly worse NP ability than those without FHD as measured by a Global Deficit Score. Thus, FHD appears to be a risk factor for HAND; the mechanism(s) underlying how FHD contributes to NP impairment among HIV+ persons warrants study.

Despite the widening use of combination antiretroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n = 251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression.

Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.

Acute/early HIV infection is a period of high risk for HIV transmission. Better understanding of behavioral aspects during this period could improve interventions to limit further transmission. Thirty-four participants with acute/early HIV infection from six US cities were assessed with the Mini International Diagnostic Interview, Beck Depression Inventory II, State-Trait Anxiety Inventory, Brief COPE, and an in-depth interview. Most had a pre-HIV history of alcohol or substance use disorder (85%); a majority (53%) had a history of major depressive or bipolar disorder. However, post-diagnosis coping was predominantly adaptive, with only mild to moderate elevations of anxious or depressive mood. Respondents described challenges managing HIV in tandem with pre-existing substance abuse problems, depression, and anxiety. Integration into medical and community services was associated with adaptive coping. The psychiatric context of acute/early HIV infection may be a precursor to infection, but not necessarily a barrier to intervention to reduce forward transmission of HIV among persons newly infected.

BackgroundIn the absence of significant opportunistic infection, the most common alterations on neuroimaging in the brains of patients with AIDS include enlarged cerebrospinal fluid spaces, white-matter loss, volume loss in striatal structures, and white-matter signal abnormalities. Although previous studies have linked brain viral levels to these alterations, other neuropathological mechanisms might also contribute to them.ObjectiveTo examine the relationship between findings on premortem magnetic resonance images and postmortem neuropathologic evidence of human immunodeficiency virus (HIV) encephalitis and neurodegeneration.DesignMorphometric analysis of magnetic resonance imaging in seropositive cases with matched seronegative controls, and the correlation of these volumes to neuropathological measures in autopsied seropositive cases.SettingUniversity of California, San Diego, HIV Neurobehavioral Research Center.SubjectsTwenty-one seropositive subjects studied at autopsy and 19 seronegative cases.Main outcome measuresIn vivo structural magnetic resonance imaging data analyzed by quantitative methods, with comparison of volumes from magnetic resonance imaging and neuropathological data from autopsies.ResultsThe HIV-seropositive subjects demonstrated cerebrospinal fluid increases relative to seronegative controls. These increases were associated with a significant decrease in the volumes of cerebral and cerebellar white matter, caudate nucleus, hippocampus, and, to a lesser extent, cerebral cortex. The volume of cerebral white-matter tissue with elevated signal was also increased. This signal elevation in white matter predicted the autopsy diagnosis of HIV encephalitis, as well as the extent of dendritic loss as assessed by analysis of microtubule-associated protein 2 immunoreactivity.ConclusionsWhite-matter and cortical damage resulting from HIV disease are closely related. In vivo magnetic resonance imaging may be a valuable adjunct in the assessment of patients at risk for developing HIV encephalitis.