Background:  Chemokines are expressed by several types of neural cells, including microglia, astrocytes, and neurons, and are implicated in HIV neuropathogenesis. The primary objective of this study was to evaluate the relationship between selected chemokines, neuropsychological  performance, and cerebral metabolites.

Methods:  In HIV-infected subjects, 2 ACTG studies evaluated the relationship between neuropsychological  performance and cerebral metabolites (measured by magnetic resonance spectroscopy [MRS]):   ACTG 700, a cross-sectional study (n = 85) and  ACTG 301, a 16-week clinical trial of memantine (n = 140). In these studies, MRS measured N-acetyl aspartate (NAA), choline (Cho), myo-inositol (mI), and creatine (Cr) in parietal cortex (PC), white matter (WM), and basal ganglia (BG). AIDS dementia complex (ADC) stage was diagnosed and neuropsychological performance was summarized as a deficit score (NPD). ELISA was used to measure 5 chemokines (MCP-1, fractalkine [FKN], IL-8, MIP-1, and IP-10) in stored plasma and CSF. The number of specimens assayed for each was determined by sample availability, ranging from 43 to 127. Assay operators were blinded to other study results. After assay completion, data were combined with neuropsychological  performance test results, disease markers, cerebral metabolites, and treatment arm, when applicable. Results were analyzed using non-parametric methods since chemokine distributions were skewed.

Results  Cross-sectionally, those with worse ADC stages had higher CSF levels of IL-8, FKN, and MIP-1. Higher CSF levels of FKN also correlated with worse NPD scores (p <  0.001). On MRS, lower NAA/Cr ratios correlated with higher CSF MCP-1 levels (p = 0.002) and higher Cho/Cr ratios correlated with higher CSF IP-10 levels (p = 0.001). In the longitudinal analysis, higher baseline CSF levels of MIP-1b (p = 0.05) and IP-10 (p = 0.02) predicted neuropsychological  worsening (change in ADC stage > 0). On MRS, increases in NAA/Cr ratios in PC correlated with increases in CSF MCP-1 levels (r = 0.49, p = 0.04) and reductions in Cho/Cr ratios in PC correlated with reductions in CSF MIP-1b (r = 0.53, p = 0.03).

Conclusion:  Chemokines predict changes in neuropsychological performance and reflect cerebral metabolites, further implicating them in HIV neuropathogenesis. In this study, chemokines were associated with NAA, a marker of neuronal integrity, and choline, a marker of gliosis, in parietal cortex.

Keywords: Chemokine; Central Nervous System; Magnetic Resonance Spectroscopy