Post-mortem MRI for improving the diagnosis of Alzheimer’s mimics in the oldest old

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The oldest old, people aged 90 years or older, are the fastest growing segment of the worldwide population with a staggering increase in the prevalence of dementia. Unlike younger groups, Alzheimer’s disease neuropathology (ADNP) is no longer the most dominant degenerative neuropathology in the oldest old and dementia is often due to the presence of multiple neuropathologies. Hippocampal sclerosis (HS) and small vessel lesions (SVL) are important contributors to dementia in the oldest old. Due to lack of reliable biomarkers, HS remains undetected and SVLs are under-recognized during life. These limitations hamper efforts in developing target-specific therapeutics. The long-term goal of this project is to improve the in vivo diagnosis of these important pathologies using insights gained from postmortem brain MRI. Compared with MRIs acquired during life, postmortem MRI has the ability to acquire significantly higher quality scans allowing for better quantification and localization of abnormalities of brain tissue. The 90+ Study, a longitudinal observational study of participants aged 90 years or older at the University of California, Irvine, provides a unique opportunity to examine the utility of postmortem brain MRI in the oldest old. Neuropathological assessments are currently being conducted on the donated brains and a considerable subset of participants will have undergone brain MRI during life allowing for comparisons between in vivo and postmortem imaging findings and translation of the insights gained from postmortem to in vivo MRIs. We have already developed the sequences and started acquisition of postmortem MRI scans proving the feasibility of our approach. We anticipate acquiring postmortem MRI scans for 50 participants and based on our current data, this sample will provide sufficient number of cases harboring the two pathologies of interest i.e. HS and SVLs. Moreover, our power calculations indicate that we will be able to test the hypotheses of this proposal with this sample size. In aim 1, we will test the hypothesis that hippocampal sclerosis will be associated with MRI detectable volume loss and signal change in the hippocampus and that postmortem MRI has a higher sensitivity to detect these compared with MRI acquired during life. In aim 2, we will test the hypothesis that postmortem MRI allows for detection of higher numbers of SVLs when compared with MRI acquired during life. At completion of this work and utilizing the insights gained from this study, we will apply for an R01 grant to prospectively study the utility of post-mortem MRI in prediction of hippocampal sclerosis and SVLs in a large cohort. The insights gained from these studies will be used to enable prediction of HS and improve the detection of SVLs in MRIs acquired during life. This will subsequently enable development of targeted therapies against these two important pathologies that significantly contribute to development of dementia in fastest growing segment of our population that will represent half of all of those suffering from dementia by 2050.