Alterations of Brain Metabolites in Adults With HIV: A Systematic Meta-analysis of Magnetic Resonance Spectroscopy Studies

Abstract

Objective: A meta-analysis of proton magnetic resonance spectroscopy studies to investigate alterations in brain metabolites in people with HIV (PWH), the relationship between metabolite alterations and combination antiretroviral therapy (cART), and the relationship between metabolite alterations and cognitive impairment.

Methods: The PubMed database was searched for studies published from 1997 to 2020. Twenty-seven studies were identified, which included 1255 PWH and 633 controls. Four metabolites (N-acetyl aspartate [NAA], myo-inositol [mI], choline [Cho], and glutamatergic metabolites [Glx]) from 5 brain regions (basal ganglia [BG], frontal gray and white matter [FGM and FWM], and parietal gray and white matter [PGM and PWM]) were pooled separately using random-effects meta-analysis.

Results: During early HIV infection, metabolite alterations were largely limited to the BG, including Cho elevation, a marker of inflammation. cART led to global mI and Cho normalization (i.e., less elevations), but improvement in NAA was negligible. In chronic PWH on cART, there were consistent NAA reductions across brain regions, along with Cho and mI elevations in the FWM and BG, and Glx elevations in the FWM. Cognitive impairment was associated with NAA reduction and to a lesser degree mI elevation.

Conclusions: The BG are the primary region affected during early infection. cART is successful in partially controlling neuroinflammation (global mI and Cho normalization). However, neuronal dysfunction (NAA reductions) and neuroinflammation (mI and Cho elevations) persist and contribute to cognitive impairment in chronic PWH. Novel compounds targeting NAA signal pathways, along with better neuroinflammation control, may help to reduce cognitive impairment in PWH.

Figure 1. PRISMA Flow Diagram of Literature Search and Study Selection

Studies were selected for the meta-analyses of 4 comparisons: (1) chronic PWH vs controls; (2) cognitively impaired PWH vs cognitively normal PWH; (3) acute/early HIV infection patients vs controls; and (4) the effect of antiretroviral treatment in cART-naive patients (pre- vs post-cART initiation). For the comparison of chronic PWH vs controls, studies were selected after reviewing the methods section of each publication to ensure that the PWH groups were not patients with acute/early infection, except 1 study, which included patients with a disease duration of approximately 6 months. However, excluding this particular study did not change the conclusion of chronic PWH vs controls meta-analysis (see sensitivity analysis). cART = combination antiretroviral therapy; PWH = people with HIV.

Figure 2. Study Effect Sizes of Chronic PWH vs Healthy Controls in the Primary Meta-Analysis

(A) Chronic PWH vs healthy controls. (B) The list of studies included in the primary meta-analysis. The results that reached p ≤ 0.05 (uncorrected) are listed here, and the study effect sizes of all metabolites and all regions from the RevMan 5 software (cochrane.org) are presented in figure e-1. The significance of difference is presented in Table 1. Note: (#) ## in (A) represents Hedges g (##) from the study (#) listed in (B); the 32 studies were extracted from 27 publications. BG = basal ganglia; FWM = frontal white matter; PWH = people with HIV; PWM = parietal white matter; FGM = frontal gray matter; PGM = parietal gray matter.

Figure 3. Study Effect Sizes of Other Comparisons in the Primary Meta-Analysis

(A) Cognitively impaired PWH vs cognitively normal PWH. (B) Patients with acute/early HIV infection vs healthy controls. (C) After vs before cART in cART-naive PWH. (D) The list of studies included in the primary meta-analysis (also see figure 1B). The results that reached p ≤ 0.05 (uncorrected) are listed here, and the study effect sizes of all metabolites and all regions from the RevMan 5 software (cochrane.org) are presented in figures e-2, e-3, and e-4. The significance of difference is presented in Table 1. Note: (#) ## in (A) to (C) represents Hedges g (##) from the study (#) listed in (D). BG = basal ganglia; CI = cognitively impaired; CN = cognitively normal; FGM = frontal gray matter; FWM = frontal white matter; PGM = parietal gray matter; PWH = people with HIV; PWM = parietal white matter.

Figure 4. Qualitative Analysis of the Association Between Alterations in Metabolites and Cognitive Impairment in PWH

A total of 17 studies were selected, including 1,585 PWH (723 cognitively impaired, 755 cognitively normal, and 107 unknown). The cognitive status was unknown in 2 studies, which conducted a correlation analysis between cognitive performance and metabolites. Gray bar represents the number of studies that examined the association between cognitive impairment/performance and metabolites at least in 1 brain region; red bar represents the number of studies that identified a significant association between cognitive impairment/performance and metabolite concentrations in at least 1 brain region. Cognitive impairment is always associated with lower NAA (100% of studies) and Glx (100% of studies) levels and more likely with higher mI (70% of studies) and Cho (57% of studies) levels. See Table e-6 (doi.org/10.5061/dryad.2280gb5rq) for a detailed list of the 17 studies. Glx = glutamatergic metabolites; NAA = N-acetyl aspartate; PWH = people with HIV.

Figure 5. Waterfall of Effect Sizes of Alterations in Metabolites

This is for illustration purposes only, and 0 represents controls. Black bar represents the effect size of metabolite alterations from controls to chronic PWH; gray bar represents the effect size of metabolite alterations from cognitively normal PWH to cognitively impaired PWH. “*” represents significant changes (after correction for multiple comparisons); “ns” represents nonsignificant changes. See Table 2 and Figure e-5 for the original results from the secondary meta-analysis. CI = cognitively impaired; CN = cognitively normal; PWH = people with HIV.