Corrilynn O Hileman1, Robert C Kalayjian1, Sausan Azzam2, Daniela Schlatzer2, Kunling Wu3, Katherine Tassiopoulos4, Roger Bedimo5, Ronald J Ellis6, Kristine M Erlandson7, Asha Kallianpur8, Susan L Koletar9, Alan L Landay10, Frank J Palella11, Babafemi Taiwo11, Muralidhar Pallaki12, Charles L Hoppel13. 1. Department of Medicine, Division of Infectious Diseases, MetroHealth Medical Center and Case Western Reserve School of Medicine, Cleveland, Ohio, USA. 2. Department of Nutrition, Proteomics and Small Molecule Mass Spectrometry, Case Western Reserve School of Medicine, Cleveland, Ohio, USA. 3. Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, Massachussets, USA. 4. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachussets, USA. 5. Infectious Diseases Section, VA North Texas Health Care System, Dallas, Texas, USA. 6. Department of Neurosciences, Psychiatry and Medicine, University of California, San Diego, California, USA. 7. Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Columbus, USA. 8. Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA. 9. Department of Medicine, The Ohio State University Medical Center, Columbus, Ohio, USA. 10. Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA. 11. Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 12. Department of Medicine Louis Stokes Cleveland VA Medical Center and Case Western Reserve School of Medicine, Cleveland, Ohio, USA. 13. Center for Mitochondrial Disease and Department of Pharmacology, Case Western Reserve University and Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Abstract
BACKGROUND: Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation-this metabolic shift may contribute to NCI and slowed gait speed in PWH. METHODS: Plasma citrate and succinate were assayed by liquid chromatography-mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed. RESULTS: Median age was 51 (range 40-78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P = .03), 0.07 SD lower time-updated NPZ-4 score (P = .01), and 0.02 m/s slower time-updated gait speed (P < .0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤ .01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline. CONCLUSIONS: Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.
BACKGROUND: Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation-this metabolic shift may contribute to NCI and slowed gait speed in PWH. METHODS: Plasma citrate and succinate were assayed by liquid chromatography-mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed. RESULTS: Median age was 51 (range 40-78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P = .03), 0.07 SD lower time-updated NPZ-4 score (P = .01), and 0.02 m/s slower time-updated gait speed (P < .0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤ .01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline. CONCLUSIONS: Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.
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