Hip fracture has negative consequences for the brain. Many patients develop delirium, a psychiatric condition during which they may lose their ability to process or sustain attention to what is happening in their environment and also may experience distressing and fearful periods of days to weeks. Although delirium is acute onset and usually transient it has become clear that these episodes are associated with new dementia diagnosis, acceleration of existing dementia and shortened time to permanent institutionalisation and/or death. How hip fracture causes these negative effects is not clear. Using blood and cerebrospinal fluid (CSF) from 470 hip fracture patients and 180 Alzheimer’s disease (AD) patients, we have recently demonstrated that this acute inflammatory trauma triggers new brain injury as measured by the neuroaxonal injury marker neurofilament light chain (NfL). In this proposal, in order to identify pathways to this acute brain injury, we will use blood and CSF from these same patients to identify and quantify molecules and pathways involved in energy metabolism and inflammation that are activated in these patients. We will integrate our findings from humans with a unique set of experiments in a custom-designed experimental mouse model. We will use the APP/PS1 mouse model for AD (transgenic mice carrying a human double mutation that leads to early onset AD in humans) and challenge these mice peripherally with IL-1ß in order to induce acute systemic inflammation. We will then examine acute cognitive impairment and new brain injury and will use innovative chemical sensors to examine brain bioenergetic changes in real-time, measuring glucose, lactate and oxygen in the brain. We will then test potential therapeutic interventions that may protect the brain against injury. We hope to elucidate mechanisms driving this injury, in order to move towards treatments that may mitigate delirium and slow dementia progression.
