Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are currently defined by their clinical features with alpha-synuclein (asyn) pathology as the gold standard to establish the definitive diagnosis. We propose that given biomarker advances enabling accurate detection of pathologic asyn in vivo using the Seed Amplification Assay, it is time to finally redefine PD and DLB based on biology as "Neuronal alpha-Synuclein Disease (NSD)" rather than as clinical syndromes. A biologic definition for PD and DLB is a major shift, but simply reflects that we now have the tools to assess the gold standard required for diagnosis, pathological neuronal-asyn (n-asyn), during life. NSD is defined by presence of pathologic n-asyn species detected in vivo (S) independent of any specific clinical syndrome. We further propose that individuals with n-asyn are at risk for dopaminergic neuronal dysfunction (D), the second biologic anchor for NSD. The biological definition allows us to propose a staging system, the NSD Integrated Staging System (NSD-ISS), rooted in the biological anchors (S and D) and degree of functional impairment caused by clinical signs/symptoms. Stages 0-1 are without signs/symptoms and defined by presence of pathogenic variants in SNCA gene (Stage 0), S alone (Stage 1A) or S and D (Stage 1B). Presence of clinical manifestations marks transition to Stage 2 and beyond. Stage 2 is characterized by subtle signs/symptoms but no functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. NSD definition and NSD-ISS research framework are essential to advancing biologically-targeted therapeutics and enabling interventional trials at early disease stages. The NSD-ISS will evolve, including incorporation of data-driven definition of stage-specific functional anchors and additional biomarkers, as they emerge and are validated. Presently, NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.