Biomarkers of postoperative delirium and cognitive dysfunction

Abstract

Elderly surgical patients frequently experience postoperative delirium (POD) and the subsequent development of postoperative cognitive dysfunction (POCD). Clinical features include deterioration in cognition, disturbance in attention and reduced awareness of the environment and result in higher morbidity, mortality and greater utilization of social financial assistance. The aging Western societies can expect an increase in the incidence of POD and POCD. The underlying pathophysiological mechanisms have been studied on the molecular level albeit with unsatisfying small research efforts given their societal burden. Here, we review the known physiological and immunological changes and genetic risk factors, identify candidates for further studies and integrate the information into a draft network for exploration on a systems level. The pathogenesis of these postoperative cognitive impairments is multifactorial; application of integrated systems biology has the potential to reconstruct the underlying network of molecular mechanisms and help in the identification of prognostic and diagnostic biomarkers.

Keywords: POCD; POD; biomarker; postoperative cognitive dysfunction; postoperative delirium; systems biology.

Figure 1

Incidence and time-course of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) incidence. Y-axis denotes the percentage on POD/POCD incidence registered by the different studies. X-axis denotes the number postoperative days on logarithmic scale. The graph does not include the data of POD/POCD incidence, if it was measured only once postoperatively, if measurement time was not precisely stated or the study includes less than 140 patients. CABG, coronary artery bypass grafting; NCS, noncardiac surgery.

Figure 2

Biomarkers of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). Biomarkers identified in POD or POCD patients are in blue and pink area respectively. The common POD/POCD biomarkers are presented in the violet area. Font color denotes a marker type: red—dopamine-related marker, green—glucocorticoid-related marker, yellow—cholinergic marker, blue—inflammation-related marker, black—others. 6-SMT, 6-sulfatoxymelatonin; ACh, acetylcholine; AchE, acetylcholinesterase; AMPK, 5′ adenosine monophosphate-activated protein kinase; APOE, apolipoprotein E; BDNF, brain-derived neurotrophic factor; BuChE, butyrylcholinesterase; CD68, cluster of differentiation 68; CRP, C-reactive protein; DRD2, dopamine receptor D2; HLA-DR, human leukocyte antigen-DR; IGF-1, insulin growth factor-1; IgM, immunoglobulin M; IL, interleukin; MCP-1, monocyte chemotactic protein 1; MMP9, matrix metalloproteinase-9; NF-kappaB, nuclear factor kappa B; NR3C1, nuclear receptor family 3, group C, member 1; NSE, neuron specific enolase; PCT, procalcitonin; S100A8, S100 calcium binding protein A8 (myeloid-related protein-8, calgranulin A); S100B, S100 calcium binding protein B; SAA, serum anticholinergic activity; SLC6A3, solute carrier family 6, member 3; Th17, T helper 17 cells; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α; TNFR1, tumor necrosis factor receptor-1; Treg, regulatory T cells; α-syn, alpha-synuclein.

Figure 3

Systems-level interaction of POD and POCD biomarkers. Biomarkers identified in POD and POCD patients are in blue and pink area respectively. The common POD/POCD biomarkers are presented in the violet area. 6-SMT, 6-sulfatoxymelatonin; ACh, acetylcholine; AchE, acetylcholinesterase; AMPK, 5′ adenosine monophosphate-activated protein kinase; APOE, apolipoprotein E; BDNF, brain-derived neurotrophic factor; BuChE, butyrylcholinesterase; CD68, cluster of differentiation 68; CRP, C-reactive protein; DRD2, dopamine receptor D2; HLA-DR, human leukocyte antigen-DR; IGF-1, insulin growth factor-1; IgM, immunoglobulin M; IL, interleukin; MCP-1, monocyte chemotactic protein 1; MMP9, matrix metalloproteinase-9; NF-kappaB, nuclear factor kappa B; NR3C1, nuclear receptor family 3, group C, member 1; NSE, neuron specific enolase; PCT, procalcitonin; S100A8, S100 calcium binding protein A8 (myeloid-related protein-8, calgranulin A); S100B, S100 calcium binding protein B; SAA, serum anticholinergic activity; SLC6A3, solute carrier family 6, member 3; Th17, T helper 17 cells; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α; TNFR1, tumor necrosis factor receptor-1; Treg, regulatory T cells; α-syn, alpha-synuclein.