Citrate and Succinate Levels Linked to Neurocognitive Impairment in Older Patients With HIV

HIV (human immunodeficiency virus) infection, computer artwork.
By exploring links between fasting plasma citrate and succinate levels, researchers tested their hypothesis that a metabolic shift may contribute to neurocognitive impairment in people with HIV.

Among older people with HIV (PWH), higher plasma citrate and succinate levels are associated with neurocognitive impairment (NCI). This according to a study published in Clinical Infectious Diseases.

There are associations between NCI and monocyte activation in PWH. Activated monocytes accumulate citrate and succinate, both of which may contribute to NCI. In this study, citrate and succinate were isolated via liquid chromatography-mass spectrometry from 957 older PWH.

The median age of participants was 51 years (interquartile range, 46-56) and 81% were men. Mean fasting plasma citrate and succinate levels at baseline were 10.08 𝜇g/mL (range, 0.98-39.91) and 0.92 𝜇g/mL (range, 0.01-7.43), respectively.

Higher plasma citrate levels were found in participants with NCI at entry than those without NCI (mean [standard deviation (SD)] citrate levels: 10.5 [4.19] 𝜇g/mL vs 9.90 [3.65] 𝜇g/mL; P =.06). Each 1-SD increase in citrate levels resulted in 1.18 times (95% CI; 1.02-1.37; P =.03) higher adjusted odds for NCI and 0.07-SD lower NPZ-4 neuropsychological test scores in adjusted models (P =-0.07; 95% CI, -0.13 to  -0.02; P =.01). This effect was driven by the oldest age quartile.

Plasma succinate levels were also higher in those with prevalent NCI at entry than those without NCI (mean [SD] succinate levels: 0.97 [0.82] 𝜇g/ml vs 0.89 [0.77] 𝜇g/ml; P =.03), but the association didn’t hold after adjustment for clinically relevant covariates (adjusted odds ratio, 1.09; 95% CI, 0.94-1.26; P =.25). Succinate levels in the oldest age quintile showed that each 1 SD increase was associated with lower NPZ-4 scores (P = -.16; 95% CI, -0.28 to  -0.03; P =.02).

High entry citrate levels were also associated with slower 4-meter gait speeds, and again the effect was modified by age (P =.08 for citrate-by-age interaction). Succinate levels were not associated with gait speed.

The evidence from this study is not sufficient to determine whether these associations are specific to HIV-associated NCI or whether these associations reflect changes to mitochondrial function, glycolysis, or other cellular pathways. The power of this study to detect potential clinically meaningful interactions was limited. The analysis was strengthened by repeated assessments using validated tests of neurocognitive function.

The investigators concluded, “Fasting plasma [tricarboxylic acid] cycle metabolites are associated with cross-sectional and longitudinal measures of neurocognitive function and gait speed in PWH in an age-dependent manner.” This supports the importance of altered bioenergetic metabolism in NCI and suggests different mechanisms among the different age groups, according to the investigators. They add that these metabolites are potential future targets for NCI therapeutics.

Disclosure: Some study authors declared affiliations with the biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Hileman CO, Azzam S, Schlatzer D, et al; ACTG A5322 team. Plasma citrate and succinate are associated with neurocognitive impairment in older people with HIV. Clin Infect Dis. Published online February 10, 2021. doi:10.1093/cid/ciab107