Neuroinflammation and Alzheimer's Pathology in POCD

Study Overview
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Brief Summary
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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
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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: Cognitive assessments a. Montreal Cognitive Assessment b. Stroop Test c. Symbol Digit Modalities Test d. Oral Trail Making Test Collect two 4-ml blood samples for biomarker evaluation Visit 2 Pre-op (day of scheduled TKA surgery) the plan is to collect: Repeat cognitive testing a. Montreal Cognitive Assessment b. Stroop Test c. Symbol Digit Modalities Test d. Oral Trail Making Test Collect two 4-ml blood samples for biomarker evaluation Collect 2cc of cerebral spinal fluid Visit 2 Post-op: 4 AT test for delirium Collect two 4ml blood samples will be taken Visit 3 (Forty-eight hours after discharge): 1. brief cognitive testing via telephone or video conferencing. Blind Montreal Cognitive Assessment 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: 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. Collect two 4-ml blood samples Visit 6 End of Study (At 6 months): Collect a final assessment of cognition ERP assessment

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

Conditions
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Post-Operative Confusion, Neuroinflammatory Response, Alzheimer Disease

Intervention / Treatment
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* Behavioral: Montreal Cognitive Assessment
* Behavioral: Stroop Test
* Diagnostic Test: 4AT Delirium
* Behavioral: Grooved Pegboard
* Behavioral: NACC Cognitive Battery
* Diagnostic Test: ERP Testing
* Diagnostic Test: Blood Plasma and Serum sampling
* Diagnostic Test: Cerebral Spinal Fluid Sample


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| With Post-Operative Cognitive Dysfunction<br>Subjects determined to have post-operative cognitive dysfunction based on the results of: 4AT Delirium Test Scoring on : Montreal Cognitive Assessment Oral Trails Test Stroop Test Symbol Digit Modalities Test All subjects will undergo: Blood sample collection Cerebral spinal fluid collection ERP testing NACC Cognitive Battery Grooved Pegboard testing | Behavioral: Montreal Cognitive Assessment<br>* Cognitive evaluation of short term memory, visuospatial abilities, executive functioning, attention, concentration, working memory, language, and orientation to time and place<br>* Other names: MOCA;Behavioral: Stroop Test<br>* Evaluates Processing Speed and Executive Control<br>Diagnostic Test: 4AT Delirium<br>* Screening tool to test for delirium post surgery<br>Behavioral: Grooved Pegboard<br>* Evaluation testing for dominant and non dominant sensory-motor speed<br>Behavioral: NACC Cognitive Battery<br>* A series of tests that evaluate attention, concentration, immediate verbal memory, immediate visual memory, discrimination, processing/motor speed, and validity and effort.<br>Diagnostic Test: ERP Testing<br>* 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.<br>Diagnostic Test: Blood Plasma and Serum sampling<br>* Up to six 4 ml samples of both serum and plasma will be obtained to assess for inflammatory markers.<br>Diagnostic Test: Cerebral Spinal Fluid Sample<br>* At the time the spinal is placed for anesthetic purposes, 2ml of cerebral spinal fluid will be obtained to assess for inflammatory markers.<br>|
| Without Post-Operative Cognitive Dysfunction<br>Subjects determined to not have post-operative cognitive dysfunction based on the results of: 4AT Delirium Test Scoring on : Montreal Cognitive Assessment Oral Trails Test Stroop Test Symbol Digit Modalities Test All subjects will undergo: Blood sample collection Cerebral spinal fluid collection ERP testing NACC Cognitive Battery Grooved Pegboard testing | Behavioral: Montreal Cognitive Assessment<br>* Cognitive evaluation of short term memory, visuospatial abilities, executive functioning, attention, concentration, working memory, language, and orientation to time and place<br>* Other names: MOCA;Behavioral: Stroop Test<br>* Evaluates Processing Speed and Executive Control<br>Diagnostic Test: 4AT Delirium<br>* Screening tool to test for delirium post surgery<br>Behavioral: Grooved Pegboard<br>* Evaluation testing for dominant and non dominant sensory-motor speed<br>Behavioral: NACC Cognitive Battery<br>* A series of tests that evaluate attention, concentration, immediate verbal memory, immediate visual memory, discrimination, processing/motor speed, and validity and effort.<br>Diagnostic Test: ERP Testing<br>* 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.<br>Diagnostic Test: Blood Plasma and Serum sampling<br>* Up to six 4 ml samples of both serum and plasma will be obtained to assess for inflammatory markers.<br>Diagnostic Test: Cerebral Spinal Fluid Sample<br>* At the time the spinal is placed for anesthetic purposes, 2ml of cerebral spinal fluid will be obtained to assess for inflammatory markers.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Interleukin-1 beta (IL-1β) | A proinflammatory cytokine that activates astrocytes and micro ganglia | Baseline | 
| Blood Interleukin-1 beta (IL-1β) | A proinflammatory cytokine that activates astrocytes and micro ganglia | Pre-op (pre-operation) -Visit 2- Day of surgery | 
| Blood Interleukin-1 beta (IL-1β) | 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) | A proinflammatory cytokine that activates astrocytes and micro ganglia | 2 Week Post-op -Visit 4 | 
| Blood Interleukin-1 beta (IL-1β) | A proinflammatory cytokine that activates astrocytes and micro ganglia | 6 Week Post-op -Visit 5 | 
| Blood Tumor necrosis factor alpha (TNF- α) | A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases | Baseline | 
| Blood Tumor necrosis factor alpha (TNF- α) | A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases | Pre-op- Visit 2- Day of surgery | 
| Blood Tumor necrosis factor alpha (TNF- α) | 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) | A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases | 2-week Post-op Visit 4 | 
| Blood Tumor necrosis factor alpha (TNF- α) | A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases | 6-week Post-op Visit 5 | 
| Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha) | A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease | Baseline | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| ERP response amplitude | Measurement of event related potentials in the brain | 6 Week post-op visit 5 | 
| ERP response latency | Measurement of event related potentials in the brain | 6 Week post-op visit 5 | 
| ERP response amplitude | Measurement of event related potentials in the brain | 6 Month post-op visit 6 | 
| ERP response latency | Measurement of event related potentials in the brain | 6 Month post-op visit 6 | 
| Stroop Test | A neurocognitive test used to assess cognitive interference. T-Scores are computed with scores above 40 being normal. | Baseline | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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POCD, Neuroinflammation