Early Biomarkers of Autism in Infants With Tuberous Sclerosis Complex (TSC)

Tuberous Sclerosis Complex Clinical Trial

Official title:

Longitudinal Study to Identify Early Biomarkers of Autism Spectrum Disorder (ASD) in Infants With Tuberous Sclerosis Complex (TSC)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01780441
• Other study ID #: IRB-P00005074
• Secondary ID: 1U01NS082320-01
• Status: Completed
• Start date: January 2013
• Est. completion date: December 2020

Study information

• Verified date: February 2021
• Source: Boston Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The investigators are enrolling 3-12 month old infants with a diagnosis of tuberous sclerosis complex (TSC) for a new study on early markers of autism. The study is looking for early signs for autism in a population (TSC) where autism is common. The goal of this project is to use behavioral testing, MRI and EEG techniques to identify children at risk for developing autism starting at 3 months of age and continuing until 36 months of age. Throughout the study, the investigators will recommend Early Intervention services for any child who shows early signs of autism.

Description:

This is a five-year multi-site study using MRI and EEG technologies to identify developmental precursors of Autism Spectrum Disorder in patients with Tuberous Sclerosis Complex (TSC). The study will be enrolling infants at five TSC centers throughout the country, including Boston Children's Hospital, Cincinnati Children's Hospital Medical Center, University of Alabama at Birmingham, University of Texas at Houston and University of California Los Angeles. The main goal of this study is to identify early signs of autism in children with TSC looking at the brain through MRI/diffusion tensor imaging, EEG and behavioral/neuropsychological methods. Eligible infants between the ages of 3-12 months will be evaluated longitudinally at regular visit intervals up to 3 years of age.

Study Objectives

1. To characterize the developmental precursors of ASD in a large number of TSC infants using a prospective multi-center design: Infants with TSC will be evaluated longitudinally at ages 3, 6, 9, 12, 18, 24 and 36 months. At each age, children will undergo standardized evaluations, using cognitive and adaptive measures. At age 24 and 36 months, formal assessment for autism will be performed. Clinical data including medication use, seizure history, EEG activity, genotypic variation, and co-morbidities will be recorded to determine if specific clinical factors modify the course of development.

2. To identify biomarkers with advanced diffusion tensor imaging (DTI) that help predict development of ASD in TSC infants: The investigators hypothesize that decreased white matter integrity performed annually for each of the first 3 years of life, including DTI sequences with tractography. Radial, axial, and mean diffusivity and fractional anisometry will be calculated for each time point and change over time correlated with development of ASD to determine relative risk. Individual measures at each time point will be compared between ASD and non-spectrum groups to assess the individual impact of each measure and timing.

3. To identify biomarkers with quantitative EEG that help predict development of ASD in TSC infants: The investigators hypothesize that altered functional connectivity, as measured by qEEG coherence and high frequency oscillations, will correlate with development of ASD in TSC. Quantitative EEG (qEEG), EEG coherence/gamma frequency (30-50Hz), and high frequency oscillations encompassing both ripples (80-250H) and fast ripples (250-500 Hz) will be measured at each time point. Changes over time will be correlated with development of ASD to determine relative risk, as will comparison of individual measures between the two groups. EEG findings will also be correlated with MR results obtained to further couple functional connectivity as measured by EEG with structural connectivity measured by DTI.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 166
• Est. completion date: December 2020
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 12 Months

Eligibility

Inclusion Criteria:

1. Meets genetic or clinical diagnostic criteria for TSC (Tuberous Sclerosis), the latter based on current recommendations for diagnostic evaluation, such as physical exam, neuroimaging, echocardiogram.

2. Age criteria: 3 months- 12 months of age at time of enrollment. For study purposes, 3 months is defined as = 9 weeks, 1 day and 12 months is defined as = 13.5 months.

Exclusion Criteria:

1. Prematurity, defined as gestational age < 36 weeks at time of delivery

2. Has taken an investigational drug as part of another research study, within 30 days prior to study enrollment

3. Is taking an mTOR inhibitor such as rapamycin, sirolimus, or everolimus (other than topical formulations) at the time of study enrollment

4. Subependymal Giant Cell Astrocytoma requiring medical or surgical treatment at the time of study enrollment

5. History of epilepsy surgery at the time of study enrollment

6. Contraindications to MRI scanning, such as metal implants/non-compatible medical devices or medical conditions

Related Conditions & MeSH terms

• Sclerosis
• Tuberous Sclerosis
• Tuberous Sclerosis Complex

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	University of Texas at Houston	Houston	Texas
United States	University of California at Los Angeles	Los Angeles	California

Sponsors (3)

Lead Sponsor	Collaborator
Boston Children's Hospital	National Institute of Neurological Disorders and Stroke (NINDS), Tuberous Sclerosis Alliance

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ADOS evaluation score at the 36 month visit	The ADOS performed at 24 and 36 months will be used as a preliminary diagnosis for data analysis. The primary outcome is the possible clinical diagnosis of autism spectrum disorder per the DSM 5 guidelines (Autistic Disorder, Asperger's and PDD-NOS).	36 months
Primary	MRI biomarkers	MRI biomarkers obtained at baseline, 12, 24, 36 months will be applied to characterize individual patients in terms of brain tissue, white matter structure and connectivity, functional networks, and pathology. Brain tissue segmentation will be based on structural images derived from T1- and T2-weighted and FLAIR sequences using automated software tools designed for these tasks. White matter integrity and organization will be inferred from DTI imaging sequences. Structural connectivity networks will be delineated by DTI tractography assessment.	36 months
Primary	EEG biomarkers	One-hour video-EEG containing both wakefulness and sleep (minimum of 20 minutes of each) will be obtained at baseline, 3, 6, 9, 12, 18, 24 and 36 months. Functional connectivity and pathological activity will be determined by measurement of EEG coherence and gamma frequency/high frequency oscillations.	36 months

External Links

•   Boston Children's Hospital - Multi-Disciplinary Tuberous Sclerosis Program
•   Study website
•   TSC Clinic at Cincinnati Children's Hospital Medical Center
•   Tuberous Sclerosis Alliance