Are we ready for a biological diagnosis of Parkinson's Disease?

The diagnosis of Parkinson's disease (PD) is currently based on clinical criteria, centered on the characteristic motor syndrome. However, motor manifestations become evident only after a significant proportion of nigro-striatal dopaminergic neurons have already undergone neurodegeneration. The recent "NSD-ISS" and "SynNeurGe" research frameworks have proposed new biological diagnostic criteria focusing on α-synucleinopathy, neurodegeneration, and genetic biomarkers, independent of clinical manifestations. These proposals intend to detect the disease at a "biologically early phase" to foster advances in research and development of disease-modifying treatments. While the shift to a biological approach is mandatory to better understand PD, challenges to the new frameworks remain, including inherent criticisms, limitations in explaining PD clinical-biological complexity, restricted clinical applicability and related ethical concerns. In this paper, we describe the historical path toward the two biological proposals, explore critical issues and knowledge gaps emerging from them, and discuss the risk of their premature application in the clinical setting.