Autism is the most common form of the Pervasive Developmental Disorders, affecting social interaction, communication, and imagination in children. According to the Center for Disease Control and Prevention in 2003, it affects an estimated 1 in 250 births. Since the early 1990's, the rate of autism diagnosis has increased dramatically throughout the world, so that figures as high as 1 in 170 births are being reported.
Although the root causes responsible for autism are unknown, both genetic and environmental factors are considered. Among autistic children, there is often a striking increase in postnatal head circumference percentile compared to age-matched controls. This increased brain volume in autism mainly results from a white matter enlargement. The cause of white matter volume cannot be explained. Recent studies on localization of white matter volume increase point to the radiate white matter, whereas deep white matter (inner zone white matter compartments) showed no volume differences from controls. The regions showing the greatest volume increases were found to be those where myelination occurs latest in normal development or where myelination occurs over a protracted time course. Thus, abnormal volume increase in this region may be related to the process of myelination, one of the most fundamental of biological processes of human brain development.
These results lead to the hypothesis that the abnormal brain enlargement as seen in autism may be caused by delayed and prolonged myelination. It is thus necessary to directly monitor the course of myelination in vivo and correlate with volumetric changes. These studies could provide valuable insights into the pathogenesis of the disease, with potential clinical applications in early diagnosis and efficacy evaluation of therapeutic interventions.
Unfortunately, in vivo monitoring of myelination is still a problem in human studies. While MRI is capable of detection of volumetric changes in the brain, it is incapable of direct measurement of myelin content. Due to the lack of biomarkers for in vivo quantification of myelin content, the direct relationship between volumetric enlargement and myelination cannot be established. In these proposed studies, we plan to meet this challenge by in vivo quantification of myelin content using positron emission tomography (PET). PET is a scanning technique, used in combination with a trace amount of chemical probes labeled with positron-emitting radionuclides such as C-11 or F-18, which can detect and quantify anatomical and functional changes in the body.
For in vivo detection and quantitation of myelin contents with PET, it is necessary to develop myelin-imaging ligands with suitable in vitro and in vivo binding properties. We have recently developed a small-molecule probe, termed [11C]BMB, which readily enters the brain and selectively binds to myelin sheaths. PET studies in baboons showed that [11C]BMB can be used as a surrogate marker of myelin sheaths in the white matter. The overall aims of this proposed project are to apply the [11C]BMB-PET technique to the mouse models containing different levels of myelination and conduct serial measurements that would eventually allow us to follow the time courses of myelination longitudinally.
The Specific Aims of the proposed research are:
1. Conduct micro-PET studies in mouse models with various levels of myelination to obtain detailed pharmacokinetic profiles of [11C]BMB in term of the brain entry, retention, and clearance;
2. Conduct histologic studies in the same mice to quantify myelin contents and correlate the extent of myelination with the pharmacokinetic profiles obtained from micro-PET studies;
3. Conduct micro-PET studies (at 2, 4, 6, 8, and 10 days after birth) in postnatal control mice to monitor longitudinally the course of myelination in the brain.
Completion of this study would lead to having a well-characterized imaging marker that can be used as a powerful tool to directly monitor the time course of myelination in vivo. This would facilitate studies of the myelination process and delineate the cause of volumetric enlargement in autistic brains. Once developed, this imaging marker could also facilitate early diagnosis and efficacy evaluation of clinical interventions.