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 4

QA, NMDAR agonists, and potential neurotoxicity.

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QA, NMDAR agonists, and potential neurotoxicity. Potentially neurotoxic ...
Potentially neurotoxic concentrations of CSF-QA, although observed in a minority of delirium patients, were much more frequent in delirium (A). Glutamate and aspartate, like QA, stimulate the NMDAR. Although there was no significant difference in CSF glutamate and aspartate concentrations in hip-fracture patients by delirium presence, the overall tendency was for the highest concentrations to occur in cognitively unimpaired adults and the lowest concentrations in medical delirium (B). QA was significantly associated with the neuronal injury marker NfL in hip-fracture patients using standardized linear regression (C and D), also adjusted for age, sex, renal function, and cognitive impairment (IQCODE ≥ 3.44), ASA score (I–II versus III–IV), and delirium status (standardized linear regression with an interaction). Data shown in A and B included 406 hip-fracture patients (excluding SSD), 112 cognitively unimpaired adults, and 24 patients with medical delirium. Data shown in C–F included all hip-fracture patients (SSD patients classified as not delirium in adjusted analyses). However, 16 cases did not have NfL measured, and thus, there were 434 patients with hip fracture in this analysis (not excluding SSD cases). The association between QA and NfL was stronger in patients with cognitive impairment (E) and high ASA scores (F).