Proteomics for the discovery of clinical delirium biomarkers: A systematic review of Major Studies

Abstract

Delirium represents a significant healthcare burden, diagnosed in over two million elderly Americans each year. In the surgical population, delirium remains the most common complication among elderly patients and is associated with longer hospital stays, higher costs of care, increased mortality and functional impairment. The pathomechanism of disease is poorly understood, with current diagnostic approaches somewhat subjective and arbitrary, and definitive diagnostic biomarkers are currently lacking. Despite the recent interest in delirium research, biomarker discovery for it remains new. Most attempts to discover biomarkers are targeted studies that seek to assess the involvement of one or more members of a focused panel of candidates in delirium. For a more unbiased, systems-biology view, we searched literature from MEDLINE, Cochrane Central, Web of Science, SCOPUS, and Dimensions between 2016 and 2021 for untargeted proteomic discovery studies for biomarkers of delirium conducted on human geriatric subjects. Two reviewers conducted independent review of all search results, and resolved discordance by concensus. From an overall search of 1172 publications, eight peer-reviewed studies met our defined inclusion criteria. The 370 unique peri-operative biomarkers identified in these reports are enriched in pathways involving the activation of the immune system, inflammatory response, and the coagulation cascade. IL-6 was the most commonly identified biomarker. By reviewing the distribution of protein biomarker candidates from these studies, we conclude that a panel of proteins, rather than a single biomarker, would allow for discriminating delirium cases from non-cases. The paucity of hypothesis-generating studies in the peer-reviewed literature also suggests that a systems-biology view of delirium pathomechanisms has yet to fully emerge.

Intraoperative plasma proteomic changes in cardiac surgery: In search of biomarkers of post‐operative delirium

“…This unbiased proteomic analyses of samples from a prior randomized control trial is the deepest unbiased plasma proteomic profiling for potential biomarkers of delirium to date [17]. We employed a rectangular biomarker workflow [43] to both discover and verify biomarkers of post-operative delirium (POD) on a single mass spectrometry platform without the use of traditional affinity-based verification methods.…”

“…Unlike any other previous proteomic attempt to discover biomarkers of POD [17], we employed extensive HPLC fractionation on a PFP column [33] to increase coverage [90]. Although SOMAScan uses three dilution bins in order to cover the wide dynamic range of plasma [91],…”

“…Efforts to improve recognition and accurate case identification has seen a steady rise in recent years, although a small fraction of these attempts has focused on biomarker discovery. Most of these biomarker studies also employed targeted quantification strategies for a selected list of genes or proteins, an approach that is inherently biased and blinded to potentially novel factors involved in the etiology or consequences of delirium [17].…”

Intraoperative Plasma Proteomic Changes in Cardiac Surgery: In Search of Biomarkers of Post-operative Delirium

“…Efforts to improve recognition and accurate case identification has seen a steady rise in recent years, although a small fraction of these attempts has focused on biomarker discovery. Most of these biomarker studies also employed targeted quantification strategies for a sub selected list of genes or proteins, an approach that is inherently biased and blinded to potentially novel factors involved in the etiology or consequences of delirium [17][manuscript].…”

Protocol For Predicting Cognitive Outcomes After Spinal Surgery v1

“…Multiple studies have demonstrated correlation between depth of anaesthesia measured using intra-operative processed EEG and postoperative neurocognitive outcomes [3]. Similarly, links between markers of systemic in ammation and neurocognitive outcomes have been explored using both targeted studies of candidate biomarkers and untargeted proteomics studies utilising high throughput multiplex assays [4]. As yet however, the link between systemic markers of in ammation, depth of anaesthesia and perioperative neurocognitive outcomes has not been the subject of prognostic modelling.…”