Elevated TDP-43 serum levels associated with postoperative delirium following major cardiac surgery.

Background: Postoperative delirium is a recurring complication among vulnerable patients undergoing major cardiac surgery. While delirium has been associated with prodromal dementia, there is minimal evidence to support the causality of this nuanced relationship. Clarification as to how postoperative delirium might lead to neurodegenerative dementias, perhaps through evidence of contemporaneous biomarkers, would heighten the plausibility of a causal correlation. TAR DNA-binding protein 43 (TDP-43), a nuclear protein essential for transcriptional events, has been linked to pathological aggregation in Alzheimer's disease (AD) and AD-related dementias (ADRD). Methods: Circulating TDP-43 levels in cardiac surgical patients aged 60 years and older were evaluated in a biobank derived from the Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) clinical trial. Serum total TDP-43 levels, measured with a single molecule array (Simoa), were compared across preoperative and postoperative day one timepoints according to delirium status assessed using the Confusion Assessment Method (CAM). To investigate the temporal changes in serum TDP-43, an independent validation cohort of 25 patients aged 60 years and older undergoing major cardiac surgery was analyzed. Results: Total serum TDP-43 levels increased by 16.5% (95% CI: 5.9%-27.9%, p = 0.0021) on postoperative day one compared to baseline levels. This increase was more pronounced in patients who experienced delirium (median increase of 55.1%, 95% CI: 22.9%-96.4%, p = 0.0002). Further, these findings were conserved in multiple logistic regression models adjusting for treatment, age, sex, and baseline cognitive scores. In the validation cohort, TDP-43 levels were found to be significantly elevated immediately following cardiopulmonary bypass from the baseline, with a gradual decrease by postoperative day one. Conclusions: Our findings demonstrate that post-cardiac surgery delirium among vulnerable patients is associated with significant elevations in circulating TDP-43. This relationship suggests that TDP-43 may serve as a prognostic biomarker for acute neurological insults and blood-brain barrier integrity following cardiac surgery. Overall, our results provide mechanistic insights into the inter-relationship between postoperative delirium and subsequent cognitive impairment, potentially offering new avenues for early intervention in at-risk surgical patients.