Dopamine, Norepinephrine and Serotonin Participate Differently in Methylphenidate Action in Concomitant Behavioral and Ventral Tegmental Area, Locus Coeruleus and Dorsal Raphe Neuronal Study in Young Rats.

Methylphenidate (MPD), known as Ritalin, is a psychostimulant used to treat children, adults, and the elderly. MPD exerts its effects through increasing concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the synaptic cleft. Concomitant behavioral and neuronal recording from the ventral tegmental area (VTA), locus coeruleus (LC), and from the dorsal raphe (DR) nucleus, which are the sources of DA, NE, and 5-HT to the mesocorticolimbic circuit, were investigated following acute and repetitive (chronic) saline, 0.6, 2.5, or 10.0 mg/kg MPD. Animals received daily saline or MPD administration on experimental days 1 to 6 (ED1-6), followed by a 3-day washout period and MPD rechallenge on ED10. Each chronic MPD dose elicits behavioral sensitization in some animals while inducing behavioral tolerance in others. The uniqueness of this study is in the evaluation of neuronal activity based on the behavioral response to chronic MPD. Neuronal excitation was observed mainly in brain areas of animals exhibiting behavioral sensitization, while neuronal attenuation following chronic MPD was observed in animals expressing behavioral tolerance. Different ratios of excitatory/inhibitory neuronal responses were obtained from the VTA, LC, or DR following chronic MPD. Thus, each brain area responds differently to each MPD dose used, suggesting that DA, NE, and 5-HT in the VTA, LC, and DR exert different effects.

Cerebrospinal fluid CD14++CD16+ monocytes in HIV-1 subtype C compared with subtype B.

CD14++CD16+ monocytes are susceptible to HIV-1 infection, and cross the blood-brain barrier. HIV-1 subtype C (HIV-1C) shows reduced Tat protein chemoattractant activity compared to HIV-1B, which might influence monocyte trafficking into the CNS. We hypothesized that the proportion of monocytes in CSF in HIV-1C is lower than HIV-1B group. We sought to assess differences in monocyte proportions in cerebrospinal fluid (CSF) and peripheral blood (PB) between people with HIV (PWH) and without HIV (PWoH), and by HIV-1B and -C subtypes. Immunophenotyping was performed by flow cytometry, monocytes were analyzed within CD45 + and CD64 + gated regions and classified in classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14lowCD16+). Among PWH, the median [IQR] CD4 nadir was 219 [32-531] cell/mm3; plasma HIV RNA (log10) was 1.60 [1.60-3.21], and 68% were on antiretroviral therapy (ART). Participants with HIV-1C and -B were comparable in terms of age, duration of infection, CD4 nadir, plasma HIV RNA, and ART. The proportion of CSF CD14++CD16+ monocytes was higher in participants with HIV-1C than those with HIV-1B [2.00(0.00-2.80) vs. 0.00(0.00-0.60) respectively, p = 0.03 after BH correction p = 0.10]. Despite viral suppression, the proportion of total monocytes in PB increased in PWH, due to the increase in CD14++CD16+ and CD14lowCD16+ monocytes. The HIV-1C Tat substitution (C30S31) did not interfere with the migration of CD14++CD16+ monocytes to the CNS. This is the first study to evaluate these monocytes in the CSF and PB and compare their proportions according to HIV subtype.

Main lymphocyte subpopulations in cerebrospinal fluid and peripheral blood in HIV-1 subtypes C and B.

HIV-1 subtype C (HIV-1C) shows reduced Tat protein chemoattractant activity compared with HIV-1B. The impact of HIV-1C Tat on the chemotaxis of the main lymphocyte subpopulations in the cerebrospinal fluid (CSF) and the peripheral blood (PB) is unclear. We hypothesized that there would be a lower frequency of specific lymphocyte subpopulations CD3+ or CD19+ in CSF in HIV-1C than in HIV-1B. The objectives were to detect the differences in the proportions of main lymphocyte subpopulations in CSF and PB, between people with HIV (PWH) and HIV-1-uninfected volunteers (PWoH) and in HIV-1B and HIV-1C. Lymphocyte immunophenotyping was studied in CSF and paired PB samples of PWH (n = 22) and PWoH (n = 14). Lymphocytes were analyzed within the CD45+ gated region. The proportions of CSF CD3+CD4+, CD3+CD8+, and CD3-CD19+ lymphocytes in CSF were comparable in HIV-1B and C. There was an increase in the proportion of CD3+CD8+ cells and a decrease in CD3+CD4+ T cells (ps = 0.016) in the CSF samples of the PWH compared with the PWoH group. In the PWH group, both CD3+CD4+ and CD3+CD8+ lymphocytes were significantly higher in the CSF than in the PB (p = 0.047 and 0.005). The proportion of CD3+CD4+ was lower and that of CD3+CD8+ was higher in the CSF samples of the aviremic group than that of HIV-negative control (p = 0.0008 and < 0.0001, respectively). HIV-1C Tat substitution (C30S) did not interfere with the CNS migration of the main lymphocyte subpopulations. This is the first study to evaluate these lymphocytes in CSF and PB of HIV-1C compared with HIV-1B.

Higher Cerebrospinal Fluid Soluble Urokinase-type Plasminogen Activator Receptor, But Not Interferon γ-inducible Protein 10, Correlate With Higher Working Memory Deficits.

BACKGROUND: We hypothesized that the induction of monocyte activation biomarkers, especially soluble urokinase-type plasminogen activator receptor (suPAR) and interferon γ-inducible protein 10 (IP-10), is lower in HIV-1C than HIV-1B, owing to a defective Tat cysteine dimotif (C30S). METHODS: A total of 68 paired cerebrospinal fluid (CSF) and blood samples from people with HIV (PWH), free of CNS opportunistic infections, from a Southern Brazil outpatient HIV clinic were evaluated such as HIV-1B subtype (n = 27), HIV-1C (n = 26), other (n = 15), and 19 HIV-negative controls. The levels of suPAR, IP-10, neopterin, and ß2 microglobulin (ß2m) in the CSF and serum were quantified using different immunoassays. RESULTS: Overall, in PWH, increases in CSF suPAR, CSF/serum suPAR, and CSF/serum ß2m correlated with worse working memory deficits (r = 0.303, 0.353, and 0.289, respectively, all P < 0.05). The medians of IP-10, suPAR, neopterin, and ß2m in CSF and serum and the CSF/serum ratio and suPAR index were comparable between the HIV-1B and HIV-1C subtypes. CSF IP-10 and neopterin and serum IP-10 and suPAR levels were higher in PWH than the HIV-negative controls (P = 0.015, P = 0.001, P < 0.0001, and P < 0.001, respectively). The serum ß2m level was higher in HIV-associated dementia than neuropsychologically normal or asymptomatic (P = 0.024). DISCUSSION: We observed that higher levels of CSF suPAR and the suPAR quotient correlated with worse working memory deficit. Elevated levels of monocyte activation were similar in both HIV-1 B and C subtypes, providing no evidence of reduced neuropathogenicity of HIV-1 subtype C Tat compared with subtype B.

Cerebrospinal fluid pleocytosis as a predictive factor for CSF and plasma HIV RNA discordance and escape.

The aims of this study were to investigate the frequency of HIV-1 RNA level discordance between the cerebrospinal fluid (CSF) and plasma and of CSF viral escape (CVE) in patients with HIV-1 subtype C on antiretroviral therapy, and evaluate the CSF white blood cell (WBC) performance characteristics in predicting CSF discordance in HIV+ group and the frequency of cognitive impairment in individuals with CSF HIV discordance or escape. HIV-1 RNA levels were assessed in plasma and CSF samples from 68 HIV+ participants without opportunistic infection. CSF discordance was found in 7.4% and CVE in 10%, with comparable frequencies between HIV-1B and C. Twenty samples (29%) showed increased CSF WBC counts. This group had higher CSF and plasma HIV-1 RNA levels than the group with normal WBC counts (p < 0.0001 and 0.006, respectively). The odds of CSF discordance were 18 times higher for a person with CSF WBC count of > 5 cells/mm3 than the group with normal CSF WBC count. CSF WBC counts (cut-off of 15 cells/mm3) showed high-performance characteristics as a predictive biomarker of CSF discordance (AUC the ROC curve 0.98). The frequency of cognitive impairment for CSF escape or discordance was 83% and 80%. The odds of cognitive impairment in these groups were 19 and 15 times higher than those for an HIV(-) person. Viral discordance or escape in the CNS occurs at a comparable frequency for HIV-1C and HIV-1B. The CSF WBC count was effective as a predictive biomarker of CSF and plasma discordance.

Blood amyloid-ß protein isoforms are affected by HIV-1 in a subtype-dependent pattern.

This study aimed to compare serum amyloid processing biomarkers among HIV subtype B (n = 25), HIV subtype C (n = 26), healthy HIV-negative controls (n = 18), and patients with Alzheimer's disease (AD; n = 24). Immunoassays were used to measure main soluble Aß isoforms Aß38, Aß40, Aß42, and Aß-total in serum and cerebrospinal fluid (CSF). People living with HIV (PLWH) and HIV(-) samples, including AD samples, were compared for gender and age, while HIV subtypes were compared for nadir CD4 and plasma viral load suppression. CSF/serum ratios of Aß40, Aß42, and Aß-total were lower in HIV-1C group than in HIV-1B group (p = 0.020, 0.025, and 0.050, respectively). In serum, these biomarkers were comparable. Serum Aß isoforms were significantly lower in PLWH than in AD. Serum Aß42 levels in PLWH were decreased compared to those in control group, thus similar to Aß42 alterations in CSF; these results were different from those observed in AD. Impaired cellular immunity, low CD4 cell count (nadir or current) influences serum Aß metabolism in HIV-1B but not HIV-1C. However, in PLWH overall, but not in individual HIV subtype groups, greater CD4 recovery, calculated as the difference between current and nadir CD4, correlated with Aß42/Aß40 ratio in serum (rs 0.246; p = 0.0479). No significant correlation was found with global deficit score (GDS), an index of neurocognitive performance, age, or duration of infection. These findings are consistent with those of subtype-dependent amyloid processing in blood in chronic HIV disease.

Neurocognitive impairment with hepatitis C and HIV co-infection in Southern Brazil.

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

Neprilysin in the Cerebrospinal Fluid and Serum of Patients Infected With HIV1-Subtypes C and B.

OBJECTIVE: Neprilysin (NEP) is the dominant Aß peptide-degrading enzyme in the brain. HIV-1 subtype B transactivator of transcription protein is known to interfere with NEP function, but whether this is true of HIV-1C transactivator of transcription, which has a defective chemokine motif, is not known. This study aimed to analyze the impact of HIV subtype on NEP-mediated cleavage of Aß by comparing cerebrospinal fluid (CSF) and serum levels of NEP between HIV+ (27 patients with HIV-1B and 26 with HIV-1C), healthy HIV- controls (n = 13), and patients with Alzheimer disease (n = 24). METHODS: NEP and Aß oligomers 38, 40, 42 levels were measured in CSF and serum by immunoassays. Ratios between NEP and Aß-38, 40, 42, and total were calculated in CSF and serum. Comparisons between HIV(+) and HIV(-) were adjusted by linear regression for sex and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression. RESULTS: Levels of NEP and ratios in CSF were comparable for HIV-1C and B subtypes. The ratio of serum NEP/Aß-40 was lower for HIV1-C than HIV1-B (P = 0.032). The CSF/serum index of NEP/Aß-40, NEP/Aß-42, and NEP/Aß-total were lower for HIV1-B than HIV1-C (P = 0.008, 0.005, and 0.017, respectively), corroborating the findings for serum. CSF NEP was comparable for HIV+, HIV-, and AD. CONCLUSION: There was impact of HIV subtype on NEP. The ratio of NEP/Aß-40 on serum was lower on HIV1-C than HIV1-B. These results are consistent with the results of CSF Aß-42 levels decreased in HIV1-C compared with HIV1-B, suggesting higher amyloid ß deposit on HIV1-C than HIV1-B.

Biomarkers of neuronal injury and amyloid metabolism in the cerebrospinal fluid of patients infected with HIV-1 subtypes B and C.

Based on prior reports that the HIV-1 Tat protein modulates amyloid-beta (Aß) metabolism, this study aimed to compare CSF neural injury biomarkers between 27 patients with HIV subtype B, 26 patients with HIV subtype C, 18 healthy HIV-negative controls, and 24 patients with Alzheimer's disease (AD). Immunoassays were used to measure soluble amyloid precursor protein α and ß (sAPPα, sAPPß), Aß oligomers 38, 40, 42, and Aß-total; phosphorylated tau (P-tau181), and total tau (T-tau). Comparisons between HIV(+) and HIV(-) (including AD) were adjusted by linear regression for gender and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression. The p values were corrected for multiple testing with the Benjamini-Hochberg procedure. CSF Aß-42 and Hulstaert (P-tau181) index were lower in HIV1-C than B (p = 0.03, and 0.049 respectively); subtypes did not differ on other CSF biomarkers or ratios. Compared to AD, HIV(+) had lower CSF levels of T-tau, P-tau181 (p < 0.001), and sAPPα (p = 0.041); HIV(+) had higher CSF Aß-42 (p = 0.002) and higher CSF indexes: [Aß-42/(240 + 1.18 T-tau)], P-tau181/Aß-42, T-tau/Aß-42, P-tau181/T-tau, sAPPα/ß (all p ≤ 0.01) than AD. Compared to HIV(-), HIV(+) had lower CSF Aß-42, and T-tau (all p ≤ 0.004). As conclusion, amyloid metabolism was influenced by HIV infection in a subtype-dependent manner. Aß-42 levels were lower in HIV1-C than B, suggesting that there may be greater deposition of Aß-42 in HIV1-C. These findings are supported by CSF Hulstaert (P-tau181) index. Differences between HIV and AD in the patterns of Aß and Tau biomarkers suggest that CNS HIV infection and AD may not share some of same mechanisms of neuronal injury.