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Changes in functional and structural brain connectome along the Alzheimer’s disease continuum

Abstract

The aim of this study was two-fold: (i) to investigate structural and functional brain network architecture in patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI), stratified in converters (c-aMCI) and non-converters (nc-aMCI) to AD; and to assess the relationship between healthy brain network functional connectivity and the topography of brain atrophy in patients along the AD continuum. Ninety-four AD patients, 47 aMCI patients (25 c-aMCI within 36 months) and 53 age- and sex-matched healthy controls were studied. Graph analysis and connectomics assessed global and local, structural and functional topological network properties and regional connectivity. Healthy topological features of brain regions were assessed based on their connectivity with the point of maximal atrophy (epicenter) in AD and aMCI patients. Brain network graph analysis properties were severely altered in AD patients. Structural brain network was already altered in c-aMCI patients relative to healthy controls in particular in the temporal and parietal brain regions, while functional connectivity did not change. Structural connectivity alterations distinguished c-aMCI from nc-aMCI cases. In both AD and c-aMCI, the point of maximal atrophy was located in left hippocampus (disease-epicenter). Brain regions most strongly connected with the disease-epicenter in the healthy functional connectome were also the most atrophic in both AD and c-aMCI patients. Progressive degeneration in the AD continuum is associated with an early breakdown of anatomical brain connections and follows the strongest connections with the disease-epicenter. These findings support the hypothesis that the topography of brain connectional architecture can modulate the spread of AD through the brain.

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Acknowledgements

The study was supported by the Italian Ministry of Health (grant number GR-2010-2303035) and Alzheimer’s Drug Discovery Foundation (grant number 20131211). The authors thank the patients and their families for the time and effort they dedicated to the research, and are grateful to Dr. Andrea Fontana for his useful statistical advice.

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Correspondence to Massimo Filippi.

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M. Filippi is Editor-in-Chief of the Journal of Neurology; has received compensation for consulting services and/or speaking activities from Biogen Idec, ExceMED, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer’s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA). E. Canu has received research supports from the Italian Ministry of Health. G. Comi has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, ExceMED. F. Agosta is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Biogen Idec, Novartis, and ExceMED—Excellence in Medical Education; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council. The remaining authors declare that they have no conflicts of interests.

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Filippi, M., Basaia, S., Canu, E. et al. Changes in functional and structural brain connectome along the Alzheimer’s disease continuum. Mol Psychiatry 25, 230–239 (2020). https://doi.org/10.1038/s41380-018-0067-8

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