Disorganized neurons in the prefrontal cortex suggest that brain abnormalities in children with autism may begin before birth, a detailed postmortem study shows.

The analysis revealed the presence of patches of disorganized neurons in areas that mediate functions that are disturbed in autism, including social, emotional, communication, and language function, according to the study authors, led by Rich Stoner, PhD, Autism Center of Excellence and the Department of Neuroscience, University of California at San Diego.

The patches suggest that brain cell activity has been disrupted during pregnancy, which possibly points more to a genetic than an environmental trigger for autism.

“Such abnormalities may represent a common set of developmental neuropathological features that underlie autism and probably result from dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages,” the authors write.

The study was published March 27 in the New England Journal of Medicine.

New Insight

Researchers obtained 42 fresh-frozen postmortem cortical tissue blocks from the superior or middle frontal gyrus of the dorsolateral prefrontal cortex, posterior superior temporal cortex, or occipital cortex of boys and girls aged 2 to 15 years with and without autism. The tissue blocks were selected for their high RNA integrity, thereby ensuring the quality of the samples.

The investigators used a large panel of highly selective markers for specific cell subtypes and a subset of 25 autism candidate genes. These included biomarkers for brain cell types in different layers of the cortex and genes implicated in autism.

They detected what they described as “pathological patches of abnormal laminar cytoarchitecture and disorganization” in samples of the prefrontal and temporal cortex samples, but not the occipital cortex. The patches were found in 91% (10 of 11) of the children with autism (cases) and 9% (1 of 11) of control individuals.

The patches had fewer cells expressing layer- or cell-type-specific markers than normally present in fully differentiated cortical neurons and decreased expression of certain autism candidate genes.

The focal patches of abnormal gene expression measured 5 to 7 mm in length and were located in areas adjacent to apparently unaffected areas of the cortex. They spanned multiple contiguous neocortical layers; the clearest evidence of abnormal expression was found in layers 4 and 5.

“This defect indicates that the crucial early developmental step of creating 6 distinct layers with specific types of brain cells ― something that begins in prenatal life ― had been disrupted,” study investigator Eric Courchesne, PhD, Autism Center of Excellence and the Department of Neuroscience, University of California at San Diego, said in a release.

“The finding that these defects occur in patches rather than across the entirety of cortex gives hope as well as insight about the nature of autism,” he added.

Patches Widespread

The fact that the researchers sampled only small portions of cortex but observed focal patches in nearly every case sample suggests that “pathological patches are widespread across prefrontal and temporal cortex in children with autism,” according to investigators.

The patches were present both in boys and girls, in high- and low-functioning children, and regardless of the cause of death or postmortem interval.

Presentation of the patches varied across cases, which, said the authors, was unexpected given the phenotypic heterogeneity of autism.

“However, the features that we describe here may explain some of the heterogeneity of autism: disorganized patches in different locations could disrupt disparate functional systems in the prefrontal and temporal cortexes and potentially influence symptom expression, response to treatment, and clinical outcome,” the researchers write.

Although the data suggest a novel pathologic mechanism in autism, the exact biological process is unknown.

“The identified laminar disorganization could result from migration defects resulting in the failure of cells to reach their targeted destination and the accumulation of such cells in nearby regions,” the authors write.

Or, they added, the patches could reflect de novo changes early in neurodevelopmental processes, which yield regions of affected progenitor cells adjacent to regions of unaffected progenitor cells.

In any case, the data are consistent with an early prenatal origin of autism, or at least prenatal processes, that may confer a predisposition to autism, according to investigators.

Although the sample size was small compared with postmortem studies of adult diseases, it is as large ― or larger ― than most previous such studies of autism, the authors note.

Key Advance

Commenting on the study for Medscape Medical News, Thomas Frazier, PhD, director, Cleveland Clinic Children’s Center for Autism, in Ohio, said it indicates that in autism, abnormalities in brain cell development occur prior to birth and that this leads to dysfunctional regions of the brain.

“The key advance from this research is that it suggests that very early developmental processes lead to autism,” said Dr. Frazier. “The findings support genetic disruptions leading to brain disorganization or possibly very early interactions between genes and the prenatal environment.”

Dr. Frazier predicted that some experts may find the results controversial because the findings “suggest that brain abnormalities begin before birth, making it less likely that a purely environmental insult causes autism.”