Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients

Alex M. Dickens, Daniel C. Anthony, Reena Deutsch, Michelle M Mielke, Timothy D W Claridge, Igor Grant, Donald Franklin, Debra Rosario, Thomas Marcotte, Scott Letendre, Justin C. McArthur, Norman J. Haughey

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Objectives: To identify prognostic surrogate markers for change in cognitive states of HIV-infected patients. Design: Longitudinal cerebrospinal fluid (CSF) samples were collected from 98 HIV-infected patients identified by temporal change in cognitive states classified as normal, stably impaired, improving and worsening. Methods: The metabolic composition of CSF was analysed using 1 H nuclear magnetic resonance (1 H NMR) spectroscopy that focused on energy metabolites. Metabolic biomarkers for cognitive states were identified using multivariate partial least squares regression modelling of the acquired spectra, combined with nonparametric analyses of metabolites with clinical features. Results: Multivariate modelling and cross-validated recursive partitioning identified several energy metabolites that, when combined with clinical variables, classified patients based on change in neurocognitive states. Prognostic identification for worsening was achieved with four features that included no change in a detectable plasma viral load, elevated citrate and acetate; decreased creatine, to produce a model with a predictive accuracy of 92%, sensitivity of 88% and 96% specificity. Prognosis for improvement contained seven features that included first visit age less than 47 years, new or continued use of antiretrovirals, elevated glutamine and glucose; decreased myo-inositol, β-glucose and creatinine to generate a model with a predictive accuracy of 92%, sensitivity of 100% and specificity of 84%. Conclusion: These CSF metabolic results suggest that worsening cognitive status in HIV-infected patients is associated with increased aerobic glycolysis, and improvements in cognitive status are associated with a shift to anaerobic glycolysis. Dietary, lifestyle and pharmacologic interventions that promote anaerobic glycolysis could protect the brain in setting of HIV infection with combined antiretroviral therapy.

Original languageEnglish (US)
Pages (from-to)559-569
Number of pages11
JournalAIDS
Volume29
Issue number5
DOIs
StatePublished - Mar 13 2015

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Metabolomics
Energy Metabolism
Cerebrospinal Fluid
Glycolysis
HIV
Biomarkers
Glucose
Creatine
Inositol
Least-Squares Analysis
Glutamine
Viral Load
Citric Acid
HIV Infections
Life Style
Creatinine
Acetates
Magnetic Resonance Spectroscopy
Sensitivity and Specificity
Brain

Keywords

  • brain energy metabolism
  • HIV
  • HIV-associated neurocognitive disorders
  • metabolomics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients. / Dickens, Alex M.; Anthony, Daniel C.; Deutsch, Reena; Mielke, Michelle M; Claridge, Timothy D W; Grant, Igor; Franklin, Donald; Rosario, Debra; Marcotte, Thomas; Letendre, Scott; McArthur, Justin C.; Haughey, Norman J.

In: AIDS, Vol. 29, No. 5, 13.03.2015, p. 559-569.

Research output: Contribution to journalArticle

Dickens, AM, Anthony, DC, Deutsch, R, Mielke, MM, Claridge, TDW, Grant, I, Franklin, D, Rosario, D, Marcotte, T, Letendre, S, McArthur, JC & Haughey, NJ 2015, 'Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients', AIDS, vol. 29, no. 5, pp. 559-569. https://doi.org/10.1097/QAD.0000000000000580
Dickens, Alex M. ; Anthony, Daniel C. ; Deutsch, Reena ; Mielke, Michelle M ; Claridge, Timothy D W ; Grant, Igor ; Franklin, Donald ; Rosario, Debra ; Marcotte, Thomas ; Letendre, Scott ; McArthur, Justin C. ; Haughey, Norman J. / Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients. In: AIDS. 2015 ; Vol. 29, No. 5. pp. 559-569.
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abstract = "Objectives: To identify prognostic surrogate markers for change in cognitive states of HIV-infected patients. Design: Longitudinal cerebrospinal fluid (CSF) samples were collected from 98 HIV-infected patients identified by temporal change in cognitive states classified as normal, stably impaired, improving and worsening. Methods: The metabolic composition of CSF was analysed using 1 H nuclear magnetic resonance (1 H NMR) spectroscopy that focused on energy metabolites. Metabolic biomarkers for cognitive states were identified using multivariate partial least squares regression modelling of the acquired spectra, combined with nonparametric analyses of metabolites with clinical features. Results: Multivariate modelling and cross-validated recursive partitioning identified several energy metabolites that, when combined with clinical variables, classified patients based on change in neurocognitive states. Prognostic identification for worsening was achieved with four features that included no change in a detectable plasma viral load, elevated citrate and acetate; decreased creatine, to produce a model with a predictive accuracy of 92{\%}, sensitivity of 88{\%} and 96{\%} specificity. Prognosis for improvement contained seven features that included first visit age less than 47 years, new or continued use of antiretrovirals, elevated glutamine and glucose; decreased myo-inositol, β-glucose and creatinine to generate a model with a predictive accuracy of 92{\%}, sensitivity of 100{\%} and specificity of 84{\%}. Conclusion: These CSF metabolic results suggest that worsening cognitive status in HIV-infected patients is associated with increased aerobic glycolysis, and improvements in cognitive status are associated with a shift to anaerobic glycolysis. Dietary, lifestyle and pharmacologic interventions that promote anaerobic glycolysis could protect the brain in setting of HIV infection with combined antiretroviral therapy.",
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AU - Claridge, Timothy D W

AU - Grant, Igor

AU - Franklin, Donald

AU - Rosario, Debra

AU - Marcotte, Thomas

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AU - McArthur, Justin C.

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