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Longitudinal brain connectivity changes and clinical evolution in Parkinson’s disease

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Abstract

Longitudinal connectivity studies might guide our understanding of the underlying neurodegenerative processes. We report the results of a longitudinal study in patients at different stages of Parkinson’s disease (PD), who performed motor and non-motor evaluations and serial resting state (RS) functional MRI (fMRI). Cluster analysis was applied to demographic and clinical data of 146 PD patients to define disease subtypes. Brain network functional alterations were assessed at baseline in PD relative to 60 healthy controls and every year for a maximum of 4 years in PD groups. Progression of brain network changes were compared between patient clusters using RS fMRI. The contribution of network changes in predicting clinical deterioration was explored. Two main PD clusters were identified: mild PD (86 patients) and moderate-to-severe PD (60 patients), with the latter group being older and having earlier onset, longer PD duration, more severe motor, non-motor and cognitive deficits. Within the mild patient cluster, two clinical subtypes were further identified: mild motor-predominant (43) and mild-diffuse (43), with the latter being older and having more frequent non-motor symptoms. Longitudinal functional connectivity changes vary across patients in different disease stages with the coexistence of hypo- and hyper-connectivity in all subtypes. RS fMRI changes were associated with motor, cognitive and non-motor evolution in PD patients. Baseline RS fMRI presaged clinical and cognitive evolution. Our network perspective was able to define trajectories of functional architecture changes according to PD stages and prognosis. RS fMRI may be an early biomarker of PD motor and non-motor progression.

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Fig. 1: Functional connectivity changes over time in moderate-to-severe vs mild PD subtypes.
Fig. 2: Functional connectivity changes over time in mild-diffuse vs mild motor-predominant PD subtypes.

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References

  1. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Prim. 2017;3:17013.

    Article  Google Scholar 

  2. Greenland JC, Williams-Gray CH, Barker RA. The clinical heterogeneity of Parkinson’s disease and its therapeutic implications. Eur J Neurosci. 2019;49:328–38.

    Article  Google Scholar 

  3. Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, et al. Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol. 2009;8:1150–7.

    Article  CAS  Google Scholar 

  4. Goedert M, Masuda-Suzukake M, Falcon B. Like prions: the propagation of aggregated tau and alpha-synuclein in neurodegeneration. Brain. 2017;140:266–78.

    Article  Google Scholar 

  5. Yau Y, Zeighami Y, Baker TE, Larcher K, Vainik U, Dadar M, et al. Network connectivity determines cortical thinning in early Parkinson’s disease progression. Nat Commun. 2018;9:12.

    Article  CAS  Google Scholar 

  6. Cerasa A, Novellino F, Quattrone A. Connectivity changes in Parkinson’s disease. Curr Neurol Neurosci Rep. 2016;16:91.

    Article  Google Scholar 

  7. Tahmasian M, Eickhoff SB, Giehl K, Schwartz F, Herz DM, Drzezga A, et al. Resting-state functional reorganization in Parkinson’s disease: An activation likelihood estimation meta-analysis. Cortex. 2017;92:119–38.

    Article  Google Scholar 

  8. Filippi M, Sarasso E, Agosta F. Resting-state functional MRI in Parkinsonian syndromes. Mov Disord Clin Pr. 2019;6:104–17.

    Article  Google Scholar 

  9. Rubinov M, Sporns O. Complex network measures of brain connectivity: uses and interpretations. Neuroimage. 2010;52:1059–69.

    Article  Google Scholar 

  10. Crossley NA, Mechelli A, Scott J, Carletti F, Fox PT, McGuire P, et al. The hubs of the human connectome are generally implicated in the anatomy of brain disorders. Brain. 2014;137(Pt 8):2382–95.

    Article  Google Scholar 

  11. Fornito A, Zalesky A, Breakspear M. The connectomics of brain disorders. Nat Rev Neurosci. 2015;16:159–72.

    Article  CAS  Google Scholar 

  12. Skidmore F, Korenkevych D, Liu Y, He G, Bullmore E, Pardalos PM. Connectivity brain networks based on wavelet correlation analysis in Parkinson fMRI data. Neurosci Lett. 2011;499:47–51.

    Article  CAS  Google Scholar 

  13. Gottlich M, Munte TF, Heldmann M, Kasten M, Hagenah J, Kramer UM. Altered resting state brain networks in Parkinson’s disease. PLoS ONE. 2013;8:e77336.

    Article  Google Scholar 

  14. Baggio HC, Sala-Llonch R, Segura B, Marti MJ, Valldeoriola F, Compta Y, et al. Functional brain networks and cognitive deficits in Parkinson’s disease. Hum Brain Mapp. 2014;35:4620–34.

    Article  Google Scholar 

  15. Fang J, Chen H, Cao Z, Jiang Y, Ma L, Ma H, et al. Impaired brain network architecture in newly diagnosed Parkinson’s disease based on graph theoretical analysis. Neurosci Lett. 2017;657:151–8.

    Article  CAS  Google Scholar 

  16. Suo X, Lei D, Li N, Cheng L, Chen F, Wang M, et al. Functional brain connectome and its relation to Hoehn and Yahr stage in Parkinson disease. Radiology. 2017;285:904–13.

    Article  Google Scholar 

  17. Abos A, Baggio HC, Segura B, Garcia-Diaz AI, Compta Y, Marti MJ, et al. Discriminating cognitive status in Parkinson’s disease through functional connectomics and machine learning. Sci Rep. 2017;7:45347.

    Article  CAS  Google Scholar 

  18. Gratton C, Koller JM, Shannon W, Greene DJ, Maiti B, Snyder AZ, et al. Emergent functional network effects in Parkinson disease. Cereb Cortex. 2019;29:1701.

    Article  Google Scholar 

  19. Lopes R, Delmaire C, Defebvre L, Moonen AJ, Duits AA, Hofman P, et al. Cognitive phenotypes in parkinson’s disease differ in terms of brain-network organization and connectivity. Hum Brain Mapp. 2017;38:1604–21.

    Article  Google Scholar 

  20. de Schipper LJ, Hafkemeijer A, van der Grond J, Marinus J, Henselmans JML, van Hilten JJ. Altered whole-brain and network-based functional connectivity in Parkinson’s disease. Front Neurol. 2018;9:419.

    Article  Google Scholar 

  21. Luo CY, Guo XY, Song W, Chen Q, Cao B, Yang J, et al. Functional connectome assessed using graph theory in drug-naive Parkinson’s disease. J Neurol. 2015;262:1557–67.

    Article  CAS  Google Scholar 

  22. Lin SJ, Baumeister TR, Garg S, McKeown MJ. Cognitive profiles and hub vulnerability in Parkinson’s disease. Front Neurol. 2018;9:482.

    Article  Google Scholar 

  23. Olde Dubbelink KT, Schoonheim MM, Deijen JB, Twisk JW, Barkhof F, Berendse HW. Functional connectivity and cognitive decline over 3 years in Parkinson disease. Neurology. 2014;83:2046–53.

    Article  CAS  Google Scholar 

  24. Zeng Q, Guan X, Law Yan Lun JCF, Shen Z, Guo T, Xuan M, et al. Longitudinal alterations of local spontaneous brain activity in Parkinson’s disease. Neurosci Bull. 2017;33:501–9.

    Article  Google Scholar 

  25. Tuovinen N, Seppi K, de Pasquale F, Muller C, Nocker M, Schocke M, et al. The reorganization of functional architecture in the early-stages of Parkinson’s disease. Parkinsonism Relat Disord. 2018;50:61–8.

    Article  Google Scholar 

  26. Sporns O, Chialvo DR, Kaiser M, Hilgetag CC. Organization, development and function of complex brain networks. Trends Cogn Sci. 2004;8:418–25.

    Article  Google Scholar 

  27. Watts DJ, Strogatz SH. Collective dynamics of ‘small-world’ networks. Nature. 1998;393:440–2.

    Article  CAS  Google Scholar 

  28. Zalesky A, Fornito A, Bullmore ET. Network-based statistic: identifying differences in brain networks. Neuroimage. 2010;53:1197–207.

    Article  Google Scholar 

  29. Wolters AF, van de Weijer SCF, Leentjens AFG, Duits AA, Jacobs HIL, Kuijf ML. Resting-state fMRI in Parkinson’s disease patients with cognitive impairment: a meta-analysis. Parkinsonism Relat Disord 2019;62:16–27.

    Article  Google Scholar 

  30. Rolinski M, Griffanti L, Piccini P, Roussakis AA, Szewczyk-Krolikowski K, Menke RA. et al. Basal ganglia dysfunction in idiopathic REM sleep behaviour disorder parallels that in early Parkinson’s disease. Brain. 2016;139:2224–34.

    Article  Google Scholar 

  31. Hepp DH, Foncke EMJ, Olde Dubbelink KTE, van de Berg WDJ, Berendse HW, Schoonheim MM. Loss of functional connectivity in patients with Parkinson disease and visual hallucinations. Radiology. 2017;285:896–903.

    Article  Google Scholar 

  32. Chung SJ, Bae YJ, Jun S, Yoo HS, Kim SW, Lee YH et al. Dysautonomia is associated with structural and functional alterations in Parkinson disease. Neurology 2019;92:e1456–67.

    Article  Google Scholar 

  33. Braak H, Bohl JR, Muller CM, Rub U, de Vos RA, Del Tredici K. Stanley Fahn Lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Mov Disord. 2006;21:2042–51.

    Article  Google Scholar 

  34. Pagano G, Ferrara N, Brooks DJ, Pavese N. Age at onset and Parkinson disease phenotype. Neurology. 2016;86:1400–7.

    Article  CAS  Google Scholar 

  35. Darweesh SK, Koudstaal PJ, Stricker BH, Hofman A, Ikram MA. Trends in the incidence of Parkinson disease in the general population: the Rotterdam study. Am J Epidemiol. 2016;183:1018–26.

    Article  Google Scholar 

  36. Kempster PA, O’Sullivan SS, Holton JL, Revesz T, Lees AJ. Relationships between age and late progression of Parkinson’s disease: a clinico-pathological study. Brain. 2010;133(Pt 6):1755–62.

    Article  Google Scholar 

  37. Greenland JC, Williams-Gray CH, Barker RA. The clinical heterogeneity of Parkinson’s disease and its therapeutic implications. Eur J Neurosci. 2019;49:328–38.

    Article  Google Scholar 

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Acknowledgements

The authors thank the patients and their families for the time and effort they dedicated to the research, and Dr. Homa Zahedmanesh, Dr. Marta Gandolla and Prof. Alessandra Pedrocchi from Politecnico di Milano, Italy for the fruitful discussion.

Funding

Ministry of Education, Science, and Technological Development of the Republic of Serbia (project #175090).

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Authors and Affiliations

  1. Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Massimo Filippi, Silvia Basaia, Elisabetta Sarasso, Noemi Piramide & Federica Agosta

  2. Neurology Unit and Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Massimo Filippi

  3. Vita-Salute San Raffaele University, Milan, Italy

    Massimo Filippi, Elisabetta Sarasso, Noemi Piramide & Federica Agosta

  4. Clinic of Neurology, School of Medicine, University of Belgrade, Belgrade, Serbia

    Tanja Stojkovic, Iva Stankovic, Aleksandra Tomic, Elka Stefanova, Vladana Markovic & Vladimir S. Kostic

  5. Unit of Biostatistics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy

    Andrea Fontana

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  1. Massimo Filippi
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Contributions

M.F. is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). S.B., E.S., I.S., A.F., A.T., N.P. and V.M. report no disclosures. T.S. has received speaker honoraria from Actavis and Alzheimer’s Association International Research Grant. E.S. has received speaker honoraria from Actavis. V.S.K. has received speaker honoraria from Actavis and Solveo. F.A. is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Novartis, Biogen Idec and Philips; 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.

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Correspondence to Massimo Filippi.

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Filippi, M., Basaia, S., Sarasso, E. et al. Longitudinal brain connectivity changes and clinical evolution in Parkinson’s disease. Mol Psychiatry 26, 5429–5440 (2021). https://doi.org/10.1038/s41380-020-0770-0

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