Neuroinflammation in Cognitive Decline Post-cardiac Surgery (FOCUS)

Neuroinflammation in Cognitive Decline Post-cardiac Surgery: The FOCUS Study

Major cardiovascular surgery is associated with postoperative cognitive decline (POCD), with a deterioration in memory, attention and speed of information processing. A multifactorial pathophysiology is presumed but this study focuses on the role of (neuro)inflammation in the development of POCD after coronary artery bypass grafting (CABG) surgery.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Postoperative Cognitive Dysfunction; Pathophysiology
• Intervention / Treatment: Diagnostic test: 18F-DPA-714 PET/CT neuroimaging

Detailed Description

Systemic inflammation can activate the innate immune cells of the brain inducing neuroinflammation, which plays an important role in the pathogenesis of neurodegenerative disease. Major cardiovascular surgery induces a severe systemic inflammatory response.There is growing support that neuroinflammation is a pivotal factor in the development of postoperative cognitive decline (POCD) due to surgery-related systemic inflammation.

Although the neuroinflammatory hypothesis is scientifically accepted, in vivo human data supporting the role of neuroinflammation in severe systemic inflammation such as major surgery are still lacking. In the last decades, several nuclear imaging tracers have been developed that can quantitatively measure microglial and astrocytic activation in vivo, by targeting the mitochondrial 18kDa translocator protein (TSPO).

The investigators hypothesize that cardiac surgery induces a neuroinflammatory response and that its presence is related to acute and long term brain dysfunction postoperatively. This will be studied by pre- and postoperative PET brain imaging using a 18F-DPA-714 tracer targeting TSPO, combined with longitudinal neuropsychological examinations. Structural changes in the brain will be recorded on MRI prior to and after cardiac surgery to enable us to correct for the potentially confounding effects of neurovascular events on cognitive outcomes after CABG surgery.

• Study Type: Observational
• Enrollment (Actual): 15

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6500HB
    • Department of Intensive Care Medicine, Radboud university medical center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients >50 years that are planned to undergo elective coronary artery bypass grafting (CABG) surgery by the cardiothoracic surgery department of the Radboud university medical center in Nijmegen (NL).

Description

Inclusion Criteria:

• Age > 50 years
• Planned for on-pump coronary artery bypass grafting surgery
• High-affinity binder or mixed-affinity binders based on rs6971 polymorphism for TSPO
• Chronic use of statins (defined as pre-hospital use)

Exclusion Criteria:

• Previous cardiac surgery.
• Pregnancy or wish to become pregnant within 2 weeks after PET-CT scan
• Contra-indication to undergo a PET/CT or MRI scan, including claustrophobia.
• Low-affinity binder based on rs6971 polymorphism for TSPO, or unable to determine rs6971 polymorphism.
• Patients with cognitive disorders that have not recovered enough to be able to understand the study leaflets and information for participation.
• Brain or spinal surgery within the last 6 months.
• Meningitis or brain infection within the last 6 months.
• Pre-existing dementia or neurodegenerative disease or cognitive impairment interfering with the ability to understand informational material about this research project.
• Presence of a CSF catheter or shunt.
• Patients with known brain tumors.
• Patients with brain injury (e.g. acute stroke, or subarachnoid hemorrhage) within the last 6 months.
• Severe brain trauma in previous medical history.
• Chronic (>2 weeks) use of immunosuppressive agents (see table 3.3.A).
• Concomitant diseases resulting in severe immunosuppression (e.g. HIV).
• Auto-immune or auto-inflammatory disease
• Active infection < 2 weeks prior to inclusion (defined as fever >38.5 or antibiotic treatment)
• Kidney failure, defined by a MDRD-GFR<15 ml/min/1.73m2
• Known contrast allergy for gadolinium
• Chronic use of neuroleptics, defined as pre-hospital use.
• Patients that do not speak Dutch or have disabilities that prevent accurate delirium diagnosis.
• Analphabetic patients.
• No written informed consent obtained.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
POCD; Patients with postoperative cognitive decline (POCD) after coronary artery bypass grafting (CABG) surgery	Diagnostic test: 18F-DPA-714 PET/CT neuroimaging; Pre- and postoperative neuroimaging using 18F-DPA-714 PET/CT and brain MRI.; Longitudinal neuropsychological examinations (up to 6 months postoperatively); Blood samples are drawn to assess the severity of the systemic inflammatory response
no POCD; Patients without postoperative cognitive decline (POCD) after coronary artery bypass grafting (CABG) surgery	Diagnostic test: 18F-DPA-714 PET/CT neuroimaging; Pre- and postoperative neuroimaging using 18F-DPA-714 PET/CT and brain MRI.; Longitudinal neuropsychological examinations (up to 6 months postoperatively); Blood samples are drawn to assess the severity of the systemic inflammatory response

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in TSPO PET tracer uptake at 3-7 days post-surgery	18F-DPA-714	3-7 days post-surgery minus preoperative (= day before surgery)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of postoperative cognitive dysfunction (POCD)	POCD diagnosis based on neuropsychological assessments including TMT A&B, Stroop I, II, III, WAIS-IV - digit span, LDST, RAVLT, RCFT, RBMT-3 face recognition, LFT and token test. POCD diagnosis is made when patients are newly impaired in one or more cognitive domains (memory, executive functioning, speed of processing and language), or when the average test rating has declined in more than one domain compared to baseline.	Baseline (preoperative), postoperative (3-7 days after surgery, 6 weeks and 6 months)
Whole brain TSPO PET tracer uptake pre- and 3-7 days post-surgery	18F-DPA-714	pre- and 3-7 days post-surgery
Pro- and anti-inflammatory in vivo cytokine concentrations [in pg/ml]	TNFa, IL6, IL-1B, IL10, IL-1RA	Day before surgery, during surgery (stop extracorporeal circulation (ECC)), after surgery (6 hours after stop ECC, 24 hours after incision, 3-7 days post-surgery and 6 weeks after surgery)
Ex vivo cytokine production of stimulated monocytes [in ng/10^9 monocytes]	TNFa, IL6, IL1B, MCP1, IL10	Day before surgery, 3-7 days and 6 weeks after surgery
Flowcytometry analysis to study the inflammatory phenotype of the cells	HLA-DR, CCR2, CD11b, CD14, CD16	Day before surgery, 3-7 days and 6 weeks after surgery
Complete blood count	including leukocyte differentiation measured on an automated hematology analyzer	Day before surgery, during surgery (stop extracorporeal circulation (ECC)), after surgery (6 hours after stop ECC, 24 hours after incision, 3-7 days post-surgery and 6 weeks after surgery)
Ex vivo cytokine production of healthy donor monocytes, after exposure to patient serum obtained during CABG surgery	Healthy donor monocytes will be exposed to patient serum obtained during surgery, to see whether this changes the ex vivo cytokine producing capacity (TNFa, IL6, IL10)	Perioperatively at stop extracorporeal circulation (ECC)
Number of newly developed (ischemic and hemorrhagic) brain and vascular wall lesions		pre- and 3-7 days post-surgery
Delta brain activity in three large scale brain networks involved in stress reactivity on resting-state fMRI		pre- and 3-7 days post-surgery

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Publications and helpful links

General Publications

• Peters van Ton AM, Duindam HB, van Tuijl J, Li WW, Dieker HJ, Riksen NP, Meijer FA, Kessels RP, Kohn N, van der Hoeven JG, Pickkers P, Rijpkema M, Abdo WF. Neuroinflammation in cognitive decline post-cardiac surgery (the FOCUS study): an observational study protocol. BMJ Open. 2021 May 11;11(5):e044062. doi: 10.1136/bmjopen-2020-044062.

Helpful Links

• Pubmed link to publication of complete study protocol

Study record dates

Study Major Dates

• Study Start (Actual): February 18, 2019
• Primary Completion (Actual): July 1, 2022
• Study Completion (Actual): July 1, 2022

Study Registration Dates

• First Submitted: July 3, 2020
• First Submitted That Met QC Criteria: August 19, 2020
• First Posted (Actual): August 20, 2020

Study Record Updates

• Last Update Posted (Actual): March 31, 2023
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Postoperative Complications; Neurocognitive Disorders; Coronary Disease; Cognition Disorders; Coronary Artery Disease; Cognitive Dysfunction; Postoperative Cognitive Complications
• Other Study ID Numbers: NL.57785.091.16; 2016-002016-40 (EudraCT Number); CMO 2016-2598 (Other Identifier: CMO Regio Arnhem-Nijmegen)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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