Neuroinflammation and Alzheimer's Pathology in POCD

Alzheimer Disease Clinical Trial

— POCD  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05378659
• Other study ID #: 4790
• Status: Recruiting
• Start date: November 1, 2021
• Est. completion date: September 30, 2022

Study information

• Verified date: May 2022
• Source: University of Tennessee Graduate School of Medicine
• Contact: Department of Anesthesiology Chair
• Phone: 8653059220
• Email: rcraft[@]utmck.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: September 30, 2022
• Est. primary completion date: June 30, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Confusion
• Neuroinflammatory Response
• Post-Operative Confusion

Intervention

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
• 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
• 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.
• Blood Plasma and Serum sampling
Up to six 4 ml samples of both serum and plasma will be obtained to assess for inflammatory markers.
• 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.

Locations

Country	Name	City	State
United States	Robert M Craft	Knoxville	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
University of Tennessee Graduate School of Medicine	Alzheimer's Association

Country where clinical trial is conducted

United States, 

References & Publications (28)

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Edipoglu IS, Celik F. The Associations Between Cognitive Dysfunction, Stress Biomarkers, and Administered Anesthesia Type in Total Knee Arthroplasties: Prospective, Randomized Trial. Pain Physician. 2019 Sep;22(5):495-507. — View Citation

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Evered L, Silbert B, Scott DA, Ames D, Maruff P, Blennow K. Cerebrospinal Fluid Biomarker for Alzheimer Disease Predicts Postoperative Cognitive Dysfunction. Anesthesiology. 2016 Feb;124(2):353-61. doi: 10.1097/ALN.0000000000000953. — View Citation

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Galvao-Carmona A, González-Rosa JJ, Hidalgo-Muñoz AR, Páramo D, Benítez ML, Izquierdo G, Vázquez-Marrufo M. Disentangling the attention network test: behavioral, event related potentials, and neural source analyses. Front Hum Neurosci. 2014 Oct 13;8:813. doi: 10.3389/fnhum.2014.00813. eCollection 2014. — View Citation

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Mason SE, Noel-Storr A, Ritchie CW. The impact of general and regional anesthesia on the incidence of post-operative cognitive dysfunction and post-operative delirium: a systematic review with meta-analysis. J Alzheimers Dis. 2010;22 Suppl 3:67-79. doi: 10.3233/JAD-2010-101086. Review. — View Citation

McMackin R, Bede P, Pender N, Hardiman O, Nasseroleslami B. Neurophysiological markers of network dysfunction in neurodegenerative diseases. Neuroimage Clin. 2019;22:101706. doi: 10.1016/j.nicl.2019.101706. Epub 2019 Feb 2. Review. — View Citation

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Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Biedler A, van Beem H, Fraidakis O, Silverstein JH, Beneken JE, Gravenstein JS. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998 Mar 21;351(9106):857-61. Erratum in: Lancet 1998 Jun 6;351(9117):1742. — View Citation

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* Note: There are 28 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Blood Interleukin-1 beta (IL-1ß)	A proinflammatory cytokine that activates astrocytes and micro ganglia	Baseline
Primary	Blood Interleukin-1 beta (IL-1ß)	A proinflammatory cytokine that activates astrocytes and micro ganglia	Pre-op (pre-operation) -Visit 2- Day of surgery
Primary	Blood Interleukin-1 beta (IL-1ß)	A proinflammatory cytokine that activates astrocytes and micro ganglia	Post-op Visit 2- In recovery room up to 12 hours post surgery
Primary	Blood Interleukin-1 beta (IL-1ß)	A proinflammatory cytokine that activates astrocytes and micro ganglia	2 Week Post-op -Visit 4
Primary	Blood Interleukin-1 beta (IL-1ß)	A proinflammatory cytokine that activates astrocytes and micro ganglia	6 Week Post-op -Visit 5
Primary	Blood Tumor necrosis factor alpha (TNF- a)	A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases	Baseline
Primary	Blood Tumor necrosis factor alpha (TNF- a)	A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases	Pre-op- Visit 2- Day of surgery
Primary	Blood Tumor necrosis factor alpha (TNF- a)	A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases	Post-op Visit 2- In recovery room up to 12 hours post surgery
Primary	Blood Tumor necrosis factor alpha (TNF- a)	A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases	2-week Post-op Visit 4
Primary	Blood Tumor necrosis factor alpha (TNF- a)	A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases	6-week Post-op Visit 5
Primary	Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)	A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease	Baseline
Primary	Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)	A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease	Pre-op Visit 2- Day of surgery
Primary	Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)	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
Primary	Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)	A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease	2-week Post-op Visit 4
Primary	Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)	A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease	6- week Post-op Visit 5
Primary	Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)	A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages	Baseline
Primary	Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)	A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages	Pre-op Visit 2- Day of surgery
Primary	Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)	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
Primary	Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)	A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages	2 week Post-op Visit 4
Primary	Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)	A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages	6 week- Post-op Visit 5
Primary	Cerebral Spinal Fluid Phosphorylated Tau Protein	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
Primary	ERP response amplitude	Measurement of event related potentials in the brain	6 Week post-op visit 5
Primary	ERP response latency	Measurement of event related potentials in the brain	6 Week post-op visit 5
Primary	ERP response amplitude	Measurement of event related potentials in the brain	6 Month post-op visit 6
Primary	ERP response latency	Measurement of event related potentials in the brain	6 Month post-op visit 6
Primary	Stroop Test	A neurocognitive test used to assess cognitive interference. T-Scores are computed with scores above 40 being "normal."	Baseline
Primary	Stroop Test	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
Primary	Stroop Test	A neurocognitive test used to assess cognitive interference. T-Scores are computed with scores above 40 being "normal."	2 Week post-op Visit 4
Primary	Montreal Cognitive Assessment	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
Primary	Montreal Cognitive Assessment	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
Primary	Blind Montreal Cognitive Assessment	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
Primary	Montreal Cognitive Assessment	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
Primary	Oral Trail Making Test	A neurocognitive test used to assess cognitive executive function with times for trail A > 78 seconds and trail B >273 seconds being deficient.	Baseline
Primary	Oral Trail Making Test	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
Primary	Oral Trail Making Test	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
Primary	Oral Trail Making Test	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
Primary	Symbol Digit Test	A neurocognitive test used to assess for cerebral dysfunction scored through statistical methods with a higher score meaning higher cognitive vitality.	Baseline
Primary	Symbol Digit Test	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
Primary	Symbol Digit Test	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
Primary	4 AT Delirium Screening	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
Primary	Grooved Pegboard Test	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
Primary	National Alzheimer's Coordinating Center Cognitive Battery	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