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Zinc and Post-Operative Cognitive Dysfunction

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: NCT04369157
Recruitment Status : Not yet recruiting
First Posted : April 30, 2020
Last Update Posted : April 30, 2020
Sponsor:
Collaborator:
Royal Berkshire NHS Foundation Trust
Information provided by (Responsible Party):
Prof Claire Williams, University of Reading

Brief Summary:

A decline in cognitive abilities following surgery (POCD: Post-Operative Cognitive Dysfunction) affects up to 47% of patients undergoing a surgical procedure. Risk factors include age, previous depression, alcohol and drug use, smoking, cognitive impairment as well as pre-operative biochemical and haematological abnormalities. Inflammation has been proposed as a potential cause, however, there is little empirical and clinical evidence in this area to determine aetiology or reduce risk of incidence.

Zinc is an important metal for brain function, with deficiency associated with poorer cognitive outcomes. In relation to POCD, biomarker studies have revealed that levels of a zinc-alpha-2-glycoprotein (AZGP1) were lower in patients with POCD. AZGP1 is a multifunctional glycoprotein implicated in cell adhesion, immune response, transmembrane transport and cellular proliferation. Microglia, the immune cells of the brain, are highly sensitive to changes in zinc which have been proposed to contribute to neurodegenerative disease as well as POCD. However, whilst animal studies looking at the effects of zinc on cognition have been promising, robust human trials are lacking.

This research aims to establish the role of zinc in POCD by determining associations between zinc status, inflammation, cognitive function, and biomarkers of POCD risk and incidence. This will be achieved by gathering clinical and cognitive data from a sample of older adults undergoing surgery. Blood samples will be taken pre and post-operatively to establish zinc status and plasma concentrations of biomarkers of POCD risk and incidence. Pre and post-operative cognitive assessments will also be conducted to measure memory and executive function. Incidence of POCD will be determined via neurological assessment according to diagnostic criteria.

Should associations between zinc status, POCD biomarkers, inflammation, cognitive performance and POCD incidence be established, not only would it lead to future work to investigate potential mechanisms of action as well as intervention studies looking to support zinc status, optimising early identification of individuals who may be at higher risk of developing POCD should lead to better patient outcomes.


Condition or disease Intervention/treatment
Cognitive Dysfunction Procedure: Elective surgery

Detailed Description:

Healthy older adults under-going elective surgery (knee replacement, hip replacement or colorectal surgery) will be recruited via the Royal Berkshire Hospital. Participants will be aged 60 years and above, will have the capacity to give fully informed consent and will be undergoing elective orthopaedic or colorectal surgery.

Participation will involve testing on 3 occasions: 48hours-3 weeks prior to surgery (in the participant's home), 1-3 days post-surgery (in the Royal Berkshire Hospital) and approximately one month post-surgery (in the participant's home).

On each occasion, the Montreal Cognitive Assessment (MoCA) and Confusion Assessment Method (CAM) will be administered along with various cognitive tests measuring executive function (Trials A & B, Stroop, Letter memory task, verbal fluency) and memory (the episodic memory tests of free recall and recognition from the CERAD: Consortium to Establish a Registry for Alzheimer's Disease neuropsychological test battery), as well as completion of questionnaires to determine mood (the Hospital Anxiety and Depression Scale [HADS] and the Positive and Negative Affect Scale [PANAS]) and sleep quality (the Pittsburgh Sleep Quality Index). The cognitive testing should take approximately 30-40 minutes.

At the first session (pre-operation) only, dietary information will also be collected via a food frequency questionnaire, as well as measures of fluid and crystallised intelligence (the National Adult Reading Test and Block Design from the Wechsler Adult Intelligence Scale - Revised respectively).

In addition, at each visit, a blood sample (maximum volume of 9mL, less than one tablespoon) will be taken from the participants for analysis of zinc concentration and markers of POCD and inflammation.

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Study Type : Observational
Estimated Enrollment : 120 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Role of Zinc and Inflammation in Susceptibility to Post-operative Cognitive Dysfunction
Estimated Study Start Date : October 1, 2020
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : March 31, 2021

Group/Cohort Intervention/treatment
Elective surgery group
Patients undergoing hip/knee replacements or colorectal surgery will be recruited and tested on 3 occasions: pre-op, post-op and at follow-up. POCD status will be determined at post-op and follow up. Cognitive function, zinc status, POCD biomarkers and inflammatory markers will be measured on all 3 occasions.
Procedure: Elective surgery
Patients will be scheduled to undergo elective orthopaedic (knee/hip replacement) or colorectal surgery.




Primary Outcome Measures :
  1. POCD incidence 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    Assessment of the presence of POCD symptoms 1-3 days post operation

  2. POCD incidence at follow-up [ Time Frame: One month post operation ]
    Assessment of the presence of POCD symptoms at follow-up

  3. Baseline zinc status as a predictor of POCD incidence 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    Concentration of zinc in plasma/serum at baseline as a predictor for development of POCD 1-3 days post operation

  4. Baseline zinc status as a predictor of POCD incidence at follow-up [ Time Frame: One month post operation ]
    Concentration of zinc in plasma/serum at baseline as a predictor for development of POCD one month post operation

  5. Baseline zinc status as a predictor of cognitive function 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    Concentration of zinc in plasma/serum at baseline as a predictor of cognitive function 1-3 days post operation

  6. Baseline zinc status as a predictor of cognitive function at follow-up [ Time Frame: One month post operation ]
    Concentration of zinc in plasma/serum at baseline as a predictor of cognitive function at follow-up


Secondary Outcome Measures :
  1. Baseline cognitive function as a predictor of POCD incidence 1-3 days post-operation [ Time Frame: 1-3 days post operation ]
    To determine whether baseline cognitive function is a predictor of development of POCD 1-3 days post operation

  2. Baseline cognitive function as a predictor of POCD incidence at follow-up [ Time Frame: One month post operation ]
    To determine whether baseline cognitive function is a predictor of development of POCD at follow-up

  3. Association between POCD risk biomarkers at baseline and POCD incidence 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To determine an association between biomarkers of POCD risk in plasma/serum at baseline and development of POCD 1-3 days post operation

  4. Association between POCD risk biomarkers at baseline and POCD incidence at follow-up [ Time Frame: One month post operation ]
    To determine an association between biomarkers of POCD risk in plasma/serum at baseline and development of POCD at follow-up

  5. Association between POCD risk biomarkers at baseline and cognitive function 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To determine an association between biomarkers of POCD risk in plasma/serum at baseline and cognitive function 1-3 days post operation

  6. Association between POCD risk biomarkers at baseline and cognitive function at follow-up [ Time Frame: One month post operation ]
    To determine an association between biomarkers of POCD risk in plasma/serum at baseline and cognitive function at follow-up

  7. Association between POCD biomarkers and POCD incidence 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To determine an association between the presence of POCD biomarkers in plasma/serum and development of POCD 1-3 days post operation

  8. Association between POCD biomarkers and POCD incidence at follow-up [ Time Frame: One month post operation ]
    To determine an association between the presence of POCD biomarkers in plasma/serum and development of POCD at follow-up

  9. Association between POCD biomarkers and cognitive function 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To determine an association between the presence of POCD biomarkers in plasma/serum and cognitive function 1-3 days post operation

  10. Association between POCD biomarkers and cognitive function at follow-up [ Time Frame: One month post operation ]
    To determine an association between the presence of POCD biomarkers in plasma/serum and cognitive function at follow-up

  11. Mediating influence of POCD risk biomarkers (including inflammatory markers) at baseline on an association between baseline zinc status and POCD incidence 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To identify whether POCD risk biomarkers (including inflammatory markers) at baseline mediate an association between concentration of zinc in plasma/serum at baseline and POCD incidence 1-3 days post operation

  12. Mediating influence of POCD risk biomarkers (including inflammatory markers) at baseline on an association between baseline zinc status and POCD incidence at follow-up [ Time Frame: One month post operation ]
    To identify whether POCD risk biomarkers (including inflammatory markers) at baseline mediate an association between concentration of zinc in plasma/serum at baseline and POCD incidence at follow-up

  13. Mediating influence of POCD risk biomarkers (including inflammatory markers) at baseline on an association between baseline zinc status and cognitive function 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To identify whether POCD risk biomarkers (including inflammatory markers) at baseline mediate an association between concentration of zinc in plasma/serum at baseline and cognitive function 1-3 days post operation

  14. Mediating influence of POCD risk biomarkers (including inflammatory markers) at baseline on an association between baseline zinc status and cognitive function at follow-up [ Time Frame: One month post operation ]
    To identify whether POCD risk biomarkers (including inflammatory markers) at baseline mediate an association between concentration of zinc in plasma/serum at baseline and cognitive function at follow-up

  15. Mediating influence of POCD biomarkers (including inflammatory markers) on an association between baseline zinc status and cognitive function 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To identify whether POCD biomarkers (including inflammatory markers) mediate an association between concentration of zinc in plasma/serum at baseline and cognitive function 1-3 days post operation

  16. Mediating influence of POCD biomarkers (including inflammatory markers) on an association between baseline zinc status and cognitive function at follow-up [ Time Frame: One month post operation ]
    To identify whether POCD biomarkers (including inflammatory markers) mediate an association between concentration of zinc in plasma/serum at baseline and cognitive function at follow-up

  17. Baseline mood as a mediator of an association between baseline zinc status and POCD incidence 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To identify whether mood at baseline is a mediator of an association between concentration of zinc in plasma/serum at baseline and POCD incidence 1-3 days post operation

  18. Baseline mood as a mediator of an association between baseline zinc status and POCD incidence at follow-up [ Time Frame: One month post operation ]
    To identify whether mood at baseline is a mediator of an association between concentration of zinc in plasma/serum at baseline and POCD incidence at follow-up

  19. Baseline mood as a mediator of an association between baseline zinc status and cognitive function 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To identify whether mood at baseline is a mediator of an association between concentration of zinc in plasma/serum at baseline and cognitive function 1-3 days post operation

  20. Baseline mood as a mediator of an association between baseline zinc status and cognitive function at follow-up [ Time Frame: One month post operation ]
    To identify whether mood at baseline is a mediator of an association between concentration of zinc in plasma/serum at baseline and cognitive function at follow-up

  21. Current mood as a mediator of an association between baseline zinc status and POCD incidence at follow-up [ Time Frame: On month post operation ]
    To identify whether current mood is a mediator of an association between concentration of zinc in plasma/serum at baseline and POCD incidence at follow-up

  22. Current mood as a mediator of an association between baseline zinc status and POCD incidence 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To identify whether current mood is a mediator of an association between concentration of zinc in plasma/serum at baseline and POCD incidence 1-3 days post operation

  23. Current mood as a mediator of an association between baseline zinc status and cognitive function 1-3 days post operation [ Time Frame: 1-3 days post operation ]
    To identify whether current mood is a mediator of an association between concentration of zinc in plasma/serum at baseline and cognitive function 1-3 days post operation

  24. Current mood as a mediator of an association between baseline zinc status and cognitive function at follow-up [ Time Frame: One month post operation ]
    To identify whether current mood is a mediator of an association between concentration of zinc in plasma/serum at baseline and cognitive function at follow-up


Biospecimen Retention:   Samples Without DNA
Plasma or serum samples processed to remove DNA, to determine zinc status and POCD biomarkers.


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.


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Ages Eligible for Study:   60 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Non-Probability Sample
Study Population
Adults aged over 60 years scheduled to undergo elective orthopaedic or colorectal surgery at the Royal Berkshire Hospital
Criteria

Inclusion Criteria:

  • Aged 60 years or over
  • Able to provide fully informed consent
  • Scheduled to undergo orthopaedic (knee/hip replacement) or colorectal surgery
  • English as their primary language

Exclusion Criteria:

  • Under 60 years of age
  • Unable to provide fully informed consent
  • English not their primary language
  • Not electing to undergo any surgery or surgery that is not a knee or hip replacement, or colorectal surgery

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): NCT04369157


Contacts
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Contact: Lesley Mokogwu +44 1183227449 leslie.mokogwu@royalberkshire.nhs.uk

Locations
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United Kingdom
School of Psychology and Clinical Languages, University of Reading
Reading, Berkshire, United Kingdom, RG6 6AL
Contact: Claire Williams, PhD    0118 378 7540    claire.williams@reading.ac.uk   
Contact: Georgina Dodd, PhD       g.dodd@reading.ac.uk   
Royal Berkshire Hospital
Reading, Berkshrie, United Kingdom
Contact: Lesley Mokogwu    +44 1183227449    leslie.mokogwu@royalberkshire.nhs.uk   
Sponsors and Collaborators
University of Reading
Royal Berkshire NHS Foundation Trust
Investigators
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Principal Investigator: Claire Williams, PhD University of Reading
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Responsible Party: Prof Claire Williams, Professor, University of Reading
ClinicalTrials.gov Identifier: NCT04369157    
Other Study ID Numbers: RDG-006
First Posted: April 30, 2020    Key Record Dates
Last Update Posted: April 30, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Only anonymised data will be shared if requested.
Time Frame: Data will be available on request following publication of the findings.
Access Criteria: Data will be shared at the discretion of the Principle Investigator.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Cognitive Dysfunction
Cognition Disorders
Neurocognitive Disorders
Mental Disorders