Using our perioperative CSF biorepository, we are currently investigating the role of complement activation and other neuroinflammatory pathways in postoperative delirium and neurocognitive disorders.

We are also conducting an NIA-funded study CASCADE-ICU to investigate the role of complement pathway activation in ICU-delirium and post-ICU long-term cognitive impairment. With the help of the Duke/UNC ADRC, we are also investigating synaptic injury and Alzheimer’s disease biomarker changes in older ICU patients.

In CASCADE-ICU, we are investigating the neurobiological underpinnings of ICU delirium and post-ICU long-term cognitive impairment. We hypothesize that cerebrospinal fluid (CSF) complement pathway activation during critical illness is associated with ICU delirium and post-ICU long term cognitive impairment. To answer this question, we are enrolling 120 age>= 65 ICU patients that will undergo CSF and blood sampling, delirium assessments and follow-up cognitive testing at 6-months, 1 year, and 3 years following hospital discharge. CSF complement pathway activation will be measured with mass spec proteomics and immunoassays. CSF and blood samples obtained here are also stored in a biorepository to enable future investigations of other mechanisms of ICU delirium.

Funding: NIA K23AG084898, Duke/UNC Alzheimer’s Disease Research Center Development Project Award, National Alzheimer’s Coordinating Center Junior Investigator Award (Completed) 

References:

1. Role of Blood-Brain Barrier Dysfunction in Delirium Following Non-cardiac Surgery in Older Adults.
2. Cognitive and Cerebrospinal Fluid Alzheimer's Disease-Related Biomarker Trajectories in Older Surgical Patients and Matched Nonsurgical Controls.
3. Immunomodulatory Lipid Mediator Profiling of Cerebrospinal Fluid Following Surgery in Older Adults.
4. Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction.

Given emerging evidence showing that adequate sleep is important to brain health, we are investigating whether sleep disruptions are associated with perioperative and ICU-acquired neurocognitive disorders. In our prior SANDMAN (Sleep Apnea, Neuroinflammation, and Cognitive Dysfunction Manifesting After Non-cardiac surgery) study we investigated the role of sleep apnea in perioperative neurocognitive disorders (10.1213/ANE.0000000000007269). Surprisingly, we found that undiagnosed sleep apnea was not a risk factor for delirium or postoperative neurocognitive disorder. Thus, our attention has turned to sleep disruptions as a risk factor, and our current studies are using in-hospital EEG to quantify sleep patterns in patients at risk for delirium. We are also investigating sleep-related changes in sustained attention following surgery.

Funding: NIA R03AG067976 (Completed), Foundation for Anesthesia and Education Research Fellowship Grant (Completed) 

References: 

1. The Role of Sleep Apnea in Postoperative Neurocognitive Disorders Among Older Noncardiac Surgery Patients: A Prospective Cohort Study.
2. The Potential Link Between Obstructive Sleep Apnea and Postoperative Neurocognitive Disorders: Current Knowledge and Possible Mechanisms.

We are carrying out a study to determine whether postoperative sleep enhancement with the orexin antagonist suvorexant increases postoperative sleep and reduces delirium severity. The REPOSE study (reducing delirium by enhancing postoperative sleep with suvorexant; NCT05733286) is a single-center, randomized, double-blind RCT that aims to evaluate the efficacy of suvorexant in increasing total sleep time and decreasing delirium in older patients undergoing non-cardiac surgery. In REPOSE, 130 older non-cardiac non-neurologic surgery patients will be randomized to receive 20 mg suvorexant vs placebo for the first three nights after surgery and undergo delirium assessments and sleep measurement with an EEG headband. Within REPOSE, we are also conducting pilot studies on the relationship of postoperative changes in sustained attention and pupillary unrest in ambient light with postoperative delirium. REPOSE is funded by an investigator-initiated study from Merck.

Funding: Investigator-Initiated grant from Merck Investigator Studies Program

It has been well known that lower anesthetic dose is needed to provide anesthesia for older adults, but few studies have determined whether anesthetic dose requirements and EEG responses to anesthesia indicate pre-existing dementia pathology and risk for postoperative delirium. Thus, with my mentor Dr. Miles Berger, I am co-leading a study to investigate whether anesthetic-dose adjusted EEG responses are associated with increased Alzheimer’s disease CSF biomarkers, functional MRI connectivity changes, neurovascular dementia risk and increased risk for postoperative delirium.  To accomplish this, 250 older non-cardiac surgery patients that require general anesthesia will undergo preoperative lumbar puncture, fMRI, and postoperative delirium assessments in the NIA R01-funded ALADDIN study: Low Neurophysiologic Resistance to Anesthetics as a Marker of Preclinical/Prodromal Alzheimer's Disease and Neurovascular Pathology, Delirium risk and Inattention.

Funding: NIA R01AG073598 (co-PI with Stanford Collaborator Dr. Miles Berger) 

2025

Congratulations to CIPHER Lab member, Dr. Tyler Reekes, on his online publication on MEDRXIV titled, “Predilection for Perplexion: Preoperative microstructural damage is linked to postoperative delirium,” which provides a novel neuroanatomic explanation (i.e. microstructural dysfunction within the posterior cingulate cortex) for the long-observed association between preoperative cognitive impairment and postoperative delirium risk among older surgical patients.