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.
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
120
Cognitive evaluation of short term memory, visuospatial abilities, executive functioning, attention, concentration, working memory, language, and orientation to time and place
Evaluates Processing Speed and Executive Control
Screening tool to test for delirium post surgery
Evaluation testing for dominant and non dominant sensory-motor speed
A series of tests that evaluate attention, concentration, immediate verbal memory, immediate visual memory, discrimination, processing/motor speed, and validity and effort.
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.
Up to six 4 ml samples of both serum and plasma will be obtained to assess for inflammatory markers.
At the time the spinal is placed for anesthetic purposes, 2ml of cerebral spinal fluid will be obtained to assess for inflammatory markers.
Robert M Craft
Knoxville, Tennessee, United States
RECRUITINGBlood Interleukin-1 beta (IL-1β)
A proinflammatory cytokine that activates astrocytes and micro ganglia
Time frame: Baseline
Blood Interleukin-1 beta (IL-1β)
A proinflammatory cytokine that activates astrocytes and micro ganglia
Time frame: Pre-op (pre-operation) -Visit 2- Day of surgery
Blood Interleukin-1 beta (IL-1β)
A proinflammatory cytokine that activates astrocytes and micro ganglia
Time frame: 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
Time frame: 2 Week Post-op -Visit 4
Blood Interleukin-1 beta (IL-1β)
A proinflammatory cytokine that activates astrocytes and micro ganglia
Time frame: 6 Week Post-op -Visit 5
Blood Tumor necrosis factor alpha (TNF- α)
A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases
Time frame: Baseline
Blood Tumor necrosis factor alpha (TNF- α)
A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases
Time frame: Pre-op- Visit 2- Day of surgery
Blood Tumor necrosis factor alpha (TNF- α)
A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases
Time frame: 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
Time frame: 2-week Post-op Visit 4
Blood Tumor necrosis factor alpha (TNF- α)
A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases
Time frame: 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
Time frame: Baseline
Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Pre-op Visit 2-Day of surgery
ERP response amplitude
Measurement of event related potentials in the brain
Time frame: 6 Week post-op visit 5
ERP response latency
Measurement of event related potentials in the brain
Time frame: 6 Week post-op visit 5
ERP response amplitude
Measurement of event related potentials in the brain
Time frame: 6 Month post-op visit 6
ERP response latency
Measurement of event related potentials in the brain
Time frame: 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."
Time frame: Baseline
Stroop Test
A neurocognitive test used to assess cognitive interference. T-Scores are computed with scores above 40 being "normal."
Time frame: 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."
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 6 month post-op Visit 6
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