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Combined Model of Aggregation and Network Diffusion Recapitulates Alzheimer's Regional Tau-Positron Emission Tomography

Authors
 Ashish Raj  ;  Veronica Tora  ;  Xiao Gao  ;  Hanna Cho  ;  Jae Yong Choi  ;  Young Hoon Ryu  ;  Chul Hyoung Lyoo  ;  Bruno Franchi 
Citation
 BRAIN CONNECTIVITY, Vol.11(8) : 624-638, 2021-10 
Journal Title
BRAIN CONNECTIVITY
ISSN
 2158-0014 
Issue Date
2021-10
MeSH
Alzheimer Disease* / diagnostic imaging ; Brain / diagnostic imaging ; Brain / metabolism ; Connectome* ; Humans ; Positron-Emission Tomography ; tau Proteins / metabolism
Keywords
Alzheimer's disease ; Smoluchowski equations ; graphs ; network diffusion ; protein aggregation ; trans-neuronal spread ; τ-PET
Abstract
Background: Alzheimer's disease involves widespread and progressive deposition of misfolded protein tau (τ), first appearing in the entorhinal cortex, coagulating in longer polymers and insoluble fibrils. There is mounting evidence for "prion-like" trans-neuronal transmission, whereby misfolded proteins cascade along neuronal pathways, giving rise to networked spread. However, the cause-effect mechanisms by which various oligomeric τ species are produced, aggregate, and disseminate are unknown. The question of how protein aggregation and subsequent spread lead to stereotyped progression in the Alzheimer brain remains unresolved. Materials and Methods: We address these questions by using mathematically precise parsimonious modeling of these pathophysiological processes, extrapolated to the whole brain. We model three key processes: τ monomer production; aggregation into oligomers and then into tangles; and the spatiotemporal progression of misfolded τ as it ramifies into neural circuits via the brain connectome. We model monomer seeding and production at the entorhinal cortex, aggregation using Smoluchowski equations; and networked spread using our prior Network-Diffusion model. Results: This combined aggregation-network-diffusion model exhibits all hallmarks of τ progression seen in human patients. Unlike previous theoretical studies of protein aggregation, we present here an empirical validation on in vivo imaging and fluid τ measurements from large datasets. The model accurately captures not just the spatial distribution of empirical regional τ and atrophy but also patients' cerebrospinal fluid phosphorylated τ profiles as a function of disease progression. Conclusion: This unified quantitative and testable model has the potential to explain observed phenomena and serve as a test-bed for future hypothesis generation and testing in silico. Impact statement The presented aggregation-network-diffusion model exhibits all hallmarks of tau progression in human patients; it accurately captures not just the spatial distribution of empirical regional tau and atrophy but also patients' cerebrospinal fluid phosphorylated tau profiles. Thus, it serves to fill a theoretical gap between microscopic biophysical processes and empirical macroscopic measurements of pathological patterns in Alzheimer's disease. This unified quantitative and testable model has the potential to explain observed phenomena and serve as a test-bed for future hypothesis generation and testing in silico.
Full Text
https://www.liebertpub.com/doi/10.1089/brain.2020.0841
DOI
10.1089/brain.2020.0841
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
Yonsei Authors
Lyoo, Chul Hyoung(류철형) ORCID logo https://orcid.org/0000-0003-2231-672X
Ryu, Young Hoon(유영훈) ORCID logo https://orcid.org/0000-0002-9000-5563
Cho, Hanna(조한나) ORCID logo https://orcid.org/0000-0001-5936-1546
Choi, Jae Yong(최재용)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187814
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