MD2, Cystatin C and DNA Methylation Tags as Serum Biomarkers for POCD.

NCT03610191 | Unknown

• 1 other identifier: KY20182029-1
• Study Type: observational
• Target: 250
• Locations: 1 country
• Sites: 1

Brief Summary

Postoperative cognitive dysfunction (POCD) is a severe complication after surgery. Currently, a complicated battery of neuropsychological tests both before and after surgery with other characteristics-matched population as control are needed for the diagnosis of POCD. This diagnosis is also delayed, which could not be used to screen for high risk patients who may need intervention beforehand. The current trial targeted a surgical population of elderly patients undergoing cardiac surgery under cardiopulmonary bypass (CPB), which is a population of the highest incidence of POCD, to screen for possible predictive or diagnostic biomarkers in the serum for POCD. Myeloid differentiation factor 2 (MD2), also known as lymphocyte antigen 96, is a protein involved in biding lipopolysaccharide with Toll like receptor-4 (TLR4). Recently the investigators have found that increased MD2 expression in the hippocampus of the mice after surgery stimuli. On the other hand, the investigators have reported that cystatin C (CysC) as an endogenous neuroprotective factor for stroke. It may also be involved in endogenous neural protection against POCD. This trial is to investigate whether serum MD2, CysC can be used for prediction and diagnosis of POCD in surgical population. Serum based DNA methylation biomarkers will also be tested for prediction or diagnosis of POCD development. Also in our orevious research, SNPs cites at rs6739405、rs12467815、rs12472215、rs11126727、rs11126731、rs993607 were revealed as possible susceptibility variations for POCD (diagnosed with MMSE only, NCT02084030) in patients undergoing CPB. This study will also test the SNP variations in study populations to varify if one or conbination of morethan one of these varuations can be a risk factor for POCD when diagonosed with NPT.

Conditions

Postoperative Cognitive Dysfunction

Keywords

biomarkers; MD2; Cystatin C; DNA methylation markers; SNP mutations in CTNNA2 gene

Outcome Measures

Primary Outcomes (4)

• Preoperative serum MD2/CysC/DAN Methylation marker/SNPs mutation rates on CTNNA2 gene before anesthesia

  Blood samples will be collected at immediately before anesthesia and tested for MD2/CysC/DAN Methylation marker value.

  Immediately before anesthesia

• Postoperative serum MD2/CysC/DAN Methylation marker/immediately after surgery

  Blood samples will be collected at immediately after surgery and tested for MD2/CysC/DAN Methylation marker value.

  Immediately after surgery

• Postoperative serum MD2/CysC/DAN Methylation marker value at 24 h after surgery

  Blood samples will be collected at 24h after surgery and tested for MD2/CysC/DAN Methylation marker value.

  Twenty-four hours after surgery

• Neuropsychological battery (NPB) assessment

  NPB will be evaluated at 3 time points: 1. one day before surgery. 2. one day before discharge. 3. 3 months after surgery. The NPB includes: 1. Grooved Pegboard Test; 2. Auditory Word Memory Test; 3. Trail Making Test (Part A, Part B); 4. Digit Span Test; 5. Digit Symbol Subtest; 6. Verbal Fluency Test; and 7. Word Recall Test. POCD at discharge or 3 months after surgery will be analyzed as follow: 2 or more tests of the NPB with a Z score over 1.96 or less than -1.96, patient is defined as POCD. And patients that have less than 2 tests with a Z score over 1.96 is defined as no-POCD. Note: the time frame of postoperative NPB test is defined as one day before discharge. It is usually within 5-9 days depending on the hospitalization time for each patient. Since NPB test is time consuming and requires patients at a comfortable state. The investigators chose one day before discharge as many clinical trials regarding POCD reported.

  From one day before surgery to 3 months after surgery

Study Arms (2)

Surgery

Patients aged over 18 scheduled for elective cardiac surgery under CPB and general anesthesia. This group will later be divided in to two sub groups based on their neuropsychological battery tests results before surgery and one day before discharge. Blood sample will be collected before, immediately after surgery and at 24h after surgery for serum biomarker tests: MD2, CysC as well as DNA methylation markers of neural system origin.

Diagnostic Test: Serum biomarker tests; Behavioral: Neuropsychological battery tests; Procedure: Cardiac surgery

non-surgical control

Age and sex matched volunteers from the community were included for neuropsychological battery tests and set as controls for the diagnosis of POCd in surgical patients.

Behavioral: Neuropsychological battery tests

Interventions

Serum biomarker tests DIAGNOSTIC_TEST

Blood was collected at preoperatively, immediately after operation and 24 h after operation in patients from the surgical group but not volunteers. Serum MD2, CysC, DNA methylation marker and SNP mutation sites on CTNNA2 gene were test.

Surgery

Neuropsychological battery tests BEHAVIORAL

both surgical patients and volunteers will accept three times of NPB tests. For surgical patients the tested time point are preoperative, one day before discharge and 3 months after surgery. For volunteers the tested time interval would be similar to that of surgical patients.

Also known as: NPB tests

Surgery; non-surgical control

Cardiac surgery PROCEDURE

patients scheduled for cardiac surgery will accept the surgical procedure.

Surgery

Eligibility Criteria

• Age: 18 Years - 108 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients undergoing cardiac surgery under cardio-pulmonary bypass (CPB) and general anesthesia. Non-surgical controls are age and gender-matched community residents.

You may qualify if:

• Patients age≥18 yrs scheduled for coronary artery bypass graft (CABG), valve replacement or CABG+valve replacement surgery under CPB and general anesthesia in Xijing Hospital, from Nov, 2018.

You may not qualify if:

• Has neurodegenerative disease: dementia, Alzheimer's or Parkinson's Disease
• Has received neuropsychological tests before
• Psychological disorder that needs medication
• Preoperative Mini-Mental State Examination (MMSE)\< 24
• Didn't finish elementary school
• Has symptomatic cerebrovascular disease.
• Has received cardiac surgery or neurosurgery before
• Has cardiac arrest experience and received cardiopulmonary resuscitation
• Renal dysfunction (serum creatinine\>2 mg/dL or 176.82 μmol/L)
• Hepatic pathology (AST, ALT exceeded 1.5 times of the upper limit of normal range)
• Unable to comply or non-cooperative
• Can't finish process under instruction
• Can't understand mandarin
• Has severe visual or auditorial impairment
• Has severe alcohol or drug dependence (has been drinking over 100 ml of ≥50° alcohol per day , for over 3 months. And other drug abuse problem)

Sponsors & Collaborators

• Xijing Hospital: lead

Study Sites (1)

Xijing Hospital

Xi'an, Shaanxi, 710032, China

RECRUITING

Related Publications (7)

• Li YC, Xi CH, An YF, Dong WH, Zhou M. Perioperative inflammatory response and protein S-100beta concentrations - relationship with post-operative cognitive dysfunction in elderly patients. Acta Anaesthesiol Scand. 2012 May;56(5):595-600. doi: 10.1111/j.1399-6576.2011.02616.x. Epub 2012 Jan 9.

  PMID: 22224444 BACKGROUND

• Bi Y, Liu S, Yu X, Wu M, Wang Y. Adaptive and regulatory mechanisms in aged rats with postoperative cognitive dysfunction. Neural Regen Res. 2014 Mar 1;9(5):534-9. doi: 10.4103/1673-5374.130084.

  PMID: 25206851 BACKGROUND

• Bianchi R, Adami C, Giambanco I, Donato R. S100B binding to RAGE in microglia stimulates COX-2 expression. J Leukoc Biol. 2007 Jan;81(1):108-18. doi: 10.1189/jlb.0306198. Epub 2006 Oct 5.

  PMID: 17023559 BACKGROUND

• Li RL, Zhang ZZ, Peng M, Wu Y, Zhang JJ, Wang CY, Wang YL. Postoperative impairment of cognitive function in old mice: a possible role for neuroinflammation mediated by HMGB1, S100B, and RAGE. J Surg Res. 2013 Dec;185(2):815-24. doi: 10.1016/j.jss.2013.06.043. Epub 2013 Jul 17.

  PMID: 23899512 BACKGROUND

• Linstedt U, Meyer O, Kropp P, Berkau A, Tapp E, Zenz M. Serum concentration of S-100 protein in assessment of cognitive dysfunction after general anesthesia in different types of surgery. Acta Anaesthesiol Scand. 2002 Apr;46(4):384-9. doi: 10.1034/j.1399-6576.2002.460409.x.

  PMID: 11952437 BACKGROUND

• Fang Z, Deng J, Wu Z, Dong B, Wang S, Chen X, Nie H, Dong H, Xiong L. Cystatin C Is a Crucial Endogenous Protective Determinant Against Stroke. Stroke. 2017 Feb;48(2):436-444. doi: 10.1161/STROKEAHA.116.014975. Epub 2016 Dec 20.

  PMID: 27999137 BACKGROUND

• Kobayashi N, Shinagawa S, Nagata T, Shimada K, Shibata N, Ohnuma T, Kasanuki K, Arai H, Yamada H, Nakayama K, Kondo K. Usefulness of DNA Methylation Levels in COASY and SPINT1 Gene Promoter Regions as Biomarkers in Diagnosis of Alzheimer's Disease and Amnestic Mild Cognitive Impairment. PLoS One. 2016 Dec 19;11(12):e0168816. doi: 10.1371/journal.pone.0168816. eCollection 2016.

  PMID: 27992572 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Patient serum with DNA fragments

MeSH Terms

Conditions

Postoperative Cognitive Complications

Interventions

Cardiac Surgical Procedures

Condition Hierarchy (Ancestors)

Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cognitive Dysfunction; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Cardiovascular Surgical Procedures; Surgical Procedures, Operative; Thoracic Surgical Procedures

Study Officials

• Lize Xiong, M.D., Ph.D.

  Xijing Hospital, the Fourth Military Medical University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jiao Deng, M.D., Ph.D.

CONTACT

+8615929779202; peazi@126.com

Lihong Hou, M.D., Ph.D.

CONTACT

+8613991183806; houlihong@fmmu.edu.cn

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 3, 2018
• First Posted: August 1, 2018
• Study Start: November 20, 2018
• Primary Completion: September 1, 2021
• Study Completion: December 1, 2021
• Last Updated: July 7, 2020

Record last verified: 2020-07

Locations

CN (1)