Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients
Leiv Otto Watne, Christian Thomas Pollmann, Bjørn Erik Neerland, Else Quist-Paulsen, Nathalie Bodd Halaas, Ane-Victoria Idland, Bjørnar Hassel, Kristi Henjum, Anne-Brita Knapskog, Frede Frihagen, Johan Raeder, Aasmund Godø, Per Magne Ueland, Adrian McCann, Wender Figved, Geir Selbæk, Henrik Zetterberg, Evandro F. Fang, Marius Myrstad, Lasse M. Giil
Leiv Otto Watne, Christian Thomas Pollmann, Bjørn Erik Neerland, Else Quist-Paulsen, Nathalie Bodd Halaas, Ane-Victoria Idland, Bjørnar Hassel, Kristi Henjum, Anne-Brita Knapskog, Frede Frihagen, Johan Raeder, Aasmund Godø, Per Magne Ueland, Adrian McCann, Wender Figved, Geir Selbæk, Henrik Zetterberg, Evandro F. Fang, Marius Myrstad, Lasse M. Giil
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Clinical Research and Public Health Inflammation Metabolism

Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients

Abstract

BACKGROUND The kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive.METHODS We undertook a multicenter observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and 1-year mortality.RESULTS In delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA) (OR 2.26 [1.78, 2.87], P < 0.001) to be increased and also found increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL) (β 0.43, P < 0.001) and was a strong predictor of 1-year mortality (HR 4.35 [2.93, 6.45] for CSF-QA ≥ 100 nmol/L, P < 0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons.CONCLUSION Our data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP.FUNDING Norwegian Health Association and South-Eastern Norway Regional Health Authorities.

Authors

Leiv Otto Watne, Christian Thomas Pollmann, Bjørn Erik Neerland, Else Quist-Paulsen, Nathalie Bodd Halaas, Ane-Victoria Idland, Bjørnar Hassel, Kristi Henjum, Anne-Brita Knapskog, Frede Frihagen, Johan Raeder, Aasmund Godø, Per Magne Ueland, Adrian McCann, Wender Figved, Geir Selbæk, Henrik Zetterberg, Evandro F. Fang, Marius Myrstad, Lasse M. Giil

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Figure 3

QA concentrations in CSF and delirium.

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QA concentrations in CSF and delirium. (A) The form of the effect size o...
(A) The form of the effect size of the QA-delirium association using logistic regression is depicted on the nmol/L scale (n = 406, 224 with delirium and 182 without delirium, 44 with SSD excluded). The marginal predictions from logistic regression using transformed CSF-QA (B) have been back-transformed to the original scale of CSF-QA in nmol/L in unadjusted (red) and adjusted (green) analyses, with age, sex, GFR, ASA score (I–II versus III–IV), and IQCODE (≥3.44 versus <3.44) as covariates. In A, CSF-QA values greater than 500 nmol/L (n = 4) have been left out for illustrative purposes, but were included in the statistical analyses. In the background, one can see the highly skewed distribution that has been transformed to approximate normality (B). On the transformed scale (B), a 1 SD increase in CSF-QA gives an OR of 2.26 (unadjusted) and 1.79 (adjusted) for delirium (Figure 1). However, this is highly nonlinear on the nmol/L scale (A), where the per unit effect of CSF-QA on the probability (Pr) of delirium decreases incrementally as CSF-QA concentrations increase. This was confirmed using per 50 nmol/L and per 100 nmol/L quantitative cutoffs as predictors of delirium (data not shown).