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.

Degradation of heme oxygenase‐1 by the immunoproteasome in astrocytes: A potential interferon‐γ‐dependent mechanism contributing to HIV neuropathogenesis

“…Nonetheless, these observations strongly suggest a plausible link between IFNγ-induced accelerated immunoproteasome-mediated HO-1 degradation in astrocytes and brain HO-1 loss in HIV-infected individuals with HAND. This potential mechanism is particularly relevant in light of recent reports of a correlation between the presence of IFNγ-secreting CD8+ T lymphocytes and increased IFNγ in CSF and the diagnosis of HAND in HIV-infected individuals (Cassol et al 2014; Schrier et al 2015). …”

Accelerated epigenetic aging in brain is associated with pre-mortem HIV-associated neurocognitive disorders

“…Early studies indicated that older individuals were at increased risk for HAND (Cherner et al, 2004). Additional evidence that HAND is due at least partially to accelerated aging includes studies of CSF metabolomics (Cassol, Misra, Dutta, Morgello, & Gabuzda, 2014), in vitro analysis in astrocytes(Ojeda et al, 2014), and neurophysiological studies (Chang, Holt, Yakupov, Jiang, & Ernst, 2013; Holt, Kraft-Terry, & Chang, 2012). Still, in clinical samples telomere length has not been consistently associated with neurocognitive impairment or other indicators of neuroHIV (Giesbrecht et al, 2014; Malan-Muller et al, 2013).…”

Application of “Omics” Technologies for Diagnosis and Pathogenesis of Neurological Infections

“…Ongoing efforts to apply high-throughput analyses to microRNA expression in brain and plasma represent exciting opportunities to gain insights in disease pathogenesis and perhaps establish new biomarkers for disease [105][106][107][108]. Similarly, metabolomics approaches using nuclear magnetic resonance and mass spectrometry [11,109] have been applied successfully to studying neurological infections and herald a new epoch in diagnosing and understanding these devastating diseases.…”