Tau/P-Tau and Neurocognitive Outcomes in Children

Tau/P-Tau as Biomarkers of Anesthesia/Surgery-associated Neurocognitive Outcomes in Children

The proposed studies are aimed to measure Tau and P-Tau levels in pre- and postoperative blood, urine, feces and saliva, as well as to assess pre- and postoperative neurocognitive function in children (3 to 5 years old) who will have surgery under general anesthesia (single versus multiple exposures). The studies will establish a system to study biomarkers of the anesthesia/surgery-associated neurocognitive impairment in children and generate hypothesis that Tau or P-Tau serves as the biomarker of such neurocognitive impairment in children.

Study Overview

• Status: Active, not recruiting
• Conditions: Postoperative Cognitive Dysfunction; Child Development; General Anesthetics Toxicity

Detailed Description

This proposed studies have two specific aims:

1. To investigate the relationship between pre-operative or postoperative blood levels of Tau or P-Tau and neurocognitive outcomes. The working hypothesis is that pre- and postoperative blood Tau/P-Tau levels are higher in participants who develop neurocognitive impairment than those in the participants who do not develop it. The investigators will perform neurocognitive test before the surgery and then at 12 months after the surgery. The investigators will collect pre-operative and postoperative blood and measure Tau/P-Tau levels in the blood. Finally, the association of the changes in the Tau/P-Tau levels and neurocognitive scores will be assessed. More importantly, this Aim will establish an eligible: recruit ratio, retention rates, safety of the protocol, and power calculation, which will provide crucial information to guide better design of future R01 study.
2. To perform the feasibility studies of measuring Tau or P-Tau in urine, feces and saliva of the participants. The working hypothesis is that Tau/P-Tau in urine, feces or saliva of children can be measured. The investigators will use the nanobeam to measure Tau/P-Tau levels before and after the surgery. The investigators will then determine whether urine, feces and saliva can be used for the future studies to develop Tau/P-Tau as the biomarker of anesthesia/surgery-associated neurocognitive impairment in children.

• Study Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Childrens Hospital
    • Boston, Massachusetts, United States, 02129-2020
      • Zhongcong Xie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The investigators will enroll participants between age 3 and 5 years old who are scheduled for the surgery under general anesthesia from Shriners Hospital for Children or Boston Children Hospital.

Description

Inclusion Criteria:

1. between age 3 and 5 at the time of the first neurocognitive test;
2. scheduled for surgery under general anesthesia

Exclusion Criteria:

1. gestational age less than 36 weeks;
2. congenital heart disease that has required surgery or will require surgery or that requires ongoing pharmacotherapy;
3. known chromosomal abnormality or any other known acquired or congenital abnormalities which are likely to affect neurodevelopment;
4. known neurological injury such as cystic periventricular leukomalacia or grade 3 or 4 intra-ventricular hemorrhage (+/- post hemorrhage ventricular dilatation);
5. children for whom follow-up would be difficult for geographic or psychosocial reasons;
6. non-native English speaker (both child and parents);
7. severe visual or auditory disorder.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
A single exposure to general anesthesia; Participants who have surgery under general anesthesia (without anesthesia/surgery before)
Multiple exposures to general anesthesia; Participants who have surgery under general anesthesia (had anesthesia/surgery before)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Tau/P-Tau level before the surgery (baseline)	300 ul venous blood before the surgery will be collected from the inserted intravenous catheter to measure the levels of Tau/P-Tau	Before the surgery
Blood Tau/P-Tau level at postoperative 3 hours	300 ul venous blood at 3 hours after the surgery will be collected from the inserted intravenous catheter to measure the levels of Tau/P-Tau	At 3 hours after the surgery
Blood Tau/P-Tau level at postoperative 6 hours	300 ul venous blood at 6 hours after the surgery will be collected from the inserted intravenous catheter to measure the levels of Tau/P-Tau	At 6 hours after the surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurocognitive function before the surgery (baseline)	Cognitive function will be assessed by using a battery of neurocognitive tests before the surgery	Before the surgery
Neurocognitive function at postoperative one year	Cognitive function will be assessed by using a battery of neurocognitive tests at postoperative one year	At postoperative one year
Feces Tau/P-Tau level before the surgery (baseline)	Feces will be collected to measure the level of Tau/P-Tau before the surgery	Before the surgery
Feces Tau/P-Tau level at postoperative one day	Feces will be collected to measure the level of Tau/P-Tau at postoperative one day	At postoperative one day
Urine Tau/P-Tau level before the surgery (baseline)	Urine will be collected to measure the level of Tau/P-Tau before the surgery	Before the surgery
Urine Tau/P-Tau level at postoperative one day	Urine will be collected to measure the level of Tau/P-Tau at postoperative one day	At postoperative one day
Saliva Tau/P-Tau level before the surgery (baseline)	Saliva will be collected to measure the level of Tau/P-Tau before the surgery	Before the surgery
Saliva Tau/P-Tau level at postoperative one day	Saliva will be collected to measure the level of Tau/P-Tau at postoperative one day	At postoperative one day

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Zhongcong Xie, MD, PhD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009 Apr;110(4):796-804. doi: 10.1097/01.anes.0000344728.34332.5d.
• Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, Sprung J, Weaver AL, Schroeder DR, Warner DO. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011 Nov;128(5):e1053-61. doi: 10.1542/peds.2011-0351. Epub 2011 Oct 3. Erratum In: Pediatrics. 2012 Mar;129(3):595.
• Kalkman CJ, Peelen L, Moons KG, Veenhuizen M, Bruens M, Sinnema G, de Jong TP. Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology. 2009 Apr;110(4):805-12. doi: 10.1097/ALN.0b013e31819c7124.
• Sun L. Early childhood general anaesthesia exposure and neurocognitive development. Br J Anaesth. 2010 Dec;105 Suppl 1(Suppl 1):i61-8. doi: 10.1093/bja/aeq302.
• Ing CH, DiMaggio CJ, Whitehouse AJ, Hegarty MK, Sun M, von Ungern-Sternberg BS, Davidson AJ, Wall MM, Li G, Sun LS. Neurodevelopmental outcomes after initial childhood anesthetic exposure between ages 3 and 10 years. J Neurosurg Anesthesiol. 2014 Oct;26(4):377-86. doi: 10.1097/ANA.0000000000000121.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2018
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: April 11, 2018
• First Submitted That Met QC Criteria: April 18, 2018
• First Posted (Actual): April 30, 2018

Study Record Updates

• Last Update Posted (Actual): April 25, 2022
• Last Update Submitted That Met QC Criteria: April 15, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: biomarker; children; outcomes; neurocognitive; Tau/P-Tau
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Postoperative Complications; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Postoperative Cognitive Complications
• Other Study ID Numbers: 2019P000757; 5R21HD098754-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data that underlie results in a publication will be available to other researchers.
• IPD Sharing Time Frame: Individual participant data will be available 6 months after publication
• IPD Sharing Access Criteria: Principle investigator will review the requests and determine what information should be shared.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No