This review advocates shifting PD to a biologically defined disorder, emphasizing molecular imaging (dopaminergic imaging, [18F]FDG PET, cardiac [123I]MIBG), the promise of α‑synuclein PET, seed amplification assays, and genetic stratification to create biomarker-driven classification systems.

By defining and prioritizing in vivo imaging and molecular biomarkers for patient stratification and endpoints, the paper has practical translational value for designing and powering trials of disease‑modifying therapies in Parkinson's disease.

In this article, we outline the ongoing conceptual transition of Parkinson disease (PD) from a clinically defined syndrome to a biologically defined disorder. We synthesize recent advances in neuropathology, genetics, and biomarker research, with particular emphasis on the central role of molecular imaging within emerging biology-based frameworks. We discuss how established imaging biomarkers-including dopaminergic imaging, [18F]FDG PET, and cardiac [123I]MIBG scintigraphy-provide objective in vivo measures of neurodegeneration that complement α-synuclein seed amplification assays and genetic stratification. In addition, we review the current state of α-synuclein PET tracer development and critically evaluate its potential to enable direct visualization of disease-defining pathology in vivo. We highlight the growing importance of biomarker-driven classification systems for patient stratification and the design of trials of disease-modifying therapies in PD. At the same time, we address key scientific, methodologic, and ethical challenges associated with implementing biologically grounded disease definitions. Together, these developments position molecular imaging as a cornerstone of future precision medicine approaches in PD.