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.

Conflict of interest statement

Conflicts of Interest: None

Figures

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 1st quartile (lower end) and the 3rd 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 1st quartile (lower end) and the 3rd 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.