Neuroinflammation and Alzheimer's Pathology in POCD (POCD)

May 13, 2022 updated by: University of Tennessee Graduate School of Medicine

Neuroinflammation and Alzheimer's Pathology in Post-operative Cognitive Dysfunction: A Pilot Study

The purpose of this project is to investigate the role of both neural inflammation and pre-existing neurodegenerative pathology in the risk and pathogenesis of post-operative cognitive dysfunction (POCD). To achieve this goal, the investigators will combine blood and cerebrospinal fluid (CSF) sampling, standardized cognitive tests, and dynamic neurophysiological markers of cortical network dysfunction in the form of event-related potentials (ERPs), to assess the link between neurodegeneration and neuroinflammation in the pathogenesis of POCD.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The purpose of this project is to investigate the role of both neural inflammation and pre-existing neurodegenerative pathology in the risk and pathogenesis of post-operative cognitive dysfunction (POCD) in 120 patients who will undergo a Total Knee Arthroscopy. The investigators will also explore neuropsychological, functional and biological measures as pre-operative risk indicators. To achieve this goal, the investigators will combine blood and cerebrospinal fluid (CSF) sampling, standardized cognitive tests, and dynamic neurophysiological markers of cortical network dysfunction in the form of event-related potentials (ERPs), to assess the link between neurodegeneration and neuroinflammation in the pathogenesis of POCD. To separate potential effects of general anesthesia from those of neuroinflammation, The investigators will recruit patients undergoing total knee replacement with the use of sedation and spinal anesthesia. To address the age risk factor, the investigators are targeting patients ages 60 and older. By using both validated and experimental biomarkers, this novel study design will isolate the effects of POCD due to systemic and neural inflammation and examine the links to pre-surgical cognitive impairment and underlying neurodegeneration as susceptibility factors.

Baseline (On the day of their final preoperative surgical visit prior to their TKA) the plan is to collect:

  1. Cognitive assessments

    a. Montreal Cognitive Assessment b. Stroop Test c. Symbol Digit Modalities Test d. Oral Trail Making Test

  2. Collect two 4-ml blood samples for biomarker evaluation

Visit 2 Pre-op (day of scheduled TKA surgery) the plan is to collect:

  1. Repeat cognitive testing

    a. Montreal Cognitive Assessment b. Stroop Test c. Symbol Digit Modalities Test d. Oral Trail Making Test

  2. Collect two 4-ml blood samples for biomarker evaluation
  3. Collect 2cc of cerebral spinal fluid

Visit 2 Post-op:

  1. 4 AT test for delirium
  2. Collect two 4ml blood samples will be taken

Visit 3 (Forty-eight hours after discharge):

1. brief cognitive testing via telephone or video conferencing.

  1. Blind Montreal Cognitive Assessment

  2. Oral Trail Making Test

    Visit 4 (two weeks for their post-operative visit):

    1. Repeat cognitive testing

    1. Montreal Cognitive Assessment 2. Stroop Test 3. Symbol Digit Modalities Test 2. Oral Trail Making Test 3. Collect two 4ml blood samples for biomarker testing.

    For patients who had pre-operative cognitive impairment, their participation in the study will end here

    For 20 participants with no indication of pre-surgical cognitive impairment (10 with no post-operative impairment and 10 with presumed POCD)

    Visit 5 (~ 6 weeks post-op) the plan is to collect:

    1. Complete initial neurophysiological recording of event-related potentials (ERPs). This ERP session is performed to establish baseline cortical network function. Neurophysiological studies will be conducted using a 128-electrode EEG system.
    2. Collect two 4-ml blood samples

    Visit 6 End of Study (At 6 months):

    1. Collect a final assessment of cognition
    2. ERP assessment

Study Type

Observational

Enrollment (Anticipated)

120

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Department of Anesthesiology Chair
  • Phone Number: 8653059220
  • Email: rcraft@utmck.edu

Study Contact Backup

Study Locations

  • United States
    • Tennessee
      • Knoxville, Tennessee, United States, 37920
        • Recruiting
        • Robert M Craft
        • Contact:
        • Contact:
          • Robert M Craft, MD
          • Phone Number: 865-305-9220
        • Principal Investigator:
          • Robert Craft, MD
        • Principal Investigator:
          • Paul Allen, MD, PhD
        • Principal Investigator:
          • Roberto Fernandez, MD
        • Sub-Investigator:
          • Brian Tonne, MD
        • Sub-Investigator:
          • Anahita Khojandi, PhD
        • Sub-Investigator:
          • Thomas Christianson, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

60 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

No one ethnic group is either targeted or excluded in the proposed study. The investigators aim to target a sample of individuals ages 60 and older who will all undergo total knee arthroplasty. This selection of participants is based upon the aims of the current study.

Due to the nature of the study, the investigators will include individuals with who are considered elderly. This population is necessary due to the increased prevalence of POCD within this group.

Description

Inclusion Criteria:

  • Males and females 60 years or older in age
  • Subjects scheduled to undergo TKA
  • Fluent and literate in English
  • Able to give consent for themselves based upon the MacArthur Competence Assessment Tool for Clinical Research
  • Able to have a subarachnoid block with only intravenous sedation

Exclusion Criteria:

  • Less than 60 years of age
  • Cognitively impaired to the point where they are unable to give consent for themselves
  • Blindness or partial blindness
  • Pre-existing neurodegenerative conditions
  • Contraindication for subarachnoid block and/or requiring general anesthesia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
With Post-Operative Cognitive Dysfunction

Subjects determined to have post-operative cognitive dysfunction based on the results of:

  1. 4AT Delirium Test

  2. Scoring on :

    1. Montreal Cognitive Assessment
    2. Oral Trails Test
    3. Stroop Test
    4. Symbol Digit Modalities Test

All subjects will undergo:

  1. Blood sample collection
  2. Cerebral spinal fluid collection
  3. ERP testing
  4. NACC Cognitive Battery
  5. Grooved Pegboard testing
Behavioral: Montreal Cognitive Assessment
Cognitive evaluation of short term memory, visuospatial abilities, executive functioning, attention, concentration, working memory, language, and orientation to time and place
Other Names:
  • MOCA
Behavioral: Stroop Test
Evaluates Processing Speed and Executive Control
Diagnostic test: 4AT Delirium
Screening tool to test for delirium post surgery
Behavioral: Grooved Pegboard
Evaluation testing for dominant and non dominant sensory-motor speed
Behavioral: NACC Cognitive Battery
A series of tests that evaluate attention, concentration, immediate verbal memory, immediate visual memory, discrimination, processing/motor speed, and validity and effort.
Diagnostic test: ERP Testing
An event-related potential ( ERP) is the measured brain response that is the direct result of a specific sensory, cognitive, or motor event. More formally, it is any stereotyped electrophysiological response to a stimulus. The study of the brain in this way provides a noninvasive means of evaluating brain functioning.
Diagnostic test: Blood Plasma and Serum sampling
Up to six 4 ml samples of both serum and plasma will be obtained to assess for inflammatory markers.
Diagnostic test: Cerebral Spinal Fluid Sample
At the time the spinal is placed for anesthetic purposes, 2ml of cerebral spinal fluid will be obtained to assess for inflammatory markers.
Without Post-Operative Cognitive Dysfunction

Subjects determined to not have post-operative cognitive dysfunction based on the results of:

  1. 4AT Delirium Test

  2. Scoring on :

    1. Montreal Cognitive Assessment
    2. Oral Trails Test
    3. Stroop Test
    4. Symbol Digit Modalities Test

All subjects will undergo:

  1. Blood sample collection
  2. Cerebral spinal fluid collection
  3. ERP testing
  4. NACC Cognitive Battery
  5. Grooved Pegboard testing
Behavioral: Montreal Cognitive Assessment
Cognitive evaluation of short term memory, visuospatial abilities, executive functioning, attention, concentration, working memory, language, and orientation to time and place
Other Names:
  • MOCA
Behavioral: Stroop Test
Evaluates Processing Speed and Executive Control
Diagnostic test: 4AT Delirium
Screening tool to test for delirium post surgery
Behavioral: Grooved Pegboard
Evaluation testing for dominant and non dominant sensory-motor speed
Behavioral: NACC Cognitive Battery
A series of tests that evaluate attention, concentration, immediate verbal memory, immediate visual memory, discrimination, processing/motor speed, and validity and effort.
Diagnostic test: ERP Testing
An event-related potential ( ERP) is the measured brain response that is the direct result of a specific sensory, cognitive, or motor event. More formally, it is any stereotyped electrophysiological response to a stimulus. The study of the brain in this way provides a noninvasive means of evaluating brain functioning.
Diagnostic test: Blood Plasma and Serum sampling
Up to six 4 ml samples of both serum and plasma will be obtained to assess for inflammatory markers.
Diagnostic test: Cerebral Spinal Fluid Sample
At the time the spinal is placed for anesthetic purposes, 2ml of cerebral spinal fluid will be obtained to assess for inflammatory markers.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood Interleukin-1 beta (IL-1β)
Time Frame: Baseline
A proinflammatory cytokine that activates astrocytes and micro ganglia
Baseline
Blood Interleukin-1 beta (IL-1β)
Time Frame: Pre-op (pre-operation) -Visit 2- Day of surgery
A proinflammatory cytokine that activates astrocytes and micro ganglia
Pre-op (pre-operation) -Visit 2- Day of surgery
Blood Interleukin-1 beta (IL-1β)
Time Frame: Post-op Visit 2- In recovery room up to 12 hours post surgery
A proinflammatory cytokine that activates astrocytes and micro ganglia
Post-op Visit 2- In recovery room up to 12 hours post surgery
Blood Interleukin-1 beta (IL-1β)
Time Frame: 2 Week Post-op -Visit 4
A proinflammatory cytokine that activates astrocytes and micro ganglia
2 Week Post-op -Visit 4
Blood Interleukin-1 beta (IL-1β)
Time Frame: 6 Week Post-op -Visit 5
A proinflammatory cytokine that activates astrocytes and micro ganglia
6 Week Post-op -Visit 5
Blood Tumor necrosis factor alpha (TNF- α)
Time Frame: Baseline
A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases
Baseline
Blood Tumor necrosis factor alpha (TNF- α)
Time Frame: Pre-op- Visit 2- Day of surgery
A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases
Pre-op- Visit 2- Day of surgery
Blood Tumor necrosis factor alpha (TNF- α)
Time Frame: Post-op Visit 2- In recovery room up to 12 hours post surgery
A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases
Post-op Visit 2- In recovery room up to 12 hours post surgery
Blood Tumor necrosis factor alpha (TNF- α)
Time Frame: 2-week Post-op Visit 4
A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases
2-week Post-op Visit 4
Blood Tumor necrosis factor alpha (TNF- α)
Time Frame: 6-week Post-op Visit 5
A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases
6-week Post-op Visit 5
Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
Time Frame: Baseline
A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease
Baseline
Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
Time Frame: Pre-op Visit 2- Day of surgery
A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease
Pre-op Visit 2- Day of surgery
Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
Time Frame: Post-op Visit 2- In recovery room up to 12 hours post surgery
A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease
Post-op Visit 2- In recovery room up to 12 hours post surgery
Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
Time Frame: 2-week Post-op Visit 4
A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease
2-week Post-op Visit 4
Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
Time Frame: 6- week Post-op Visit 5
A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease
6- week Post-op Visit 5
Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)
Time Frame: Baseline
A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages
Baseline
Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)
Time Frame: Pre-op Visit 2- Day of surgery
A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages
Pre-op Visit 2- Day of surgery
Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)
Time Frame: Post-op Visit 2- In recovery room up to 12 hours post surgery
A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages
Post-op Visit 2- In recovery room up to 12 hours post surgery
Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)
Time Frame: 2 week Post-op Visit 4
A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages
2 week Post-op Visit 4
Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)
Time Frame: 6 week- Post-op Visit 5
A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages
6 week- Post-op Visit 5
Cerebral Spinal Fluid Phosphorylated Tau Protein
Time Frame: Pre-op Visit 2-Day of surgery
A helical protein known to be a biomarker in the cerebral spinal fluid in brains with Alzheimer's Disease
Pre-op Visit 2-Day of surgery
ERP response amplitude
Time Frame: 6 Week post-op visit 5
Measurement of event related potentials in the brain
6 Week post-op visit 5
ERP response latency
Time Frame: 6 Week post-op visit 5
Measurement of event related potentials in the brain
6 Week post-op visit 5
ERP response amplitude
Time Frame: 6 Month post-op visit 6
Measurement of event related potentials in the brain
6 Month post-op visit 6
ERP response latency
Time Frame: 6 Month post-op visit 6
Measurement of event related potentials in the brain
6 Month post-op visit 6
Stroop Test
Time Frame: Baseline
A neurocognitive test used to assess cognitive interference. T-Scores are computed with scores above 40 being "normal."
Baseline
Stroop Test
Time Frame: Pre-op Visit 2- Day of surgery
A neurocognitive test used to assess cognitive interference. T-Scores are computed with scores above 40 being "normal."
Pre-op Visit 2- Day of surgery
Stroop Test
Time Frame: 2 Week post-op Visit 4
A neurocognitive test used to assess cognitive interference. T-Scores are computed with scores above 40 being "normal."
2 Week post-op Visit 4
Montreal Cognitive Assessment
Time Frame: Baseline
A neurocognitive test used to assess cognitive function across multiple domains. Scoring is on a scale from 0-30 with a score >26 being normal.
Baseline
Montreal Cognitive Assessment
Time Frame: Pre-op Visit 2- Day of surgery
A neurocognitive test used to assess cognitive function across multiple domains. Scoring is on a scale from 0-30 with a score >26 being normal.
Pre-op Visit 2- Day of surgery
Blind Montreal Cognitive Assessment
Time Frame: 48 Hours post-op- Visit 3
A neurocognitive test used to assess cognitive function across multiple domains. Scoring is on a scale from 0-22 with a score >18 being normal.
48 Hours post-op- Visit 3
Montreal Cognitive Assessment
Time Frame: 2 Week post-op- Visit 4
A neurocognitive test used to assess cognitive function across multiple domains. Scoring is on a scale from 0-30 with a score >26 being normal.
2 Week post-op- Visit 4
Oral Trail Making Test
Time Frame: Baseline
A neurocognitive test used to assess cognitive executive function with times for trail A > 78 seconds and trail B >273 seconds being deficient.
Baseline
Oral Trail Making Test
Time Frame: Pre-op Visit 2- Day of surgery
A neurocognitive test used to assess cognitive executive function with times for trail A > 78 seconds and trail B >273 seconds being deficient.
Pre-op Visit 2- Day of surgery
Oral Trail Making Test
Time Frame: 48 Hours post-op Visit 3
A neurocognitive test used to assess cognitive executive function with times for trail A > 78 seconds and trail B >273 seconds being deficient.
48 Hours post-op Visit 3
Oral Trail Making Test
Time Frame: 2- Week post-op Visit 4
A neurocognitive test used to assess cognitive executive function with times for trail A > 78 seconds and trail B >273 seconds being deficient.
2- Week post-op Visit 4
Symbol Digit Test
Time Frame: Baseline
A neurocognitive test used to assess for cerebral dysfunction scored through statistical methods with a higher score meaning higher cognitive vitality.
Baseline
Symbol Digit Test
Time Frame: Pre-op Visit 2- Day of surgery
A neurocognitive test used to assess for cerebral dysfunction scored through statistical methods with a higher score meaning higher cognitive vitality.
Pre-op Visit 2- Day of surgery
Symbol Digit Test
Time Frame: 2- Week post-op Visit 4
A neurocognitive test used to assess for cerebral dysfunction scored through statistical methods with a higher score meaning higher cognitive vitality.
2- Week post-op Visit 4
4 AT Delirium Screening
Time Frame: Post-op Visit 2- In recovery room up to 12 hours post surgery
Bedside screening to detect delirium with a score of 4 or more indicating delirium +/- cognitive impairment, and a score of 1-3 indicating possible cognitive impairment.
Post-op Visit 2- In recovery room up to 12 hours post surgery
Grooved Pegboard Test
Time Frame: 6 month post-op Visit 6
A neurocognitive test consisting of varying key shapes and matching holes used to test visual motor coordination with a higher score indicating less or no impairment based on the individual's age and sex.
6 month post-op Visit 6
National Alzheimer's Coordinating Center Cognitive Battery
Time Frame: 6 month post-op Visit 6
Cognitive assessment to test for deficits across multiple domains with a score of 95/995 =physical problem; 96/996 = cognitive/behavioral problem
6 month post-op Visit 6

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Tennessee Graduate School of Medicine

Collaborators

Alzheimer's Association

Investigators

  • Principal Investigator: Robert M Craft, MD, University of Tennessee Graduate School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2021

Primary Completion (Anticipated)

June 30, 2022

Study Completion (Anticipated)

September 30, 2022

Study Registration Dates

First Submitted

April 25, 2022

First Submitted That Met QC Criteria

May 13, 2022

First Posted (Actual)

May 18, 2022

Study Record Updates

Last Update Posted (Actual)

May 18, 2022

Last Update Submitted That Met QC Criteria

May 13, 2022

Last Verified

May 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 4790

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data that underlie the results reported in the article after deidentification (text, tables, figures, and appendices).

IPD Sharing Time Frame

Beginning 3 months and ending 5 years following article publication.

IPD Sharing Access Criteria

Investigators who proposed use of the data has been approved by an independent review committee identified for this purpose.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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