Neurobiological Correlates of Delirium Symptoms

It remains largely unknown how systemic peripheral changes (i.e., inflammation, dehydration, electrolyte imbalance) translate to acute cognitive and behavioral symptoms. Cortical atrophy, ventricular enlargement, and increased white matter lesions may predispose individuals to develop delirium [100].

Inattention, a core feature of delirium, is thought to result from dysfunctional communication between prefrontal and parietal cortices and/or impaired neuromodulation from cholinergic basal forebrain neurons [101]. A study using resting-state functional MRI during an episode of delirium showed disruption in reciprocity of the dorsolateral prefrontal cortex with the posterior cingulate cortex and reversible

Table 7.6 Summary of current and potential delirium biomarkers [58-95]

Biomarker

Available evidence

Inflammation

CRP

Medical patients: Higher baseline plasma CRP associated with increased rates of delirium [58, 59], but other studies were negative [60-64]

Surgical patients: Maximum postoperative level of plasma CRP associated with delirium [65]. Higher levels in patients with delirium, without statistical significance [60], while other studies did not find this association [66].

TNF-a and IL-1

ICU patients: STNFR1, STNFR2, IL-ip plasma levels were higher in delirium patients [67]

Higher CSF levels of IL-1 p in incident delirium after hip fracture [68]

IL-6

Higher plasma levels in delirious patients following abdominal [69] and cardiac surgery [70], as well as in patients with delirium after hip fracture, with a peak during delirium episode [71, 72]

Preoperative CSF levels significantly lower in elderly hip fracture patients who developed delirium postoperatively [73]

Preoperative high plasma level of IL-6 significantly associated with onset of postoperative delirium (POD) [74]

Negative studies [62, 63, 75, 76]

IL-8

Higher plasma levels in delirious patients following hip fracture with a peak before delirium onset [71, 72]

Negative study [76]:

Higher CSF levels in delirium cases [77]

IL-10

Higher postoperative elevation in patients with delirium [60]

No association with delirium [61] or in most cases below detection limit

[71]

IFN-y

Plasma levels correlated with delirium severity [63], whereas no association was found in another study [62]. CSF levels were below the detection limit [68]

Others

Preoperative levels of interleukin-1 receptor antagonist significantly lower in CSF of elderly hip fracture patients who developed delirium postoperatively [73]

In ICU patients, high baseline plasma procalcitonin predicted prolonged periods of delirium [78] and increased blood NK cell activity during delirium [79]

IL-12: very low detection levels and without relation to delirium [71]

IL-1ra: low plasma levels associated with delirium [63]

LIF: no association with delirium [62, 63]

Blood-brain barrier and brain dysfunction

S100b

Medical patients: plasma levels higher in delirium, with a peak following the episode [80]

Surgical patients: postoperative plasma levels higher in delirium following cardiac [81], abdominal [82], and orthopedic [80, 83] surgery

Critical patients: plasma levels higher in delirium with sepsis [84]. Abnormal levels on day 1 or day 8 (or both) associated with higher delirium duration [85]

(continued)

Table 7.6 (continued)

Biomarker

Available evidence

NSE

ICU: plasma levels higher in patients with delirium [86]

GFAP

Not increased in delirium [68]

Neuroendocrine

Cortisol

High serum cortisol level on the first operative day associated with increased risk of postoperative delirium after CABG [87]

Higher cortisol levels in plasma [66, 84] and CSF [88] during a delirium episode. Increased plasma cortisol responses to surgical stress in delirious subjects [89-92]

IGF-1

Low plasma levels of IGF-1 associated with delirium in medically ill subjects [62, 93] but not in surgical patients [75, 92]

Adiponectin

Higher plasma levels in delirious critical patients [57]

Copeptin

Plasma copeptin levels higher in patients with POD or POCD following CABG surgery [94]

CSF amyloid and tau proteins

Lowest quartile of CSF Ap40/tau and CSF Ap2/tau ratios had the highest incidence and severity of delirium after hip replacement surgery [95]

Abbreviations: CRP C-reactive protein, IFN-y interferon-y, IL interleukin, IL-1ra IL-1 receptor antagonist, LIF leukemia inhibitory factor, TNF tumor necrosis factor, ICU Intensive Care Unit.

reduction of functional connectivity of subcortical regions [102]. Adequate function of attentional networks requires sufficient arousal provided by the ascending reticular activating system which is located in the upper brain stem tegmentum and central thalamus [103]. Connections between these subcortical structures are associated with acetylcholine and dopamine. The role of cholinergic deficiencies has received the greatest amount of attention, as this neurotransmitter system is involved in sleep, attention, arousal, and memory. Dopamine excess may also be involved as it exerts a regulatory influence over the release of acetylcholine [102].

In the absence of human studies, studies in aged animals on inflammation provide accumulating evidence that supports an acute systemic inflammatory process (e.g., LPS challenge) that results in acute hippocampal dysfunction and cognitive inflexibility [104], as well as deficits in attention/executive function [101]. These findings support a direct link between inflammation and the defining clinical symptoms of delirium.

Studies investigating the association of genetic polymorphisms with delirium have provided conflicting results. The epsilon 4 allele of apolipoprotein E (ApoE e4) was a risk factor for postoperative delirium in patients undergoing noncardiac surgery [105] and a predictor of longer duration of delirium in critical patients [106]. However, this was not confirmed in other studies that included medical [107] and surgical [108, 109] patients. Thus, the link between the APOE genotype and delirium remains to be further elucidated.

Variations in the SLC6A3 gene and possibly the DRD2 gene [110 ] , but not catechol-O-methyltransferase gene [111], and IL-6 and IL-8 gene polymorphisms [112] have been associated with delirium in patients after hip fracture. This suggests that genetic and/or phenotypic expression of these cytokines does not play a role with the actual physiological inflammatory response associated with delirium though further study is required to assess for potential genetic associations of other cytokines. It is worth highlighting that the COMT val158met polymorphisms are associated with impaired executive function in Parkinson’s disease (PD) [113] and as such may have a role in attention. Since PD subjects are at higher risk of developing delirium [114], it is interesting to speculate that this genetic polymorphism may contribute to the susceptibility of people with PD to delirium. In subjects undergoing coronary artery bypass surgery, the presence of AG haplotype of GRIN3A gene (a genetic variation of NR3A subunit of NMDA receptor) independently increased the risk of postoperative delirium, whereas GRIN2B and 5HT2A gene polymorphisms were not associated with delirium [115]. None of the polymorphisms of MTNR1B gene were found to be associated with the occurrence of delirium [116].

 
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