Proteome-Wide Analysis Identifies and Validates Chitinase-3-Like Protein 1 as a Risk and Disease Marker of Delirium

TL;DR

This study identifies a protein called CHI3L1/YKL-40 as a potential biomarker for delirium after surgery, offering a new way to predict and understand this condition in older adults.

Contribution

The study is the first to validate CHI3L1/YKL-40 as a preoperative and postoperative biomarker for delirium using proteomic analysis.

Findings

CHI3L1/YKL-40 was the only protein consistently associated with delirium in both preoperative and postoperative models.

High levels of CHI3L1/YKL-40 and IL6 increased the risk of delirium after surgery.

CHI3L1/YKL-40 is linked to aging and age-related conditions like Alzheimer’s disease, suggesting a shared biological mechanism.

Abstract

Delirium (an acute change in cognition) is a common, morbid, and costly syndrome seen primarily in aging adults. Despite increasing knowledge of its epidemiology, delirium remains a clinical diagnosis with no established biomarkers to guide diagnosis or management. Advances in proteomics now provide opportunities to identify novel markers of risk and disease progression for postoperative delirium and its associated long-term consequences (eg, long-term cognitive decline and Alzheimer’s disease [AD]). In a nested matched case-control study (18 delirium/no-delirium pairs) within the Successful Aging after Elective Surgery study (N = 556), we evaluated the association of 1305 plasma proteins preoperatively [PREOP] and on postoperative day 2 [POD2]) with delirium using SOMAscan. Generalized linear models were applied to enzyme-linked immunosorbant assay (ELISA) validation data of one protein across the full cohort. Multi-protein modeling included delirium biomarkers identified in prior work (C-reactive protein, interleukin-6 [IL6]). We identified chitinase-3-like-protein-1 (CHI3L1/YKL-40) as the sole delirium-associated protein in both a PREOP and a POD2 predictor model, a finding confirmed by ELISA. Multi-protein modeling found high PREOP CHI3L1/YKL-40 and POD2 IL6 increased the risk of delirium (relative risk [95% confidence interval] Quartile [Q]4 vs Q1: 2.4[1.2-5.0] and 2.1[1.1-4.1], respectively). Our identification of CHI3L1/YKL-40 in postoperative delirium parallels reports of CHI3L1/YKL-40 and its association with aging, mortality, and age-related conditions including AD onset and progression. This highlights the type 2 innate immune response, involving CHI3L1/YKL-40, as an underlying mechanism of postoperative delirium, a common, morbid, and costly syndrome that threatens the independence of older adults.