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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Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.
Manly JJ, Tang MX, Schupf N, Stern Y, Vonsattel JP, Mayeux R. Frequency and course of mild cognitive impairment in a multiethnic community. Ann Neurol. 2008;63:494–506.
Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013;501:45–51.
Frost B, Diamond MI. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci. 2010;11:155–9.
Bullmore E, Sporns O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci. 2009;10:186–98.
Fornito A, Zalesky A, Breakspear M. The connectomics of brain disorders. Nat Rev Neurosci. 2015;16:159–72.
Buckner RL, Sepulcre J, Talukdar T, Krienen FM, Liu H, Hedden T, et al. Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer’s disease. J Neurosci. 2009;29:1860–73.
Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron. 2009;62:42–52.
Sepulcre J, Sabuncu MR, Li Q, El Fakhri G, Sperling R, Johnson KA. Tau and amyloid-beta proteins distinctively associate to functional network changes in the aging brain. Alzheimer’s & Dement: J Alzheimer’s Assoc. 2017;13:1261–9.
Mandelli ML, Vilaplana E, Brown JA, Hubbard HI, Binney RJ, Attygalle S, et al. Healthy brain connectivity predicts atrophy progression in non-fluent variant of primary progressive aphasia. Brain. 2016;139(Pt 10):2778–91.
Raj A, Kuceyeski A, Weiner M. A network diffusion model of disease progression in dementia. Neuron. 2012;73:1204–15.
Collins JA, Montal V, Hochberg D, Quimby M, Mandelli ML, Makris N, et al. Focal temporal pole atrophy and network degeneration in semantic variant primary progressive aphasia. Brain. 2017;140(Pt 2):457–71.
Zhou J, Gennatas ED, Kramer JH, Miller BL, Seeley WW. Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron. 2012;73:1216–27.
Mallio CA, Schmidt R, de Reus MA, Vernieri F, Quintiliani L, Curcio G, et al. Epicentral disruption of structural connectivity in Alzheimer’s disease. CNS Neurosci Ther. 2015;21:837–45.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–9.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:270–9.
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.
Novelli G, Papagno C, Capitani E, Laiacona N, Vallar G, Cappa SF. Tre test clinici di ricerca e produzione lessicale. Taratura su soggetti Norm Arch Psicol Neurol Psichiatr. 1986;47:477–506.
Rey A. L’examen Clinique en Psychologie. Paris: Presses Universitaires; 1964.
Orsini A, Grossi D, Capitani E, Laiacona M, Papagno C, Vallar G. Verbal and spatial immediate memory span: normative data from 1355 adults and 1112 children. Ital J Neurol Sci. 1987;8:539–48.
Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A. Rey-Osterrieth complex figure: normative values in an Italian population sample. Neurol Sci. 2002;22:443–7.
Spinnler H, Tognoni G. Standardizzazione e taratura italiana di test neuropsicologici. Ital J Neurol Sci. 1987;6:1–120.
Basso A, Capitani E, Laiacona M. Raven’s coloured progressive matrices: normative values on 305 adult normal controls. Funct Neurol. 1987;2:189–94.
Manos PJ. Ten-point clock test sensitivity for Alzheimer’s disease in patients with MMSE scores greater than 23. Int J Geriatr Psychiatry. 1999;14:454–8.
De Renzi E, Vignolo LA. The token test: a sensitive test to detect receptive disturbances in aphasics. Brain. 1962;85:665–78.
Filippi M, Basaia S, Canu E, Imperiale F, Meani A, Caso F, et al. Brain network connectivity differs in early-onset neurodegenerative dementia. Neurology. 2017;89:1764–72.
Sporns O, Chialvo DR, Kaiser M, Hilgetag CC. Organization, development and function of complex brain networks. Trends Cogn Sci. 2004;8:418–25.
Watts DJ, Strogatz SH. Collective dynamics of ‘small-world’ networks. Nature. 1998;393:440–2.
Zalesky A, Fornito A, Bullmore ET. Network-based statistic: identifying differences in brain networks. Neuroimage. 2010;53:1197–207.
Jenkinson M, Bannister P, Brady M, Smith S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage. 2002;17:825–41.
Andersson JL, Jenkinson M, Smith S. Non-linear registration, aka spatial normalisation. FMRIB technical report TR07JA2 2007.
Schmidt R, de Reus MA, Scholtens LH, van den Berg LH, van den Heuvel MP. Simulating disease propagation across white matter connectome reveals anatomical substrate for neuropathology staging in amyotrophic lateral sclerosis. Neuroimage. 2016;124(Pt A):762–9.
Zeileis A, Hothorn T, Hornik K. Model-based recursive partitioning. J Comput Graph Stat. 2008;17:492–514.
Tijms BM, Wink AM, de Haan W, van der Flier WM, Stam CJ, Scheltens P, et al. Alzheimer’s disease: connecting findings from graph theoretical studies of brain networks. Neurobiol Aging. 2013;34:2023–36.
Dipasquale O, Cercignani M. Network functional connectivity and whole-brain functional connectomics to investigate cognitive decline in neurodegenerative conditions. Funct Neurol. 2016;31:191–203.
Prescott JW, Guidon A, Doraiswamy PM, Roy Choudhury K, Liu C, Petrella JR. The Alzheimer structural connectome: changes in cortical network topology with increased amyloid plaque burden. Radiology. 2014;273:175–84.
Raj A, LoCastro E, Kuceyeski A, Tosun D, Relkin N, Weiner M. Network diffusion model of progression predicts longitudinal patterns of atrophy and metabolism in Alzheimer’s disease. Cell Rep. 2015. [Epub ahead of print; https://doi.org/10.1016/j.celrep.2014.12.034]
Schmidt R, Verstraete E, de Reus MA, Veldink JH, van den Berg LH, van den Heuvel MP. Correlation between structural and functional connectivity impairment in amyotrophic lateral sclerosis. Hum Brain Mapp. 2014;35:4386–95.
Filippi M, Agosta F. Structural and functional network connectivity breakdown in Alzheimer’s disease studied with magnetic resonance imaging techniques. J Alzheimer’s Dis: JAD. 2011;24:455–74.
Honey CJ, Sporns O, Cammoun L, Gigandet X, Thiran JP, Meuli R, et al. Predicting human resting-state functional connectivity from structural connectivity. Proc Natl Acad Sci USA. 2009;106:2035–40.
van den Heuvel MP, Mandl RC, Kahn RS, Hulshoff Pol HE. Functionally linked resting-state networks reflect the underlying structural connectivity architecture of the human brain. Hum Brain Mapp. 2009;30:3127–41.
Sun Y, Yin Q, Fang R, Yan X, Wang Y, Bezerianos A, et al. Disrupted functional brain connectivity and its association to structural connectivity in amnestic mild cognitive impairment and Alzheimer’s disease. PLoS ONE. 2014;9:e96505.
Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging. 1995;16:271–8. discussion 278−284
Whitwell JL, Josephs KA, Murray ME, Kantarci K, Przybelski SA, Weigand SD, et al. MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology. 2008;71:743–9.
Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13:614–29.
Azeez AK, Biswal BB. A review of resting-state analysis methods. Neuroimaging Clin N Am. 2017;27:581–92.
Johansen-Berg H, Rushworth MF. Using diffusion imaging to study human connectional anatomy. Annu Rev Neurosci. 2009;32:75–94.
Zalesky A, Fornito A, Harding IH, Cocchi L, Yucel M, Pantelis C, et al. Whole-brain anatomical networks: does the choice of nodes matter? Neuroimage. 2010;50:970–83.
de Reus MA, van den Heuvel MP. Estimating false positives and negatives in brain networks. Neuroimage. 2013;70:402–9.
van den Heuvel MP, de Lange SC, Zalesky A, Seguin C, Yeo BTT, Schmidt R. Proportional thresholding in resting-state fMRI functional connectivity networks and consequences for patient-control connectome studies: issues and recommendations. Neuroimage. 2017;152:437–49.
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.
Conflict of interest
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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