Fragile X Imaging Study Reveals Differences in Infant Brains

Summary: A new neuroimaging study reveals babies with Fragile X syndrome have less developed white matter in the brain compared to children without the condition.

Source: University of North Carolina Health Care.

For the first time, UNC School of Medicine researchers have used MRIs to show that babies with the neurodevelopmental condition fragile X syndrome had less-developed white matter compared to infants that did not develop the condition. Imaging various sections of white matter from different angles can help researchers focus on the underlying brain circuitry important for proper neuron communication.

The study, published in JAMA Psychiatry, shows that there are brain differences related to the neurodevelopmental disorder established well before a diagnosis is typically made at age three or later.

“It’s our hope that earlier diagnosis and intervention will help children with fragile X and their families,” said co-first author Meghan Swanson, PhD, postdoctoral research fellow at the Carolina Institute for Developmental Disabilities at the UNC School of Medicine. “We also hope that this knowledge might inform drug development research.”

So far, drug clinical trials have failed to demonstrate change in treatment targets in individuals with fragile X. One of the challenges has been identifying good treatment outcome measures or biomarkers that show response to intervention.

Fragile X syndrome is a genetic disorder and the most common inherited cause of intellectual disability in males. Symptoms include intellectual disabilities, problems with social interaction, delayed speech, hyperactivity, repetitive behaviors and speech. About 10 percent of people with fragile X experience seizures. About one-third of people with fragile X meet the diagnostic criteria for autism spectrum disorder.

“One of the exciting things about our findings is that the white matter differences we observe could be used as an objective marker for treatment effectiveness,” said co-senior author Heather C. Hazlett, PhD, assistant professor of psychiatry at the UNC School of Medicine.

For this study, Swanson, Hazlett, and colleagues imaged the brains of 27 infants who went on to be diagnosed with fragile X and 73 who did not develop the condition. The researchers focused on 19 white matter fiber tracts in the brain. Fiber tracts are bundles of myelinated axons – the long parts of neurons that extend across the brain or throughout the nervous system. Think of bundles of cables laid across the brain. These bundles of axons connect various parts of the brain so that neurons can rapidly communicate with each other. This communication is essential, especially for proper neurodevelopment during childhood.

Imaging and analytical analysis showed significant differences in the development of 12 of 19 fiber tracts in babies with fragile X from as early as six months of age. The babies who wound up being diagnosed with fragile X had significantly less-developed fiber tracts in various parts of the brain.

white matter
This image shows all of the white matter fiber tracts investigated in this study. NeuroscienceNews.com image is credited to Meghan Swanson, PhD, UNC-Chapel Hill.

“These results substantiate what other researchers have shown in rodents – the essential role of fragile X gene expression on early development of white matter in babies,” said co-first author Jason Wolff, PhD, former postdoctoral fellow at UNC-Chapel Hill and now assistant professor of educational psychology at the University of Minnesota. “Our work highlights that white matter circuitry is a potentially promising and measurable target for early intervention. However, achieving the goal of infant intervention for fragile X would likely require expanded newborn screening efforts.”

Other authors are Mark Shen, PhD, Martin Styner, PhD, and Joseph Piven, MD, of the University of North Carolina at Chapel Hill; Annette Estes, PhD, of the University of Washington; Guido Gerig, PhD, of New York University; and Robert McKinstry, MD, PhD, and Kelly Botteron, MD, of Washington University in St. Louis.

Funding was provided by the National Institutes of Health and the Simons Foundation.

This study, which used data collected from 2008 to 2016, would have been impossible without the dedication to research from families who had another older child already diagnosed with fragile X syndrome.

About this neuroscience research article

Funding: National Institutes of Health, Simons Foundation funded this study.

Source: Mark Derewicz – University of North Carolina Health Care
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Meghan Swanson, PhD, UNC-Chapel Hill.
Original Research: Abstract for “Development of White Matter Circuitry in Infants With Fragile X Syndrome” by Meghan R. Swanson, PhD; Jason J. Wolff, PhD; Mark D. Shen, PhD; Martin Styner, PhD; Annette Estes, PhD; Guido Gerig, PhD; Robert C. McKinstry, MD, PhD; Kelly N. Botteron, MD; Joseph Piven, MD; Heather C. Hazlett, PhD; for the Infant Brain Imaging Study (IBIS) Network in JAMA Psychiatry. Published April 4 2018.
doi:10.1001/jamapsychiatry.2018.0180

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]University of North Carolina Health Care “Fragile X Imaging Study Reveals Differences in Infant Brains.” NeuroscienceNews. NeuroscienceNews, 4 April 2018.
<https://neurosciencenews.com/fragile-x-baby-brains-8726/>.[/cbtab][cbtab title=”APA”]University of North Carolina Health Care (2018, April 4). Fragile X Imaging Study Reveals Differences in Infant Brains. NeuroscienceNews. Retrieved April 4, 2018 from https://neurosciencenews.com/fragile-x-baby-brains-8726/[/cbtab][cbtab title=”Chicago”]University of North Carolina Health Care “Fragile X Imaging Study Reveals Differences in Infant Brains.” https://neurosciencenews.com/fragile-x-baby-brains-8726/ (accessed April 4, 2018).[/cbtab][/cbtabs]


Abstract

Development of White Matter Circuitry in Infants With Fragile X Syndrome

Importance Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy.

Objective
To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls.

Design, Setting, and Participants Longitudinal behavioral and brain imaging data were collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second-degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder.

Main Outcomes and Measures Nineteen major white matter pathways were defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development.

Results There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age × group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate, F = 10.06; false discovery rate–corrected P = .03; right uncinate, F = 21.8; P = .004).

Conclusions and Relevance
The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age.

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