Transthyretin, a novel prognostic marker of POCD revealed by time-series RNA-sequencing analysis

Postoperative cognitive dysfunction (POCD) is defined as a declined cognition, measured by neuropsychological tests, that persists for months or even longer after surgery. Heterogeneities in the diagnosis of POCD usually involve differences in the test batteries, the cutoffs, and the timing of assessments. Although peripheral and CSF markers of neuroinflammation have been shown to correlate with increased risk of POCD, most of them are non-specific and cannot be used for POCD diagnosis. These factors hampered the understanding of the pathogenesis of POCD as well as the development of effective preventions/treatments. In this study, we found Ttr in a panel of potential POCD biomarkers identified using time-series analysis of the transcriptomes and proteomes of the hippocampi of POCD mice that diagnosed on individual basis with composite Z-scores of test batteries consisting of Y maze and open field test. Compared with their counterparts without POCD, the levels of Ttr were significantly lower in the peripheral circulation as well as in the hippocampi of the mice developed POCD at all indicated time points after surgery. The levels of peripheral TTR in human patients with delayed neurocognitive recovery were found to be reduced at 24 h after abdominal surgery, compared with those who did not. Endogenous expression of Ttr was verified in microglia cells both in vitro and in vivo. Results of in vitro assay indicated a potential role of Ttr in ameliorating LPS-induced microglial priming and protecting the differentiation of oligodendrocyte progenitor cells (OPCs) in proinflammatory microenvironment, which was one of the determinant factors in regulating the pathological progression of POCD.