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Table 1 Summary of current evidence on biomarkers in elderly delirious patients determined by literature search

From: Serum biomarkers of delirium in the elderly: a narrative review

Biomarker Study Country Medical specialty ICU Sample size Assessment tool Event rate (%) Biomarker value Main findings
Acetylcholine Larsen (2010) USA S   196a DRS-R98 14.3 L Anticholinergic treatment (olanzapine) associated with significantly lower incidence of delirium
      204 DSM-III 40.2   
Adenylate kinase
Albumin Zhang (2018) China S Yes 700 CAM-ICU 15.9 L Preoperative severe hypoalbuminemia (≤ 30 g/L) was associated with increased risk of postoperative delirium
Guo (2016) China S   572 CAM, DSM-IV 21 L Older age, history of stroke, lower albumin, higher blood glucose, higher total bilirubin, higher CRP, longer surgery duration, and higher volume of red blood cell transfusions are independent risk factors for postoperative delirium
Capri (2014) Italy S   351 CAM 13.4 ND High preoperative IL-6 level is a risk factor for postoperative delirium
Larsen (2010) USA S   196a DRS-R98 14.3 L Anticholinergic treatment (olanzapine) associated with significantly lower incidence of delirium
204 DSM-III 40.2
Lee (2010) Korea S   81 CAM 13.6 L Albumin level before surgery significantly lower in patients developing postoperative delirium
Amyloid β1-40 Sun (2016) China S   257 CAM 21.8 H Elevated levels of inflammatory cytokines, cortisol, and amyloid β1-40 after surgery under general anesthesia may be involved in the onset of postoperative delirium among elderly oral cancer patients
ASAT Plaschke (2016) Germany M   100 NuDESC 29 L Plasma ChEA (AChE and BChE) not associated with delirium
Guo (2016) China S   572 CAM, DSM-IV 21 ND Older age, history of stroke, lower albumin, higher blood glucose, higher total bilirubin, higher CRP, longer surgery duration, and higher volume of red blood cell transfusions are independent risk factors for postoperative delirium
BDNF Brum (2015) Brazil M   70 CAM NA L BDNF levels significantly lower in delirium in oncology inpatients
Cholecystokinin
Cholinesterase Plaschke (2016) Germany M   100 NuDESC 29 ND Plasma ChEA (AChE and BChE) not associated with delirium
Cerejeira (2012) Portugal S   101 CAM, DSM-IV 36.6 L Delirium associated with dysfunctional interaction between cholinergic and immune systems
Cortisol Sun (2016) China S   257 CAM 21.8 H Elevated levels of inflammatory cytokines, cortisol, and amyloid β1-40 after surgery under general anesthesia may be involved in the onset of postoperative delirium among elderly oral cancer patients
Creatine kinase
Creatine kinase BB
CREB
CRP Slor (2019) The Netherlands S   121 CAM, DRS-R98 33.1 NDd CRP level trajectory after hip surgery coincides with delirium from the second day after surgery
Miao (2018) China S   112 DSM-IV 43.8 H Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery
Vasunilashorn (2018) USA S   560 CAM 24 NA The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers: CRP and AZGP1) and others during delirium (disease markers: IL-2, IL-6, and CRP). CRP, AZGP1, and SERPINA3 were identified as top set of delirium-related proteins
Cizginer (2017) USA S   556 CAM 24 ND Vocabulary knowledge, cognitive activities, and education significantly modified association of CRP and postoperative delirium
Vasunilashorn (2017) USA S   560 CAM, Chart Review 24 H High preoperative and postoperative day 2 CRP are independently associated with incidence of delirium
Egberts (2017) The Netherlands M   86 DSM-IV 15.1 H No significant difference of CRP level among delirious and non-delirious patients
Plaschke (2016) Germany M   100 NuDESC 29 H Plasma ChEA (AChE and BChE) is not associated with delirium
Nguyen (2016) Belgium M + S Yes 101 CAM-ICU 78 ND High prolactin levels possible risk factor for delirium in septic patients
Sun (2016) China S   257 CAM 21.8 H Elevated levels of inflammatory cytokines, cortisol, and amyloid β1-40 after surgery under general anesthesia may be involved in the onset of postoperative delirium among elderly oral cancer patients
Ritchie (2014) UK M   710 CAM 12.3 H Association between elevated CRP and delirium
Guo (2016) China S   572 CAM, DSM-IV 21 H Older age, history of stroke, lower albumin, higher blood glucose, higher total bilirubin, higher CRP, longer surgery duration, and higher volume of red blood cell transfusions are independent risk factors for postoperative delirium
Cerejeira (2012) Portugal S   101 CAM, DSM-IV 36.6 H Delirium is associated with unbalanced inflammatory response
Lee (2011) Korea S   65 K-DRS-98 28 H CRP levels within 24 and 72 h after hospitalization are significantly higher in patients with delirium
Beloosesky (2004) Israel S   32 CAM 31.3 H CRP kinetics over 30 days after hip surgery is significantly associated with delirium and cardiovascular complications
Dopamine
Histamine H1
Heat Shock Protein 70
IL-2 Capri (2014) Italy S   351 CAM 13.4 ND High preoperative IL-6 level is a risk factor for postoperative delirium
Vasunilashorn (2018) USA S   560 CAM 24 NA The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers: CRP and AZGP1) and others at the time of delirium (disease markers: IL-2, IL-6, and CRP). CRP, AZGP1, and SERPINA3 were identified as top set of delirium-related proteins
IL-6 Gao (2018) China S Yes 64 CAM-ICU 15.6 NA TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduced neuroinflammation by lowering BBB permeability
Miao (2018) China S   112 DSM-IV 43.8 H Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery
Vasunilashorn (2018) USA S   560 CAM 24 NA The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers: CRP and AZGP1) and others at the time of delirium (disease markers: IL-2, IL-6, and CRP). CRP, AZGP1, and SERPINA3 were identified as top set of delirium-related proteins
Kuswardhani (2017) Indonesia M   60 MDAS NA NA CACI score, IL-6 levels, and sepsis have a strong relationship with delirium severity
Xin (2017) China S   60c NuDESC 11.7 ND TNF-α significantly associated with postoperative delirium
     60   38.3   
Sun (2016) China S   257 CAM 21.8 H Elevated levels of inflammatory cytokines, cortisol, and amyloid β1-40 after surgery under general anesthesia may be involved in the onset of postoperative delirium among elderly oral cancer patients
Capri (2014) Italy S   351 CAM 13.4 H High preoperative IL-6 level is a risk factor for postoperative delirium
Jia (2014) China S   117b DRS-R98 3.4 H The lower incidence of delirium is at least partly attributable to the reduced systemic inflammatory response mediated by IL-6
     116   12.9   
Cerejeira (2012) Portugal S   101 CAM, DSM-IV 36.6 H Delirium is associated with unbalanced inflammatory response
van Munster (2011) The Netherlands M + S   870 CAM 35.7 NA Functional genetic variations in the IL-6, IL-6R, and IL-8 genes are not associated with delirium
van Munster (2008) The Netherlands S   98 CAM, DOS, DRS-R98 NA H Patients with hyperactive or mixed subtype of delirium had significantly higher IL-6 levels than patients with hypoactive delirium. IL-6 and IL-8 may contribute to pathogenesis of postoperative delirium
IL-8 Xin (2017) China S   60c NuDESC 11.7 ND TNF-α significantly associated with postoperative delirium
      60   38.3   
  Capri (2014) Italy S   351 CAM 13.4 ND High preoperative IL-6 level is a risk factor for postoperative delirium
  Cerejeira (2012) Portugal S   101 CAM, DSM-IV 36.6 H Delirium is associated with unbalanced inflammatory response
  van Munster (2011) The Netherlands M + S   870 CAM 35.7 NA Functional genetic variations in the IL-6, IL-6R, and IL-8 genes are not associated with delirium
  van Munster (2008) The Netherlands S   98 CAM, DOS, DRS-R98 NA H IL-6 and IL-8 may contribute to pathogenesis of postoperative delirium
IL-18          
Lactate dehydrogenase          
Leptin Chen (2014) China S   186 CAM 37.6 L Preoperative plasma leptin level may be a useful, complementary tool to predict delirium in general and prolonged delirium in elderly patients after hip surgery
  Sanchez (2013) Colombia M + S   115 CAM, DSM-IV 23.5 L Leptin levels could be a useful clinical biomarker to establish risk in elderly patients
Neopterin Egberts (2019) The Netherlands S Yes 211 CAM-ICU, DSM-IV 38.4 H Acutely ill medical patients with delirium had higher levels of neopterin and higher phenylalanine/tyrosine ratios after elective cardiac surgery
  Miao (2018) China S   112 DSM-IV 43.8 H Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery
NSE          
PI3K          
Procalcitonin Sun (2016) China S   257 CAM 21.8 H Elevated levels of inflammatory cytokines, cortisol, and amyloid β1-40 after surgery under general anesthesia may be involved in the onset of postoperative delirium among elderly oral cancer patients
Protein C          
S-100β Gao (2018) China S Yes 64 CAM-ICU 15.6 NA TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduced neuroinflammation by lowering BBB permeability
  Xin (2017) China S   60c NuDESC 11.7 ND TNF-α is significantly associated with postoperative delirium
      60   38.3   
SDNF          
Thioredoxin Wu (2017) China S   192 CAM 36.5 H Thioredoxin in postoperative serum may be a potential biomarker to predict postoperative delirium and POCD in elderly patients
TNF-α Gao (2018) China S Yes 64 CAM-ICU 15.6 NA TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduced neuroinflammation by lowering BBB permeability
  Xin (2017) China S   60c NuDESC 11.7 H TNF-α is significantly associated with postoperative delirium
      60   38.3   
  Brum (2015) Brazil M   70 CAM NA ND No cross-sectional relationship of BDNF and TNF-α blood levels with delirium in oncology inpatients has been demonstrated
  Capri (2014) Italy S   351 CAM 13.4 ND High preoperative IL-6 level is a risk factor for postoperative delirium
  Cerejeira (2012) Portugal S   101 CAM, DSM-IV 36.6 ND Delirium is associated with unbalanced inflammatory response (see CRP, IL-6, and IL-8)
8-iso-prostaglandin F2α Zheng (2016) China S   182 CAM 37.4 H Postoperative plasma 8-iso-prostaglandin F2α levels may have the potential to predict postoperative delirium and POCD in elderly patients
Additional reported biomarkers resulting from literature search          
AZGP1 Vasunilashorn (2018) USA S   560 CAM 24 L The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers: CRP and AZGP1) and others at the time of delirium (disease markers: IL-2, IL-6, and CRP). CRP, AZGP1, and SERPINA3 were identified as top set of delirium-related proteins
BUN Miao (2018) China S   112 DSM-IV 43.8 ND Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery
  Kuswardhani (2017) Indonesia M   60 MDAS NA NA BUN only has a weak role in delirium severity in elderly patients with infection
Creatinine Miao (2018) China S   112 DSM-IV 43.8 ND Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery
  Bakker (2012) The Netherlands S Yes 201 CAM-ICU 31.3 H Creatinine level is one of the three independent risk factors for delirium after cardiac surgery
ILGF-1 Miao (2018) China S   112 DSM-IV 43.8 L Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery
IL-1β Xin (2017) China S   60c NuDESC 11.7 ND TNF-α significantly associated with postoperative delirium
      60 NuDESC 38.3 ND  
  Capri (2014) Italy S   351 CAM 13.4 ND High preoperative IL-6 level is a risk factor for postoperative delirium
  Cerejeira (2012) Portugal S   101 CAM, DSM-IV 36.6 ND Delirium is associated with unbalanced inflammatory response (see CRP, IL-6, and IL-8)
IL-12 van Munster (2008) The Netherlands S   98 CAM, DOS, DRS-R98 NA ND IL-6 and IL-8 may contribute to the pathogenesis of postoperative delirium
ILGF-1 Chu (2016) China S   103 CAM, DSM-IV 22.3 ND No association found between preoperative ILGF-1 levels and postoperative delirium
MMP-9 Gao (2018) China S Yes 64 CAM-ICU 15.6 NA TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduced neuroinflammation by lowering BBB permeability
NLR Egberts (2017) The Netherlands M   86 DSM-IV 15.1 H NLR levels are significantly increased in patients with delirium
Prolactin Nguyen (2016) Belgium M + S Yes 101 CAM-ICU 78 H High prolactin levels are a possible risk factor for delirium in septic patients
Phenylalanine–tyrosine ratio Egberts (2019) The Netherlands S Yes 211 CAM-ICU, DSM-IV 38.4 H Acutely ill medical patients with delirium had higher levels of neopterin and higher phenylalanine–tyrosine ratios after elective cardiac surgery
SERPINA3 Vasunilashorn (2018) USA S   560 CAM 24 H The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers: CRP and AZGP1) and others at the time of delirium (disease markers: IL-2, IL-6, and CRP). CRP, AZGP1, and SERPINA3 were identified as top set of delirium-related proteins
  1. Data are presented as event rate of delirium. Biomarker value refers to comparison of biomarker level in delirious patients to non-delirious patients. Authors bold, main biomarker investigated in the indicated study; biomarkers italic = no data available with the search terms used; authors underlined, interventional studies
  2. M medical, S surgical, H biomarker level higher in delirious patients, L biomarker level lower in delirious patients, NA not applicable, ND no difference of biomarker level among groups, AChE acetylcholinesterase, ASAT aspartate aminotransferase, AZGP1 alpha-2 glycoprotein, BBB blood–brain barrier, BChE butyrylcholinesterase, BDNF brain-derived neurotrophic factor, BUN blood urea nitrogen, CAM Confusion Assessment Method, ChEA cholinergic enzyme activity, CREB cyclic AMP response element-binding protein, CRP C-reactive protein, DOS Delirium Observation Scale, DRS-R98 Delirium Rating Scale Revised-98, DSM Diagnostic and Statistical Manual of Mental Disorders, ICU intensive care unit, IL interleukin, ILGF-1 insulin-like growth factor-1, IQR interquartile range, K-DRS-98 Korean version of DRS, MDAS Memorial Delirium Assessment Scale, MMP-9 metalloproteinase-9, NLR neutrophil–lymphocyte ratio, NSE neuron-specific enolase, NuDESC Nursing Delirium Screening Scale, PI3K phosphatidylinositol-3-kinases, POCD postoperative cognitive dysfunction, SDNF striatal-derived neuronotrophic factor, SERPINA3 alpha 1-antichymotrypsin, TEAS transcutaneous electrical acupoint stimulation, TNF tumor necrosis factor
  3. aExperimental arm (olanzapine)
  4. bExperimental arm (fast-track surgery)
  5. cExperimental arm (hypertonic saline)
  6. dOn postoperative day 1; significant difference thereafter