We appreciate Espay et al.'s letter 1 written in response to our recently published article. 2 Interestingly, we found these comments not a “refutation” of the Neuronal α‐Synuclein Disease‐Integrated Staging System (NSD‐ISS) research framework, but largely an endorsement of this approach, highlighting a need for additional research to study and refine it, with which we agree. We fully agree that the field currently lacks quantitative fluid and imaging biomarkers to define progression through all disease stages; we and others are focused on developing quantitative alpha‐synuclein (α‐syn) and other key markers of neurodegeneration. Despite this limitation, we demonstrated that NSD‐ISS provides a valuable research framework to guide future disease‐targeting clinical trials. The focus of our article was on participants diagnosed clinically with “typical” early Parkinson's disease (PD), and we showed that overall they progress, as expected, through pivotal early NSD stages (ie, Stages 2–4) over a 5‐year period. This confirmation of progression through the staging system will inform clinical trials.
We also agree that the NSD‐ISS staging system will likely identify large numbers of Stage 1 individuals who may not become symptomatic during life, or only after many years, similar to what has been reported for Alzheimer's disease. This likelihood is supported by emerging data that 6–8% of otherwise healthy individuals above the age of 60 years have evidence of α‐syn pathology, 3 but the prevalence of clinical PD in this age group is only 1%. Detecting additional biomarkers that determine which Stage 1 NSD‐ISS individuals are likely to progress is a current research focus, to enable recruitment for clinical trials, to prevent disease progression, and, ultimately, population screening. For now, the Parkinson's Progression Markers Initiative (PPMI) is prioritizing recruitment of individuals in NSD Stage 2A as the next step in assessing early NSD and its progression. Development of an α‐syn blood biomarker or a synuclein positron emission spectrometry (PET) tracer would allow PPMI to assess Stage 1 as well.
Our current article focusing on 5‐year progression through and from Stages 2–4 shows that initiation of symptomatic motor therapy resulted in some stage reversion from Stages 3 (8%) and 4 (41%). We highlighted that this is an expected effect of anchoring Stages 3–6 to functional impairment rather than quantitative biomarkers, as the former can be affected by effective treatments. Ultimately, assessment of functional impairment in conjunction with impact on biology will be the essential drivers for documenting therapeutic efficacy that is most meaningful for patients and provides support for regulatory approval, and will distinguish symptomatic therapies from disease‐targeted therapies. 4 The NSD‐ISS was put forward as an initial research framework with a goal for evolution, with clear anticipation that this will happen as the field develops and validates new biomarkers and functional measures.
The NSD‐ISS research framework informs the progression of disease in the key “early PD” population and will evolve to inform progression of all stages of NSD as biomarker research evolves. The world of neurodegenerative diseases (eg, Alzheimer's disease, Huntington's disease, multiple sclerosis) has moved into the era of biological definitions, in combination with clinical measures anchored to degree of functional impairment, to enable development of disease‐targeted therapies that millions of individuals suffering from these devastating diseases impatiently await. We have eagerly embraced this new era while humbly recognizing that our framework is just the first step in an ongoing, rapidly evolving process that will require a concerted effort from all of us in the global research community.
Author Roles
(1) Manuscript Preparation: A. Writing of the First Draft, B. Editing and Final Approval.T.S.: 1A.
T.S., L.M.C., K.L.P., C.M.K., D.W., B.D., K.M.: 1B.
Relevant conflicts of interest/financial disclosures: T.S. declares consultancies for AcureX, Adamas, AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson's Consortium, Denali, The Michael J. Fox Foundation, Neuroderm, Roche, Sanofi, Sinopia, Takeda, and Vanqua Bio; on advisory boards for AcureX, Adamas, AskBio, Biohaven, Denali, GAIN, Neuron23, and Roche; on scientific advisory boards for Koneksa, Neuroderm, Sanofi, and UCB; and received research funding from Amneal, Biogen, Roche, Neuroderm, Sanofi, Prevail, and UCB and an investigator for the National Institute of Neurological Disorders and Stroke (NINDS), The Michael J. Fox Foundation, Parkinson's Foundation. L.M.C. declares grants to her institution from Biogen (clinical trial funding), The Michael J. Fox Foundation, UPMC Competitive Medical Research Fund, National Institutes of Health (NIH), and University of Pittsburgh; grant and travel support from The Michael J. Fox Foundation; royalties from Wolters Kluwer (for authorship); and in‐kind donation by Advanced Brain Monitoring of equipment for research study to her institution. K.L.P. declares consultancies for Curasen; was on a scientific advisory board for Curasen and Amprion; honoraria from invited scientific presentations to universities and professional societies not exceeding $5000 per year from California Congress of Clinical Neurology, California Neurological Society, and Johns Hopkins University; and patents or patent applications numbers 17/314,979 and 63/377,293. K.L.P. also declares grants to her institution (Stanford University School of Medicine) from NIH/NINDS NS115114, NS062684, NS075097, NIH/NIA U19 AG065156, P30 AG066515, The Michael J. Fox Foundation, Lewy Body Dementia Association, Alzheimer's Drug Discovery Foundation, and Sue Berghoff. C.M.K. declares employment for The Michael J. Fox Foundation. D.W. declares salary support from The Michael J. Fox Foundation for serving on an Executive Steering Committee for the Parkinson's Progression Markers Initiative (PPMI) and consultancies for Roche Pharma. In addtion, he has received research funding or support from The Michael J. Fox Foundation for Parkinson's Research, International Parkinson and Movement Disorder Society (IPMDS), NIH, The Parkinson's Foundation, and the U.S. Department of Veterans Affairs; honoraria for consultancy from AbbVie, Boehringer Ingelheim, Cerevel Therapeutics, CHDI Foundation, Citrus Health Group, Medscape, Modality.AI, Sage Therapeutics, Scion NeuroStim, Signant Health, and Vanqua Bio; and license fee payments from the University of Pennsylvania for the QUIP and QUIP‐RS. B.D. has received consulting fees and travel support for his role as an advisor for Arch Venture Partners, Cerveau Technologies, Epilepsy Foundation, Loulou Foundation, and The Michael J. Fox Foundation. B.D. has a leadership or fiduciary role in the Virginia Neurological Society (Past President) and Prothena (Director). B.D. holds stock options with Prothena. K.M. declares support to his institution (Institute for Neurodegenerative Disorders) from The Michael J. Fox Foundation. K.M. also declares consultancies for Invicro, The Michael J. Fox Foundation, Roche, Calico, Coave, Neuron23, Orbimed, Biohaven, Anofi, Koneksa, Merck, Lilly, Inhibikase, Neuramedy, IRLabs, and Prothena and participates on a Data and Safety Monitoring Board (DSMB) at Biohaven.
Funding agency: No relevant funding is associated with the publication of this letter.
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
References
- 1. Espay AJ, Cardoso F, Frucht SJ, Imarisio A, Halliday GM, Lees AJ. Refutation of the αSyn‐SAA‐based staging for Parkinson's progression (Neuronal α‐Synuclein Disease‐Integrated Staging System [NSD‐ISS]). Mov Disord 2025. [DOI] [PubMed] [Google Scholar]
- 2. Simuni T, Gochanour C, Nair AR, et al. Neuronal alpha‐synuclein disease stage progression over 5 years. Mov Disord 2025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Palmqvist S, Rossi M, Hall S, et al. Cognitive effects of Lewy bodypathology in clinically unimpaired individuals. Nat Med 2023;29:1971–1978. [DOI] [PMC free article] [PubMed]
- 4.Cummings JL, Teunissen CE, Fiske BK, et al. Biomarker‐guided decision making in clinical drug development for neurodegenerative disorders. Nat Rev Drug Discov 2025; Apr 4. 10.1038/s41573-025-01165-w. [DOI] [PubMed]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.