The challenges with the identification of Parkinson’s disease subtypes

Introduction: Parkinson's disease (PD) exhibits distinct phenotypes with specific pathophysiological features. Their definition is essential to inform therapeutic choices and trials design. Areas covered: We searched in September 2025 PubMed/MEDLINE, Scopus, and Web of Science to review current PD stratifications strategies based on clinical, tissue, and imaging biomarkers, highlighting their specific strengths and limitations. We provide an overview of the proposed pathophysiological mechanisms underlying distinct phenotypes and the open challenges in the field. Expert opinion: Subtyping of PD based on clinical phenotype is rapidly evolving, driven by advances in understanding its pathological mechanisms and clinical heterogeneity. Identifying distinct PD phenotypes is essential to deliver personalized care and optimize clinical trial design, particularly for disease-modifying therapies. Neurotransmitter-based subtyping (cholinergic/noradrenergic/serotonergic) provides a biologically grounded framework that partially overlaps with anatomical models such as the brain-first/body-first distinction. However, validity of such models is also controversial, especially in more advanced stages of PD where many pathways merge. Integrating multimodal data, including clinical/imaging/biomarker/genetic measures, is crucial to improve stratification accuracy and account for comorbidities/copathology. Future progress relies on hypothesis-supervised data-driven approaches, longitudinal validation, and globally inclusive cohorts to achieve robust, biologically informed, and clinically meaningful PD subtyping.