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Dementia biomarkers and long-term cognitive decline following hospital admissions

Grant Title
Dementia biomarkers and long-term cognitive decline following hospital admissions
Chief Investigator/s
ANZCA Area of Research
Project Summary
Recent advances in blood-based biomarkers (BBBs) promise a revolution in diagnostic capabilities for Alzheimer’s Disease and Related Dementias with high diagnostic sensitivity and specificity in the earliest phases of disease that manifest years before clinical symptoms. This provides a critical window in which early interventions and secondary prevention strategies could be deployed, when the possibility to arrest disease progression is likely to be greatest. During this window of vulnerability prior to the onset of dementia, hospital admissions exert a cumulative cognitive burden. Medical and surgical admissions can be associated with cognitive impairments, yet the mechanism as to how they exert a long-term cognitive impact remain unclear. Given that ageing is associated with increased acute illness and hospital admissions, the opportunity to prevent cognitive harm with these admissions is a promising concept. Nonetheless identification of neuroprotective therapies requires a thorough understanding of how medical and surgical admissions can modulate the underlying pathology of cognitive decline.

This study will evaluate a range of biomarkers associated with cognitive decline and as secondary outcomes we will determine whether these other neuropathological BBB are associated with cumulative hospital admissions. Using model comparison with Deviance Information Criterion (a Bayesian implementation of the Akaike Information Criterion) we will detect which BBB is best explained by cumulative hospital admissions.

Current data show that phosphorylated Tau (pTau) is the most promising biomarker for detecting Alzheimer’s Disease pathology and cognitive decline. Based on prior findings, the investigators have recently shown that surgery is associated with rises in systemic inflammation that correlate with changes in plasma dementia (neuronal injury) biomarkers, neurofilament light (NfL) and total Tau. Our preliminary data show similar changes in the CSF for these biomarkers and for pTau (plasma and CSF). These biomarker changes correlated with delirium severity showing important links to short-term cognition. However so far it is unknown if long-term, sustained changes in dementia biomarkers are associated with hospital admissions explaining how they can alter cognition long-term. This information is critical to establishing which pathologies should be targeted in the perioperative period to stop long-term changes in cognition.

Based on this, the investigators will conduct secondary analyses to determine if hospital admissions lead to changes in other dementia BBBs. As secondary hypotheses, we will determine whether different surgeries and emergency vs. elective admissions, hospital length of stay, duration of intensive care unit admission and length of time on a ventilator in ICU are associated with sustained accumulation of dementia biomarkers in blood. We will adjust for important demographic information and confounders such as comorbid chronic diseases as part of these analyses. Finally, we will confirm prior reports that accumulating blood dementia biomarkers are associated with decreases in cognition. We will also test whether blood inflammation (existing data) is associated with dementia blood biomarkers in the Concord Healthy Ageing in Men Project (CHAMP) community sample.

Understanding the type of pathology that is associated with cumulative hospital admissions, and that likely underly the associated long-term changes in cognition, is critical to the development of neuroprotective strategies for use during acute illness and surgery. While accumulating data suggest that inflammatory changes may mediate this cognitive harm, the exact pathways remain to be elucidated. Our overarching aim is to detect a safe way of providing perioperative (and peri-illness) neuroprotection.
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