Authors: Thomas S Genovese, Dina Ramadane, Charles Kingsley, Pramod N Nehete, Bharti P Nehete, Akash G Patel, Henry Rusinek, Lawrence E Williams, Youssef Zaim‐Wadghiri, Thomas Wisniewski, Henrieta Scholtzova
Published: 2020-12-07
DOI: 10.1002/alz.045327
Source: Full article
AbstractBackgroundThere has been a growing interest in developing MRI technologies to visualize Aβ plaques in animals, using approaches that may eventually be applied to humans. A non‐human primate model, squirrel monkey (SQM), was utilized in the present study due to their unique property of naturally developing age‐dependent cerebral amyloid angiopathy (CAA) identical to that seen in humans. It has been demonstrated that the transverse relaxation rate (R2*) has a linear correlation with iron content, a component of amyloid deposits and microhemorrhages. Here we proposed to evaluate whether the region of interest (ROI)‐based quantitative R2* assessment is able to detect age related differences in SQM neuropathology. An additional focus was to validate the ability of our novel MRI methodology using bi‐functional nanoparticles (USPIO‐PEG‐Aβ) to detect amyloid deposits.MethodMulti‐gradient echo MR images were acquired in three different SQM age cohorts (ages 5, 16, 21) at various stages of Aβ pathology development. The R2* map of pre‐ and post‐Aβ nanoprobe injection MRI scans were generated (Firevoxel parametric map tool) from each subject to enable (ROI)‐based quantitative R2* analyses. 6E10 immunohistochemistry was used to confirm the presence of CAA and parenchymal plaques to correlate with the R2*.ResultMGE imaging was effective in differentiating between the MRI brains of a 5 year old SQM with no Aβ deposits and aged SQMs with established Aβ pathology. Absolute quantitation of R2* values, defined by ROI circumventing the cortex, revealed significant differences between the young and old subjects, with the highest R2* counts detected in the 21 year old monkey. Further increase in R2* values was observed 36 hrs post‐contrast injection scans in specific brain regions in our oldest cohort, indicative of plaque labeling with our contrast agent. No toxicity was observed during the scans, demonstrating the safety of our Aβ nanoprobe. The degree of correspondence between amyloid deposits detected by MRI and 6E10 immunohistochemistry was confirmed via matched histological sections.