TY - JOUR
T1 - Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients
AU - Dickens, Alex M.
AU - Anthony, Daniel C.
AU - Deutsch, Reena
AU - Mielke, Michelle M.
AU - Claridge, Timothy D.W.
AU - Grant, Igor
AU - Franklin, Donald
AU - Rosario, Debra
AU - Marcotte, Thomas
AU - Letendre, Scott
AU - McArthur, Justin C.
AU - Haughey, Norman J.
N1 - Publisher Copyright:
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2015/3/13
Y1 - 2015/3/13
N2 - 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.
AB - 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.
KW - HIV
KW - HIV-associated neurocognitive disorders
KW - brain energy metabolism
KW - metabolomics
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U2 - 10.1097/QAD.0000000000000580
DO - 10.1097/QAD.0000000000000580
M3 - Article
C2 - 25611149
AN - SCOPUS:84926524046
SN - 0269-9370
VL - 29
SP - 559
EP - 569
JO - AIDS
JF - AIDS
IS - 5
ER -