Authors :
Presenting Author: Yanming Wang, PhD – Case Western Reserve University
Chunying Wu, PhD – Case Western Reserve University; Junqing Zhu, PhD – Case Western Reserve University; tiffany Bartel, PhD – The Cleveland Clinic Foundation; Lisa Ellison, PhD – The Cleveland Clinic Foundation; Kelly Bryant, PhD – The Cleveland Clinic Foundation; Imad Najm, MD, PhD – The Cleveland Clinic Foundation
Rationale:
Epilepsy is a chronic neurological disorder characterized by recurrent seizures. The mechanisms underlying epileptogenesis and seizure generations have not been fully understood. It is essential to conduct molecular imaging studies in appropriate animal models to delineate the neuropathological and functional changes in vivo in search of new strategies for therapeutic intervention.
Methods:
An irradiation rodent model of cortical dysplasia was prepared by irradiating pregnant dams on E17 to produce pups with malformed cortices (XRT). The corresponding XRT adult animals were then subjected to microPET/CT scan for imaging of synaptic activity in the gray matter and myelination in the white matter. Subsequent autoradiography and in vivo pharmacokinetic characterization were conducted to provide new insights into the pathogenesis of epilepsy with cortical dysplasia.
Results:
Longitudinal microPET/CT scans of the XRT rats were conducted using [18F]MNI-1038 to monitor synaptic activity or [11C]MeDAS to investigate myelin changes in vivo in the brain. As shown in Figure 1, the uptake of [18F]MNI-1038 in terms of SUV in XRT rats’ whole brain, left hemisphere, right hemisphere, and cerebellum were 0.72±0.22, 0.80±0.34, 0.83±0.37, and 0.65±0.14 respectively, while the uptake of [18F]MNI-1038 in normal rats’ whole brain, left hemisphere, right hemisphere, and cerebellum were 1.14±0.11, 1.31±0.17, 1.25±0.15, and 0.84±0.11. Subsequent ex vivo autoradiography (40min post [18F]MNI-1038 injection, Image J) showed that there is a significant difference in radioactivity in typical brain regions in XRT rat brain than that in normal rat brain. In terms of myelin changes, [11C]MeDAS-PET studies showed that the uptake in the XRT rat was 0.39±0.21 compared to normal rat brain uptake of 0.47±0.32. Additionally, histochemical and autoradiographic staining of MeDAS/[11C]MeDAS in XRT rat brain and post-mortem epilepsy patient’s brain showed significant myelin changes in the white matter.Conclusions:
PET imaging studies in the XRT rat model of cortical dysplasia reveal a significant reduction of synaptic activity and destruction of myelin in the brain. Concurrent pathological changes in gray matter and white matter offer new insights into understanding epileptogenesis and developing novel therapeutic interventions.
Funding: This work is supported by UCB Inc.