Neuropathology Core

SUMMARY – NP CORE YALE ADRC Contemporary biobanking of human samples is emerging as cornerstone for a wide range of biomedical analyses. The neuropathological assessment of brains provides a critical resource for disease oriented neuroscience by connecting clinical, biomarker based, genetic and neuroimaging observations to pathogenic tissue-based changes. Alzheimer’s Disease is a devastating neurodegenerative disorder with tremendous morbidity and mortality. While we have begun to disentangle some of the underlying pathways, we are far from fully understanding basic AD biology and its devastating effects on brain function. Most model systems do not fully capture the complexity of human AD pathology, particularly as it frequently coexists with other AD related dementias (ADRD), a unique human feature. Further, while increasing efforts now seek to uncover disease- specific biofluid and molecular imaging biomarkers for the identification of early steps in disease pathogenesis, it is critical to include tissue-based validations. Precise, high-resolution postmortem analyses are essential for the validation of candidate antemortem biomarkers and imaging characteristics. A biobank of high quality, optimally preserved and characterized postmortem AD/ADRD brains, which can adapt to multimodal analyses has the potential to lead to significant contributions in the field. One of the key features of the Neuropathology Core is its distinct interactive nature with all other cores of the Yale ADRC. Without this engagement, the establishment of a successful biobank would not be possible. Our main goal is to provide optimally preserved human samples with the utilization of the Rapid Autopsy Program at Yale, which is aiming to limit ischemia times to 1-3 hours postmortem (Aim1). Samples are preserved so that they are suitable for a wide range of state-of- the-art-technologies, ranging from single nucleus multiomics to immuno-EM. Materials will be widely available to qualified investigators within and outside the Yale ADRC environment, distribution decisions are based on executive committee decisions. All cases will be diagnosed by a Board Certified Neuropathologist and based on national standards developed by NIH-NIA (Aim 2). Integrated diagnoses and data are uploaded to NACC in collaboration with the Clinical and DMS cores, a final diagnostic report is also provided to the next-of kin. Similar diagnostic standards are applied to non-human primate brains (Aim 3), which form a critical and unique resource to study the earliest stages of tau pathology not possible in human brains due to longer PMIs. Aim 4 is focused on the establishment of a digital Neuropathology archive which will be an invaluable resource for AI directed analysis methods. Similarly, postmortem images of fixed brains have the potential to detect novel MRI signatures reflective of AD pathology. The NP Core has a long tradition of teaching and mentoring a wide range of trainees and investigators, and this effort will continue in the new cycle in collaboration with several cores within the ADRC (Aim 5).