Meta-analysis of brain metabolite differences in HIV infection

Abstract

Background: Numerous studies have used magnetic resonance spectroscopy (MRS) neurometabolite measurements to study HIV infection effects. While many have reported differences in total N-Acetylaspartate (tNAA), myo-Inositol (mI), and total Choline (tCho), there have been no meta-analyses performed to evaluate concordance across studies.

Purpose: To evaluate the consistency of HIV serostatus effects on brain metabolites.

Study selection: The sample included studies conducted between 1993 and 2019 reporting HIV infection effects measured using proton MRS. tNAA/tCr ratios (21 papers), tCho/tCr ratios (21 papers), mI/tCr ratios (17 papers) and quantitative tCr (9 papers), sampling from basal ganglia (BG), gray matter (GM), and white matter (WM) were included.

Data analysis: Random effects meta-analysis using inverse variance weighting and bias corrected standardized mean differences (SMDs) was used. Meta-regression examined effects of publication year and data acquisition technique differences.

Data synthesis: BG SMDs related to positive serostatus were -0.10 [-0.39; 0.18] tNAA/tCr, 0.27 [0.05; 0.49] tCho/tCr, 0.60 [0.31; 0.90] mI/tCr, and -0.26 [-0.59; 0.06] tCr. GM SMDs related to serostatus were -0.29 [-0.49; -0.09] tNAA/tCr, 0.37 [0.19; 0.54] tCho/tCr, 0.41 [0.15; 0.68] mI/tCr, and -0.24 [-0.45; -0.03] tCr. WM SMDs related to serostatus were -0.52 [-0.79; -0.25] tNAA/tCr, 0.41 [0.21; 0.61] tCho/tCr, 0.59 [0.24; 0.94] mI/tCr, and -0.03 [-0.25; 0.19] tCr. WM regions showed larger serostatus effect sizes than BG and GM. I² ranged from 52 to 88% for the metabolite ratios. Both GM and WM tNAA/tCr SMDs were lower with increasing calendar year.

Limitations: Many studies pooled participants with varying treatment, infection, and comorbidity durations.

Conclusions: HIV neurometabolite studies showed consistently lower tNAA/tCr, higher tCho/tCr and higher mI/tCr ratios associated with chronic HIV infection. Substantial between-study variation may have resulted from measurement technique variations, study population differences and HIV treatment changes over time. Higher WM tCho/tCr and mI/tCr may reflect reactive gliosis or myelin turnover. Neurometabolite measurements can reliably detect chronic HIV infection effects and may be useful in understanding the pathophysiology of cognitive and sensorimotor decline following HIV infection.

Classification of evidence: This study provides Class II evidence of neurometabolite differences in chronic HIV infection.

Keywords: ART; Anti-retroviral therapy; HAND; HIV associated neurocognitive disorder; Inflammation; MRS; Magnetic resonance spectroscopy; Neurons.

Graphical abstract

Fig. 1

Meta-analysis flow diagram for study selection.

Fig. 2

Representative voxel locations in (A) white matter, (B) basal ganglia and (C) gray matter used in sampled studies with spectra recorded (bottom row) using short TE (35 ms) at 3 T from each voxel. Peaks are identified from total creatine (tCr), total choline (tCho), total N-acetylaspartate (NAA), as well as myo-inositol (mI) and the combination of glutamate and glutamine (Glx). Broader spectral linewidths in the basal ganglia compared to GM and WM, likely due to the increased iron content of this region.

Fig 3

Basal Ganglia. Forest plots showing standardized mean differences (SMD) across studies comparing seropositive to seronegative participants in BG ROIs for (A) tNAA/tCr ratios, (B) tCho/tCr ratios, and (C) mI/tCr ratios.

Fig 4

Gray Matter. Forest plots showing standardized mean differences (SMD) across studies comparing seropositive to seronegative participants in GM ROIs for (A) tNAA/tCr ratios, (B) tCho/tCr ratios, and (C) mI/tCr ratios.

Fig 5

White Matter. Forest plots showing standardized mean differences (SMD) across studies comparing seropositive to seronegative participants in WM ROIs for (A) tNAA/tCr ratios, (B) tCho/tCr ratios, and (C) mI/tCr ratios.

Fig 6

Forest plots showing standardized mean differences (SMD) in tCr across studies comparing seropositive to seronegative participants in BG (A), GM (B) and WM (C) ROIs for tCr.

Fig. 7

Summary of regional effect sizes of HIV seropositivity in the BG, GM and WM for tNAA/tCr ratios, tCho/tCr ratios, mI/tCr ratios and tCr. Bars show effect size and associated 95% confidence interval for the different regions and metabolites. The related Z score is plotted above each bar.

Fig. 8

There was progressive, but non-significant, reduction in between-group serostatus effects with calendar year in (A) GM and (B) WM tNAA/tCr ratios.