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Selegiline and oxidative stress in HIV-associated cognitive impairment.

ABSTRACT: To assess the effectiveness of the selegiline transdermal system (STS) in reversing HIV-induced metabolic brain injury (as measured by proton magnetic resonance spectroscopy [MRS]) and in decreasing oxidative stress, measured by CSF protein carbonyl concentration.Sixty-two subjects with HIV-associated cognitive impairment were coenrolled in a 24-week placebo-controlled study (AIDS Clinical Trial Group protocol A5090) and were randomly assigned to receive STS 3 mg/24 h, STS 6 mg/24 h, or matching placebo. Cognitive performance was evaluated using the neuropsychological z score (NPZ)-8 and NPZ-6, as well as cognitive domain scores. Subjects underwent proton MRS at study entry and weeks 12 and 24. CSF protein carbonyl was measured at baseline and week 24.A slight increase in N-acetyl aspartate/creatine from baseline to week 24 was found in the basal ganglia (p = 0.023) and centrum semiovale (p = 0.072) of the placebo group compared with the STS groups; however, there were no significant changes when the absolute metabolite concentrations were analyzed. The levels of choline/creatine in the midfrontal cortex were also significantly higher during the week 12 visit in the combined STS groups. This persisted to the week 24 visit (p = 0.002). Evaluation of the change in NPZ-8, NPZ-6, and cognitive domain scores from baseline to weeks 12 and 24 revealed no significant differences between treatment arms. Protein carbonyl analysis revealed no significant changes among the groups.In this 24-week study, the selegiline transdermal system (STS) had no effect on either magnetic resonance spectroscopy (MRS) metabolites or oxidative stress, as measured by CSF protein carbonyl concentration. The lack of effect on these biomarkers is also reflected in the lack of cognitive improvement in the STS groups compared to placebo.This study provides Class II evidence that STS had no effect on either MRS metabolites or oxidative stress, as measured by CSF protein carbonyl concentration over a period of 24 weeks.

SUBMITTER: Schifitto G

PROVIDER: S-EPMC2790227 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Selegiline and oxidative stress in HIV-associated cognitive impairment.

Schifitto G G Yiannoutsos C T CT Ernst T T Navia B A BA Nath A A Sacktor N N Anderson C C Marra C M CM Clifford D B DB

Neurology 20091104 23

<h4>Objective</h4>To assess the effectiveness of the selegiline transdermal system (STS) in reversing HIV-induced metabolic brain injury (as measured by proton magnetic resonance spectroscopy [MRS]) and in decreasing oxidative stress, measured by CSF protein carbonyl concentration.<h4>Methods</h4>Sixty-two subjects with HIV-associated cognitive impairment were coenrolled in a 24-week placebo-controlled study (AIDS Clinical Trial Group protocol A5090) and were randomly assigned to receive STS 3 m ...[more]

PMID: 19890073

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Project description:BackgroundCerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer's disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal and leptomeningeal blood vessels, are the source of radicals through the Aβ-binding innate immunity receptor CD36, leading to neurovascular dysfunction, CAA, and cognitive impairment.MethodsTg2576 mice and WT littermates were transplanted with CD36-/- or CD36+/+ bone marrow at 12-month of age and tested at 15 months. This approach enables the repopulation of perivascular and leptomeningeal compartments with CD36-/- BAM. Neurovascular function was tested in anesthetized mice equipped with a cranial window in which cerebral blood flow was monitored by laser-Doppler flowmetry. Amyloid pathology and cognitive function were also examined.ResultsThe increase in blood flow evoked by whisker stimulation (functional hyperemia) or by endothelial and smooth muscle vasoactivity was markedly attenuated in WT → Tg2576 chimeras but was fully restored in CD36-/- → Tg2576 chimeras, in which BAM ROS production was suppressed. CAA-associated Aβ1-40, but not Aβ1-42, was reduced in CD36-/- → Tg2576 chimeras. Similarly, CAA, but not parenchymal plaques, was reduced in CD36-/- → Tg2576 chimeras. These beneficial vascular effects were associated with cognitive improvement. Finally, CD36-/- mice were able to more efficiently clear exogenous Aβ1-40 injected into the neocortex or the striatum.ConclusionsCD36 deletion in BAM suppresses ROS production and rescues the neurovascular dysfunction and damage induced by Aβ. CD36 deletion in BAM also reduced brain Aβ1-40 and ameliorated CAA without affecting parenchyma plaques. Lack of CD36 enhanced the vascular clearance of exogenous Aβ. Restoration of neurovascular function and attenuation of CAA resulted in a near complete rescue of cognitive function. Collectively, these data implicate brain BAM in the pathogenesis of CAA and raise the possibility that targeting BAM CD36 is beneficial in CAA and other conditions associated with vascular Aβ deposition and damage.

Project description:OBJECTIVE:We determined whether there are sex differences in the prevalence and profile of HIV-associated neurocognitive impairment, and whether sex moderates the effect of HIV-serostatus on neurocognitive impairment among HIV-positive and HIV-negative individuals. Secondarily, we assessed whether differences were explained by greater biopsychosocial risk factors in HIV-positive women. DESIGN:An observational cohort study. METHODS:Analyses included 1361 HIV-positive (204 women) and 702 HIV-negative (214 women) (ages?=?18-79 years) participants from the UCSD HIV Neurobehavioral Research Program. Demographically corrected standardized T-scores from 15 neuropsychological tests were used to calculate domain-specific and global deficit scores (GDS). GDS at least 0.5 defined neurocognitive impairment. Biopsychosocial risk factors included low education, low reading level (education quality), lifetime substance use disorders, depressed mood (clinically significant depressive symptoms and/or current major depressive disorder) and a cumulative syndemic count (sum of biopsychosocial risk factors, range?=?0-4). Race-stratified analyses were conducted. Analyses were adjusted for relevant demographic and clinical factors. RESULTS:HIV-associated neurocognitive impairment was more prevalent in women versus men; however, the difference was eliminated after adjustment for reading level. In sex-stratified logistic regressions, the association between HIV-seropositivity and higher likelihood of neurocognitive impairment was stronger in women versus men; however, the association was attenuated in women, but not men, after adjusting for reading level. These results in the overall sample were specific to blacks. Sex differences in the profile of HIV-associated neurocognitive impairment varied by race. CONCLUSION:Women, particularly black women, were most at-risk for HIV-associated neurocognitive impairment. Higher rates of HIV-associated neurocognitive impairment in women versus men may reflect differences in educational quality.

Project description:IntroductionThe aim of our study was to investigate the potential relationship between liver fibrosis (LF) and cognitive performance in HIV+ patients.Materials and methodsWe performed a cross-sectional cohort study by consecutively enrolling HIV+ patients during routine outpatient visits at two clinical centres in Italy. Subjects with decompensated liver disease were excluded. All subjects underwent a comprehensive neuropsychological battery exploring memory, attention, psychomotor speed and language; cognitive impairment was defined as at least two abnormal [1.5 SD below the mean for appropriate norms] cognitive domains. LF was explored by calculating FIB4 index; in a subgroup of patients, LF was also assessed by transient elastography. Factors associated with cognitive impairment were investigated by logistic regression models.ResultsA total of 413 patients [77% males, median age 46 (IQR 39-52), 17% with past AIDS-defining events, 19% past IDU, 3% with diabetes, 94% on cART, 90% with HIV RNA <50 copies/mL, 18% co-infected with HCV] were enrolled. Seventeen patients (4%) had FIB4 >3.25 and 14/129 (3%) had liver stiffness >14KPa. Forty-seven patients (11%) were diagnosed with cognitive impairment. At multivariate analyses patients with FIB4 >1.45 showed a higher risk of cognitive impairment in comparison with those with lower values (OR 2.19, 95% CI 1.02-4.72; p=0.044) after adjusting for education (OR 0.79, 95% CI 0.71-0.88; p<0.001), past IDU (OR 1.69, 95% CI 0.67-4.23; p=0.264), diabetes (OR 2.35, 95% CI 0.62-8.86; p=0.207), HIV RNA <50 copies/mL (OR 0.47, 95% CI 0.19-1.14; p=0.095) and HCV co-infection (OR 0.88, 95% CI 0.33-2.39; p=0.807). Analyzing any single cognitive domain, a higher risk of abnormal psychomotor speed was associated with fibroscan score >14KPa in comparison with fibroscan score <7KPa (OR 285.07; 95% CI 2.42-33574.06; p=0.020) after adjusting for education (OR 0.54, 95% CI 0.31-0.92; p=0.024), age (for 10 years increase) (OR 2.03, 95% CI 0.55-7.53; p=0.288), past IDU (OR 4.43, 95% CI 0.35-7.57; p=0.526), HIV RNA <50 copies/mL (OR 0.01, 95% CI 0.00-0.18; p=0.003), HIV history (for 1 year increase) (OR 0.96, 95% CI 0.83-1.12; p=0.641), CD4 cells count at nadir (OR 1.10, 95% CI 0.56-2.16; p=0.779), and HCV co-infection (OR 0.06; 95% CI 0.00-1.93; p=0.113).ConclusionsIn HIV-infected patients higher LF, estimated through non-invasive methods, is associated to a higher risk of cognitive impairment.

Project description:ObjectiveTo assess the efficacy and safety of transdermal rivastigmine for the treatment of HIV-associated cognitive impairment.MethodsWe recruited HIV-infected patients with cognitive impairment on stable antiretroviral therapy in a randomized controlled pilot trial with a 48-week follow-up. An additional assessment was held at 12 weeks. Participants received transdermal rivastigmine (9.5 mg daily), lithium (400 mg twice daily, titrated progressively), or remained in a control group (no new medication). The primary efficacy endpoint was change in a global cognitive score (NPZ-7). Secondary endpoints included change in specific cognitive measures, domains, and functional parameters. Safety covered the frequency of adverse events and changes in laboratory results.ResultsSeventy-six subjects were screened, and 29 were finally enrolled. Better cognitive outcomes were observed in all groups, although there were no significant differences between the arms (mean NPZ-7 change [SD]): rivastigmine, 0.35 (0.14); lithium, 0.25 (0.40); control, 0.20 (0.44) (p = 0.78). The rivastigmine group showed the highest positive trend (mean NPZ-7 [SD], baseline vs week 48): rivastigmine, -0.47 (0.22) vs -0.11 (0.29), p = 0.06; lithium, -0.50 (0.40) vs -0.26 (0.21), p = 0.22; control, -0.52 (0.34) vs -0.32 (0.52), p = 0.44. The cognitive domains with the highest positive trends were information processing speed at week 12 and executive function at week 48 (rivastigmine vs control): information processing speed, 0.35 (0.64) vs -0.13 (0.25), p = 0.17, d = 0.96; and executive functioning, 0.73 (0.33) vs 0.03 (0.74), p = 0.09, d = 1.18. No relevant changes were observed regarding functional outcomes. A total of 12 (41%) individuals dropped out of the study: 2 (20%) were due to medication-related effects in the rivastigmine group and 4 (36%) in the lithium group. No severe adverse events were reported.ConclusionsThe results from this small randomized trial indicate that transdermal rivastigmine did not provide significant cognitive benefits in people with HAND on stable antiretroviral therapy, even though positive trends were found in specific cognitive domains. Relevant tolerability issues were not observed.

Project description:BACKGROUND:Microglia function is essential to maintain the brain homeostasis. Evidence shows that aged microglia are primed and show exaggerated response to acute inflammatory challenge. Systemic inflammation signals to the brain inducing changes that impact cognitive function. However, the mechanisms involved in age-related cognitive decline associated to episodic systemic inflammation are not completely understood. The aim of this study was to identify neuropathological features associated to age-related cognitive decline in a mouse model of episodic systemic inflammation. METHODS:Young and aged Swiss mice were injected with low doses of LPS once a week for 6 weeks to induce episodic systemic inflammation. Sickness behavior, inflammatory markers, and neuroinflammation were assessed in different phases of systemic inflammation in young and aged mice. Behavior was evaluated long term after episodic systemic inflammation by open field, forced swimming, object recognition, and water maze tests. RESULTS:Episodic systemic inflammation induced systemic inflammation and sickness behavior mainly in aged mice. Systemic inflammation induced depressive-like behavior in both young and aged mice. Memory and learning were significantly affected in aged mice that presented lower exploratory activity and deficits in episodic and spatial memories, compared to aged controls and to young after episodic systemic inflammation. Systemic inflammation induced acute microglia activation in young mice that returned to base levels long term after episodic systemic inflammation. Aged mice presented dystrophic microglia in the hippocampus and entorhinal cortex at basal level and did not change morphology in the acute response to SI. Regardless of their dystrophic microglia, aged mice produced higher levels of pro-inflammatory (IL-1? and IL-6) as well as pro-resolution (IL-10 and IL-4) cytokines in the brain. Also, higher levels of Nox2 expression, oxidized proteins and lower antioxidant defenses were found in the aged brains compared to the young after episodic systemic inflammation. CONCLUSIONS:Our data show that aged mice have increased susceptibility to episodic systemic inflammation. Aged mice that showed cognitive impairments also presented higher oxidative stress and abnormal production of cytokines in their brains. These results indicate that a neuroinflammation and oxidative stress are pathophysiological mechanisms of age-related cognitive impairments.

Dataset Information

Selegiline and oxidative stress in HIV-associated cognitive impairment.

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Selegiline and oxidative stress in HIV-associated cognitive impairment.

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