Network mediation of pathology pattern in sporadic Creutzfeldt–Jakob disease Benjamin Freeze, 1, * Pedro Maia, 2 Sneha Pandya 1 and Ashish Raj 1,2 *Present address: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA. Sporadic Creutzfeldt–Jakob disease is a rare fatal rapidly progressive dementia caused by the accumulation and spread of patho- logically misfolded prions. Evidence from animal models and in vitro experiments suggests that prion pathology propagates along neural connectivity pathways, with the transmission of misfolded prions initiating a corruptive templating process in newly encoun- tered brain regions. Although particular regional patterns of disease have been recognized in humans, the underlying mechanistic basis of these patterns remains poorly understood. Here, we demonstrate that the spatial pattern of disease derived from publicly available human diffusion-weighted MRI data demonstrates stereotypical features across patient cohorts and can be largely explained by intrinsic connectivity properties of the human structural brain network. Regional diffusion-weighted MRI signal abnormalities are predicted by graph theoretical measures of centrality, with highly affected regions such as cingulate gyrus demon- strating strong structural connectivity to other brain regions. We employ network diffusion modelling to demonstrate that the spa- tial pattern of disease can be predicted by a diffusion process originating from a single regional pathology seed and operating on the structural connectome. The most likely seeds correspond to the most highly affected brain regions, suggesting that pathological prions could originate in a single brain region and spread throughout the brain to produce the regional distribution of pathology observed on MRI. Further investigation of top seed regions and associated connectivity pathways may be a useful strategy for developing therapeutic approaches. 1 Department of Radiology, NewYork-Presbyterian Hospital/Weill Cornell Medicine, New York, NY 10065, USA 2 Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA Correspondence to: Benjamin Freeze, MD, PhD, Department of Radiology Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA E-mail: bfreeze@mgh.harvard.edu Keywords: Creutzfeldt–Jakob disease; prion; MRI; structural connectivity; network diffusion Abbreviations: ABA ¼ Allen Brain Atlas; dMRI ¼ diffusion-weighted MRI; GM ¼ grey matter; NDM ¼ network diffusion mod- elling; PrP Sc ¼ scrapie prion protein; sCJD ¼ sporadic Creutzfeldt–Jakob disease; SR ¼ seed region likelihood Received August 5, 2019. Revised April 15, 2020. Accepted April 17, 2020. Advance Access publication May 15, 2020 V C The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com B BR AIN COMMUNICATIONS AIN COMMUNICATIONS doi:10.1093/braincomms/fcaa060 BRAIN COMMUNICATIONS 2020: Page 1 of 12 | 1 Downloaded from https://academic.oup.com/braincomms/article-abstract/2/1/fcaa060/5837663 by guest on 04 August 2020