Multimodal Spatio-Temporal Model of the Natural History of Alzheimer's Disease from Joint Serial Assessment of Amyloidosis, Tauopathy, Hypometabolism, and Atrophy

Abstract

Background: Alzheimer's is a chronic condition spanning over 30 years and consisting of a cascade of spatially and temporally ordered brain changes and clinical symptoms whose dynamics is incompletely understood. A mathematical model capturing all the key changes of the disease into a single quantitative framework would provide a unique opportunity for elucidating the pathophysiology of the disease, discovering the determinants of progression, and facilitating the development of preventive strategies. In this study we develop and validate a multimodal spatiotemporal computational model of the molecular, metabolic, and structural spatio-temporal changes of the brain affected by Alzheimer's disease. Material and methods: We selected serial florbetapir-, flortaucipir-, and FDG-PET and T1-weighted MR images of 561 ADNI participants who were amyloid positive at inception or turned positive during the study. The multimodal image time series were interpolated in time to estimate longitudinal trajectories from individual changes and normalized in space and time onto a common spatio-temporal template. A fully data-driven multimodal model of group-wise spatio-temporal brain changes was trained on the ADNI dataset and validated in an independent memory clinic cohort of 88 individuals. Results: The modelled progression spans roughly sixteen years from initial amyloid buildup to widespread brain structural and functional damage. The model identified amyloid deposition in parietal, precuneus, and frontal regions as the initial event. Tau spreading closely follows the Braak stages. Atrophy appears in the medial temporal region roughly two years from the initial amyloid accumulation, followed by hypo-metabolism in the parietal and temporal regions. The model allowed to predict global cognitive performance and dementia severity in the testing cohort. Conclusions: This novel multimodal computational model recapitulates the progression of the key changes of Alzheimer's disease into a unified spatiotemporal framework. This comprehensive approach enables the elucidation of the dynamics of putative pathophysiological mechanisms, along with the exploration of alternative pathophysiological cascades. By allowing biomarker-based staging in individual cases, the model may be used to derive sensitive markers of efficacy in clinical trials of disease modifying drugs. Funding: This work was supported by the French government, through the UCA- JEDI Investments in the Future project managed by the National Re-search Agency (ANR) with the reference number ANR-15-IDEX-01 (project Meta-ImaGen), by the grant AAP Sante 06 2017-260 DGA-DSH, and by the Inria Sophia Antipolis - Mediterranee, NEF computation cluster. The Centre de la memoire at Geneva University Hospital is funded by private donors: A.P.R.A. - Association Suisse pour la Recherche sur la Maladie d’Alzheimer, Geneve; Fondation Segre, Geneve; Ivan Pictet, Geneve; Fondazione Agusta, Lugano; Fondation Chmielewski, Geneve. Competitive research projects have been funded by: H2020, Human Brain Project, Innovative Medicines Initiative (IMI), IMI2, Swiss National Science Foundation (SNF 320030_169876); VELUX Foundation (project 1123). FB is supported by the NIHR biomedical research centre at UCLH, by AMYPAD (IMI), and EuroPOND (H2020). Declaration of Interest: The authors do not report any conflict of interest. Ethical Approval: Our research mainly involves further processing of previously collected personal data (secondary use). In particular, our work was based on the data from the Alzheimer’s Disease NeuroImaging Inititative (ADNI), acquired according to the HIPAA rules which govern ethical issues in the USA. We have explicit authorization and we have signed the relevant papers guaranteeing that we abide to the ethics standards. Concerning the Geneva memory clinic cohort used for testing, the local ethic committee approved these studies, which have been conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice. Each subject provided a voluntary written informed consent for participation in the studies.