Journal article
A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research
Lancet neurology, Vol.23(2), pp.178-190
02/2024
DOI: 10.1016/S1474-4422(23)00405-2
PMID: 38267190
Abstract
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.
Details
- Title: Subtitle
- A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research
- Creators
- Tanya Simuni - Northwestern UniversityLana M Chahine - University of PittsburghKathleen Poston - Stanford UniversityMichael Brumm - University of IowaTeresa Buracchio - Center for Drug Evaluation and ResearchMichelle Campbell - Center for Drug Evaluation and ResearchSohini Chowdhury - Michael J. Fox FoundationChristopher Coffey - University of IowaLuis Concha-Marambio - Amprion (United States)Tien Dam - Biogen (United States)Peter DiBiaso - Clinical SolutionsTatiana Foroud - Indiana University – Purdue University IndianapolisMark Frasier - Michael J. Fox FoundationCaroline Gochanour - University of IowaDanna Jennings - Denali Therapeutics (United States)Karl Kieburtz - University of Rochester Medical CenterCatherine M Kopil - Michael J. Fox FoundationKalpana Merchant - Northwestern UniversityBrit Mollenhauer - Paracelsus Elena Klinik KasselThomas Montine - Stanford UniversityKelly Nudelman - Indiana University – Purdue University IndianapolisGennaro Pagano - Roche (Switzerland)John Seibyl - Institute for Neurodegenerative DisordersTodd Sherer - Michael J. Fox FoundationAndrew Singleton - National Institute on AgingDiane Stephenson - Critical Path InstituteMatthew Stern - University of PennsylvaniaClaudio Soto - Amprion (United States)Caroline M Tanner - University of California, San FranciscoEduardo Tolosa - Universitat de BarcelonaDaniel Weintraub - University of PennsylvaniaYuge Xiao - Michael J. Fox FoundationAndrew Siderowf - University of PennsylvaniaBilly Dunn - Michael J. Fox FoundationKenneth Marek - Institute for Neurodegenerative Disorders
- Resource Type
- Journal article
- Publication Details
- Lancet neurology, Vol.23(2), pp.178-190
- DOI
- 10.1016/S1474-4422(23)00405-2
- PMID
- 38267190
- NLM abbreviation
- Lancet Neurol
- ISSN
- 1474-4422
- eISSN
- 1474-4465
- Grant note
- DOI: 10.13039/100017312, name: Lewy Body Dementia Association; DOI: 10.13039/501100000304, name: Parkinson's UK; DOI: 10.13039/501100009307, name: Parkinson Society Canada; DOI: 10.13039/100000864, name: Michael J Fox Foundation for Parkinson's Research; DOI: 10.13039/100015659, name: Cure Parkinson's
- Language
- English
- Date published
- 02/2024
- Academic Unit
- Biostatistics
- Record Identifier
- 9984548853002771
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