The heterogeneity of Parkinson's disease

Research output: Contribution to journalReview articleInvitedpeer-review


  • Ullrich Wüllner - , University of Bonn Medical Center, German Center for Neurodegenerative Diseases (DZNE) - Partner Site Bonn (Author)
  • Per Borghammer - , Aarhus University Hospital (AUH) (Author)
  • Chi-Un Choe - , Hospital Itzehoe (Author)
  • Ilona Csoti - , Gertrudis Klinik Biskirchen – Parkinson Zentrum (Author)
  • Björn Falkenburger - , Department of Neurology, Department of Child and Adolescent Psychiatry and Psychotherapy (Author)
  • Thomas Gasser - , German Center for Neurodegenerative Diseases (DZNE) - Partner Site Tübingen, University of Tübingen (Author)
  • Paul Lingor - , Klinikum Rechts der Isar (MRI TUM) (Author)
  • Peter Riederer - , University Hospital of Würzburg, University of Southern Denmark (Author)


The heterogeneity of Parkinson's disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also the various implicated pathophysiological pathways pose a major challenge for future research projects and therapeutic trail design. We outline several pathophysiological concepts, pathways and mechanisms, including the presumed roles of α-synuclein misfolding and aggregation, Lewy bodies, oxidative stress, iron and melanin, deficient autophagy processes, insulin and incretin signaling, T-cell autoimmunity, the gut-brain axis and the evidence that microbial (viral) agents may induce molecular hallmarks of neurodegeneration. The hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) agents in susceptible individuals upon entry via the olfactory bulb (brain first) or the gut (body-first), which would support the idea that disease mechanisms may change over time. The unresolved heterogeneity of PD may have contributed to the failure of past clinical trials, which attempted to slow the course of PD. We thus conclude that PD patients need personalized therapeutic approaches tailored to specific phenomenological and etiologic subtypes of disease.


Original languageEnglish
Pages (from-to)827-838
Number of pages12
JournalJournal of neural transmission
Issue number6
Publication statusPublished - Jun 2023

External IDs

PubMedCentral PMC10174621
Scopus 85159367945
ORCID /0000-0002-2387-526X/work/150328942



  • Humans, Parkinson Disease/drug therapy, alpha-Synuclein/metabolism, Lewy Bodies/metabolism, Brain/metabolism, T-Lymphocytes/metabolism