# Administrative Supplement: Postoperative Delirium and Alzheimer's Disease Related Dementias

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $404,038

## Abstract

Postoperative delirium (POD) is the most common postoperative complication among older patients and is
associated with substantially increased rates of morbidity and mortality, increased cost of care, and risk of
developing Alzheimer’s disease (AD) and AD related dementias (AD/ADRD). However, the pathogenesis of
POD is still largely unknown, and this gap in knowledge impedes current efforts in preventing and treating
POD. To further study the POD pathogenesis, we have established a nanoneedle technology to measure
blood concentrations of Tau phosphorylation at threonine 217 (Tau-pT217) and threonine 181 (Tau-pT181).
Consistent with the notion that Tau-pT217 and Tau-pT181 are the newly identified biomarker of early stage of
AD, our preliminary studies showed that open abdominal surgery under isoflurane anesthesia
(anesthesia/surgery) increased Tau-pT217 and Tau-pT181 amounts in blood, lungs and brain, accompanied
by decreases in B cells in blood of aged mice. Thus, the proposed research will extend these studies to
establish trafficking of Tau-pT217 and Tau-pT181 from blood to brain as the pathogenesis of POD by testing
the following hypothesis: anesthesia/surgery enhances Tau-pT217 and Tau-pT181 generation and promotes
Tau-pT217 and Tau-pT181 trafficking from blood to brain, leading to delirium-like behavior in mice. We will
employ biochemical and genetic tools through in vivo (mice) approach to accomplish three Specific Aims: 1)
We will evaluate the effects of anesthesia/surgery on the amounts of Tau-pT217 and Tau-pT181 in blood,
lungs and brain of adult (3 months-old) and aged (18 months-old) wild-type mice, and adult (3 months-old) AD
transgenic mice. 2) We will perform studies to determine the trafficking of Tau-pT217 and Tau-pT181 from
blood to brain in wild-type mice and Tau knockout mice by using conditioned blood, synthesized Tau-pT217
and Tau-pT181 peptides or parabiosis in mice. 3) We will assess whether treatment with WS635 or Vitamin K2
(protector of mitochondrial function), or B cells can mitigate the anesthesia/surgery-induced increases in Tau-
pT217 and Tau-pT181 amounts, and delirium-like behaviors in aged wild-type mice and AD transgenic mice.
We will include adult wild-type (3 months-old) mice versus age matched (3 months-old) AD transgenic and
aged wild-type (18 months-old) mice (with higher pTau levels), and employ a label-free nano-biosensing
system for biomolecular analysis (nanoneedle technology). This proposal aims to investigate an understudied
topic in innovative systems through testing novel hypotheses. Our efforts could ultimately help to develop
prevention and treatment methods towards POD, leading to safer surgical care and better post-operative
outcomes for senior and AD/ADRD patients, leading to the development of strategies to prevent AD/ADRD.

## Key facts

- **NIH application ID:** 10625200
- **Project number:** 3R01AG062509-04S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Zhongcong Xie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $404,038
- **Award type:** 3
- **Project period:** 2019-04-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10625200

## Citation

> US National Institutes of Health, RePORTER application 10625200, Administrative Supplement: Postoperative Delirium and Alzheimer's Disease Related Dementias (3R01AG062509-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10625200. Licensed CC0.

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