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International Parkinson and Movement Disorder Society
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        VOLUME 28, ISSUE 1 • March, 2024.  Full issue »

Navigating controversies: Exploring advancement of Parkinson's disease classification and staging and the potential role of the International Parkinson and Movement Disorders Society 

The community of movement disorders specialists is in a race to redefine the diagnosis of Parkinson's disease and create a clinical staging system to track its progression. 

Recently, two groups of scientists have independently proposed new ontologies for Parkinson's and related disorders — the neuronal alpha-synuclein disease integrated staging system (NSD-ISS)[1] and the SynNeurGe criteria[2]. The purpose of both of these frameworks is to classify disease subtypes, including the earliest stages of the disease that occur before the onset of clinically apparent parkinsonism. The NSD-ISS also offers a staging system that describes the extent or severity of the disease in an individual. 

The benefits of adopting these proposals more widely have been hotly debated [3,4,5,6], particularly the NSD-ISS's revolutionary proposal that eliminates ‘Parkinson's disease' as a category, in its place defines a new disease — neuronal alpha-synuclein disease — and proposes a conceptual, rather than a data-driven, staging system. 

The existence of these proposals and the debate that ensued isitself very beneficial for the advancement of the field. However, there are a few sticking points that need resolution, namely: 

1) The implications of diagnosis based on clinical symptomatology rather than diagnosis based on biomarkers 

Medical care relies heavily on accurate diagnoses. When people seek medical attention, they are often anxious to know the cause of their symptoms. Receiving a diagnosis can bring comfort by providing a sense of certainty and the possibility of effective treatment. 

The development of therapies to prevent rather than treat neurodegeneration changes the diagnostic paradigm from a focus on symptomatic individuals seeking care to educating the asymptomatic population about actively maintaining their health. This paradigm shift has already taken place in oncology, cardiovascular diseases and infectious diseases. However, it requires a solid evidentiary basis to engage the many stakeholders involved in this type of change. 

2) The implications of diagnosis based on the alpha-synuclein test 

May a positive test for the presence of aggregated alpha-synuclein alone be equated with being diagnosed with a disease (either neuronal alpha-synuclein disease or Parkinson's disease)? Or does such a positive test merely identify a risk factor for disease? 

This is a crucial difference with vast public health implications. This question has not been formally addressed. However, the NSD-ISS seems to treat a positive test as diagnostic of disease, while SynNeurGe implies the test result is a disease risk factor. 

3) Validation of the NSD-ISS and the SynNeurGe classifcation methodologies in independent datasets 

This effort has already started [7] but needs to be continued. For example, in the case of SynNeurGe, comparative data from the different methods used to establish neurodegeneration is needed to develop equivalent measurement standards using different methodologies across various populations. 

4) The conceptual staging system must evolve to become data-driven 

In order to make progress in the field and address contentious issues, it is necessary to have a safe environment for mediation, which the MDS may provide. Additionally, there is a need to generate and share data. 

I believe that the creation of new diagnostic methods for Parkinson's disease and related disorders, along with data-driven clinical staging systems, are essential for developing treatments that modify the disease course, and ultimately for improving medical care. The MDS, as the largest and most internationally organized association of experts in this field, is in a privileged position to aid in this endeavor.



  1. Simuni T, Chahine LM, 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 CM, Merchant K, Mollenhauer B, Montine T, Nudelman K, Pagano G, Seibyl J, Sherer T, Singleton A, Stephenson D, Stern M, Soto C, Tanner CM, Tolosa E, Weintraub D, Xiao Y, Siderowf A, Dunn B, Marek K. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024 Feb;23(2):178-190. doi: 10.1016/S1474-4422(23)00405-2. PMID: 38267190. 

  1. Höglinger GU, Adler CH, Berg D, Klein C, Outeiro TF, Poewe W, Postuma R, Stoessl AJ, Lang AE. A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria. Lancet Neurol. 2024 Feb;23(2):191-204. doi: 10.1016/S1474-4422(23)00404-0. Erratum in: Lancet Neurol. 2024 Mar;23(3):e7. PMID: 38267191. 

  1. Höglinger GU, Adler CH, Berg D, Klein C, Outeiro TF, Poewe W, Postuma R, Stoessl AJ, Lang AE. A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria. Lancet Neurol. 2024 Feb;23(2):191-204. doi: 10.1016/S1474-4422(23)00404-0. Erratum in: Lancet Neurol. 2024 Mar;23(3):e7. PMID: 38267191. 

  1. Jack CR Jr. Criteria for a biological definition of neuronal α-synuclein disease-a major conceptual step forward. Lancet Neurol. 2024 Feb;23(2):129-130. doi: 10.1016/S1474-4422(23)00456-8. PMID: 38267173. 

  1. Darweesh SKL, Sampaio C, Bloem BR. Has the time come to redefine Parkinson's disease? Lancet Neurol. 2024 Feb;23(2):130-133. doi: 10.1016/S1474-4422(23)00503-3. PMID: 38267174. 

  1. Obeso JA, Calabressi P. Parkinson's disease is a recognisable and useful diagnostic entity. Lancet Neurol. 2024 Feb;23(2):133-134. doi: 10.1016/S1474-4422(23)00512-4. Erratum in: Lancet Neurol. 2024 Mar;23(3):e7. PMID: 38267175. 

  1. Tien Dam, Gennaro Pagano, Michael C Brumm, Caroline Gochanour, Kathleen LPoston, Daniel Weintraub, Lana M. Chahine, Christopher Coffey, Caroline M. Tanner, Catherine M. Kopil, Yuge Xiao, Sohini Chowdhury, Luis Concha-Marambio, PeterDiBiaso, Tatiana Foroud, Mark Frasier, Danna Jennings, Karl Kieburtz, KalpanaMerchant, Brit Mollenhauer, Thomas J Montine, Kelly Nudelman, John Seibyl, ToddSherer, Andrew Singleton, Diane Stephenson, Matthew Stern, Claudio Soto, EduardoTolosa, Andrew Siderowf, Billy Dunn, Tanya Simuni, Kenneth Marek, the Parkinson’s Progression Markers Initiative. Neuronal alpha-Synuclein Disease Integrated Staging System performance in PPMI, PASADENA, and SPARK baseline cohort. MedRxiv 2024.02.14.24302818; doi:


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