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Tittel Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients
Medansvarlig Pollmann, Christian Thomas Neerland, Bjørn Erik Quist-Paulsen, Else Halaas, Nathalie Bodd Idland, Ane-Victoria Hassel, Bjørnar Henjum, Kristi Knapskog, Anne-Brita Frihagen, Frede Ræder, Johan Godø, Aasmund Ueland, Per Magne McCann, Adrian Figved, Wender Selbæk, Geir Zetterberg, Henrik Fang, Evandro Fei Myrstad, Marius Giil, Lasse Melvaer
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Serienummer 2023 Jan 17;133(2):e163472
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Noter 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.
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*000 ap
*00141882
*100 $aWatne, Leiv Otto
*245 $aCerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients$cLeiv 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
*260 $c2023
*300 $ahttps://doi.org/10.1172/JCI163472
*440 $aThe Journal of Clinical Investigation$v2023 Jan 17;133(2):e163472
*505 $aBACKGROUND: 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.
*650 $aDelirium
*700 $aPollmann, Christian Thomas
*700 $aNeerland, Bjørn Erik
*700 $aQuist-Paulsen, Else
*700 $aHalaas, Nathalie Bodd
*700 $aIdland, Ane-Victoria
*700 $aHassel, Bjørnar
*700 $aHenjum, Kristi
*700 $aKnapskog, Anne-Brita
*700 $aFrihagen, Frede
*700 $aRæder, Johan
*700 $aGodø, Aasmund
*700 $aUeland, Per Magne
*700 $aMcCann, Adrian
*700 $aFigved, Wender
*700 $aSelbæk, Geir
*700 $aZetterberg, Henrik
*700 $aFang, Evandro Fei
*700 $aMyrstad, Marius
*700 $aGiil, Lasse Melvaer
*856 $uhttps://doi.org/10.1172/JCI163472
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