Post-Operative Confusion, Neuroinflammatory Response, Alzheimer Disease
Conditions
Keywords
POCD, Neuroinflammation
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
Interventions
BEHAVIORALMontreal Cognitive Assessment
Cognitive evaluation of short term memory, visuospatial abilities, executive functioning, attention, concentration, working memory, language, and orientation to time and place
BEHAVIORALStroop Test
Evaluates Processing Speed and Executive Control
DIAGNOSTIC_TEST4AT Delirium
Screening tool to test for delirium post surgery
BEHAVIORALGrooved Pegboard
Evaluation testing for dominant and non dominant sensory-motor speed
BEHAVIORALNACC 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_TESTERP 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.
DIAGNOSTIC_TESTBlood Plasma and Serum sampling
Up to six 4 ml samples of both serum and plasma will be obtained to assess for inflammatory markers.
DIAGNOSTIC_TESTCerebral 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.
Sponsors
Alzheimer's Association
University of Tennessee Graduate School of Medicine
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood Interleukin-1 beta (IL-1β) | Baseline | A proinflammatory cytokine that activates astrocytes and micro ganglia |
| Blood Tumor necrosis factor alpha (TNF- α) | Baseline | A proinflammatory cytokine associated with neuroinflammation associated with neurodegenerative diseases |
| Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha) | Baseline | A chemotactic cytokine which plays a role in the inflammatory process of Alzheimer's Disease |
| Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2) | Baseline | A chemotactic cytokine which plays a role in the inflammatory process through the regulation of monocytes/macrophages |
| 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 amplitude | 6 Week post-op visit 5 | Measurement of event related potentials in the brain |
| ERP response latency | 6 Week post-op visit 5 | Measurement of event related potentials in the brain |
| Stroop Test | Baseline | A neurocognitive test used to assess cognitive interference. T-Scores are computed with scores above 40 being normal. |
| Montreal Cognitive Assessment | Baseline | 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 | Baseline | 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 | Baseline | A neurocognitive test used to assess for cerebral dysfunction scored through statistical methods with a higher score meaning higher cognitive vitality. |
| 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 |
Countries
United States
Contacts
Primary ContactDepartment of Anesthesiology Chair
Backup ContactAimee Pehrson, MPH
Outcome results
None listed