|Authors: Anderson AM, Fennema-Notestine C, Umlauf A, Clifford D, Marra C, Gelman B, McArthur J, McCutchan A, Morgello S, and Letendre S, for the CHARTER group|
|Abstract:Background: HIV-associated neurocognitive disorders (HAND) persist in the cART era. These disorders adversely affect quality of life, work ability, and overall survival. Persistent immune activation appears to contribute to the pathology of HAND and evidence exists that biomarkers of immune activation correlate with cerebral metabolites measured by magnetic resonance spectroscopy (MRS). The purpose of this analysis was to determine associations between cerebrospinal fluid (CSF) biomarkers and regional cerebral metabolites in a multicenter cohort.
Methodology: Data from 91 participants were analyzed from five sites in the US (Galveston, Baltimore, New York, Seattle, and San Diego) as part of the CHARTER study. MRS concentrations of N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), and creatine (Cr) were quantified using LCModel in frontal white matter (FWM), frontal gray matter (FGM), and basal ganglia (BG). CSF biomarkers were measured by immunoassay. Multivariable mixed effects models accounted for demographic and disease characteristics as well as proportion of relevant tissue volume within each voxel.
Results: Participants were mostly middle-aged (median age 44) men (84%) on ART (76%). 47% were European-American and 43% African-American. Other median values were: current CD4+ count 458/mm3 (IQR 311-600), nadir CD4+ count 145/mm3 (IQR 24-238), log10 HIV RNA 1.72 (plasma) and 1.7 (CSF). 26% were hepatitis C seropositive. Higher (↑) levels of MCP-1 and IP-10 were each associated with ↑levels of MI and Cr in FWM (see Table for adjusted R2 and p value). A particularly strong association was found between ↑MCP-1 and ↑Cho in BG while a weaker association was found between ↑IP-10 and ↑NAA in FWM. No statistically significant associations were present for sCD14 and SDF-1α.
Conclusions: In this cross-sectional analysis of HIV infected individuals from multiple sites, two CSF biomarkers were associated with cerebral metabolites reflecting energy metabolism, membrane remodeling, neuronal integrity, and glial proliferation. The biomarkers are indicators of monocyte chemotaxis (MCP-1) and antiviral immune responses (IP-10). While Cr was not used as a denominator for metabolite-biomarker associations as in previous studies, the unexpected positive association between IP-10 and FWM NAA warrants further investigation. Frontal white matter was the most commonly involved brain region, which may reflect the impact of immune activation on myelin and axonal integrity.|