Neuroinflammation and Alzheimer's Pathology in POCD

• Conditions: Neuroinflammatory Response; Post-Operative Confusion; Alzheimer Disease

• Registration Number: NCT05378659
• Lead Sponsor: University of Tennessee Graduate School of Medicine

Brief 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.

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 Timeline

• Study Start: 2021-11-01
• Study First Submitted: 2022-04-25
• Status Verified: 2022-05
• Study First Submitted QC: 2022-05-13
• Last Update Submitted: 2022-05-13
• Study First Posted: 2022-05-18
• Last Update Posted: 2022-05-18
• Primary Completion: 2022-06-30
• Study Completion: 2022-09-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 120

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 & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Blood Interleukin-1 beta (IL-1β)	6 Week Post-op -Visit 5	A proinflammatory cytokine that activates astrocytes and micro ganglia
Blood Tumor necrosis factor alpha (TNF- α)	6-week Post-op Visit 5	A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases
Cerebral Spinal Fluid Phosphorylated Tau Protein	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
ERP response latency	6 Month post-op visit 6	Measurement of event related potentials in the brain
Stroop Test	2 Week post-op Visit 4	A neurocognitive test used to assess cognitive interference. T-Scores are computed with scores above 40 being "normal."
Montreal Cognitive Assessment	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.
Blind Montreal Cognitive Assessment	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.
Oral Trail Making Test	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.
Symbol Digit Test	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.
Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)	6- week Post-op Visit 5	A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease
Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)	6 week- Post-op Visit 5	A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages
ERP response amplitude	6 Month post-op visit 6	Measurement of event related potentials in the brain
4 AT Delirium Screening	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.
Grooved Pegboard Test	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.
National Alzheimer's Coordinating Center Cognitive Battery	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

Trial Locations

Locations (1)

Robert M Craft; 🇺🇸 Knoxville, Tennessee, United States