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

“…Structural connectivity studies show that loss of integrity in the inter-hemispheric corpus callosum is associated with increased delirium duration 185 , and diffusion tensor imaging demonstrated that abnormalities in the hippocampus, thalamus, basal forebrain and cerebellum (and associated white matter tracts: fimbria, fornix, internal capsule, corpus callosum) are correlated with delirium incidence and severity 186 . These results are consistent with data from animal studies showing that prior synaptic and axonal damage in the hippocampus, thalamus and cholinergic basal forebrain all increase the risk of acute cognitive deficits after acute systemic inflammation 45,155,187 and human CSF studies suggest that further synaptic damage seems to occur in acute infection 188 .…”

What SARS-CoV-2 does to our brains

“…Per definition, sepsis-related encephalopathy and its neuroinflammatory changes are not due to a direct infection of neurons or glial cells but mediated by systemic inflammation. Cellular changes in the CNS are very similar to what is described in COVID-19-related neuroinflammation with microglial activation and astrogliosis as well as BBB alterations, the presence of inflammatory cytokines in the CSF (Lemstra et al, 2007;Zrzavy et al, 2019), alterations in neuronal synapses, and neurovascular changes (Ehler et al, 2017;Peters van Ton et al, 2020).…”

“…Quantifying cellular or tissue damage in the CNS of critically ill individuals suffers from the obvious lack of adequate data in humans. However, a first study hints at a disturbed microglial homeostasis and suggests an association with synaptopathy similar to Alzheimer's disease based on protein expression signatures in the CSF of COVID-19 cases with infectious delirium (Peters van Ton et al, 2020). In addition, fever as a hallmark of systemic infection is regulated in clusters of thermo-sensitive hypothalamic neurons via cytokine-triggered prostaglandin E2 (PGE2) production in the CVO (for more information on CVO see Box 2), enabling an immune-triggered crosstalk between blood and/or the periphery and neurons of the hypothalamus (Biddle, 2006).…”

High Cerebrospinal Fluid CX3CL1 Levels in Alzheimer’s Disease Patients but Not in Non-Alzheimer’s Disease Dementia

“…Van Ton et al [ 26 ] recently evaluated the CSF expression of many proteins, including FKN, in AD patients, reporting that the chemokine is upregulated in AD patients. Despite the similarity in the results obtained, it is worth noting that Van Ton et al used a proximity extension assay (PEA) to measure CSF protein levels, whose analytical features (sensitivity, specificity, and accuracy) are distinct from those of the methods used in the current study [ 23 ].…”