SynNeurGe: The road ahead for a biological definition of Parkinson's disease.

While significant progress has been made in treating Parkinson's disease (PD) symptoms, disease-modifying therapies (DMTs) have consistently failed. To address the underlying molecular mechanisms of PD, two biology-based criteria have been proposed: the "Synucleinopathy-Neurodegeneration-Genetics" (SynNeurGe) and "neuronal α-synuclein disease" (NSD) frameworks. Both frameworks emphasize the importance of biological markers over clinical symptoms. They recognize α-synuclein aggregation and genetic mutations (such as SNCA) as key diagnostic elements, with α-synuclein seed amplification assays (SAA) in cerebrospinal fluid (CSF) used to detect early disease stages. Dopaminergic neurodegeneration, measured by DAT imaging, is also central to both frameworks. These shared features aim to improve early diagnosis and precision medicine for PD. However, SynNeurGe provides a broader, more flexible framework that integrates α-synuclein pathology (S), neurodegeneration (N), and genetics (G), linked to clinical features (C). It aims to accommodate the complexity of PD and related Lewy body diseases, facilitating research on targeted DMTs. In contrast, NSD focuses specifically on PD and Lewy body dementia, introducing a staging system (NSD-ISS) based on biological markers and clinical impairment, helping track disease progression from preclinical to symptomatic stages. Despite their differences, both approaches highlight the need for more specific biomarkers and prospective studies to improve early intervention and personalized treatment. Harmonizing SynNeurGe and NSD concepts will be key in creating a universally accepted framework for precise PD diagnosis and therapy development.