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A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research
Open accessAbstract
Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-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 α-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 α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn 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-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-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 α-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.
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Metadata
- Authors
- Simuni, T., Chahine, L. M., Poston, K., Brumm, M., Buracchio, T., Campbell, M., Chowdhury, S., Coffey, C., Concha-Marambio, L., Dam, T., DiBiaso, P., Foroud, T., Frasier, M., Gochanour, C., Jennings, D., Kieburtz, K., Kopil, C. M., Merchant, K., Mollenhauer, B., Montine, T., Nudelman, K., Pagano, G., Seibyl, J., Sherer, T., Singleton, A., Stephenson, D., Stern, M., Soto, C., Tanner, C. M., Tolosa, E., Weintraub, D., Xiao, Y., Siderowf, A., Dunn, B., & Marek, K.
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2024-02
- Volume
- 23
- Issue
- 2
- Pages
- 178-190
- ISSN
- 1474-4422 (ISSN-L)
- OpenAlex
- W4391090353
- Cited by
- 629
- References
- 94
- FWCI
- 144.42
- Type
- journal article
- Language
- en
- Open access
- green
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- Simuni, T., Chahine, L. M., Poston, K., Brumm, M., Buracchio, T., Campbell, M., Chowdhury, S., Coffey, C., Concha-Marambio, L., Dam, T., DiBiaso, P., Foroud, T., Frasier, M., Gochanour, C., Jennings, D., Kieburtz, K., Kopil, C. M., Merchant, K., Mollenhauer, B., . . . Marek, K. (2024). A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. The Lancet Neurology. https://doi.org/10.1016/s1474-4422(23)00405-2
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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