Biologic Definition of Parkinson Disease: A Pivotal Role for Molecular Imaging.

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.