Michigan Alzheimer’s Disease Research Center-Supplement

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ABSTRACT – SUPPLEMENT We seek to define the MR correlates of white matter histopathological features in Alzheimer’s disease and related disorders (ADRD) by combining the resources at MADRC Neuropathology core, with its repository of post-mortem frozen tissue with a wealth of accompanying pre-mortem MR studies, with the resources of MADRC Neuroimaging core and its advanced MR facility comprised of experts in the fields of MR acquisition, post-processing, and parameterization. Post-mortem histological studies and pre-mortem imaging studies indicate that multiple pathologies often co-exist and that single pathologies are often the exception, as demonstrated by the frequent presence of brain lesions of presumed vascular origin, such as white matter (WM) lesions, microbleeds, and microinfarcts. The clinical significance and the degree to which such lesions contribute to clinical decline is unclear, partly because routine MRI techniques such as T1 and T2 weighted imaging lack the specificity to further characterize their pathological underpinnings such as demyelination, gliosis, or axonal loss. Guided by pre-mortem MR studies of donors with a diagnosis of vascular dementia (VD), Alzheimer’s disease (AD), and neurologically intact donors (ND), we will analyze frozen post-mortem tissue both from brain regions surrounding LPVO’s and brain regions without any T2 abnormalities. We will obtain advanced MR (MWF, ihMT, and multi-shell, multi-directional diffusion) parameters from these tissue blocks as well as conventional T1-weighted and T2-weighted MRI’s at 7T. Tissue fixation, histological/immunohistochemical techniques, and light-microscopy will be used to classify and quantify the presence of various pathological parameters, including myelin density, microglia proliferation, oligodendrocyte density, phosphorylated tau, tissue iron content, vessel wall thickness, and amyloid deposition. Our goal is to characterize the MR signature patterns that correlated with various pathological features in white matter abnormalities. Defining the multi-modal MR signatures that correlate with ominous histopathological features, and the relationship between pathological diagnosis and MR signal in the normal-appearing white matter will allow us to disentangle MR features that reflect pathological changes driving cognitive decline from those that are related to other factors such as aging. Establishing this histo-radiological link will sharpen the focus of in- vivo MR methods and allow their incorporation in future studies to more precisely monitor and predict cognitive decline in ADRD. In addition to its non-amyloid approach, this proposal brings together resources of multiple cores at MADRC and involves the expertise from three major universities in Michigan, each with its own set of skill sets to drive the project forwards. In addition, the raw data from these efforts will be shared among other centers to allow for future collaborative work in the field.