Associations of regional amyloid-ß plaque and phospho-tau pathology with biological factors and neuropsychological functioning among HIV-infected adults.

With increasing age, the general population is increasingly vulnerable to the development of cerebral amyloid-ß (Aß) plaque and neuronal phospho-tau (p-tau) pathology. In HIV disease, prior studies of these neuropathologic changes were relatively limited. Here, we characterized Aß plaques and p-tau lesions by immunohistochemistry in relevant brain regions (prefrontal neocortex, putamen, basal-temporal neocortex, and hippocampus) of HIV-infected adults. We used multivariable logistic regression to predict regional Aß plaque or p-tau pathology based on demographic factors, apolipoprotein E (APOE) genotypes, HIV disease-related factors, and regional gliosis. We used multiple linear regression to predict T-scores in neuropsychological domains based on regional Aß plaque or p-tau pathology. We found that APOE ε4 alleles, older age, and higher plasma HIV-1 RNA predicted prefrontal Aß plaques (odds ratio (OR) 5.306, 1.045, and 0.699, respectively, n = 168). Older age predicted putamen Aß plaques (OR 1.064, n = 171). APOE ε4 alleles, hepatitis C virus seropositivity, and higher plasma HIV-1 RNA predicted hippocampus Aß plaques (OR 6.779, 6.138, and 0.589, respectively, n = 56). The p-tau lesions were sparse in the vast majority of affected cases. Lifetime substance use disorder and higher plasma HIV-1 RNA predicted putamen p-tau lesions (OR 0.278 and 0.638, respectively, n = 67). Older age and gliosis predicted hippocampus p-tau lesions (OR 1.128 and 0.592, respectively, n = 59). Prefrontal Aß plaques predicted lower speed of information processing (n = 159) and putamen Aß plaques predicted lower levels of attention and working memory (n = 88). Regional p-tau lesions were not significantly predictive of any neuropsychological domains. In conclusion, Aß plaque or p-tau pathology in different brain regions was predicted by different sets of biological factors. Aß plaques in prefrontal neocortex and putamen predicted poorer functioning in cognitive domains relevant to these brain regions. The absence of significant impact of regional p-tau lesions on neuropsychological functioning might be explained by the subthreshold burden of p-tau lesions.

Genetic correlations among psychiatric and immune-related phenotypes based on genome-wide association data.

Individuals with psychiatric disorders have elevated rates of autoimmune comorbidity and altered immune signaling. It is unclear whether these altered immunological states have a shared genetic basis with those psychiatric disorders. The present study sought to use existing summary-level data from previous genome-wide association studies to determine if commonly varying single nucleotide polymorphisms are shared between psychiatric and immune-related phenotypes. We estimated heritability and examined pair-wise genetic correlations using the linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics methods. Using LDSC, we observed significant genetic correlations between immune-related disorders and several psychiatric disorders, including anorexia nervosa, attention deficit-hyperactivity disorder, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia, smoking behavior, and Tourette syndrome. Loci significantly mediating genetic correlations were identified for schizophrenia when analytically paired with Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus, and ulcerative colitis. We report significantly correlated loci and highlight those containing genome-wide associations and candidate genes for respective disorders. We also used the LDSC method to characterize genetic correlations among the immune-related phenotypes. We discuss our findings in the context of relevant genetic and epidemiological literature, as well as the limitations and caveats of the study.

No reliable gene expression biomarkers of current or impending neurocognitive impairment in peripheral blood monocytes of persons living with HIV.

Events leading to and propagating neurocognitive impairment (NCI) in HIV-1-infected (HIV+) persons are largely mediated by peripheral blood monocytes. We previously identified expression levels of individual genes and gene networks in peripheral blood monocytes that correlated with neurocognitive functioning in HIV+ adults. Here, we expand upon those findings by examining if gene expression data at baseline is predictive of change in neurocognitive functioning 2 years later. We also attempt to validate the original findings in a new sample of HIV+ patients and determine if the findings are HIV specific by including HIV-uninfected (HIV-) participants as a comparison group. At two time points, messenger RNA (mRNA) was isolated from the monocytes of 123 HIV+ and 60 HIV- adults enrolled in the Multicenter AIDS Cohort Study and analyzed with the Illumina HT-12 v4 Expression BeadChip. All participants received baseline and follow-up neurocognitive testing 2 years after mRNA analysis. Data were analyzed using standard gene expression analysis and weighted gene co-expression network analysis with correction for multiple testing. Gene sets were analyzed for GO term enrichment. Only weak reproducibility of associations of single genes with neurocognitive functioning was observed, indicating that such measures are unreliable as biomarkers for HIV-related NCI; however, gene networks were generally preserved between time points and largely reproducible, suggesting that these may be more reliable. Several gene networks associated with variables related to HIV infection were found (e.g., MHC I antigen processing, TNF signaling, interferon gamma signaling, and antiviral defense); however, no significant associations were found for neurocognitive function. Furthermore, neither individual gene probes nor gene networks predicted later neurocognitive change. This study did not validate our previous findings and does not support the use of monocyte gene expression profiles as a biomarker for current or future HIV-associated neurocognitive impairment.

Plasma soluble CD163 is associated with postmortem brain pathology in human immunodeficiency virus infection.

OBJECTIVE: Higher plasma soluble cluster of differentiation (CD)163 (sCD163), shed by monocytes and macrophages, correlates with neurocognitive impairment in HIV infection. We hypothesized that higher antemortem plasma or cerebrospinal fluid (CSF) sCD163 would be associated with greater postmortem neurodegeneration and/or microgliosis. DESIGN: Retrospective, postmortem observational study. METHODS: We measured sCD163 levels in antemortem plasma (n = 54) and CSF (n = 32) samples from 74 HIV-seropositive participants (median 5 months before death) who donated their brains to research at autopsy. Postmortem, we quantified markers of synaptodendritic damage (microtubule-associated protein 2, synaptophysin), microgliosis [human leukocyte antigen DR (HLA-DR), ionized calcium-binding adaptor molecule 1], astrocytosis (glial fibrillary acidic protein), and impaired protein clearance (ß-amyloid) in frontal cortex, hippocampus, putamen, and internal capsule. Multivariable least-squares regression was used to evaluate the association between plasma or CSF sCD163 and histological measures, correcting for multiple comparisons. RESULTS: Higher plasma sCD163 was associated with lower microtubule-associated protein 2 in frontal cortex [B = -0.23, 95% confidence interval (CI) -0.41 to -0.06, P = 0.04], putamen (B = 0.32, 95% CI -0.52 to -0.12, P = 0.02), and hippocampus (B = -0.23, 95% CI -0.35 to -0.10, P = 0.01), and with lower synaptophysin in hippocampus (B = -0.25, 95% CI -0.42 to -0.03, P = 0.02) but not putamen or frontal cortex (P > 0.05). Higher plasma sCD163 was associated with higher HLA-DR in putamen (B = 0.17, 95% CI 0.08 to 0.26, P = 0.008). CSF sCD163 was not associated with any histological measure (P > 0.05). CONCLUSION: Higher plasma sCD163 in life is associated with greater synaptodendritic damage and microglial activation in cortical and subcortical brain regions.

BK virus capsid antibodies are associated with protection against subsequent development of PML in HIV-infected patients.

Progressive multifocal leukoencephalopathy (PML) is caused by JC polyomavirus (JCPyV). Because a reciprocal relationship has been described between antibody levels to JCPyV and BK polyomavirus (BKPyV), we performed a nested case control study with pre-diagnostic serum samples from HIV infected subjects to examine the relationship between BKPyV capsid antibodies and the risk of PML. Serum samples collected 0.5-2 years before PML diagnosis from 25 cases (66 samples) and 80 matched controls (204 samples) were tested in ELISA for JCPyV, BKPyV type 1 and type 4 capsid antibodies. High levels of BKPyV 1 and 4 antibodies were associated with a lower risk of PML (BKPyV 1 OR, 0.56, 95% CI, 0.35-0.89; BKPyV 4 OR, 0.40, 95% CI, 0.24-0.0.67). Our study demonstrates that antibodies to BKPyV capsids are an immunological marker of protection against development of PML. Further studies are needed to define the mechanism.

The role of chemokine C-C motif ligand 2 genotype and cerebrospinal fluid chemokine C-C motif ligand 2 in neurocognition among HIV-infected patients.

OBJECTIVES: We examined interrelationships between chemokine C-C motif ligand 2 (CCL2) genotype and expression of inflammatory markers in the cerebrospinal fluid (CSF), plasma viral load, CD4 cell count and neurocognitive functioning among HIV-infected adults. We hypothesized that HIV-positive carriers of the 'risk' CCL2 -2578G allele, caused by a single nucleotide polymorphism (SNP) at rs1024611, would have a higher concentration of CCL2 in CSF, and that CSF CCL2 would be associated with both higher concentrations of other proinflammatory markers in CSF and worse neurocognitive functioning. DESIGN: A cross-sectional study of 145 HIV-infected individuals enrolled in the National NeuroAIDS Tissue Consortium cohort for whom genotyping, CSF and neurocognitive data were available. METHODS: Genomic DNA was extracted from peripheral blood mononuclear cells and/or frozen tissue specimens. CSF levels of CCL2, interleukin (IL)-2, IL-6, tumour necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), soluble tumor necrosis factor receptor 2, sIL-6Rα, sIL-2, sCD14 and B-cell activating factor were quantified. Neurocognitive functioning was measured using a comprehensive battery of neuropsychological tests. RESULTS: Carriers of the CCL2 -2578G allele had a significantly higher concentration of CCL2 in CSF. CSF CCL2 level was positively and significantly associated with other CSF neuroinflammatory markers and worse cognitive functioning. There was a significant association between genotype and plasma viral load, such that carriers of the CCL2 -2578G allele with high viral load expressed greater levels of CCL2 and had higher neurocognitive deficit scores than other genotype/viral load groups. CONCLUSION: Individuals with the CCL2 -2578G allele had higher levels of CCL2 in CSF, which was associated with increased pro-inflammatory markers in CSF and worse neurocognitive functioning. The results highlight the potential role of intermediate phenotypes in studies of genotype and cognition.

Systems analysis of human brain gene expression: mechanisms for HIV-associated neurocognitive impairment and common pathways with Alzheimer's disease.

BACKGROUND: Human Immunodeficiency Virus-1 (HIV) infection frequently results in neurocognitive impairment. While the cause remains unclear, recent gene expression studies have identified genes whose transcription is dysregulated in individuals with HIV-association neurocognitive disorder (HAND). However, the methods for interpretation of such data have lagged behind the technical advances allowing the decoding genetic material. Here, we employ systems biology methods novel to the field of NeuroAIDS to further interrogate extant transcriptome data derived from brains of HIV + patients in order to further elucidate the neuropathogenesis of HAND. Additionally, we compare these data to those derived from brains of individuals with Alzheimer's disease (AD) in order to identify common pathways of neuropathogenesis. METHODS: In Study 1, using data from three brain regions in 6 HIV-seronegative and 15 HIV + cases, we first employed weighted gene co-expression network analysis (WGCNA) to further explore transcriptome networks specific to HAND with HIV-encephalitis (HIVE) and HAND without HIVE. We then used a symptomatic approach, employing standard expression analysis and WGCNA to identify networks associated with neurocognitive impairment (NCI), regardless of HIVE or HAND diagnosis. Finally, we examined the association between the CNS penetration effectiveness (CPE) of antiretroviral regimens and brain transcriptome. In Study 2, we identified common gene networks associated with NCI in both HIV and AD by correlating gene expression with pre-mortem neurocognitive functioning. RESULTS: Study 1: WGCNA largely corroborated findings from standard differential gene expression analyses, but also identified possible meta-networks composed of multiple gene ontology categories and oligodendrocyte dysfunction. Differential expression analysis identified hub genes highly correlated with NCI, including genes implicated in gliosis, inflammation, and dopaminergic tone. Enrichment analysis identified gene ontology categories that varied across the three brain regions, the most notable being downregulation of genes involved in mitochondrial functioning. Finally, WGCNA identified dysregulated networks associated with NCI, including oligodendrocyte and mitochondrial functioning. Study 2: Common gene networks dysregulated in relation to NCI in AD and HIV included mitochondrial genes, whereas upregulation of various cancer-related genes was found. CONCLUSIONS: While under-powered, this study identified possible biologically-relevant networks correlated with NCI in HIV, and common networks shared with AD, opening new avenues for inquiry in the investigation of HAND neuropathogenesis. These results suggest that further interrogation of existing transcriptome data using systems biology methods can yield important information.

The National NeuroAIDS Tissue Consortium brain gene array: two types of HIV-associated neurocognitive impairment.

BACKGROUND: The National NeuroAIDS Tissue Consortium (NNTC) performed a brain gene expression array to elucidate pathophysiologies of Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders. METHODS: Twenty-four human subjects in four groups were examined A) Uninfected controls; B) HIV-1 infected subjects with no substantial neurocognitive impairment (NCI); C) Infected with substantial NCI without HIV encephalitis (HIVE); D) Infected with substantial NCI and HIVE. RNA from neocortex, white matter, and neostriatum was processed with the Affymetrix® array platform. RESULTS: With HIVE the HIV-1 RNA load in brain tissue was three log(10) units higher than other groups and over 1,900 gene probes were regulated. Interferon response genes (IFRGs), antigen presentation, complement components and CD163 antigen were strongly upregulated. In frontal neocortex downregulated neuronal pathways strongly dominated in HIVE, including GABA receptors, glutamate signaling, synaptic potentiation, axon guidance, clathrin-mediated endocytosis and 14-3-3 protein. Expression was completely different in neuropsychologically impaired subjects without HIVE. They had low brain HIV-1 loads, weak brain immune responses, lacked neuronally expressed changes in neocortex and exhibited upregulation of endothelial cell type transcripts. HIV-1-infected subjects with normal neuropsychological test results had upregulation of neuronal transcripts involved in synaptic transmission of neostriatal circuits. INTERPRETATION: Two patterns of brain gene expression suggest that more than one pathophysiological process occurs in HIV-1-associated neurocognitive impairment. Expression in HIVE suggests that lowering brain HIV-1 replication might improve NCI, whereas NCI without HIVE may not respond in kind; array results suggest that modulation of transvascular signaling is a potentially promising approach. Striking brain regional differences highlighted the likely importance of circuit level disturbances in HIV/AIDS. In subjects without impairment regulation of genes that drive neostriatal synaptic plasticity reflects adaptation. The array provides an infusion of public resources including brain samples, clinicopathological data and correlative gene expression data for further exploration (http://www.nntc.org/gene-array-project).

Genome-wide association study of neurocognitive impairment and dementia in HIV-infected adults.

The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. Candidate gene studies have implicated genetic susceptibility loci within immune-related genes; however, these have not been reliably validated. Here, we employed genome-wide association (GWA) methods to discover novel genetic susceptibility loci associated with HAND, and validate susceptibility loci implicated in prior candidate gene studies. Data from 1,287 participants enrolled in the Multicenter AIDS Cohort Study between 1985 and 2010 were used. Genotyping was conducted with Illumina 1M, 1MDuo, or 550K platform. Linear mixed models determined subject-specific slopes for change over time in processing speed and executive functioning, considering all visits including baseline and the most recent study visit. Covariates modeled as fixed effects included: time since the first visit, depression severity, nadir CD4+ T-cell count, hepatitis C co-infection, substance use, and antiretroviral medication regimen. Prevalence of HIV-associated dementia (HAD) and neurocognitive impairment (NCI) was also examined as neurocognitive phenotypes in a case-control analysis. No genetic susceptibility loci were associated with decline in processing speed or executive functioning among almost 2.5 million single nucleotide polymorphisms (SNPs) directly genotyped or imputed. No association between the SNPs and HAD or NCI were found. Previously reported associations between specific genetic susceptibility loci, HIV-associated NCI, and HAD were not validated. In this first GWAS of HAND, no novel or previously identified genetic susceptibility loci were associated with any of the phenotypes examined. Due to the relatively small sample size, future collaborative efforts that incorporate this dataset may still yield important findings.

CCL3 genotype and current depression increase risk of HIV-associated dementia.

BACKGROUND: The prevalence of Human immunodeficiency virus (HIV)-associated dementia (HAD) has continued to rise even as incidence has fallen. Several host genetic variants have been identified that modify risk for HAD. However, the findings have not been replicated consistently and most studies did not consider the multitude of factors that might themselves confer risk for HAD. In the current study, we sought to replicate the findings of previous studies in a neurologically and behaviorally well-characterized cohort. METHODS: The sample consisted of 143 HIV+ individuals enrolled in the National NeuroAIDS Tissue Consortium (NNTC). Based on consensus diagnosis, 117 were considered neurologically normal upon study entry, and 26 had HAD. Seven single-nucleotide polymorphisms (SNPs) were genotyped within seven genes (CCL2, CCL3, CCL5, interleukin-1α [IL-1α], IL-10, stromal cell-derived factor 1, and tumor necrosis factor-α). Logistic regression analysis was used to predict group membership (normal vs HAD), with predictor variables including length of infection, age, current drug dependence, current depression, and genotype. RESULTS: The two groups were statistically similar with regards to demographic characteristics, current drug use, and disease factors. The HAD group had significantly greater number of individuals with current depression. Only one SNP, rs1130371 within the gene for CCL3, was entered into the analysis as the others showed symmetric distribution between groups. Logistic regression indicated that current depression and CCL3 genotype were significant predictors of HAD. Depression conferred a fivefold greater risk of HAD, while the TT genotype for CCL3 SNP (rs1130371) was associated with twofold risk for HAD. CONCLUSION: Depression and CCL3 genotype predicted HAD. The fact that SNPs previously found to be associated with HAD were not in our analysis, and that rs1130371 is in high linkage disequilibrium with neighboring genes indicates that more dense genotyping in significantly larger cohorts is required to further characterize the relationship between genotype and risk for HAD.

The role of host genetics in the susceptibility for HIV-associated neurocognitive disorders.

Despite progress in the treatment of the Human Immunodeficiency virus (HIV), there continues to be a high prevalence of infected individuals who develop neurocognitive deficits and disorders. Our understanding of the potential cause of HIV-associated neurocognitive disorders (HAND) continues to develop on many fronts. Among them is the study of host genetics. Here, we review the most current information regarding the association between host genetics and risk for HIV infection, AIDS, and HAND. We focus on the role of dopamine dysfunction in the etiology of HAND, and propose a number of genetic polymorphisms within genes related to dopaminergic functioning and other neurobiological factors that may confer vulnerability or protection against HAND.

Terapia de reemplazo hormonal y riesgo de enfermedades neurodegenerativas / Hormone replacement therapy and risk for neurodegenerative diseases

En los últimos años se han dado controversias importantes acerca de los efectos de la estrogenoterapia sustitutiva y, en términos más generales, la terapia de reemplazo hormonal (TRH) sobre la enfermedad de Alzheimer (EA) y otras enfermedades neurodegenerativas. Esta revisión presenta algunos de los hallazgos y aportes más recientes en estudios de ciencias básicas, ensayos clínicos aleatorizados e investigación epidemiológica relacionada con los efectos neuroprotectores potenciales de la TRH en EA, demencia asociada con VIH y enfermedad de Parkinson (EP). Ha ido ganado más adeptos la convicción acerca de la capacidad de la TRH de reducir el riesgo de EA y mejorar el funcionamiento cognitivo de las mujeres posmenopáusicas, sobre todo cuando se consideran también las limitaciones del Women’s Health Initiative Memory Study de 2002. También se está prestando mayor atención a los efectos sintomáticos y neuroprotectores de la TRH en el tratamiento de la EP, así como al papel de la TRH como estrategia novedosa en la prevención y el tratamiento de la demencia asociada con VIH. Existen limitaciones importantes en la investigación actual, pero también razones convincentes para volver a examinar el modo en que algunas formas de TRH pueden ayudar a preservar las capacidades cognitivas en mujeres posmenopáusicas y evitar las enfermedades neurodegenerativas.

In the past several years, there has been a significant amount of controversy about the effects of estrogen replacement therapy (ERT) and, more generally, hormonereplacement therapy (HRT) on Alzheimer’s (AD) and otherneurodegenerative conditions. This review presents some of the more recent findings and developments in basicscience studies, randomized clinical trials, and epidemiological research regarding the potential neuroprotective effects of HRT in AD, HIV-associated dementia (HAD), and Parkinson’s disease (PD). Increased support iscontinuing to emerge for HRT’s ability to reduce the riskof AD and improve the cognitive functioning ofpostmenopausal women, particularly when consideredalongside the limitations of the 2002 Women’s HealthInitiative Memory Study. Greater attention is also beinggiven to the symptomatic and neuroprotective effects ofHRT in the management of PD, as well as the role of HRTas a novel strategy in the prevention and treatment of HAD. There are important limits to the existing research, but there are also persuasive reasons for reexamininghow some forms of HRT may help preserve cognitiveabilities in post-menopausal women and stave off neurodegenerative diseases.