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Principal Investigator: TOWIA A. LIBERMANN
Organization: BETH ISRAEL DEACONESS MEDICAL CENTER
Fiscal Year: 2024
Award: $870,666
Funding agency: National Institute on Aging
Project Summary/Abstract
Delirium (acute confusion), is a major complication of surgery in older patients, strongly associated with long
term cognitive decline (LTCD) and Alzheimer's Disease and Related Dementias (AD/ADRD). Prevention of
postoperative delirium and its long-term complications would be advanced if we could better identify at-risk
patients preoperatively, and if targeted pathophysiologically-based interventions could be implemented. To
address these gaps, we conducted the NIA-funded “Advancing the Understanding of Postoperative Delirium
Mechanisms via Multi-Omics” R01 project and program project that funded the SAGES (Successful Aging after
Elective Surgery) I and II studies. We identified and validated pre- and post-operative delirium protein
signatures, demonstrating that pro-inflammatory proteins, acute phase reactants, angiogenic, and neuronal
injury markers are elevated in patients who develop delirium. A model of delirium pathophysiology has
emerged that stipulates a systemic pre-inflammatory state predisposes to a hyperactive inflammatory response
from major surgery, leading to delirium, and potentially LTCD and AD/ADRD in individuals with a vulnerable
brain. While intriguing, this model does not fully address the complex inter-relationship between delirium and
AD/ADRD. For our R01 renewal, we hypothesize that AD/ADRD susceptibility and accelerated biological aging
are key predisposing factors for delirium and delirium with LTCD, which in turn may increase risk for
AD/ADRD. SomaScan-based plasma proteomic signatures predicting AD/ADRD up to 20 years before onset,
and proteomic aging clocks, panels of plasma proteins measuring biological aging relative to chronological
age, have been developed and extensively validated in large cohorts. We will use the state-of-the-art
SomaScan proteomics platform that measures 7,000 proteins to test our hypotheses that AD/ADRD proteomic
signatures (Aim 1) and proteomic aging clocks (Aim 2) predict postoperative delirium and delirium with LTCD.
We will capitalize upon the pre- and post-operative banked specimens from SAGES I (N=560) with continuous
follow-up to 72 months after major scheduled surgery, and a second, recently accrued independent cohort,
SAGES II (N=400), with similar characteristics and follow-up to 18 months. We will combine proteins from the
AD/ADRD and aging proteomic signatures, along with additional proteins from the 7,000 protein SomaScan
covering many biological pathways, for a deep etiopathological characterization of the plasma proteome for
delirium and delirium with LTCD in SAGES I (Aim 3) and independent validation of the proteomic signature for
delirium using both SomaScan and ELISA with plasma from SAGES II (Aim 4). Our R01 renewal Aims will
provide new insights into molecular mechanisms underlying delirium pathogenesis and its association with
AD/ADRD and biological aging. This project holds great promise to develop accurate blood-based biomarkers
for preoperative delirium risk prediction, postoperative prognostication of LTCD following delirium, and to lay
the groundwork for targeted interventions to improve outcomes of older adults at risk of delirium.
Terms: <AD dementia><AD related dementia><ADRD><Acceleration><Active Follow-up><Acute><Acute-Phase Proteins><Acute-Phase Reactants><Address><Age><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimer's disease risk><Alzheimers Dementia><BH4><BPH4><Biological><Biological Aging><Biological Specimen Banks><Biological Substance Banks><Blood><Blood Plasma><Blood Reticuloendothelial System><Brain><Brain Nervous System><Cessation of life><Characteristics><Chronology><Clinical><Clinical Data><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex><Confusion><Confusional State><Death><Delirium><Development><Disturbance in cognition><Dysfunction><ELISA><Encephalon><Enzyme-Linked Immunosorbent Assay><Functional disorder><Funding><Future><H4B><H4biopterin><Hyperactivity><Impaired cognition><Individual><Inflammation><Inflammatory><Inflammatory Response><Intervention><Intervention Strategies><Investments><Measures><Memory><Mental Confusion><Modeling><Molecular><National Institute of Aging><National Institute on Aging><Neuronal Injury><Nursing Homes><Operative Procedures><Operative Surgical Procedures><Outcome><Pathogenesis><Pathway interactions><Patients><Physiopathology><Plasma><Plasma Proteins><Plasma Serum><Post-Operative><Postoperative><Postoperative Period><Predicting Risk><Predisposing Factor><Predisposition><Prevention><Primary Senile Degenerative Dementia><Proteins><Proteome><Proteomics><Reticuloendothelial System, Serum, Plasma><Risk><Schedule><Surgical><Surgical Interventions><Surgical Procedure><Surgical complication><Susceptibility><THBP><Techniques><Testing><Thinking><Validation><accelerated aging><accelerated biological age><accelerated biological aging><active followup><age acceleration><age associated effects><age clock><age effect><age related effects><ages><aging clocks><aging effect><alzheimer risk><biologic><biological process of age><biological specimen repository><biomarker discovery><biosample repository><biospecimen bank><biospecimen repository><blood-based biomarker><blood-based marker><clock measuring biological age><clock measuring biological aging><clock of biological aging><cognitive dysfunction><cognitive loss><cohort><delirious><developmental><elderly patient><enzyme linked immunoassay><follow up><follow-up><followed up><followup><forecasting risk><hospital re-admission><hospital readmission><impact of age><improved outcome><influence of age><insight><interventional strategy><multiomics><multiple omics><neuron injury><nursing home><older adult><older adulthood><older patient><panomics><pathophysiology><pathway><post-operative delirium><postoperative delirium><precision medicine><precision-based medicine><predict risk><predict risks><predicted risk><predicted risks><predicting risks><predictive panel><predictive risk><predictive signature><predicts risk><primary degenerative dementia><prognostication><programs><proteomic signature><re-admission><re-hospitalization><readmission><rehospitalization><risk prediction><risk predictions><senile dementia of the Alzheimer type><specimen bank><specimen repository><surgery><surgery complication><tetrahydrobiopterin><thoughts><validations>