Exploring the relationship of macrophage colony-stimulating factor levels on neuroaxonal metabolism and cognition during chronic human immunodeficiency virus infection

Abstract

Macrophage colony-stimulating factor (M-CSF) promotes macrophage differentiation, increases susceptibility of macrophages to viral infection, and enhances human immunodeficiency virus (HIV) replication in infected macrophages. Given the current model of HIV neuropathogenesis, which involves monocyte trafficking into the central nervous system, immune factors linked with macrophage maturation and survival may be associated with cognitive decline (measured by neuropsychological z-score [NPZ-8] or Memorial Sloan-Kettering [MSK] score) and alterations in a marker of neuronal integrity, N-acetylaspartate (NAA). Fifty-four chronically infected HIV+ subjects underwent neuropsychological assessment, magnetic resonance spectroscopic imaging, and quantification of M-CSF in plasma and cerebrospinal fluid (CSF) at baseline. Thirty-nine of those subjects underwent further examination at 3 and 10 months after initiation of combination antiretroviral therapy (ART) regimens. Within 3 months of therapy use, CSF M-CSF and viral RNA levels were reduced, whereas NAA concentrations in many brain regions were increased. Neither baseline levels nor the change in M-CSF levels had the ability to predict changes in NAA levels observed after 10 months of combination ART use. At study entry those with the lowest M-CSF levels in the CSF had the least cognitive impairment (NPZ-8). Those who had higher baseline CSF M-CSF levels and exhibited larger decreases in M-CSF after therapy, tended to have greater cognitive improvement after 10 months. Increased prevalence of M-CSF in the setting of HIV infection could contribute to neuronal injury and may be predictive of cognitive impairment.

Figure 1

T1-weighted images of a chronically HIV-infected male with dementia (MSK = 2) indicate voxel placement used in this study. NAA metabolite concentrations were evaluated within the following regions: basal ganglia (BG), thalamus (TH), frontal gray matter (FGM), frontal white matter (FWM), centrum semiovale (CSO), and both parietal gray (PGM) and white matter (PWM).

Figure 2

(A) Average NAA concentrations as measured by MRSI at study entry in subjects with HIV-associated dementia (N = 24) and those without (N = 30). Reported P values represent the results from nonparametric Wilcoxon rank sum test performed between the two cohorts for each region. (B) Average NAA concentrations in all seven brain regions of the 39 subjects who underwent repeat imaging at 3 and 10 months after initiating combination ART. RM ANOVA performed indicated that NAA levels recover with therapy, with significant increases seen in the parietal gray matter, frontal white matter, and parietal white matter (P = .004, P = .001, P = .0002, respectively). All error bars represent standard error of the mean.