TY - JOUR
T1 - Plasma Citrate and Succinate Are Associated with Neurocognitive Impairment in Older People with HIV
AU - Hileman, Corrilynn O.
AU - Kalayjian, Robert C.
AU - Azzam, Sausan
AU - Schlatzer, Daniela
AU - Wu, Kunling
AU - Tassiopoulos, Katherine
AU - Bedimo, Roger
AU - Ellis, Ronald J.
AU - Erlandson, Kristine M.
AU - Kallianpur, Asha
AU - Koletar, Susan L.
AU - Landay, Alan L.
AU - Palella, Frank J.
AU - Taiwo, Babafemi
AU - Pallaki, Muralidhar
AU - Hoppel, Charles L.
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - 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.
AB - 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.
KW - Citrate
KW - Human immunodeficiency virus
KW - Neurocognitive impairment
KW - Succinate
KW - Tricarboxylic acid cycle
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U2 - 10.1093/cid/ciab107
DO - 10.1093/cid/ciab107
M3 - Article
C2 - 33564870
AN - SCOPUS:85113713469
SN - 1058-4838
VL - 73
SP - E765-E772
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 3
ER -