Structural and Functional imaging approaches Advanced imaging technology affords a detailed understanding of altered brain function in the developmental disabilities as well as a means with which to test therapies. The molecular biology revolution has revealed a myriad of genotypes that affect brain development. Neuroimaging permits us to characterize phenotypes that associate with particular mutations. The combination of multiple imaging modalities - MRI, MEG, CT, PET and SPECT - offers a unique regional profiling of disease. Imaging has several distinct advantages: 1. Imaging is non-invasive. 2. Imaging offers regional (spatially-localized) assessment of structural, physiological, functional and biochemical aspects of brain tissue. Although a single modality cannot offer this broad characterization, spatially registered integration of MRI, CT, SPECT and PET information can provide an "imaging" phenotype, or profile. Combined with the temporal and spectral informafion from MEG, this "phenotype" can be extended to 5-dimensions. 3. It allows whole-body screening for potential toxicifies and side effects as well as non-local spread. 4.The "Imaging" phenotype can be quantified in each of its domains to provide objective indices of disease progression and response to therapy. Such quantificafion may be volumetric (e.g. region size), morphologic (e.g. encapsulated vs. infiltrative, stellate tumor) or parametric along physiological axes (such as fracfional tissue blood volume, microvascular permeability or rate of glucose metabolism). 5. Use of imaging criteria as "inclusion criteria" for preclinical (and by extension clinical) trials will improve the homogeneity of the sample populafion and speed up the drug evaluafion process as well as providing an objective criterion or set of criteria for patient stratification/selection for treatment. 6.Imaging is translational. MRI, CT, SPECT and PET can be performed in human preclinical and clinical trials. The same biomarkers can be used in humans as were established in the animal models. Furthermore, imaging may provide eariy evidence of biological response. Conversely a non-responding patient can be identified at an eariier stage and management can be altered. 7. Preclinical imaging is ethically appropriate, thus minimizing use of laboratory animals. Preclinical imaging can use a serial design. This has many advantages: (i) By using each mouse as its own "control", it is not necessary to know the precise rate of disease progression. Consequently, small differences in the response of a cohort can be identified without assuming a cohort mean, (ii) Statistical power is Improved. For example, a paired t test can be used to screen for tumor volume post-treatment, (ili) Non-invasive imaging discloses disease prior to onset of symptomatology, (iv) individual differences within a cohort can be studied, thereby reflecting patient variability.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Center Core Grants (P30)
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Special Emphasis Panel (ZHD1-MRG-C)
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Children's Hospital of Philadelphia
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