A breakthrough in understanding autism hopefully leads to new directions for future studies.

Autism Linked to Excess Neurons

By Crystal Phend, Senior Staff Writer, MedPage Today Published: November 08, 2011 Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

Children with autism appear to have bigger brains with more neurons than normal for their age, a small preliminary study affirmed. Postmortem examinations of seven boys with autism showed 67% more neurons in the prefrontal cortex (1.94 billion), which controls social and emotional development as well as communication, compared with six controls (1.16 billion, P=0.002), Eric Courchesne, PhD, of the University of California San Diego, and colleagues found. Autistic brains also weighed 17.6% above normal for age (P=0.001), the group reported in the Nov. 9 issue of the Journal of the American Medical Association.   Neuron counts in the autistic children should have been accompanied by brain weights of 29.4% versus the observed 17.6% enlargement, they said. "Thus, the size of the autistic brain, overlarge though it is, might actually underestimate the pathology of excess neuron numbers," the group explained. Researchers have long documented abnormal enlargement of the brain during childhood that persists for about 20% of individuals with autism. These new findings are the first direct evidence that neurons, and not glial or other cell types, appear to be responsible, the researchers pointed out. Neurons in nearly all regions of the brain are generated before birth and the excessive head and brain growth also occur before clinical manifestations of the disorder, an accompanying editorial noted. Thus, the results "add significantly to mounting biological evidence that the developmental neuropathology of idiopathic autism begins before birth in some, possibly all, cases," Janet E. Lainhart, MD, of the University of Utah in Salt Lake City, and Nicholas Lange, ScD, of Harvard University Schools of Medicine and Public Health in Belmont, Mass., wrote in the editorial. What may be happening is unchecked proliferation of neurons, or a failure of the normal process of neuronal pruning through apoptosis in the third trimester and early postnatal period, Courchesne's group suggested. They obtained brains from several tissue banks and had expert anatomists, blinded to diagnosis, conducted unbiased stereotactic cell counts for the entire dorsolateral and mesial portions of the prefrontal cortex, rather than just estimating counts from density in small blocks. The donors were all boys, ages 2 to 16 years, who had died in 2000 to 2006, largely due to hypoxia (drowning, hanging, or electrocution). There also was one death from a car crash, one from rhabdomyosarcoma, and one from possible cardiac arrest. The seven autism cases fell across the spectrum of disability, with some having had normal language and daily functional abilities and others being highly impaired on both counts. None had Asperger's syndrome or pervasive development disorder-not otherwise specified. Neuron counts in the children with autism were: 79% higher in dorsolateral prefrontal cortex at 1.57 billion compared with 0.88 billion in controls (P=0.003) 29% higher in the mesial prefrontal cortex at 0.36 billion versus 0.28 billion in controls (P=0.009) These differences as well as the overall prefrontal cortex counts remained significant between groups after controlling for age and time since death. Whereas brain weight in controls correlated strongly with their number of prefrontal neurons (P=0.004), the same wasn't true for the children with autism. Glia counts overall and in the prefrontal cortex regions came out similar between groups. The researchers cautioned that their sample of autism cases wasn't big enough to determine any links with behavior, nor could the small sample of controls be taken as representative of all healthy young children. Importantly, girls with autism may differ, so further studies may be needed to test whether that is the case, they noted. This study was supported by Autism Speaks, Cure Autism Now, The Peter Emch Family Foundation, the Simons Foundation, The Thursday Club Juniors, and the University of California San Diego-National Institutes of Health Autism Center of Excellence, and by a grant from the National Institute of Mental Health. Tissue was provided by the National Institute of Child Health and Development Brain and Tissue Bank for Developmental Disorders, the Brain and Tissue Bank for Developmental Disorders, Autism Tissue Program, and direct donations to the Courchesne laboratory. One of the researchers reported being owner and employee of Sinq Systems, a contract research organization that performed data collection and analysis for the study, and also being an applicant on a pending patent for analysis of microscopic structure. Lainhart and Lange reported having no conflicts of interest to disclose.

Primary source: Journal of the American Medical Association Source reference: Courchesne E, et al "Neuron number and size in prefrontal cortex of children with autism" JAMA 2011; 306(18): 2001-2010. Additional source: Journal of the American Medical Association Source reference: Lainhart JE, Lange N "Increased neuron number and head size in autism" JAMA 2011; 306(18): 2031-2032.