Abstract

Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with a-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological a-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal a-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal a-synuclein (n-asyn) in human beings during life. Neuronal a-synuclein disease is defined by the presence of pathological n-asyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-asyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal a-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal a-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.

View details for DOI 10.1016/S1474-4422(23)00405-2

View details for PubMedID 38267190