Differential MRI relaxation in Alzheimer’s patients with mutant hfe and transferrin genotypes


      Iron accumulation in the brain and oxidative stress are observed in a number of neurodegenerative disorders such as Alzheimer’s disease (AD). Common mutations that lead to high iron overload has been associated with two gene variants within the HFE gene, C282Y and H63D, and within the transferrin (Tf) gene, C2. Within Alzheimer’s disease these mutations are found with increased frequency in patients (estimates are between 20-50%). The goal of this work was to understand how HFE and C2 mutations effect transverse relaxation in the AD brain with the hypothesis that these mutations will result in increased transverse relaxation rate within the brains of AD C282Y, H63D, or C2 carriers.


      Thirty-eight mild Alzheimer’s disease patients (13M, 25F) were enrolled. Of these, 7 subjects (1M, 6F) were heterozygous and 1 subject homozygous (1F) for the H63D mutation, 3 subjects (2M, 1F) were heterozygous C282Y mutation, and 4 subjects were heterozygous (2M, 2F) for the TfC2 mutation. All patients were scanned on a 3.0 T system and group based parametric map analysis was performed on the stratified patient populations: those with high iron mutations (IRON +; H63D, C282Y, or C2) and those with all wild-type genes (IRON –).


      The group based R2 parametric analysis demonstrates that AD patients with high iron mutations (IRON+) have increased R2 rates specifically within white matter regions of interest.


      The stratification of AD patients based on IRON + genetics and determination that there are relaxation differences specifically in white matter is a highly novel finding. The cause for the white matter relaxation metrics are believed to be multi-faceted and not only related to the high iron status of AD IRON + carriers. As the relaxation rate alterations are found exclusively in white matter, we hypothesize that there are white matter modifications in AD IRON + patients. Considering that R2 relaxation rate is a factor of iron content and tissue structure, this pattern could be indicative of white matter alterations in Alzheimer’s disease. This hypothesis is congruent with data showing that AD has an integral white matter component.
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