Biomarkers Associated With Postoperative Cognitive Dysfunction

Feasibility Study of the Use of Biomarkers to Detect Perioperative Brain Injury: the Association Between Serum Neurofilament Light Chains, Tau Proteins, Continuous Intra-operative Electroencephalography, and the Development of Post Operative Cognitive Dysfunction After Surgery

Loss of cognitive function after major surgery is a significant risk in older people. It can occur acutely in the days after surgery as delirium or in months to years later as a persistent reduction in brain function termed neurocognitive decline. Together these conditions are called post operative cognitive dysfunction (POCD). They can be acutely distressing for patients and are associated with other problems after surgery.

The causes of post operative cognitive dysfunction are poorly understood. Studies have been limited by a lack of biomarkers to predict which patients are at high risk of developing POCD. Research suggests silent strokes occurring during surgery and different sensitivities to anaesthetic medicines are associated with POCD.

The project consists of a feasibility study to investigate markers that might predict people over 65 years old getting POCD. The first biomarker is a non-invasive monitor of anaesthetics effects on brain function called electroencephalography (EEG): The investigators will identify which EEG patterns predict delirium within five days surgery. The second set of biomarkers are two blood tests of proteins that increase after strokes: these are neurofilament light chains and tau proteins. The investigators will establish if these can be used to predict having POCD up to one year after surgery and long term cognitive impairment up to 5 years after surgery.

Study Overview

• Status: Recruiting
• Conditions: Delirium; Cognitive Impairment; Postoperative Cognitive Dysfunction; Cognitive Decline
• Intervention / Treatment: Procedure: Intraoperative electroencephalography recording; Procedure: Neurofilament light chain measurement; Procedure: Tau protein measurement

• Study Type: Observational
• Enrollment (Estimated): 45

Contacts and Locations

• Study Contact: Name: Martyn Ezra; Phone Number: +44 1865572878; Email: martyn.ezra@ndcn.ox.ac.uk
• Study Contact Backup: Name: Matthew Luney; Phone Number: +44 1865572878; Email: matthew.luney@conted.ox.ac.uk

Study Locations

• United Kingdom
  • Berkshire
    • Reading, Berkshire, United Kingdom, RG1 5AN
      • Recruiting
      • Royal Berkshire NHS foundation trust
      • Contact: Martyn Ezra; Email: martyn.ezra@royalberkshire.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adults over 65 years of age having major elective surgery under general anaesthesia

Description

Inclusion Criteria:

• Greater than or equal to 65 years of age
• Having elective non-cardiac surgery under general anaesthesia
• Anticipated to have at least 48 hours of inpatient admission
• Able & willing to give informed consent

Exclusion Criteria:

• Unable to participate in neurocognitive assessments
• Presence of delirium prior to surgery
• Contraindication to use of EEG electrodes (e.g. known allergy to a component of the electrodes)
• Known history of severe traumatic brain injury
• Learning disability specifically with a known structural brain lesion
• Known history of dementia
• Participants undergoing operations on the carotid artery

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Biomarker monitoring

Procedure: Intraoperative electroencephalography recording; Intraoperative electroencephalography measurements, a non-invasive routine monitoring device used during anaesthesia to measure the brain's electrical activity; Other Names: EEG recording; Procedure: Neurofilament light chain measurement; Measurement of the level of neurofilament light chain in a blood sample; Other Names: NfL; Procedure: Tau protein measurement; Measurement of the level of tau protein in a blood sample

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility to conduct the study	The total number of participants who are successfully recruited, receive the study procedures and complete both 90 day and 1 year follow up after surgery.	1 year after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative delirium incidence and severity	Postoperative delirium identified as being present according to a positive result using 3-Minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) and severity according to the absolute value on the 3D-CAM-Severity which is a scale converting the 3-Minute Diagnostic Interview for Confusion Assessment Method into a scale from 0-7. Higher scores are associated with worse outcome.	Up to 5 days after surgery
Days alive and at home up to 90 days after surgery	The number of days a participant is alive and how many are spent at home after surgery	90 days after surgery
Change in neurofilament light chains and tau proteins levels pre- to post operatively	Measurements of the level of the biomarkers neurofilament light chain and tau protein in plasma	Up to 2 days after surgery
Postoperative neurocognitive dysfunction and severity	Cognitive impairment measured on Montreal Objective Cognitive Assessment administered by telephone. The scale is 0-22 with higher scores representing better outcome.	Up to 1 year after surgery
Long term cognitive impairment	Incidence of new diagnosis in primary or secondary care of dementia or mild cognitive impairment	Up to 5 years after surgery

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Oxford University Hospitals NHS Trust
• Investigators: Principal Investigator: Martyn Ezra, University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2023
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): November 1, 2029

Study Registration Dates

• First Submitted: July 11, 2022
• First Submitted That Met QC Criteria: July 15, 2022
• First Posted (Actual): July 19, 2022

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Neurofilament light chain; Electroencephalography; Delirium; Tau protein
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Cognition Disorders; Delirium; Cognitive Dysfunction; Postoperative Cognitive Complications
• Other Study ID Numbers: PID16101; 302168 (Other Identifier: Integrated Research Application System); Protocol version 13/06/2022 (Other Identifier: University of Oxford)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Participants will be asked for consent to share anonymized data with other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No