Mariana Cherner

Interrater Reliability of Clinical Ratings and Neurocognitive Diagnoses in HIV

We examined the interrater reliability (IRR) of clinical ratings of neuropsychological (NP) impairment and neurocognitive diagnoses in HIV. Thirty participants with advanced HIV-infection who were enrolled in a multicenter HIV brain banking research project underwent comprehensive NP and neuromedical evaluations. Using a standardized system of guidelines, neuropsychologists from six participating sites independently assigned clinical ratings of NP impairment, as well as multilevel diagnoses reflecting the inferred etiology of the impairments and their effects on everyday functioning. Findings indicated excellent IRR in rating the presence and severity of NP impairment, but overall modest IRR for neurocognitive diagnoses. Not surprisingly, most diagnostic disagreements concerned the etiology of impairments in persons with medical and neuropsychiatric risk factors in addition to HIV.

Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy

Objective: To rigorously evaluate the time course of cognitive change in a cohort of individuals with HIV-associated neurocognitive disorders (HAND) initiating combination antiretroviral therapy (CART), and to investigate which demographic, laboratory, and treatment factors are associated with neuropsychological (NP) outcome (or “any NP improvement”). Methods: Study participants included 37 HIV+ individuals with mild to moderate NP impairment who initiated CART and underwent NP testing at 12, 24, 36, and 48 weeks thereafter. NP change was assessed using a regression-based change score that was normed on a separate NP-stable group thereby controlling for regression toward the mean and practice effect. Mixed-effect regression models adjusting for loss to follow-up were used to evaluate the time course of cognitive change and its association with baseline and time-varying predictors. Results: In persons with HAND initiating CART, cognitive improvement happens soon after initiation (13% at week 12), but more often 24, 36, and up to 48 weeks after initiation (up to 41%), with fewer than 5% demonstrating significant worsening. In multivariate analyses, unique predictors of NP improvement included more severe baseline NP impairment and higher CART CNS penetration index. Greater viral load decrease was associated with NP improvement only in univariate analyses. Conclusion: Clinically meaningful neuropsychological improvement seemed to peak around 24–36 weeks after combination antiretroviral therapy initiation and was prolonged over the 1-year study period. This study also provides new evidence that benefit may be maximized by choosing antiretroviral medications that reach therapeutic concentrations in the CNS.

Neurocognitive dysfunction predicts postmortem findings of HIV encephalitis

Objective: To investigate the value of antemortem cognitive functioning in predicting postmortem evidence of HIV encephalitis (HIVE). Methods: Thirty-nine subjects were assessed during life with a comprehensive neuropsychological battery and went on to autopsy within 18 months of testing. Cognitive impairment was determined by blind clinical ratings, based on demographically corrected test scores. Presence of HIVE was based on postmortem immunocytochemical detection of the viral protein gp41 or by measurement of HIV RNA by PCR in multiple brain areas as well as by histopathologic evidence such as microgliosis, presence of multinucleated giant cells, and myelin pallor in several brain regions. Results: The sensitivity and specificity of neurocognitive impairment in detecting the occurrence of HIVE were 67 and 92%. Eighteen of 19 subjects with antemortem neurocognitive impairment had evidence of HIV-related brain disease (positive predictive value = 95%). Conclusion: Neuropsychological assessment can help select HIV-positive patients for treatment of CNS disease.

Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment.

Objective:To determine the association of markers of regional neurodegeneration (ND) at autopsy to degree of neurocognitive impairment in persons with HIV. Design:In a prospectively followed cohort of HIV-infected individuals we examined the relationship between antemortem neuropsychological (NP) abilities and postmortem neuropathological data. Methods:Twenty-seven HIV-infected individuals with both neuropsychological and neuropathological data were identified. Laser confocal scanning microscopy was used to determine the degree of ND based on: (1) microtubule-associated protein (MAP2; reflecting neuronal cell bodies and dendrites) and (2) synaptophysin (SYN; a measure of presynaptic terminals). A regional combined score, based on the distribution of percentage neuropil occupied by MAP2 and SYN and emphasizing severity of ND, was created for each brain region: midfrontal cortex, hippocampus, and putamen. Results:The regional combined scores from each brain region studied were better correlated with level of global NP impairment than measures of SYN and MAP2 individually. In a regression, hippocampal and putamen regional combined scores were independent predictors of degree of antemortem NP impairment (F3,23 = 6.17; P < 0.01; R2 = 0.45). The correlations among regional ND measures demonstrated that ND is unevenly distributed across multiple brain regions. Conclusions:As the anatomic distribution and temporal progression of neuropathologic changes appears to differ across individuals, it is important to consider both cortical and subcortical brain regions in studies of neuropathogenesis and treatment of HIV-related brain disease. Furthermore, combining information from several markers of neural injury provided the strongest association with degree of neurocognitive impairment during life.

Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine

Objective: To examine the contribution of hepatitis C virus (HCV) infection to neurocognitive dysfunction in individuals with comorbid HIV infection or methamphetamine (METH) dependence. Methods: Neurocognitive functioning was examined in 430 study participants who were either normal controls or had HCV infection, HIV infection, history of METH dependence, or combinations of these factors as risks for cognitive deficits. Results: Rates of global and domain-specific neuropsychological (NP) impairment increased with the number of risk factors. HCV serostatus was a significant predictor of NP performance both globally and in the areas of learning, abstraction, and motor skills, with trends in speeded information processing and delayed recall. HCV serostatus did not predict scores in attention/working memory or verbal fluency. Conclusion: Hepatitis C virus infection contributes to the neuropsychological deficits observed among HIV-infected and stimulant-dependent populations.

Relationship of psychosocial factors to HIV disease progression.

Based on the existing empirical evidence that psychosocial variables may predict the course of human immunodeficiency virus (HIV) illness, disease progression (described by advance in symptoms, decline in CD4+ cell count, and mortality) in 414 HIV-positive (HIV+) males was studied using Cox Proportional Hazards Models (survival analysis). Depressive symptoms predicted shorter longevity after controlling for symptoms and CD4+ cell count. Large social network sizes predicted longevity among those with acquired immune deficiency syndrome (AIDS)-defining symptoms at baseline, but not among other subjects. Therefore, psychosocial variables and affective states may be related to disease outcome only during later stages of HIV disease. Although the results provide support for psychoneuroimmunologic effects in HIV, other confounding explanations may still apply.

Cliniconeuropathologic correlates of human immunodeficiency virus in the era of antiretroviral therapy.

The objective of this study was to examine the spectrum of human immunodeficiency virus (HIV) brain pathology and its clinical correlates in the antiretroviral era. We carried out a cross-sectional survey, analyzing prospective clinical and neuropathological data collected by the National NeuroAIDS Tissue Consortium (NNTC), comprising 589 brain samples from individuals with advanced HIV disease collected from 1999 onwards. We assessed gender, ethnicity/race, mode of transmission, age, year of death, nadir CD4, plasma viral load, last antiretroviral regimen, presence of parenchymal HIV brain pathology, HIV-associated neurocognitive disorder, and major depressive disorder. We compared cohort demographic variables with Centers for Disease Control and Prevention US HIV/AIDS statistics and examined associations of parenchymal HIV brain pathology with demographic, clinical, and HIV disease factors. With regard to Centers for Disease Control and Prevention US data, the NNTC was similar in age distribution, but had fewer females and African Americans and more Hispanics and men who have sex with men. Only 22% of the brains examined were neuropathologically normal. Opportunistic infections occurred in 1% to 5% of the cohort. Parenchymal HIV brain pathology was observed in 17.5% of the cohort and was associated with nadir CD4 and plasma viral load. Brains without parenchymal HIV brain pathology often had other noninfectious findings or minimal nondiagnostic abnormalities that were associated with HIV-associated neurocognitive disorder. Clinically, 60% of the cohort reported a lifetime episode of major depressive disorder and 88% had a HIV-associated neurocognitive disorder. No pathological finding correlated with major depressive disorder. Both antiretroviral treatment regimen and elevated plasma HIV viral load were associated with presence of parenchymal HIV brain pathology; however, multivariate analyses suggest a stronger association with plasma viral load. The frequency of HIV brain pathology was lower than previous pre-antiretroviral reports, and was predicted by lower nadir CD4 and higher plasma viral load. Noninfectious pathologies and minimal changes correlated with HIV-associated neurocognitive disorder, suggesting a shift in pathogenesis from florid HIV replication to other, diverse mechanisms.

Pathogenesis of Hepatitis C Virus Coinfection in the Brains of Patients Infected with HIV

Involvement of the nervous system by human immunodeficiency virus (HIV) continues to be a serious problem. Among individuals with HIV who have a history of illicit drug use, those coinfected with hepatitis C virus (HCV) are a fast-growing population. However, few studies have assessed the penetration of HCV into the central nervous system (CNS) and its clinical and neuropathological impacts on HIV-infected individuals. For this purpose, the distribution of HCV was investigated in the brains of patients infected with HIV. The presence of HCV RNA in the CNS as detected by nested polymerase chain reaction was associated with a history of methamphetamine use, considerable antemortem cognitive impairment and abundant astrogliosis, and less-severe HIV encephalitis. HCV antigens were detected by immunoblot analysis, using heparin-purified brain samples, and HCV immunoreactivity was detected in astrocytes and in macrophage-microglial cells. The results support the hypothesis that HCV traffics into the HIV-infected brain, where it might lead to a productive coinfection associated with cognitive impairment.

The effects of hepatitis C, HIV, and methamphetamine dependence on neuropsychological performance : biological correlates of disease

Objective:To determine the effects of hepatitis C virus (HCV) infection on neuropsychological (NP) performance. Design:Cross-sectional analysis of a prospectively enrolled cohort. Methods:A total of 239 HIV-seropositive and 287 HIV-seronegative subjects enrolled in prospective cohort studies at a single center. Subjects underwent standardized assessments, including comprehensive neuropsychological testing, substance use inventory neuromedical examination, venipuncture, and lumbar puncture. HCV antibody was measured in serum. In seropositive individuals, HCV RNA was measured in plasma and cerebrospinal fluid (CSF). Results:HCV-seropositive subjects performed worse on neuropsychological testing and were almost twice as likely to be diagnosed as globally impaired, compared with those who were HCV seronegative. In a multivariate analysis, HCV, HIV, and methamphetamine dependence were independently associated with worse performance, even after adjusting for Centers for Disease Control stage and antiretroviral use. HCV-RNA levels in plasma were higher in those with memory, but not global, impairment. In cerebrospinal fluid, HCV RNA was below 100 copies/ml in all specimens. In HIV-infected subjects, HCV was associated with higher levels of HIV RNA in CSF, but not in plasma. HCV was also associated with higher levels of monocyte chemotactic protein 1, TNF-α, and soluble TNF receptor II. HCV-seropositive subjects did not appear to have advanced liver disease. Conclusions:HIV, HCV, and methamphetamine independently injure the central nervous system, leading to global neuropsychological impairment. HCV may injure the brain by viral or immune-mediated mechanisms. HCV-associated brain injury may be preventable or reversible because HCV infection is potentially curable.

Molecular and pathologic insights from latent HIV-1 infection in the human brain

Objective: We aimed to investigate whether HIV latency in the CNS might have adverse molecular, pathologic, and clinical consequences. Methods: This was a case-control comparison of HIV-1 seropositive (HIV+) patients with clinical and neuropathologic examination. Based on the levels of HIV-1 DNA, RNA, and p24 in the brain, cases were classified as controls, latent HIV CNS infection, and HIV encephalitis (HIVE). Analysis of epigenetic markers including BCL11B, neurodegeneration, and neuroinflammation was performed utilizing immunoblot, confocal microscopy, immunochemistry/image analysis, and qPCR. Detailed antemortem neurocognitive data were available for 23 out of the 32 cases. Results: HIV+ controls (n = 12) had no detectable HIV-1 DNA, RNA, or p24 in the CNS; latent HIV+ cases (n = 10) showed high levels of HIV-1 DNA but no HIV RNA or p24; and HIVE cases (n = 10) had high levels of HIV-1 DNA, RNA, and p24. Compared to HIV+ controls, the HIV+ latent cases displayed moderate cognitive impairment with neurodegenerative and neuroinflammatory alterations, although to a lesser extent than HIVE cases. Remarkably, HIV+ latent cases showed higher levels of BCL11B and other chromatin modifiers involved in silencing. Increased BCL11B was associated with deregulation of proinflammatory genes like interleukin-6, tumor necrosis factor–α, and CD74. Conclusion: Persistence of latent HIV-1 infection in the CNS was associated with increased levels of chromatin modifiers, including BCL11B. Alteration of these epigenetic factors might result in abnormal transcriptomes, leading to inflammation, neurodegeneration, and neurocognitive impairment. BCL11B and other epigenetic factors involved in silencing might represent potential targets for HIV-1 involvement of the CNS.