Phosphorylated Tau as Biomarkers of Perioperative Neurocognitive Disorder in Older Adults

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Perioperative neurocognitive disorders (PND) – including postoperative delirium, delayed neurocognitive recovery, and postoperative neurocognitive disorders – are associated with increased morbidity and mortality, high costs of care, and Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD). Consistent with the recent findings that blood Tau-PT217 and Tau-PT181 are specific biomarkers for the early stage of AD, our preliminary data have shown that the patients who go on to develop postoperative delirium have more than five- and two-fold higher concentration of preoperative blood Tau-PT217 and Tau-PT181 than the patients without postoperative delirium, respectively. In addition, blood inflammation biomarker interleukin-6 and C-reactive protein (CRP) are associated with PND. Thus, the objective of the proposed prospective cohort study is to determine whether blood Tau-PT217 and Tau-PT181 can serve as biomarkers (primary objective) of PND and enhancers (secondary objective) of the association between inflammation and PND. The hypothesis is that blood inflammation biomarkers are associated with PND only in the participants with higher blood amounts of Tau-PT217 or Tau-PT181. Because it is difficult to measure the low concentrations of pTau in blood, we will employ a newly developed and innovative nanoneedle technology, an ultra-highly sensitive method to detect low concentrations of molecules, to measure the Tau-PT217 and Tau-PT181 in blood. We will establish a system for future studies by recruiting 40 participants (> 70 years old) who will have non- cardiac surgery under general anesthesia in two Specific Aims. In Aim 1, we will establish a system to measure Tau-PT217 and Tau-PT181 (using both nanoneedle and Simoa for comparison) and IL-6 and CRP (using both nanoneedle and ELISA for comparison) concentrations. We will determine their relationships with the incidence and severity of postoperative delirium on the first three days postoperatively. In Aim 2, we will use the recruited participants in Aim 1 to investigate the associations between these blood biomarkers and delayed neurocognitive recovery (21 days after surgery) and postoperative neurocognitive disorder (9 months after the surgery). PNDs will be defined using 3D Confusion Assessment Method (3D-CAM) and CAM-Severity for postoperative delirium, and neuropsychological tests for delayed neurocognitive recovery and postoperative neurocognitive disorders. This high-impact prospective cohort study in older adults could provide vital information for an R01 application to further establish Tau-PT217 and Tau-PT181 in blood as biomarkers and parts of pathogenesis of PND. Such outcomes will promote the identification of patients with a higher risk of PND, enable the determination of the effects of intervention(s) to reduce PND, and target PT217 and Tau- PT181 in blood as the potential intervention of PND, promoting the development of strategies to prevent and treat PND, ultimately mitigating the establishment of AD/ADRD.