TABLE 5.

Candidate delirium biomarkers for animal model validation

	Humans		Animals		Human evidence for:
Marker	Human evidence	References	Evidence of causal effects in animal models	Refs	Risk markers	Disease markers	Outcome markers
Biofluid Based
Inflammatory
• AGP	↑ CSF	145
• CHI3L1/YKL-40	↑ Blood	146			X	X
• Complement factor C3	↑ Blood, CSF	147
• CCL2	↑ Blood	148				X
• CRP	↑ Blood, CSF	149–151			X	X
• FGF-21, FGF-23	↑ Blood	152				X
• Gal-3BP	↑ Blood	153
• IGF-1	↓ Blood	148,154				X
• IL-1β	↑ Blood, CSF	155	Causal in multiple models			X
• IL-1RA	↑ Blood, CSF	156,160	Protective in some models
• IL-2	↑ Blood	157				X
• IL-6	↑ Blood, CSF	156–162			X	X
• sIL-6R	↑ Blood, CSF	163
• IL-8	↑ Blood, CSF	162				X
• IL-12	↑ CSF	164
• MCP-1	↑ Blood	165				X
• Natural killer (NK) cells	↑ Blood	166
• Syndecan-1	↑ Blood	167				X
• TNF-α	↑ Blood, CSF	168	Causal in some models		X	X
Neurodegeneration or neuronal injury
• Aβ	↑ CSF	169,170
• GFAP	↑ Blood, CSF	170–173				X
• Neurogranin	↑ Blood	174				X
• Neutrophil:Lymphocyte ratio	↑ Blood	175,176			X	X
• NSE	↑ Blood	173,177,178				X
• NfL	↑ Blood	170,171,179				X
• P-tau	↑ CSF	180				X
• PAI-1	↑ Blood	161
• S100β	↑ Blood, CSF	162,178,181				X
• T-tau	↑ Blood, CSF	170,180,182				X
• UCHL1	↓ Blood	183				X
Biochemical:
• AChE	↓ Blood, CSF	168,183,184			X	X
• Adrenaline	↓ CSF	176				X
• Anticholinergic activity	↑ Blood, CSF	185	Disruption of relevantfunctions by cholinergic antagonists
• BuChE	↓ Blood, CSF	186,187				X
• Dopamine	↓ CSF	187				X
• FA5	↑ CSF	188
• Troponin	↑ Blood	175				X
Neurophysiological
• EEG—oscillatory dynamics	Relative power increase in slow frequencies and decrease in fast frequencies	87,89–102,189–192	↑ slow wave activity	107		X
	—↑ θ
	—↑ δ
	—↓ β
	—↓ α
	And loss of high-frequency activity, especially in posterior brain regions					X
	Altered α/θ, α/(θ+δ) or (α+β)/(θ+δ) ratio	94,101,192				X
	Reduced peak frequency	101			X
	High preoperative alpha power	95			X	X
• EEG—connectivity	↓ α band connectivity (possible marker for disturbed consciousness) and loss of directionality	94,102,103,191,192	↓ α band connectivity	107		X
	↑ θ band connectivity (possible marker for attention/memory deficits)	94,192				X
	↓ β band connectivity (possible marker for instability of cognitive processes)	192				x
	↑ δ band connectivity directed to frontal regions	191,192				X
	Disturbance in default mode (DMN), salience (SN), and executive control (ECN) networks	192				X
	Decrease in frontal-occipitoparietal connectivity	95				X
• SSEP/BAEP	↑ Short- and long-latency sensory evoked potentials (SEP)	113				X
Local field potentials (LFPs), Single neuron activity	↓ Hippocampal θ frequency; ↓θ frequency and amplitude in medial prefrontal cortex; ↑ short-term δ frequency	118
Imaging
• Structural (MRI, DTI-MRI)
	↑ Ventricular size (as a vulnerability marker)	193				X
	New ischemic lesions, ↑ white matter hyperdensity/disruption	194–198			X	X	X
	↓ Gray matter volume	196			X
	↓ Brain volume	199					X
• Functional (fMRI)
	↓ Connectivity strength (in aging and dementia)	103			X
	↓ Efficiency and local clustering	103				X
	Imbalanced connectivity in default mode network (DMN) and disrupted connectivity between DMN and dorsolateral prefrontal cortex (executive network)	74,200				X
	Excessive striatum-salience network (anterior cingulate cortex and insula) connectivity	200				X
	Disconnection of mesencephalic tegmentum, ventral tegmental area, and nucleus basalis with striatum/thalamus	74,200	LPS-induced T-maze deficits reversed by peripheral glucose			X	X
• Functional (PET, SPECT)
	↓ Whole-brain glucose consumption, especially in posterior cingulate cortex	200		59
	↓ Blood flow ratios in frontal and parietal cortex	201	↓ glucose consumption in neocortex			X

Abbreviations: AChE, acetylcholinesterase; AGP, alpha-1-Acid glycoprotein; BuChE, butyryl cholinesterase; CRP, C-reactive protein; CSF, cerebrospinal fluid; FA5, coagulation factor V; GFAP, glial fibrillary acidic protein; IGF, insulin-like growth factor; IL, interleukin; CHI3L1/YKL-40, chitinase 3-like protein 1; fMRI, functional magenetic resonance imaging; Gal-3BP, galectin-3 binding protein; LPS, lipopolysaccharide; NfL, neurofilament light chain; MCP-1, monocyte chemoattractant protein-1; NSE, neuron-specific enolase; PAI-1, plasminogen activating inhibitor-1; R, receptor; PET, positron emission tomography; RA, receptor agonist; s, soluble; S100β, S100 calcium binding B; UCHL1, ubiquitin carboxyl-terminal-esterase-L1.