Quantification of Localized Brain Iron Sources Using Magnetic Resonance Phase

Abstract

Brain microbleeds (BMB), often present in cerebrovascular and neurodegenerative diseases and neurotrauma, are associated with both chronic and acute illness of significant social and economic impact. Because BMB present a source of potentially cyctotoxic iron to the brain proportional to the amount of extravasated blood, non-invasive quantification of this iron pool is potentially valuable both to assess tissue risk and as a biomarker to monitor disease progression, treatment efficacy, and inform treatment. Past efforts to quantify brain iron have focused on distributed (e.g., anatomical) brain regions. However, BMB represent localized sources of iron deposition. In addition, conventional magnitude MR images have significant limitations, especially for localized iron quantification. Moreover, due to susceptibility effects, the localized bypointensities in gradient recalled T2* magnitude images associated with BMB typically appear larger than the actual tissue lesion (the blooming effect) and obscure the true dimensions of an iron susceptibility source. In the present research, we proposed a family of techniques that use magnetic resonance phase images (instead of magnitude images) to quantify the iron content and dimensions of localized iron sources such as BMB. The techniques were tested in four systems: 1) magnetic resonance agarose phantom and 2) postmortem rat brain, using a ferric iron oxy0hydroxide mimic for hemosiderin, 3) the living rat brain, using collagenase-induced bleeds, and 4) with actual BMB in postmortem cerebral amyloid angiopathy brain. Measurements of geometric features in phase images were related to source iron content and diameter using mathematical models. Iron samples and BMB lesions were assayed for iron content using atomic absorption spectrometry. Results from experiments 1 and 3 in particular showed very good agreement with predictions of the theory underlying the techniques, providing validation for the methods and demonstrating that prominent phase image features can potentially be used to measure localized iron content including iron in real BMB. Our methods potentially allow the calculation of brain iron load indices based on BMB iron content as well as classification of BMB by size unobscured by the blooming effect. These results represent significant steps toward the use of similar localized iron quantification methods in experimental and clinical settings