Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment.
Title | Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Cassol, E, Misra, V, Dutta, A, Morgello, S, Gabuzda, D |
Journal | AIDS |
Volume | 28 |
Issue | 11 |
Pagination | 1579-91 |
Date Published | 2014 Jul 17 |
ISSN | 1473-5571 |
Keywords | Adult, Aging, AIDS Dementia Complex, Anti-Retroviral Agents, Cerebrospinal Fluid, Chromatography, Liquid, Cohort Studies, Cross-Sectional Studies, Cytokines, External, Female, Gas Chromatography-Mass Spectrometry, HIV Infections, Humans, Male, Metabolic Clearance Rate, Metabolome, Metabolomics, Middle Aged |
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. |
DOI | 10.1097/QAD.0000000000000303 |
Alternate Journal | AIDS |
PubMed ID | 24752083 |
PubMed Central ID | PMC4086755 |
Grant List | U01MH083500 / MH / NIMH NIH HHS / United States T32 AG00222 / AG / NIA NIH HHS / United States U24 MH100929 / MH / NIMH NIH HHS / United States U01 MH083507 / MH / NIMH NIH HHS / United States U01 MH083500 / MH / NIMH NIH HHS / United States U24 MH100931 / MH / NIMH NIH HHS / United States R01 MH097659 / MH / NIMH NIH HHS / United States T32 AG000222 / AG / NIA NIH HHS / United States U24 MH100928 / MH / NIMH NIH HHS / United States R24MH59724 / MH / NIMH NIH HHS / United States R24MH59745 / MH / NIMH NIH HHS / United States R24NS45491 / NS / NINDS NIH HHS / United States R24 NS038841 / NS / NINDS NIH HHS / United States N01MH22005 / MH / NIMH NIH HHS / United States R24NS38841 / NS / NINDS NIH HHS / United States P30 AI060354 / AI / NIAID NIH HHS / United States / / Canadian Institutes of Health Research / Canada DA28994 / DA / NIDA NIH HHS / United States U01MH083501 / MH / NIMH NIH HHS / United States DP1 DA028994 / DA / NIDA NIH HHS / United States P30 CA06516 / CA / NCI NIH HHS / United States U01 MH083501 / MH / NIMH NIH HHS / United States U01MH083506 / MH / NIMH NIH HHS / United States U01 MH083545 / MH / NIMH NIH HHS / United States U01 MH083506 / MH / NIMH NIH HHS / United States U01MH083507 / MH / NIMH NIH HHS / United States N01MH32002 / MH / NIMH NIH HHS / United States U01MH083545 / MH / NIMH NIH HHS / United States |