Preschool-Aged Biomarker Discovered For Autism

Summary: The levels of a protein called FABP4 are significantly lower in children aged four-to-six in children with autism.

Source: RIKEN

Researchers led by Takeo Yoshikawa at the RIKEN Center for Brain Science in Japan have discovered a biomarker that can detect autism spectrum disorder (ASD) in preschool-aged children. Published in Brain Communications, the new study found that levels of the protein FABP4 were much lower in four- to six-year-old children with ASD than they were in other typically developing children. Experiments in mice that lacked FABP4 revealed changes in neurons that resemble those found in the postmortem brains of people with ASD.

ASD is a developmental disorder that begins in early childhood and affects learning, communication, and social behavior. The severity of symptoms falls on a broad spectrum, which researchers believe is related to genetic and environmental factors that interact during brain development. Because young children with ASD are at particular risk for being overweight, the RIKEN CBS group hypothesized a link between ASD and fat-cell metabolism.

Fat cells make hundreds of important biomolecules called adipokines, some of which regulate brain activity. The researchers took blood samples from preschool-aged children with and without ASD and compared their adipokine levels. The team examined adipokines known to be associated with ASD as well as the protein FABP4.

“We previously found lower levels of FABP4 in the hair follicles of patients with schizophrenia,” explains first author Motoko Maekawa.

“Although the disorders themselves are very different, we knew that FABP4 was an adipokine that can modulate brain function, especially during development.”

The researchers found that preschool-aged children with ASD had much lower levels of FABP4 in their blood than other children did, but that other adipokines did not differ between groups. A second test in two other groups of children confirmed these results. This makes FABP4 a potential early biomarker for ASD.

“The identification of FABP4 as a biomarker that can detect ASD in four- to -six-year old children is good news,” says Maekawa, “especially because early diagnosis and intervention can lead to better long-term prognosis.”

Further analysis showed that the story is a little more complex. Similar comparisons in older children and in postmortem brains showed equal levels of FABP4 between ASD and non-ASD groups. This means that FABP4 levels differ during a critical period during brain development, making it more than just a biomarker. Its lack could be a factor that leads to the disease, rather than being just a byproduct.

To confirm the importance of FABP4, the researchers created knockout mice that lacked the FABP4 gene. Compared with wildtype mice, behavior testing showed that these mice interacted less with unknown mice and had more difficulty with spatial learning and memory, all reminiscent of difficulties shared by those with ASD.

Additionally, when the team examined the neurons in the mouse brains, they found shape and structural characteristics that match those found in postmortem brains from people with ASD.

This shows neurons
Dendritic spines of cortical neurons in layers II and III (left) and layer V (right) in 4-week-old wildtype (top) and FABP4 KO mice (bottom). Like postmortem brains of people with autism spectrum disorders, the number and density of dendritic spines was greater in the FABP4 KO mice than in the control mice. Image is credited to RIKEN.

Looking forward, there are three questions that the researchers hope to answer. “We hope to replicate our findings in a larger group, which will allow us to determine whether specific ASD symptoms or their severity are related to low levels of FABP4,” says Maekawa.

“We also hope to conduct a prospective cohort study of newborns to determine if FABP4 levels at birth can predict the future manifestation of ASD.”

Lastly, the researchers will continue studying the FABP4 mouse model of ASD to understand exactly how the FABP4 protein affects the developing brain.

About this ASD research article

Source:
RIKEN
Contacts:
Adam Phillips – RIKEN
Image Source:
The image is credited to RIKEN.

Original Research: Open access
“A potential role of fatty acid binding protein 4 in the pathophysiology of autism spectrum disorder” by Motoko Maekawa, Tetsuo Ohnishi, Manabu Toyoshima, Chie Shimamoto-Mitsuyama, Kei Hamazaki, Shabeesh Balan, Yuina Wada, Kayoko Esaki, Shu Takagai, Kenji J Tsuchiya, Kazuhiko Nakamura, Yasuhide Iwata, Takahiro Nara, Yoshimi Iwayama, Tomoko Toyota, Yayoi Nozaki, Hisako Ohba, Akiko Watanabe, Yasuko Hisano, Shigeru Matsuoka, Masatsugu Tsujii, Norio Mori, Hideo Matsuzaki, Takeo Yoshikawa. Brain Communications.


Abstract

A potential role of fatty acid binding protein 4 in the pathophysiology of autism spectrum disorder

Autism spectrum disorder is a neurodevelopmental disorder characterized by difficulties in social communication and interaction, as well as repetitive and characteristic patterns of behavior. Although the pathogenesis of autism spectrum disorder is unknown, being overweight or obesity during infancy and low weight at birth are known as risks, suggesting a metabolic aspect. In this study, we investigated adipose tissue development as a pathophysiological factor of autism spectrum disorder by examining the serum levels of adipokines and other metabolic markers in autism spectrum disorder children (n = 123) and typically developing children (n = 92) at 4–12 years of age. Among multiple measures exhibiting age-dependent trajectories, the leptin levels displayed different trajectory patterns between autism spectrum disorder and typically developing children, supporting an adipose tissue-dependent mechanism of autism spectrum disorder. Of particular interest, the levels of FABP4 (fatty acid binding protein 4) were significantly lower in autism spectrum disorder children than in typically developing subjects, at preschool age (4–6 years old: n = 21 for autism spectrum disorder and n = 26 for typically developing). The receiver operating characteristic curve analysis discriminated autism spectrum disorder children from typically developing children with a sensitivity of 94.4% and a specificity of 75.0%. We re-sequenced the exons of the FABP4 gene in a Japanese cohort comprising 659 autism spectrum disorder and 1,000 control samples, and identified two rare functional variants in the autism spectrum disorder group. The Trp98Stop, one of the two variants, was transmitted to the proband from his mother with a history of depression. The disruption of the Fabp4 gene in mice evoked autism spectrum disorder -like behavioral phenotypes and increased spine density on apical dendrites of pyramidal neurons, which has been observed in the postmortem brains of autism spectrum disorder subjects. The Fabp4 knockout mice had an altered fatty acid composition in the cortex. Collectively, these results suggest that an “adipo-brain axis” may underlie the pathophysiology of autism spectrum disorder, with FABP4 as a potential molecule for use as a biomarker.

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