The researchers, led by Mustafa Sahin, MD, PhD, from the department of neurology, Simon Warfield, PhD, director of the Computational Radiology Laboratory, and first author Jurriaan Peters, MD, of both departments at Children’s Hospital Boston (MA, USA), used an innovative magnetic resonance imaging (MRI) technique to image the brains of 40 patients (infants to age 25) with tuberous sclerosis complex and 29 age-matched, healthy controls. Tuberous sclerosis is a rare genetic condition often associated with cognitive and behavioral deficits, including ASDs approximately 50% of the time.

“Patients with tuberous sclerosis can be diagnosed at birth or potentially before birth, because of cardiac tumors that are visible on ultrasound, giving us the opportunity to understand the circuitry of the brain at an early age,” explained Dr. Sahin. “Our ultimate goal is to use imaging in infancy to find which tuberous sclerosis patients are at high risk for autism so we can intervene early. This may have implications for autism in patients without tuberous sclerosis as well.”

The investigators used a comparatively new MRI technique called diffusion tensor imaging (DTI) to track the pathways of nerve fibers by measuring the diffusion of water in the brain. In the January 2011 issue of the journal Academic Radiology, they report findings in the corpus callosum, the brain's largest white-matter structure.

Of the 40 patients with tuberous sclerosis, 24 had clinically significant developmental delays or intellectual disability, and 12 had ASDs. ASDs were diagnosed clinically by a pediatric neurologist, and in most cases, by the Autism Diagnostic Observation Schedule (ADOS).

Typically, compared with controls, patients with tuberous sclerosis had higher radial diffusivity values, a measure of water diffusion out of (perpendicular to) the nerve fibers (axons). Radial diffusivity is an indirect measure of how well insulated the axons are. Having higher radial diffusivity means axons are poorly insulated with myelin, suggesting abnormalities in the white matter (which is partially composed of myelin).

Patients with both tuberous sclerosis and ASDs not only had increased radial diffusivity-- compared with both non-ASD patients and controls --but they also had distinctly disorganized axon pathways.

Axons in the control subjects followed well-defined directions in organized bundles, whereas the ASD patients’ axons tended not to orient together in common directions (referred to in the article as having lower fractional anisotropy). Tuberous sclerosis patients without ASDs showed only slight disorganization compared to controls. “This study shows that we can use diffusion tensor imaging to differentiate tuberous patients with autism from those without autism,” said Dr. Sahin.

“Our advances in imaging and in image analysis are enabling us to identify and quantitatively characterize alterations in brain development that are not readily visible in conventional imaging,'” added Dr. Warfield.

The findings add to earlier human imaging research by Drs. Sahin and Warfield showing similar differences in the brain’s visual cortex, and are consistent with brain MRI scans in older, high-functioning individuals with ASDs, revealing abnormalities in connectivity in the corpus callosum and in areas of brain involved in language and social skills.

The findings are also consistent with studies in Dr. Sahin’s lab using mouse models of tuberous sclerosis. The neurons in these mice grew multiple axons (normal neurons grow just one), causing too many connections being made, and axons originating in the retina failed to land in the appropriate places in the brain and did not respond to navigation cues.

Further studies revealed that the axons in these mice had less myelination, identified the biochemical pathway causing these defects, known as the mTOR pathway, and showed that the pathway and the myelination defects could be reversed in mice with the mTOR-inhibiting drug rapamycin.

Equipped with these data, Dr. Sahin has launched a phase II clinical trial of a rapamycin-like drug called Afinitor (everolimus; formerly RAD001), sponsored by Novartis (Basel, Switzerland), the Tuberous Sclerosis Alliance and Autism Speaks. The trial will enroll 50 patients with TSC to test whether Afinitor improves neurocognition, autism, seizures, and sleep disorders. “Specifically modulating neurocognition with a small molecule is only starting to be done,” stated Dr. Sahin.

“Ultimately, imaging will play a crucial role in identifying who may benefit from treatment, and in seeing the changes in the brain in response to treatment,” concluded Dr. Warfield.

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