Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”

Tiago F. Outeiro*, Roy N. Alcalay, Angelo Antonini, Johannes Attems, Vincenzo Bonifati, Francisco Cardoso, Marie Françoise Chesselet, John Hardy, Graziella Madeo, Ian McKeith, Brit Mollenhauer, Darren J. Moore, Olivier Rascol, Michael G. Schlossmacher, Hermona Soreq, Leonidas Stefanis, Joaquim J. Ferreira*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Background: More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them. Objective: This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for “defining the riddle” will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD. Conclusion: Accuracy in defining endophenotypes of “typical PD” across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine.

Original languageEnglish
Pages (from-to)1127-1142
Number of pages16
JournalMovement Disorders
Issue number7
StatePublished - Jul 2023
Externally publishedYes


FundersFunder number
Advanced ERC
Israel Science Fund
Parkinson Fonds Deutschland
Stichting Parkinson Fonds
National Institutes of Health
U.S. Department of Defense
Michael J. Fox Foundation for Parkinson's Research
National Parkinson Foundation
Parkinson's Foundation
European Commission
Deutsche Forschungsgemeinschaft2067/1‐390729940
Horizon 2020
Deutsche Parkinson Vereinigung


    • Lewy body
    • Parkinson's disease
    • biological definition
    • biomarker
    • diagnostic criteria
    • neurodegeneration
    • neuropathology


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