Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Neuroinflammation in Cognitive Decline Post-cardiac Surgery (FOCUS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04520802
Recruitment Status : Recruiting
First Posted : August 20, 2020
Last Update Posted : August 20, 2020
Sponsor:
Information provided by (Responsible Party):
Wilson F. Abdo, Radboud University

Brief Summary:
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.

Condition or disease Intervention/treatment
Postoperative Cognitive Dysfunction Coronary Artery Disease Pathophysiology 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.

Layout table for study information
Study Type : Observational
Estimated Enrollment : 30 participants
Observational Model: Other
Time Perspective: Prospective
Official Title: Neuroinflammation in Cognitive Decline Post-cardiac Surgery: The FOCUS Study
Actual Study Start Date : February 18, 2019
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : March 1, 2022

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




Primary Outcome Measures :
  1. Change in TSPO PET tracer uptake at 3-7 days post-surgery [ Time Frame: 3-7 days post-surgery minus preoperative (= day before surgery) ]
    18F-DPA-714


Secondary Outcome Measures :
  1. Occurrence of postoperative cognitive dysfunction (POCD) [ Time Frame: Baseline (preoperative), postoperative (3-7 days after surgery, 6 weeks and 6 months) ]
    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.

  2. Whole brain TSPO PET tracer uptake pre- and 3-7 days post-surgery [ Time Frame: pre- and 3-7 days post-surgery ]
    18F-DPA-714

  3. Pro- and anti-inflammatory in vivo cytokine concentrations [in pg/ml] [ Time Frame: 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) ]
    TNFa, IL6, IL-1B, IL10, IL-1RA

  4. Ex vivo cytokine production of stimulated monocytes [in ng/10^9 monocytes] [ Time Frame: Day before surgery, 3-7 days and 6 weeks after surgery ]
    TNFa, IL6, IL1B, MCP1, IL10

  5. Flowcytometry analysis to study the inflammatory phenotype of the cells [ Time Frame: Day before surgery, 3-7 days and 6 weeks after surgery ]
    HLA-DR, CCR2, CD11b, CD14, CD16

  6. Complete blood count [ Time Frame: 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) ]
    including leukocyte differentiation measured on an automated hematology analyzer

  7. Ex vivo cytokine production of healthy donor monocytes, after exposure to patient serum obtained during CABG surgery [ Time Frame: Perioperatively at stop extracorporeal circulation (ECC) ]
    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)

  8. Number of newly developed (ischemic and hemorrhagic) brain and vascular wall lesions [ Time Frame: pre- and 3-7 days post-surgery ]
  9. Delta brain activity in three large scale brain networks involved in stress reactivity on resting-state fMRI [ Time Frame: pre- and 3-7 days post-surgery ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes 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).
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04520802


Contacts
Layout table for location contacts
Contact: Annemieke M. Peters van Ton, MD +0031 243665010 nienke.petersvanton@radboudumc.nl

Locations
Layout table for location information
Netherlands
Department of Intensive Care Medicine, Radboud university medical center Recruiting
Nijmegen, Netherlands
Contact: Annemieke M. Peters van Ton, MD    +0031 243665010    nienke.petersvanton@radboudumc.nl   
Sponsors and Collaborators
Radboud University
Investigators
Layout table for investigator information
Principal Investigator: Wilson F Abdo, MD PhD Radboud University
Layout table for additonal information
Responsible Party: Wilson F. Abdo, Principal Investigator, Radboud University
ClinicalTrials.gov Identifier: NCT04520802    
Other Study ID Numbers: NL.57785.091.16
2016-002016-40 ( EudraCT Number )
CMO 2016-2598 ( Other Identifier: CMO Regio Arnhem-Nijmegen )
First Posted: August 20, 2020    Key Record Dates
Last Update Posted: August 20, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Coronary Artery Disease
Cognitive Dysfunction
Coronary Disease
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cognition Disorders
Neurocognitive Disorders
Mental Disorders