Excessive brain growth linked to severity of autism symptoms

Summary: Researchers have identified a link between brain growth and the severity of social and communication symptoms in children with autism spectrum disorder (ASD).

By analyzing MRI images and conducting experiments on brain organoids, the study found that children with the most severe symptoms of ASD had significantly larger brains. This enlargement is associated with altered activity of the enzyme Ndel1, which plays a crucial role in neuron development.

These results open new avenues for understanding ASD and the varying severity of its symptoms.

Key facts:

• Excessive brain growth in children with severe ASD symptoms was up to 41% greater than in controls.
• The enzyme Ndel1, which is crucial for neuron development, is linked to this brain hypertrophy.
• The study suggests potential biomarkers in the blood to predict the severity of ASD symptoms.

Source: FAPESP

A study conducted by researchers based in Brazil and the United States has demonstrated that there is a link between brain growth and the severity of social and communication symptoms in children with autism spectrum disorder (ASD).

An article describing the study is published in the journal Molecular autism.

The findings are based on an analysis of magnetic resonance images of the brains of more than 900 children with ASD (conducted as part of a study the group led in 2017) and recent experiments with brain organoids – “mini-brains” that mimic the structural and functional features of normal-sized brains. The organoids were grown in the lab from induced plenipotentiary stem cells (iPSCs) derived from blood donated by the children who participated in the previous study.

Increased brain size correlates with symptom severity in MRI and organoid scans. Mini-brains derived from cells donated by children with the most severe symptoms were up to 41 percent larger than controls, the paper found.

“Not all children with ASD and severe symptoms will have an enlarged brain, but symptoms are more severe when the brain is enlarged,” said Mirian Hayashi, penultimate author of the paper and professor in the Department of Pharmacology at the Federal University of São Paulo School of Medicine (EPM-UNIFESP) in Brazil.

This brain hypertrophy appears to be associated with alterations in the activity of Ndel1, an enzyme that plays an important role in the differentiation and migration of embryonic neurons.

An equivalent phenomenon has already been observed by the UNIFESP group in children with Zika virus-induced microcephaly. Ndel1 is associated with several neurological disorders, such as schizophrenia, first episode psychosis and bipolar disorder, as well as congenital Zika syndrome.

As the researchers point out, social and communication symptoms are common in people with autism, but their severity varies from person to person. Although the biological mechanism that determines the intensity of symptoms remains unknown, the results of this research open new avenues for understanding ASD.

Methodology

The study was divided into two stages. The first consisted of an analysis of MRI brain images and diagnostic data for more than 900 children with ASD evaluated as part of a cohort study led by Eric Courchesne, one of the world’s leading experts in the neurobiology of autism. Professor Courchesne is the Executive Director and Principal Investigator of the Autism Center of Excellence at the University of California, San Diego (UCSD) in the United States and leads the UCSD Autism Center’s MRI Project on Early Brain Development in Autism.

The second step involved experiments with mini-brains grown in the lab led by Alysson R. Muotri, a professor in the departments of pediatrics and cellular and molecular medicine at UCSD. The experiments showed that problems with cell migration and neuron formation are already present when the brain is formed, which can affect its size.

In particular, Ndel1 plays a key role in brain enlargement in children with ASD.

“Neural alterations had already been detected in people with autism. Analysis of the mini-brains confirmed that the number of neural progenitors (multipotent neural stem cells capable of differentiating into neurons, astrocytes and oligodendrocytes) increased when brain enlargement occurred.

“Our experiments suggested that brain enlargement in these cases could be due to a large number of neural progenitors that failed to differentiate during embryogenesis,” said João Nani, who led the analysis in Professor Muotri’s laboratory with support from FAPESP.

Many neuron cells were not behaving as they should or were not creating connections (synapses) as expected. “The number of connections is more important than the number of neurons. That is why having more neurons (as in excessive brain growth) and having fewer neurons (as in microcephaly) are both harmful,” Nani said.

The researchers also measured Ndel1 activity and expression in the mini-brains, detecting an imbalance in cases of brain hypertrophy.

“Ndel1 is associated with cell division and neuron differentiation. These processes of course involve other proteins, but the whole system is likely deregulated in excessive brain growth, and Ndel1 may be a biomarker of impairment. We found that this imbalance can lead to both brain hypertrophy and brain shrinkage.

“However, in the cases we analyzed, there were more mononuclear cells in the peripheral blood of autistic children and a severity of communication and social symptoms,” Nani said.

The researchers plan to conduct further studies to identify biomarkers associated with ASD severity in blood samples from patients.

About this autism research news

Author: Heloise Reinert
Source: FAPESP
Contact: Heloisa Reinert – FAPESP
Picture: Image credited to Neuroscience News

Original research: Free access.
“Embryonic origin of two ASD subtypes of social symptom severity: the larger the cerebral cortical organoid size, the more severe the social symptoms” by Mirian Hayashi. Molecular autism

Abstract

Embryonic origin of two ASD subtypes of social symptom severity: the larger the cerebral cortical organoid size, the more severe the social symptoms

Background

Social-emotional and communication symptoms are at the core of autism spectrum disorders (ASD), but their severity varies among toddlers: some toddlers with ASD display abilities that improve over time and develop good social and language skills, while others with “profound” autism have persistently poor social, language, and cognitive skills and require lifelong care. The biological origins of these contrasting subtypes of social severity and developmental trajectories of ASD are not known.

Methods

Given that ASD involves early brain growth and excess neurons, we measured the size and growth of 4,910 embryonic-stage cerebral cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (average of 196 individual BCOs measured per subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we tested the reproducibility of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects.

BCO size was analyzed in the context of our large, unique normative datasets on social symptoms, social attention, social brain, and social and linguistic psychometrics, ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1 and 2 months of organoid development.

Neurogenesis markers at 2 months were examined at the cellular level. At the molecular level, we measured Ndel1 activity and expression; Ndel1 is a preferred target for cell cycle-activated kinases; known to regulate the cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric disorders.

Results

At the BCO level, analyses showed that BCO size was significantly enlarged by 39% and 41% in ASD in batches 2021 and 2022. The larger the embryonic BCO size, the more severe the ASD social symptoms. The correlations between BCO size and social symptoms were r = 0.719 in batch 2021 and r = 0.873 in replication batch 2022. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cellular level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was strongly correlated with BCO growth rate and size.

Two subtypes of BCO were observed in toddlers with ASD: those with one subtype had a greatly increased BCO size with an accelerated growth rate and neurogenesis; a clinical phenotype of profound autism with severe social symptoms, reduced social attention, reduced cognitive abilities, very low language and social IQ; and substantially impaired growth in specific social, language, and sensory cortical regions. Those with a second subtype had a milder increase in BCO and milder social, attentional, cognitive, language, and cortical differences.

Boundaries

Larger BCO samples derived from toddlers with ASD and clinical phenotypes may reveal additional embryonic ASD subtypes.

Conclusions

Embryogenetically, the biological bases of two subtypes of social and brain development in ASD—profound autism and mild autism—are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the early child’s social symptoms and the more reduced social attention, language ability, and IQ are, and the more atypical the growth of social and language brain regions.