The Tryptophan Depletion Theory in Delirium: Not Confirmed in Elderly Hip Fracture Patients

Jonghe, Annemarieke de; Munster, Barbara C. Van; Fekkes, Durk; Oosten, Hannah E. van; Rooij, Sophia E. de

doi:10.1016/j.psym.2011.09.009

Cited by 15 publications

(13 citation statements)

References 26 publications

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“…The low tryptophan levels might be associated with delirium via decreased synthesis of brain serotonin (van der Mast et al, 2000 ; Robinson et al, 2008 ; Pandharipande et al, 2009 ). de Jonghe et al ( 2012 ) questioned the association between lower levels of tryptophan and delirium. Following the inflammatory response, tryptophan catabolisation via the kynurenine pathway is increased (Adams Wilson et al, 2012 ).…”

Section: Biological Markers Of Postoperative Deliriummentioning

confidence: 99%

Biomarkers of postoperative delirium and cognitive dysfunction

Androsova

Krause

Winterer

et al. 2015

Front. Aging Neurosci.

197

145

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Elderly surgical patients frequently experience postoperative delirium (POD) and the subsequent development of postoperative cognitive dysfunction (POCD). Clinical features include deterioration in cognition, disturbance in attention and reduced awareness of the environment and result in higher morbidity, mortality and greater utilization of social financial assistance. The aging Western societies can expect an increase in the incidence of POD and POCD. The underlying pathophysiological mechanisms have been studied on the molecular level albeit with unsatisfying small research efforts given their societal burden. Here, we review the known physiological and immunological changes and genetic risk factors, identify candidates for further studies and integrate the information into a draft network for exploration on a systems level. The pathogenesis of these postoperative cognitive impairments is multifactorial; application of integrated systems biology has the potential to reconstruct the underlying network of molecular mechanisms and help in the identification of prognostic and diagnostic biomarkers.

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Section: Biological Markers Of Postoperative Deliriummentioning

confidence: 99%

Biomarkers of postoperative delirium and cognitive dysfunction

Androsova

Krause

Winterer

et al. 2015

Front. Aging Neurosci.

197

145

View full text Add to dashboard Cite

show abstract

“…In the current study, evidence of an upregulation was found in tryptophan metabolism in delirious patients because tryptophan concentrations were lower, tryptophan metabolite concentrations were higher, and the kynurenine‐to‐tryptophan ratio was increased, suggesting an increase in indoleamine 2,3‐dioxygenase (IDO) activity. IDO is upregulated by inflammatory cytokines including interferon‐γ, interleukins 1 and 12, lipopolysaccharide, and tumor necrosis factor‐α 8,23 . Tryptophan depletion was previously associated with acute brain dysfunction (characterized by days without delirium or coma) in critically ill medical and surgical ICU patients 8 .…”

Section: Discussionmentioning

confidence: 99%

“…Tryptophan depletion was previously associated with acute brain dysfunction (characterized by days without delirium or coma) in critically ill medical and surgical ICU patients 8 . However, upregulation in this pathway was not determined in a targeted analysis of tryptophan and metabolites in non‐critically ill older adult patients undergoing elective hip surgery 23 . A possible explanation for the discordant findings is that the proinflammatory state common in critical illness may lead to an upregulation in IDO and a shift in kynurenine metabolism toward neurotoxic metabolites.…”

Section: Discussionmentioning

confidence: 99%

Intensive Care Unit Delirium in Surgical Patients Is Associated with Upregulation in Tryptophan Metabolism

et al. 2020

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INTRODUCTION In intensive care unit (ICU) patients, delirium is frequent, occurs early in ICU admission, and is associated with poor outcomes. Risk models based on clinical factors have shown variable performance in terms of predictive ability. Identification of a candidate biomarker that associates with delirium may lead to a better understanding of disease mechanism, validation biomarker studies, and the ability to develop targeted interventions for prevention and treatment of delirium. This study analyzed metabolite concentrations early in the course of ICU admission to assess the association with delirium onset. METHODS Within 24 hours of ICU admission, blood samples for global and targeted metabolomics analyses in adult surgical ICU patients were collected prospectively. Metabolites were determined using mass spectrometry/ultra-high-pressure liquid chromatography and analyzed in patients with delirium and a group of controls matched on age, sex, and admission Sequential Organ Function Assessment (SOFA) score. RESULTS Patients in the study (65 per group) were a mean age of 59 years, had a median SOFA score of 6, and were most commonly admitted to the ICU following major trauma. In the delirium group, median onset of delirium was 3 (interquartile range 1-6) days, and the most common delirium subtype was mixed (56%). Kynurenic acid was significantly increased, and tryptophan concentration was significantly decreased in the delirium group (p=0.04). The ratio of kynurenine-to-tryptophan concentration was significantly higher in the delirium group (p=0.005). CONCLUSIONS Evidence of upregulation was found in the tryptophan metabolic pathway in delirious patients because tryptophan concentrations were lower, tryptophan metabolites were higher, and the kynurenine-to-tryptophan ratio was increased. These findings suggest a role of increased inflammation and accumulation of neurotoxic metabolites in the pathogenesis of ICU delirium. Future studies should target this pathway to validate metabolites in the tryptophan pathway as risk biomarkers in patients with ICU delirium.

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“…Therefore, a reduced ratio may result in a decreased synthesis of serotonin. Several studies have found decreased levels of tryptophan and tryptophan/LNAAs ratios in patients with delirium,10,12–15 whereas other studies did not report differences in these parameters between patients with and without delirium 16–18…”

Section: Introductionmentioning

confidence: 99%

<p>Differences in potential biomarkers of delirium between acutely ill medical and elective cardiac surgery patients</p>

Egberts¹,

Osse²,

Fekkes³

et al. 2019

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Background/aimsThe pathophysiology of delirium is poorly understood. Increasing evidence suggests that different pathways might be involved in the pathophysiology depending on the population studied. The aim of the present study was to investigate potential differences in mean plasma levels of neopterin, amino acids, amino acid ratios and homovanillic acid between two groups of patients with delirium.MethodsData from acutely ill medical patients aged 65 years and older, and patients aged 70 years and older undergoing elective cardiac surgery, were used. Differences in biomarker levels between the groups were investigated using univariate ANOVA with adjustments for age, sex, comorbidities, C-reactive protein (CRP) and the estimated glomerular filtration rate (eGFR), where appropriate. Linear regression analysis was used to identify potential determinants of the investigated biochemical markers.ResultsEighty patients with delirium were included (23 acutely ill medical patients and 57 elective cardiac surgery patients). After adjustment, higher mean neopterin levels (93.1 vs 47.3 nmol/L, P=0.001) and higher phenylalanine/tyrosine ratios (1.39 vs 1.15, P=0.032) were found in acutely ill medical patients when compared to elective cardiac surgery patients. CRP levels were positively correlated with neopterin levels in acutely ill medical patients, explaining 28.4% of the variance in neopterin levels. eGFR was negatively correlated with neopterin in elective cardiac surgery patients, explaining 53.7% of the variance in neopterin levels.ConclusionIn this study, we found differences in mean neopterin levels and phenylalanine/tyrosine ratios between acutely ill medical and elective cardiac surgery patients with delirium. Moreover, our findings may suggest that in acutely ill medical patients, neopterin levels are mainly determined by inflammation/oxidative stress whereas in elective cardiac surgery patients, neopterin levels are mainly driven by renal function/fluid status. These findings suggest that the markers and pathways that might be involved in the pathophysiology of delirium may differ between specific groups of patients.

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The Tryptophan Depletion Theory in Delirium: Not Confirmed in Elderly Hip Fracture Patients

Cited by 15 publications

References 26 publications

Biomarkers of postoperative delirium and cognitive dysfunction

Biomarkers of postoperative delirium and cognitive dysfunction

Intensive Care Unit Delirium in Surgical Patients Is Associated with Upregulation in Tryptophan Metabolism

<p>Differences in potential biomarkers of delirium between acutely ill medical and elective cardiac surgery patients</p>

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