Operationalizing postmortem pathology-MRI association studies in Alzheimer's disease and related disorders with MRI-guided histology sampling.

Journal: Acta neuropathologica communications
Published Date: May 28, 2025

Abstract

Postmortem neuropathological examination, while the gold standard for diagnosing neurodegenerative diseases, often relies on limited regional sampling that may miss critical areas affected by Alzheimer's disease and related disorders. Ultra-high resolution postmortem MRI can help identify regions that fall outside the diagnostic sampling criteria for additional histopathologic evaluation. However, there are no standardized guidelines for integrating histology and MRI in a traditional brain bank. We developed a comprehensive protocol for whole hemisphere postmortem 7T MRI-guided histopathological sampling with whole-slide digital imaging and histopathological analysis, providing a reliable pipeline for high-volume brain banking in heterogeneous brain tissue. Our method uses patient-specific 3D printed molds built from postmortem MRI, allowing standardized tissue processing with a permanent spatial reference frame. To facilitate pathology-MRI association studies, we created a semi-automated MRI to histology registration pipeline and developed a quantitative pathology scoring system using weakly supervised deep learning. We validated this protocol on a cohort of 29 brains with diagnosis on the AD spectrum that revealed correlations between cortical thickness and phosphorylated tau accumulation. This pipeline has broad applicability across neuropathological research and brain banking, facilitating large-scale studies that integrate histology with neuroimaging. The innovations presented here provide a scalable and reproducible approach to studying postmortem brain pathology, with implications for advancing diagnostic and therapeutic strategies for Alzheimer's disease and related disorders.

Authors

  • Chinmayee Athalye
    Division of Cardiology, Department of Medicine, Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, California, United States of America.
  • Alejandra Bahena
    Department of Neurology, University of Pennsylvania, Philadelphia, USA.
  • Pulkit Khandelwal
    Penn Image Computing and Science Laboratory (PICSL), Department of Radiology, University of Pennsylvania, Philadelphia, USA.
  • Sheina Emrani
    Department of Psychology, Rowan University, Glassboro, NJ, USA.
  • Winifred Trotman
    Department of Neurology, University of Pennsylvania, Philadelphia, USA.
  • Lisa M Levorse
    Department of Radiology, University of Pennsylvania, Philadelphia, USA.
  • Zahra Khodakarami
    Department of Bioengineering, University of Pennsylvania, Philadelphia, USA.
  • Daniel T Ohm
    Department of Neurology, University of Pennsylvania, Philadelphia, USA.
  • Eric Teunissen-Bermeo
    Department of Neurology, University of Pennsylvania, Philadelphia, USA.
  • Noah Capp
    Department of Neurology, University of Pennsylvania, Philadelphia, USA.
  • Shokufeh Sadaghiani
    Department of Neurology, University of Pennsylvania, Philadelphia, USA.
  • Sanaz Arezoumandan
    Department of Neurology, University of Pennsylvania, Philadelphia, USA.
  • Sydney A Lim
    Department of Radiology, University of Pennsylvania, Philadelphia, USA.
  • Karthik Prabhakaran
    Department of Neurology, University of Pennsylvania, Philadelphia, USA.
  • Ranjit Ittyerah
    Department of Radiology, University of Pennsylvania, Philadelphia, USA.
  • John L Robinson
    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA.
  • Theresa Schuck
    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA.
  • Edward B Lee
    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA.
  • M Dylan Tisdall
    Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
  • Sandhitsu R Das
    Penn Image Computing and Science Laboratory (PICSL), Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States; Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, United States; Penn Memory Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
  • David A Wolk
    Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
  • David J Irwin
    Department of Neurology, University of Pennsylvania, Philadelphia, USA.
  • Paul A Yushkevich
    Penn Image Computing and Science Laboratory (PICSL), Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States; Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States.

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