Blood Brain Barrier Dysfunction and Postoperative Neurocognitive Disorders

Completed

• Conditions: Neurocognitive Disorders; Postoperative Cognitive Dysfunction
• Interventions: Diagnostic Test: Brain Imaging; Diagnostic Test: Cognitive Testing; Diagnostic Test: Blood Biomarkers

• Registration Number: NCT04566562
• Lead Sponsor: University of California, Los Angeles

Brief Summary

Postoperative neurocognitive disorders (PND), which include postoperative delirium and both acute and longlasting neurocognitive deficits, are a significant public health problem, leading to a cascade of deleterious complications. Older adults are particularly at-risk of developing PND both in the short and long term. Although age is consistently reported as an important risk factor, the exact pathophysiology of PND remains poorly understood, but may include postsurgery-compromised blood brain barrier (BBB) function. This project proposes that perioperative BBB dysfunction is associated with measurable brain morphologic findings in cognitive control areas that can be discovered with non-invasive magnetic resonance imaging (MRI). Patients scheduled for surgery with an age range of 65-75 years of age, will participate in brain diffusion-weighted pseudo-continuous arterial spin labeling (DW-pCASL) and diffusion tensor imaging (DTI), cognitive assessments, and evaluation of a BBB marker from blood (at baseline, at two weeks, and at six months after surgery).

All patients will have a brain scan (MRI) within before surgery and two weeks and six months after surgery. During this visit cognitive function will be assessed. Patients will also be asked to participate in a blood draw.

Detailed Description

The investigators will examine the potential mechanisms contributing to PND in an older surgical population. It is proposed that BBB will be altered contributing to brain tissue changes in cognitive control areas that can be examined with MD measures and blood biomarkers. Therefore, the specific aims are to:

AIM #1: Examine BBB function, using DW-pCASL procedures, and BBB marker (S100β levels), in older adult subjects between pre- ) and post-surgery

AIM #2: Assess brain tissue changes, using DTI-based MD measures, and cognition function, between pre- and post-surgery in older adult subjects.

AIM #3: Examine the relationships between BBB blood biomarker, BBB function index, and MD values from cognitive control areas (prefrontal cortex, caudate, and hippocampus) between pre- and post-surgery in an older surgical population.

A One-group comparative and longitudinal study design will be used in this proposal. A total of 34 older subjects scheduled for surgery will be recruited. Patients of either sex, in the age range 65-75 years scheduled for abdominal, gynecologic or urologic.

To assess cognitive function, the WRAML2 and MoCA tests will be performed within one week before surgery and at two weeks and six months after surgery. These tests have been used by our team in several conditions, and will be introduced just before MRI procedures. An average mean score of 100±15 on WRAML2 and a score ≥26 on MoCA will be considered normal.

Examination of BBB integrity from blood. To account for interindividual variation, baseline systemic biomarkers will be measured preoperatively (within one week before surgery). Postoperative samples will also be collected at two weeks and 6 months of surgery. Samples will be batch analyzed using Enzyme-linked immunosorbent assay (S100β) by the UCLA Department of Pathology \& Laboratory Medicine.

Magnetic Resonance Imaging. All brain MRI studies will be performed on a 3.0-Tesla MRI scanner (Siemens, Magnetom, Prisma) at the Department of Radiology, UCLA. MRI studies will be performed within one week before surgery, and at two weeks and six months after surgery.

Study Timeline

• Study Start: 2020-08-03
• Study First Submitted: 2020-09-22
• Study First Submitted QC: 2020-09-22
• Study First Posted: 2020-09-28
• Primary Completion: 2024-01-30
• Study Completion: 2024-02-29
• Status Verified: 2024-08
• Last Update Submitted: 2024-12-05
• Last Update Posted: 2024-12-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

Inclusion Criteria

• 65-75 years old
• Scheduled for abdominal, gynecologic or urological surgery

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Exclusion Criteria

• Subjects undergoing surgery with a previous history of stroke, myocardial infarction, current pregnancy (if female), diagnosed neuropsychological and neuropsychiatric diseases, airway or chest deformities that would interfere with breathing, chronic obstructive pulmonary disease, cystic fibrosis, presence of space-occupying brain lesions, any history of drug abuse (e.g., cocaine or tobacco use), chronic kidney disease requiring dialysis.
• Body weight >300 pounds (restrictions of MRI scanner table).
• All subjects with any contraindication to the MRI procedures, such as metallic and electronic implants (phrenic or cardiac pacemakers), claustrophobia, metallic-based tattoos, will also be excluded. Non-english speaking patients will also be excluded as the cognitive tests have not been validated in other languages.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Study Group	Blood Biomarkers	Brain scans, cognitive tests, blood biomarkers
Study Group	Brain Imaging	Brain scans, cognitive tests, blood biomarkers
Study Group	Cognitive Testing	Brain scans, cognitive tests, blood biomarkers

Primary Outcome Measures

Name	Time	Method
Preoperative cognitive function II	Pre-surgery (within five days before surgery)	Wide Range Assessment of Memory and Learning (WRAML2)
Postoperative cognitive dysfunction - delayed cognitive recovery II	Post-surgery (within two weeks post surgery)	Wide Range Assessment of Memory and Learning (WRAML2)
Postoperative cognitive dysfunction - neurocognitive disorder II	Post-surgery (6 months after surgery)	Assessment of Memory and Learning (WRAML2)
Postoperative cognitive dysfunction - neurocognitive disorder	Post-surgery (6 months after surgery)	Montreal Cognitive Assessment (MoCA) test
Preoperative cognitive function	pre-surgery (within five days before)	Montreal Cognitive Assessment (MoCA) test
Postoperative cognitive dysfunction - delayed cognitive recovery	Post-surgery (within two weeks post surgery)	Montreal Cognitive Assessment (MoCA) test

Secondary Outcome Measures

Name	Time	Method
Blood Serum anti-inflammatory Biomarkers	pre- (within five days before surgery)	Assess blood inflammatory biomarkers (IL6, TNFa and IL1B) using enzyme-linked immunosorbent assay
Brain changes	pre- surgery (within five days before)	Using non-invasive magnetic resonance imaging diffusion weighted (DW) pseudo-continuous arterial spin labeling (pCASL)
Brain changes II	Post-surgery (within two days post surgery)	non-invasive magnetic resonance imaging diffusion weighted (DW) pseudo-continuous arterial spin labeling (pCASL)
Blood Serum anti-inflammatory Biomarkers II	post-surgery (within two weeks of surgery)	Assess blood inflammatory biomarkers (IL6, TNFa and IL1B) using enzyme-linked immunosorbent assay
Brain changes III	Post-surgery (within six months post surgery)	Using non-invasive magnetic resonance imaging diffusion weighted (DW) pseudo-continuous arterial spin labeling (pCASL)

Trial Locations

Locations (1)

Ronald Reagan UCLA Medical Center, Department of Anesthesiology & Perioperative Medicine; 🇺🇸 Los Angeles, California, United States