title: Multifactorial causal model of brain (dis)organization and therapeutic intervention: Application to Alzheimer's disease.
abstract: Generative models focused on multifactorial causal mechanisms in brain disorders are scarce and generally based on limited data. Despite the biological importance of the multiple interacting processes, their effects remain poorly characterized from an integrative analytic perspective. Here, we propose a spatiotemporal multifactorial causal model (MCM) of brain (dis)organization and therapeutic intervention that accounts for local causal interactions, effects propagation via physical brain networks, cognitive alterations, and identification of optimum therapeutic interventions. In this article, we focus on describing the model and applying it at the population-based level for studying late onset Alzheimer's disease (LOAD). By interrelating six different neuroimaging modalities and cognitive measurements, this model accurately predicts spatiotemporal alterations in brain amyloid-β (Aβ) burden, glucose metabolism, vascular flow, resting state functional activity, structural properties, and cognitive integrity. The results suggest that a vascular dysregulation may be the most-likely initial pathologic event leading to LOAD. Nevertheless, they also suggest that LOAD it is not caused by a unique dominant biological factor (e.g. vascular or Aβ) but by the complex interplay among multiple relevant direct interactions. Furthermore, using theoretical control analysis of the identified population-based multifactorial causal network, we show the crucial advantage of using combinatorial over single-target treatments, explain why one-target Aβ based therapies might fail to improve clinical outcomes, and propose an efficiency ranking of possible LOAD interventions. Although still requiring further validation at the individual level, this work presents the first analytic framework for dynamic multifactorial brain (dis)organization that may explain both the pathologic evolution of progressive neurological disorders and operationalize the influence of multiple interventional strategies.
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada; Ludmer Centre for NeuroInformatics and Mental Health, Montreal, Canada. Electronic address: iturria.medina@gmail.com.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Iturria-Medina
authors.affiliation: Biospective Inc., Montreal, Canada.
authors.forename: Félix M
authors.initials: FM
authors.lastname: Carbonell
authors.affiliation: Department of Radiology and Hotchkiss Brain Institute, University of Calgary, Canada.
authors.forename: Roberto C
authors.initials: RC
authors.lastname: Sotero
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada; Ludmer Centre for NeuroInformatics and Mental Health, Montreal, Canada.
authors.forename: Francois
authors.initials: F
authors.lastname: Chouinard-Decorte
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada; Ludmer Centre for NeuroInformatics and Mental Health, Montreal, Canada.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Evans
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D001931:Brain Mapping / Q000379:methods; D018450:Disease Progression; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D008959:Models, Neurological; D009434:Neural Pathways / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D012815:Signal Processing, Computer-Assisted
chemical_list: D005947:Glucose
keywords: Alzheimer’s disease; Computational therapeutic design; Control theory of networks; Intra-brain pathological spreading; Multifactorial causal model; Multimodal direct interactions; Neurodegeneration; Triggering pathological event