The neuroinflammatory reaction to acute systemic inflammation during delirium and its impact in the cognitive trajectory and progression to dementia: a case-control longitudinal study using imaging and molecular biomarkers

Overview

Project Summary

Introduction: acutely medically-ill older patients are at risk to develop delirium (acute confusional state) which is associated with adverse outcomes including long term worsening of cognitive function and higher rates of progression to dementia. Supported by animal studies, we have proposed that a deregulated neuroinflammatory response with exaggerated microglial activation to acute systemic inflammation not only underlie the transient symptoms of delirium but also induce long lasting structural damage with neuronal cell loss. Even normal levels of acute systemic inflammation can induce such hazardous events when the brain has become more vulnerable due to the effects of aging and/or chronic neurodegeneration. The recently available PET imaging with (18)F-PBR111 offers a unique opportunity to evaluate the degree of microglia activation in a noninvasive manner and this can be correlated with the levels of miRNAs in circulating monocytes and in exosomes from plasma and CSF. We hypothesize that the level of the acute neuroinflammatory response measured by PET imaging and peripheral biomarkers can be used as a disease marker of delirium and a predictor of more rapid cognitive decline, independent of relevant covariates. Ultimately, if the degree of neuroinflammation during delirium irreversibly impacts cognitive decline at long term, this finding would hold substantial clinical implications for prevention and management of delirium and dementia.

Objectives: this study aims to determine i) the level of neuroinflammation during an episode of delirium; ii) in what extent the degree of neuroinflammation during delirium predicts long term cognitive decline and progression to dementia.

Methods: case-control prospective study on subjects aged 65 or more hospitalized with an acute medical illness. The baseline sample will consist of 105 participants classified in 4 groups according to their cognitive status at baseline and during hospitalization: dementia and delirium; dementia no delirium; delirium no dementia; no delirium no dementia. Subjects will undergo a PET scan and inflammatory mediators will be measured both in CSF and blood. Cognitive function with be reassessed 12 months after hospital admission in 10 participants in each group. Expected results: we will determine the relation between the degree of microglial activation, peripheral biomarkers of neuroinflammation, delirium and cognitive deterioration at long term, which will allow the development of new approaches for prevention, diagnosis and treatment of delirium and dementia.

Main Goals

i) To determine the magnitude of the neuroinflammatory response triggered by acute systemic inflammation in older subjects with and without prior dementia

ii) to determine in what extent a higher neuroinflammatory response to acute systemic inflammation is associated with delirium symptoms in older subjects with and without prior dementia

iii) to determine if a higher neuroinflammatory response to acute systemic inflammation is associated with a worse trajectory of cognitive function in older patients with and without prior dementia.

Project Details