Published September 27, 2023 | Version v2
Preprint Open

Biological Definition of Neuronal alpha-Synuclein Disease: Towards an Integrated Staging System for Research

Authors/Creators

  • 1. Department of Neurology, Northwestern University Feinberg School of Medicine,
  • 2. Department of Neurology, University of Pittsburgh, Pittsburgh,
  • 3. Department of Neurology, Stanford University School of Medicine,
  • 4. Department of Biostatistics, College of Public Health, University of Iowa,
  • 5. Center for Drug Evaluation and Research, Food and Drug
  • 6. The Michael J. Fox Foundation for Parkinson's Research,
  • 7. Department of Biostatistics, College of Public Health, University of
  • 8. Amprion Inc.
  • 9. Biogen
  • 10. Patient Council, The Michael J. Fox Foundation for Parkinson's Research, and Clinical Solutions and Strategic Partnerships, WCG Clinical
  • 11. Department of Medical and Molecular Genetics, Indiana University
  • 12. The Michael J. Fox Foundation for Parkinson's
  • 13. Department of Biostatistics, College of Public Health, University of Iowa
  • 14. Denali Therapeutics Inc.
  • 15. Department of Neurology, University of Rochester Medical Center
  • 16. The Michael J. Fox Foundation for Parkinson's Research
  • 17. Department of Neurology, Northwestern University Feinberg School of Medicine
  • 18. Department of Neurology, University Medical Center Göttingen and Paracelsus-Elena-Klinik
  • 19. Department of Pathology, Stanford University School of Medicine
  • 20. F. Hoffmann-La Roche Ltd.
  • 21. Institute for Neurodegenerative Disorders
  • 22. National Institute on Aging, National Institutes of Health
  • 23. Critical Path for Parkinson's, Critical Path Institute
  • 24. Department of Neurology, Perelman School of Medicine
  • 25. Amprion Inc. and Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology
  • 26. Movement Disorders and Neuromodulation Center, Department of Neurology, Weill Institute for Neuroscience and Parkinson's Disease Research Education and Clinical Center, San Francisco Veteran's Affairs Health Care System
  • 27. Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona and Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic, IDIBAPS, Universitat de Barcelona
  • 28. 24. University of Pennsylvania and the Parkinson's Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC), Philadelphia Veterans Affairs Medical Center
  • 29. Department of Neurology, Perelman School of Medicine, University of Pennsylvania
  • 30. Senior Advisor, The Michael J. Fox Foundation for Parkinson's Research

Contributors

Researcher:

  • 1. Unviersity of Innsbruck
  • 2. Community Representative
  • 3. Parkinson Canada
  • 4. Shake It Up Australia Foundation
  • 5. Parkinson's UK
  • 6. Lewy Body Dementia Association
  • 7. Cure Parkinson's
  • 8. Parkinson's Foundation
  • 9. The Critical Path Institute

Description

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are currently defined by their clinical features with alpha-synuclein (asyn) pathology as the gold standard to establish the definitive diagnosis.  We propose that given biomarker advances enabling accurate detection of pathologic asyn in vivo using the Seed Amplification Assay, it is time to finally redefine PD and DLB based on biology as "Neuronal alpha-Synuclein Disease (NSD)" rather than as clinical syndromes.  A biologic definition for PD and DLB is a major shift, but simply reflects that we now have the tools to assess the gold standard required for diagnosis, pathological neuronal-asyn (n-asyn), during life. NSD is defined by presence of pathologic n-asyn species detected in vivo (S) independent of any specific clinical syndrome. We further propose that individuals with n-asyn are at risk for dopaminergic neuronal dysfunction (D), the second biologic anchor for NSD. The biological definition allows us to propose a staging system, the NSD Integrated Staging System (NSD-ISS), rooted in the biological anchors (S and D) and degree of functional impairment caused by clinical signs/symptoms. Stages 0-1 are without signs/symptoms and defined by presence of pathogenic variants in SNCA gene (Stage 0), S alone (Stage 1A) or S and D (Stage 1B). Presence of clinical manifestations marks transition to Stage 2 and beyond. Stage 2 is characterized by subtle signs/symptoms but no functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. NSD definition and NSD-ISS research framework are essential to advancing biologically-targeted therapeutics and enabling interventional trials at early disease stages. The NSD-ISS will evolve, including incorporation of data-driven definition of stage-specific functional anchors and additional biomarkers, as they emerge and are validated. Presently, NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.

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Lancet Manuscript Revision 09_27_23.pdf

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Additional details

Related works

Is new version of
Preprint: 10.5281/zenodo.8178862 (DOI)

Dates

Accepted
2023-09-27