Downregulation of synapse-associated protein expression and loss of homeostatic microglial control in cerebrospinal fluid of infectious patients with delirium and patients with Alzheimer's disease.

Delirium is a complex and multifactorial condition associated with long-term cognitive decline. Due to the strong links between systemic inflammation, delirium and dementia we hypothesized that responses within the brain in patients who develop delirium could show biochemical overlap with patients with Alzheimer's disease (AD). In this observational study we analyzed protein expression signatures in cerebrospinal fluid (CSF) from 15 patients with infectious delirium and compared these to 29 patients with AD, 30 infectious patients without delirium and 15 non-infectious controls free of neurological disease. A proximity extension assay was performed measuring a total of 184 inflammatory and neurology-related proteins. Eight inflammatory proteins (4%), including the key neuron-microglia communication marker CX3CL1 (fractalkine), were significantly upregulated in both delirium and AD, compared to infectious patients without delirium. Likewise, 23 proteins (13%) showed downregulation in both delirium and AD, relative to infectious patients without delirium, which interestingly included CD200R1, another neuron-microglia communication marker, as well as a cluster of proteins related to synapse formation and function. Synaptopathy is an early event in AD and correlates strongly with cognitive dysfunction. These results were partially mediated by aging, which is an important predisposing risk factor among many others for both conditions. Within this study we report the first in vivo human evidence suggesting that synapse pathology and loss of homeostatic microglial control is involved in the pathophysiology of both infectious delirium and AD and thus may provide a link for the association between infections, delirium and long-term cognitive decline.