Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment

Abstract

Objective(s): HIV-associated neurocognitive disorders (HAND) remain prevalent in HIV-infected patients on antiretroviral therapy (ART), but the underlying mechanisms are unclear. Some features of HAND 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 HAND. These CSF metabolites correlated with worse neurocognitive test scores, plasma inflammatory biomarkers [interferon (IFN)-α, IFN-γ, interleukin (IL)-8, IL-1β, IL-6, IL-2Ra], and intrathecal IFN responses (IFN-γ 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 HAND that may be augmented with aging.

Fig. 1

Cerebrospinal fluid metabolomics identifies metabolites that distinguish HIV patients on antiretroviral therapy from HIV-negative controls.

Fig. 2

Alterations in the cerebrospinal fluid metabolome associated with aging in HIV-negative controls.

Fig. 3

Metabolites altered in the cerebrospinal fluid metabolome of young HIV patients on antiretroviral therapy overlap with those altered in older HIV-negative controls.

Fig. 4

Cerebrospinal fluid metabolites associated with neurocognitive impairment in HIV patients on antiretroviral therapy.

Fig. 5

Integrative analysis and correlation matrix visualization reveals relationships between cerebrospinal fluid classifiers of neurocognitive impairment, plasma lysophosphocholines and steroids, global and domain T scores, and markers of systemic and intrathecal inflammation in HIV patients on antiretroviral therapy.