Multi-scale and multi-modality imaging of neuropathology in VCID

PROJECT SUMMARY

MRI and histopathology are two key methods for all research into age-related cognitive impairment and dementia and they have brought key insights into disease mechanisms and therapeutic implications. A major challenge is to characterize the integrative properties of these two modalities, which differ in resolution, coverage, and markers; furthermore, in vivo, vascular abnormalities by nature are difficult to be characterized on post-mortem exams.

Post-mortem MRI has emerged as a technique to bridge the gap but necessary techniques are still not fully developed. In this proposal, we propose to develop novel post-mortem MR imaging protocols and computational tools to enable the collection of multi-modal multi-scale brain MR/histopathology/ proteomics data analysis to advance our understanding of gray and white matter neurodegeneration associated with vascular contributions to cognitive impairment and dementia (VCID).

We have assembled a multi-disciplinary research team with leading experts in several key aspects of the proposed study to achieve the following specific aims. Aim 1: Develop a robust, state-of-the-art post-mortem pipeline for human brain autopsy, fixation, and blocking/sectioning that meet the need for combined MRI/histopathology full-scale analysis of AD/ADRD.

These include (a) characterization of the effects of post-mortem interval (PMI) and formalin fixation (i.e., hours to weeks) for modeling such effect in both spatial and temporal domains; and (b) establishing standardized ex vivo MRI procedures that focus on streamlining fixation and sectioning protocols to minimize imaging and tissue deformation/degradation, enabling dependable co-registration between imaging procedures and ensuring precise top-down correlation with histopathology and proteomic analysis. Aim 2: Develop a multi-modality atlas and database of the human medial temporal lobe (MTL) and prefrontal cortex (PFC) pathology based on co-registered multimodal and multiscale MRI and neuropathology data from a well-characterized cohort at NYU Langone Health ADRC that includes AD, TBI-related and other ADRD vs control subjects, focusing on Aβ, Tau, vascular, and microstructural pathology.

The multi-modality vascular and microstructural atlases will be reconstructed and integrated with vascular pathology staining. Aim 3: Study white matter hyperintensities (WMHs) by performing high-fidelity and multi-contrast voxel-wise mapping of post-mortem MRI and histopathology that enable a better understanding of in vivo and ex vivo findings of small vessel disease (SVD).

This aim tackles two major obstacles in the research of SVD associated with VCID: cross-modality interpretation and heterogeneity of WMHs. Aim 4: Develop digital libraries for imaging and pathology protocols, software tools, and brain atlases, as well as relevant pre- and post-mortem MRI and biomaterial data to be shared in the research community. Collectively, this project will make contributions to develop standardized and accessible MRI- histology protocols, novel post-mortem and co-registration tools, as well as resources of all imaging and biomaterial data from 75 elderly brains to advance the study of VCID pathology in AD/ADRD.