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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