MRI detection of ferritin iron overload and associated neuronal pathology in iron regulatory protein-2 knockout mice

Genetic ablation of iron regulatory protein 2 (IRP-2), a protein responsible for post-transcriptional regulation of expression of several iron metabolism proteins, predisposes IRP-2 -/- mice to develop adult onset neurodegenerative disease. Ferric iron reproducibly accumulates within axonal tracts and neuronal cell bodies in discrete regions of the brain, and areas of iron accumulation colocalize with areas of high ferritin expression. To better evaluate the onset and progression of neurodegeneration in IRP-2 -/- mice, we performed a high-resolution magnetic resonance imaging study comparing live, age-matched wild-type and IRP-2 -/- mice, using an 11.7-Tesla magnet and a custom-designed head coil. The mice were perfused after imaging, and iron stains and immunohistochemical studies were performed. We detected increases in the number of pixels with low T(2) values expected from accumulations of iron in IRP-2 -/- mice. Moreover, in several areas of the brain, including the substantia nigra and the superior colliculus, we detected areas with unusually high T(2) values that likely represented accumulation of water. On histopathological examination we discovered relatively small vacuoles in these brain regions of IRP-2 -/- mice. Our ability to gather T(2) data within regions of interest enabled us to define a bimodal T(2) intensity pattern that likely represents both ferritin iron accumulation and its associated pathological consequences within the brain. Our discoveries may have significant applications for the diagnosis and treatment of human diseases if such high-resolution techniques can be adapted for use in human subjects.