Cassol, E, et al. Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment. AIDS, 2014.
OBJECTIVE(S): HIV-associated neurocognitive disorders (HANDs) remain prevalent in HIV-infected patients on antiretroviral therapy (ART), but the underlying mechanisms are unclear. Some features of HANDs resemble those of age-associated cognitive decline in the absence of HIV, suggesting that overlapping mechanisms may contribute to neurocognitive impairment.
DESIGN: Cross-sectional analysis of cerebrospinal fluid (CSF) from 100 individuals (46 HIV-positive patients and 54 HIV-negative controls). METHODS:: Untargeted CSF metabolite profiling was performed using liquid/gas chromatography followed by mass spectrometry. Cytokine profiling was performed by Bioplex. Bioinformatic analyses were performed in Metaboanalyst and R.
RESULTS: Alterations in the CSF metabolome of HIV patients on ART mapped to pathways associated with neurotransmitter production, mitochondrial function, oxidative stress, and metabolic waste. Many CSF metabolites altered in HIV overlapped with those altered with advanced age in HIV-negative controls, suggesting a pattern indicative of accelerated aging. Machine learning models identified neurotransmitters (glutamate, N-acetylaspartate), markers of glial activation (myo-inositol), and ketone bodies (beta-hydroxybutyric acid, 1,2-propanediol) as top-ranked classifiers of HANDs. These CSF metabolites correlated with worse neurocognitive test scores, plasma inflammatory biomarkers [interferon (IFN)-alpha, IFN-gamma, interleukin (IL)-8, IL-1beta, IL-6, IL-2Ra], and intrathecal IFN responses (IFN-gamma and kynurenine : tryptophan ratio), suggesting inter-relationships between systemic and intrathecal inflammation and metabolic alterations in CSF.
CONCLUSIONS: Alterations in the CSF metabolome of HIV patients on ART suggest that persistent inflammation, glial responses, glutamate neurotoxicity, and altered brain waste disposal systems contribute to mechanisms involved in HANDs that may be augmented with aging.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.