Clinical trial NCT05378659: Neuroinflammation and Alzheimer's Pathology in POCD
Official title: Neuroinflammation and Alzheimer's Pathology in Post-operative Cognitive Dysfunction: A Pilot Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Post-Operative Confusion
Neuroinflammatory Response
Alzheimer Disease
Keywords: POCD
Neuroinflammation
Lead sponsor: University of Tennessee Graduate School of Medicine
Sponsor class: OTHER
Collaborators: name: Alzheimer's Association
First posted: 2022-05-18
Enrollment: 120
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: No one ethnic group is either targeted or excluded in the proposed study. The investigators aim to target a sample of individuals ages 60 and older who will all undergo total knee arthroplasty. This selection of participants is based upon the aims of the current study.

Due to the nature of the study, the investigators will include individuals with who are considered elderly. This population is necessary due to the increased prevalence of POCD within this group.

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

Eligibility criteria: 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

Primary outcomes:
measure: Blood Interleukin-1 beta (IL-1β)
timeFrame: Baseline
measure: Blood Interleukin-1 beta (IL-1β)
timeFrame: Pre-op (pre-operation) -Visit 2- Day of surgery
measure: Blood Interleukin-1 beta (IL-1β)
timeFrame: Post-op Visit 2- In recovery room up to 12 hours post surgery
measure: Blood Interleukin-1 beta (IL-1β)
timeFrame: 2 Week Post-op -Visit 4
measure: Blood Interleukin-1 beta (IL-1β)
timeFrame: 6 Week Post-op -Visit 5
measure: Blood Tumor necrosis factor alpha (TNF- α)
timeFrame: Baseline
measure: Blood Tumor necrosis factor alpha (TNF- α)
timeFrame: Pre-op- Visit 2- Day of surgery
measure: Blood Tumor necrosis factor alpha (TNF- α)
timeFrame: Post-op Visit 2- In recovery room up to 12 hours post surgery
measure: Blood Tumor necrosis factor alpha (TNF- α)
timeFrame: 2-week Post-op Visit 4
measure: Blood Tumor necrosis factor alpha (TNF- α)
timeFrame: 6-week Post-op Visit 5
measure: Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
timeFrame: Baseline
measure: Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
timeFrame: Pre-op Visit 2- Day of surgery
measure: Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
timeFrame: Post-op Visit 2- In recovery room up to 12 hours post surgery
measure: Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
timeFrame: 2-week Post-op Visit 4
measure: Blood Macrophage inflammatory protein-1 alpha (MIP-1alpha)
timeFrame: 6- week Post-op Visit 5
measure: Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)
timeFrame: Baseline
measure: Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)
timeFrame: Pre-op Visit 2- Day of surgery
measure: Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)
timeFrame: Post-op Visit 2- In recovery room up to 12 hours post surgery
measure: Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)
timeFrame: 2 week Post-op Visit 4
measure: Blood Monocyte chemoattractant protein-1 (MCP-1/CCL2)
timeFrame: 6 week- Post-op Visit 5
measure: Cerebral Spinal Fluid Phosphorylated Tau Protein
timeFrame: Pre-op Visit 2-Day of surgery
measure: ERP response amplitude
timeFrame: 6 Week post-op visit 5
measure: ERP response latency
timeFrame: 6 Week post-op visit 5
measure: ERP response amplitude
timeFrame: 6 Month post-op visit 6
measure: ERP response latency
timeFrame: 6 Month post-op visit 6
measure: Stroop Test
timeFrame: Baseline
measure: Stroop Test
timeFrame: Pre-op Visit 2- Day of surgery
measure: Stroop Test
timeFrame: 2 Week post-op Visit 4
measure: Montreal Cognitive Assessment
timeFrame: Baseline
measure: Montreal Cognitive Assessment
timeFrame: Pre-op Visit 2- Day of surgery
measure: Blind Montreal Cognitive Assessment
timeFrame: 48 Hours post-op- Visit 3
measure: Montreal Cognitive Assessment
timeFrame: 2 Week post-op- Visit 4
measure: Oral Trail Making Test
timeFrame: Baseline
measure: Oral Trail Making Test
timeFrame: Pre-op Visit 2- Day of surgery
measure: Oral Trail Making Test
timeFrame: 48 Hours post-op Visit 3
measure: Oral Trail Making Test
timeFrame: 2- Week post-op Visit 4
measure: Symbol Digit Test
timeFrame: Baseline
measure: Symbol Digit Test
timeFrame: Pre-op Visit 2- Day of surgery
measure: Symbol Digit Test
timeFrame: 2- Week post-op Visit 4
measure: 4 AT Delirium Screening
timeFrame: Post-op Visit 2- In recovery room up to 12 hours post surgery
measure: Grooved Pegboard Test
timeFrame: 6 month post-op Visit 6
measure: National Alzheimer's Coordinating Center Cognitive Battery
timeFrame: 6 month post-op Visit 6
Secondary outcomes:
Other outcomes:
Locations:
city: Knoxville
country: United States
facility: Robert M Craft
state: Tennessee
Study officials:
affiliation: University of Tennessee Graduate School of Medicine
name: Robert M Craft, MD
role: PRINCIPAL_INVESTIGATOR
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