Co-Registration of DTI and MTR MRI Data to Quantitative Immunohistochemistry in a Novel Mouse Model of Inflammatory Cerebral Demyelination (P06.124)

OBJECTIVE: Determine the neuropathological correlates of in vivo diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) MRI measures using a novel mouse model of inflammatory cerebral demyelination. BACKGROUND: Conventional MRI is routinely utilized to evaluate the efficacy of therapeutic agents in MS clinical studies. However, the relationship between non-conventional, in vivo imaging measures and underlying pathophysiological processes remains poorly understood. In order to maximize the information gleaned from MRI data and appropriately steer clinical development of novel therapeutics, we have performed a rigorous correlation analysis between in vivo 3D MRI measures and gold-standard, post-mortem quantitative immunohistochemistry (qIHC) measures in mice with focal inflammatory/demyelinating cerebral lesions. DESIGN/METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in C57Bl/6 mice (n=12) using MOG 35-55 peptide emulsified in CFA containing Mycobacterium tuberculosis . One week post-EAE induction, mice underwent unilateral stereotaxic injections of TNF-α and IFN-γ into the corpus callosum. Two weeks post-EAE induction, 3D DTI and MTI images were acquired using 7T MRI. MR images were processed using a fully-automated pipeline to generate DTI fractional anisotropy/diffusivity and MTR maps. Following euthanasia, formalin-fixed, paraffin-embedded, whole brains were serially-sectioned. The sections underwent IHC staining to assess myelin density and inflammation. The IHC sections were digitized, reconstructed into 3D qIHC volumes, and spatially normalized to the MRI data (PERMITS TM , Biospective Inc.). Lesion-based correlation analyses were performed between MRI and qIHC measures. RESULTS: All mice developed MRI-visible, focal inflammatory/demyelinating lesions in the vicinity of the corpus callosum. Details of the correlation analysis between in vivo MRI (FA, mean/axial/radial diffusivity, MTR) and post-mortem qIHC (myelin, edema) measures will be presented. CONCLUSIONS: Accurate co-registration of MRI and qIHC volumes from relevant mouse models is a powerful approach to interrogate the biological underpinnings of non-invasive, non-conventional imaging data and potentially guide the rational use of novel imaging biomarkers in MS clinical development. Supported by: Biogen Idec. Disclosure: Dr. Zehntner has received personal compensation for activities with Biospectives Inc. as an employee. Dr. Zehntner holds stock and/or stock options in Biospective Inc, which sponsored research in which Dr. Zehntner was involved as an investigator. Dr. Zijdenbos has received personal compensation for activities with Biospective Inc. as an employee. Dr. Zijdenbos has received compensation for serving on the board of Biospective Inc. Dr. Zijdenbos holds stock and/or stock options in Biospective Inc., which sponsored research in which Dr. Zijdenbos was involved as an investigator. Dr. Bedell has received personal compensation for activities with Biospective Inc. Dr. Bedell holds stock and/or stock options in Biospective Inc., which sponsored research in which Dr. Bedell was involved as an investigator. Dr. Bedell has received research support from Biospective Inc. Dr. Cadavid has received personal compensation for activities with Biogen Idec as an employee.