title: Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: aDepartment of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston bDepartment of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts cDepartment of Neurology, Neuroscience and Pathology, The Mount Sinai Medical Center, New York, New York dDepartment of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Edana
authors.initials: E
authors.lastname: Cassol
authors.forename: Vikas
authors.initials: V
authors.lastname: Misra
authors.forename: Anupriya
authors.initials: A
authors.lastname: Dutta
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.forename: Dana
authors.initials: D
authors.lastname: Gabuzda
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology*; D000328:Adult; D000375:Aging; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D002853:Chromatography, Liquid; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000032:analysis; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged
chemical_list: D044966:Anti-Retroviral Agents; D016207:Cytokines
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