Has the time come to redefine Parkinson's disease?

[...]the predictive value of the criteria that define each stage is unclear. [...]the proposed staging system can only be considered as a working hypothesis at this moment, to be tested in future research. [...]an open question remains as to how these frameworks will be used in practice. NSD-ISS1 SynNeurGe2 Overlap Characteristics Purpose Biological definition Yes Yes Yes Classification No Yes No Integrated staging system Yes No No Disease label Neuronal α-synuclein disease Parkinson's disease No Key components Genetic variants Yes Yes Yes Fully penetrant variants Only rare SNCA variants Several No Variants that convey a substantially increased risk No Several Partial Variants associated with clinical Parkinson's disease without α-synuclein pathology No Yes No α-synuclein pathology Yes Yes Yes CSF seed amplification assays Yes Yes Yes Other assays No Skin seed amplification assays, skin immunohistochemistry, or immunohistofluorescence No Discrimination of neuronal α-synuclein disease or Parkinson's disease versus multiple system atrophy According to CSF seed amplification assays On the basis of α-synuclein pathology assays and additional exclusionary plasma or neuroimaging measures Partial Neuronal dysfunction or neurodegeneration Yes Yes Yes DAT scan Yes Yes Yes Other dopaminergic imaging modalities No Yes No Non-dopaminergic imaging modalities No [18F]fluorodeoxyglucose-PET as marker of Parkinson's disease-related metabolic pattern; metaiodobenzylguanidin SPECT as marker of peripheral autonomic involvement No Clinical signs and symptoms Not used to diagnose neuronal α-synuclein disease Not used to diagnose Parkinson's disease No Considered for diagnosis (of neuronal α-synuclein disease or Parkinson's disease) No No Yes Used for other purpose To distinguish stages with increasing functional impairment A list of motor and non-motor features is provided to distinguish whether signs and symptoms are possibly or probably related to Parkinson's disease No Case definition* Sporadic disease (neuronal α-synuclein disease or Parkinson's disease) α-synuclein pathology and neurodegeneration Yes Yes Yes α-synuclein pathology without neurodegeneration Yes No† No Genetic disease (neuronal α-synuclein disease or Parkinson's disease) Fully penetrant variant, regardless of α-synuclein pathology or neuronal dysfunction Yes (rare SNCA variants only) Yes Yes Variant that conveys a substantially increased risk; and neuronal dysfunction; and α-synuclein pathology Yes Yes Yes V