We presented a unique study on transgenic Alzheimer rats at 10, 15 and 24 months, comparing DTI, NODDI and MAP-MRI-derived metrics, in grey and white matter areas known to manifest age-dependent cerebral amyloidosis that precedes neurofibrillary tangles and apoptotic loss of neurons. We found that NODDI’s ODI and MAP-MRI’s PA metrics uniformly changed over time, likely indicating that they are sensitive to age-dependent neuronal demise due to amyloid accumulation. It is relevant to note that both of these metrics require b-values higher than 1000 s/mm2. Conversely, we found that DTI’s MD, NODDI’s IsoVF and MAPMRI’s RTOP, RTAP, RTPP and NG all follow a two-step progression from 10 to 15 to 24 months—either an increase-decrease or a decrease-increase— likely indicating sensitivity to the neuroinflammatory response at 15 months and potentially, atrophy of the microstructure at 24 months. While this study does not have enough subjects to statistically differentiate between the different disease stages, it does provide valuable insight on which biomarkers and models come closest to explaining the biological changes in the cerebral tissue.

Acknowledgements This work was partly supported by ANR “MOSIFAH” under ANR-13- MONU-0009-01, the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC Advanced Grant agreement No 694665: CoBCoM) and NIH grants U54 EB020403 and R01NS076794.

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