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• W2897675393 abstract "Prion disease is characterized by a chain reaction in which infectious misfolded proteins force native proteins into a similar pathogenic structure. Recent studies have reinforced the hypothesis that the prion paradigm–the templated growth and spreading of misfolded proteins–could help explain the progression of a variety of neurodegenerative disorders. However, our current understanding of prion-like growth and spreading is rather empirical. Here we show that a physics-based reaction-diffusion model can explain the growth and spreading of misfolded protein in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. To characterize the progression of misfolded proteins across the brain, we combine the classical Fisher–Kolmogorov equation for population dynamics with an anisotropic diffusion model and simulate misfolding across a sagittal section and across the entire brain. In a systematic sensitivity analysis, we probe the role of the individual model parameters and show that the misfolded protein concentration is sensitive to the coefficients of growth, extracellular diffusion, and axonal transport, to the axonal fiber orientation, and to the initial seeding region. Our model correctly predicts amyloid-β deposits and tau inclusions in Alzheimer’s disease, α-synuclein inclusions in Parkinson’s disease, and TDP-43 inclusions in amyotrophic lateral sclerosis and displays excellent agreement with the histological patterns in diseased human brains. When integrated across the brain, our concentration profiles result in biomarker curves that display a striking similarity with the sigmoid shape and qualitative timeline of clinical biomarker models. Our results suggest that misfolded proteins in various neurodegenerative disorders grow and spread according to a universal law that follows the basic physical principles of nonlinear reaction and anisotropic diffusion. Our findings substantiate the notion of a common underlying principle for the pathogenesis of a wide variety of neurodegenerative disorders, the prion paradigm. A more quantitative understanding of the growth and spreading of misfolded amyloid-β, tau, α-synuclein, and TDP-43 would allow us to establish a prognostic timeframe of disease progression. This could have important clinical implications, ranging from more accurate estimates of the socioeconomic burden of neurodegeneration to a more informed design of clinical trials and pharmacological intervention." @default.
• W2897675393 created "2018-10-26" @default.
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• W2897675393 date "2019-03-01" @default.
• W2897675393 modified "2023-10-13" @default.
• W2897675393 title "A physics-based model explains the prion-like features of neurodegeneration in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis" @default.
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• W2897675393 doi "https://doi.org/10.1016/j.jmps.2018.10.013" @default.
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