Cerebrospinal Fluid Spermidine, Glutamine and Putrescine Predict Postoperative Delirium Following Elective Orthopaedic Surgery

Abstract

Delirium is a marker of brain vulnerability, associated with increasing age, pre-existing cognitive impairment and, recently, cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease. This nested case-control study used a targeted quantitative metabolomic methodology to profile the preoperative CSF of patients (n = 54) who developed delirium following arthroplasty (n = 28) and those who did not (n = 26). The aim was to identify novel preoperative markers of delirium, and to assess potential correlations with clinical data. Participants without a diagnosis of dementia (≥65 years) undergoing elective primary hip or knee arthroplasty were postoperatively assessed for delirium once-daily for three days. Groups were compared using multivariate, univariate and receiving operator characteristic (ROC) methods. Multivariate modelling using Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) of metabolomic data readily distinguished between delirium and control groups (R2 ≤ 0.56; Q2 ≤ 0.10). Three metabolites (spermidine, putrescine and glutamine) significantly differed between groups (P < 0.05; FDR < 0.07), and performed well as CSF biomarkers (ROC > 0.75). The biomarker performance of the two polyamines (spermidine/putrescine) was enhanced by ratio with CSF Aβ42 (ROC > 0.8), and spermidine significantly correlated with Aβ42 (pearson r = −0.32; P = 0.018). These findings suggest that spermidine and putrescine levels could be useful markers of postoperative delirium risk, particularly when combined with Aβ42, and this requires further investigation.

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

“…The authors postulated a decrease in the fatty acid metabolic pathway, increase in oxidative stress with mitochondrial dysfunction, and disorders in the glutamate‐glutamine cycle as an explanation of findings. In a similar study that used cerebrospinal fluid samples for metabolomics, spermidine, putrescine, and glutamine were associated with postoperative delirium, although significance was not retained after FDR correction 20 …”

Potential involvement of monoamine oxidase activity in delirium onset and SARS-COV2 infection

“…Delirium, an acute disorder of attention and cognition (American Psychiatric Association, 2013) is an unpleasant experience for patients, relatives and healthcare staff and is associated with negative outcomes such as dementia and death. As has been described by Fong et al (2015), whilst even those with the most resilient of brains can develop delirium in the face of severe stressors, delirium in the face of more moderate insults may be a sign of underlying neurodegeneration (Cunningham et al 2019). An improved understanding of the causes of postoperative delirium could provide a better appreciation of the vulnerabilities causing delirium following surgery, as well as following SARS-CoV-2 infection.…”

“…Preoperative blood and CSF samples were collected within an observational cohort study of patients aged over 65 years without a diagnosis of dementia presenting for planned hip and knee replacements prior to the SARS-CoV-2 pandemic (approved by Office for Research Ethics Committee for Northern Ireland (REC ref: 10/NIR01/5)). The study methodology has been described in detail previously (Cunningham et al 2019). The study population had a mean age of 74.4 years and 57% were female.…”

“…Metabolomic analysis of body fluids, including blood and CSF, provides a wide-ranging molecular window into the major processes of the body including an insight into the brain metabolism. CSF metabolite biomarkers of delirium risk have already been identified (Pan et al 2019). Major differences in the concentrations of polyamines (including spermidine and putrescine) are present in delirium-prone patients even before surgery or the presentation of delirium.…”

Not So Fast: Searching for Behavioral Effects of Putrescine in Direct and Conceptual Replications of Wisman and Shrira (2015)

“…Diamines such as putrescine and cadaverine are produced in decaying flesh by decarboxylation of amino acids and are strongly malodorous. Putrescine is one of many trace amines found in the body and may be useful diagnostically as a tumor marker (Soda, 2011) and as a risk factor for post-surgery confusion in the elderly (Pan et al, 2019). Putrescine is found in saliva upon awakening and after eating (Cooke, Leeves, & White; illustrating the highly interactive presence of these amines in food and in our bodies.…”