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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

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
NameTimeMethod
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 ProteinPre-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 latency6 Month post-op visit 6

Measurement of event related potentials in the brain

Stroop Test2 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 Assessment2 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 Assessment48 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 Test2- 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 Test2- 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 amplitude6 Month post-op visit 6

Measurement of event related potentials in the brain

4 AT Delirium ScreeningPost-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 Test6 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 Battery6 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

Secondary Outcome Measures
NameTimeMethod

Trial Locations

Locations (1)

Robert M Craft

🇺🇸

Knoxville, Tennessee, United States

Robert M Craft
🇺🇸Knoxville, Tennessee, United States
Robert M Craft, MD
Contact
865-305-9220
Aimee Pehrson, MPH
Contact
8653055432
apehrson@utmck.edu
Robert Craft, MD
Principal Investigator
Paul Allen, MD, PhD
Principal Investigator
Roberto Fernandez, MD
Principal Investigator
Brian Tonne, MD
Sub Investigator
Anahita Khojandi, PhD
Sub Investigator
Thomas Christianson, MD
Sub Investigator

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