Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment

Abstract

Objective: To determine whether cognitive impairment and brain injury as measured by proton magnetic resonance spectroscopy (MRS) persist in the setting of HAART.

Design: This study is an observational cohort study.

Methods: MRS was performed in 268 patients: HIV-negative controls (N = 28), HIV-positive neuroasymptomatic individuals (N = 124), and individuals with AIDS dementia complex (ADC; N = 50) on stable antiretroviral therapy (ART) with a mean duration of infection of 12 years and CD4 cell count of 309 cells/μl. Four metabolites were measured over creatine: N-acetyl aspartate (NAA), marker of neuronal integrity; choline (Cho), myoinositol, markers of inflammation, and glutamate and glutamine (Glx) in the basal ganglia, frontal white matter (FWM), and mid-frontal cortex. Analyses included analysis of variance, analysis of covariance, linear, and nonparametric regression models.

Results: Cognitive impairment was found in 48% of HIV-infected individuals. Both HIV-positive groups showed significant increases in myoinositol/creatine or Cho/creatine in all brain regions when compared to controls; a significant decrease in Glx/creatine in the FWM was observed in the neuroasymptomatic group; and only individuals with ADC showed a significant reduction in NAA/creatine, although a significant trend for decreasing NAA/creatine in the basal ganglia was found across the groups. Effects related to aging and duration of infection, but not central nervous system penetration effectiveness were observed.

Conclusion: Brain inflammatory changes remain ubiquitous among HIV-infected individuals, whereas neuronal injury occurs predominantly in those with cognitive impairment. Together these findings indicate that despite the widespread use of HAART, HIV-associated cognitive impairment and brain injury persist in the setting of chronic and stable disease.

Figure 1

Boxplots of MRS metabolites are shown for the control and the three patient subgroups (NA, ADC stage 0.5 and ADC stage > 1) and for three regions of interest (BG, FWM, MFC). Black dots depict the median metabolite level and the box is the 1^st quartile (lower end) and the 3^rd quartile (upper end) of the metabolite level distribution.

Figure 1

Boxplots of MRS metabolites are shown for the control and the three patient subgroups (NA, ADC stage 0.5 and ADC stage > 1) and for three regions of interest (BG, FWM, MFC). Black dots depict the median metabolite level and the box is the 1^st quartile (lower end) and the 3^rd quartile (upper end) of the metabolite level distribution.

Figure 2

The interaction effects of age and group membership (NA, ADC) were studied using semi-parametric and linear models and the model which best fit the data was selected (see Methods). The colors of the curves indicate different groups: HIV− (red), NA (green), sub-clinical (blue) and ADC (black). TOP LEFT PANEL: MI/Cr ratio in Frontal White Matter as a function of age, HIV status, ADC stage and their interactions. MI/Cr ratio in the HIV− group is consistently the lowest at all ages, the NA and subclinical groups exhibit increasing MI/Cr ratio as a function of age, while the ADC group shows a decreasing MI/Cr ratio trend as a function of age. TOP RIGHT PANEL: NAA/Cr ratio in mid-frontal cortex as a function of age, HIV status and ADC stage. All groups show a decreasing NAA/Cr trends as a function of age. BOTTOM LEFT PANEL: Glx/Cr ratio in frontal white matter as a function of age, HIV status, ADC stage and their interactions. All groups show a decreasing Glx/Cr trend as a function of age with the HIV− group consistently higher than the HIV+ groups.