The publication in Lancet Neurology in early 2024 of two proposals for biological definitions and classification of Parkinson’s disease (PD) (1, 2) has provided a timely and important challenge to our field. In this article, I would like to summarize the MDS response to these proposals, and to provide an update on how the MDS is planning to help lead the next steps.
It is important to have some background knowledge of what has been happening in the Alzheimer’s disease field for context. The United States-based Alzheimer’s Association Workgroup has, since 2018 and reinforced in a publication of revised diagnostic criteria in 2024, promoted a conceptual change in the research and clinical definition of Alzheimer’s disease (3, 4). They propose that Alzheimer’s disease should be defined and diagnosed based solely on the presence of approved biomarkers (e.g. amyloid positron emission tomography, specific plasma biomarkers such as phosphorylated tau 21), dissociated from any clinical manifestations of cognitive impairment or dementia: “the biology is the disease.” Their hope is that this will allow for earlier, and consequently, more effective institution of potential disease-modifying therapies. However, this concept is by no means universally accepted. The European-led but International Working Group recommend that Alzheimer’s disease should continue to be defined as a clinical-biological entity, with those people who are biomarker-positive but clinically asymptomatic be classified as “Asymptomatic At Risk for Alzheimer Disease,” and not be considered as having Alzheimer’s disease (AD) (5). The rationale is that the lifetime risk of an asymptomatic, AD biomarker-positive individual developing clinical manifestations may be as low as in the order of 20%, and it currently remains unknown how to determine which patients will convert to clinical disease, and when. It has been suggested that the situation of an asymptomatic person with a positive AD biomarker is analogous to someone with monoclonal gammopathy of undetermined significance (MGUS). The prevalence of MGUS is around 3% of the older population (6), and such persons are considered as being at risk of transformation to, but not actually having, a hematological cancer, with a risk of transformation to malignancy of around 30% over 25 years (7, 8).
The neuronal α-synuclein disease (NSD) (1) and SynNeurGe (2) frameworks are both anchored around the concept that, similar to the Alzheimer's Association Workgroup proposal, PD biomarker positivity can and should be considered a disease state, independent of whether a person has any motor or non-motor clinical manifestations of PD. There are also differences between the two, with the former being focused on research diagnostic and staging criteria that are implied to be ready for implementation in clinical trial settings, the latter being more of a call for conceptual change on how we classify PD. The differences between diagnosis, staging, and classification of PD are well summarized in an MDS Statement published in early 2024 (9). The SynNeurGe proposal is also broader, allowing for a synuclein-negative category as well as greater range of tissue, imaging, and genetic biomarkers to be taken into consideration. However, both proposals emphasize that a diagnostic label can be based purely on biomarker status, independent and agnostic of any clinical manifestations. Both proposals acknowledge that theirs are first iterations or steps, which in addition to forming new conceptual frameworks, also highlight knowledge gaps that need to be filled.
The MDS, led by Dr. Lorraine Kalia and the other Co-Chairs of the Scientific Issues Committee, with representation from the Co-Chairs of the Cognition and Lewy Bodies Study Group as well as the current Officers, have recently published an MDS Viewpoint in response to the NSD and SynNeurGe proposals (10).
Dr. Kalia also delivered a lecture on “Current Proposals and Future Directions for Re-defining and Classifying Parkinson's Disease” at a Plenary Session on “The Neurobiology of Parkinson's Disease” at the recent 2024 MDS International Congress in Philadelphia in September (available online, free for MDS Members, until April 2025.)
The MDS has a long history of leadership in the development and refinement of clinical and research definitions of PD. In 2011, then-President Prof. Günter Deuschl convened a Task Force on the Definition of Parkinson’s Disease that has led to a number of influential publications (11-14). In 2018, Dr. Christopher Goetz as President convened a Task Force on the Biological Definition of Parkinson’s Disease that resulted in a publication that summarizes the challenges of defining Parkinson's disease in the modern era of genetics and pathology (15). In the concluding paragraph of the recently published Viewpoint, we stated that the MDS intends to convene and foster collaborative efforts to progress the topic of clinical and biological frameworks for Parkinson's disease.
I am pleased to announce that an Ad Hoc MDS Parkinson's Disease Tiered Diagnostic Framework Committee has just been convened. The goal of this committee is to develop a diagnostic framework that advances the current proposed biological frameworks, yet integrates them with the current clinical-pathological concept of PD, in order to provide clarity and guidance for the clinical and scientific community. This committee will begin its work this month, culminating in an in-person meeting in February 2025, with plans for submission of an MDS Statement for publication soon afterwards.
The MDS commends and acknowledges the contribution of both the NSD and SynNeurGe groups for their proposals for advancing the field. Many of the authors on both proposals are longstanding members who have contributed to MDS clinical, research, and educational activities, and the MDS has a tradition of working closely and collaborating with organizations such as the Michael J. Fox Foundation, the Critical Path Institute (C-Path) and the US Therapeutic Goods Administration, who were integral contributors to the NSD proposal. However, the MDS is a global organisation, with over 12,000 members from over 150 countries around the world. We represent clinicians and researchers from both resource-rich/technology-enabled and resource- and technology-limited corners of the globe. We do not believe a dichotomised or separate frameworks that dissociate clinical and biological criteria for PD are in the best interests of PD patients and carers, clinicians, or researchers. The challenge and work of the Ad Hoc Committee will be to create an integrated framework that can be adapted and made fit for purpose for different clinical and research scenarios, and MDS looks forward to this collaborative effort and reporting back to our membership in the coming months.
References
1. Simuni T, Chahine LM, Poston K, Brumm M, Buracchio T, Campbell M, et al. A biological definition of neuronal alpha-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024;23(2):178-90.
2. Hoglinger GU, Adler CH, Berg D, Klein C, Outeiro TF, Poewe W, et al. A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria. Lancet Neurol. 2024;23(2):191-204.
3. Jack CR, Jr., Andrews JS, Beach TG, Buracchio T, Dunn B, Graf A, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024;20(8):5143-69.
4. Jack CR, Jr., Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-62.
5. Dubois B, Villain N, Schneider L, Fox N, Campbell N, Galasko D, et al. Alzheimer Disease as a Clinical-Biological Construct-An International Working Group Recommendation. JAMA Neurol. 2024.
6. Villain N, Planche V. Disentangling clinical and biological trajectories of neurodegenerative diseases. Nat Rev Neurol. 2024;20(12):693-4.
7. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354(13):1362-9.
8. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346(8):564-9.
9. Cardoso F, Goetz CG, Mestre TA, Sampaio C, Adler CH, Berg D, et al. A Statement of the MDS on Biological Definition, Staging, and Classification of Parkinson's Disease. Mov Disord. 2024;39(2):259-66.
10. Kalia LV, Berg D, Kordower JH, Shannon KM, Taylor JP, Cardoso F, et al. International Parkinson and Movement Disorder Society Viewpoint on Biological Frameworks of Parkinson's Disease: Current Status and Future Directions. Mov Disord. 2024;39(10):1710-5.
11. Berg D, Adler CH, Bloem BR, Chan P, Gasser T, Goetz CG, et al. Movement disorder society criteria for clinically established early Parkinson's disease. Mov Disord. 2018;33(10):1643-6.
12. Berg D, Postuma RB, Bloem B, Chan P, Dubois B, Gasser T, et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease. Mov Disord. 2014;29(4):454-62.
13. Heinzel S, Berg D, Gasser T, Chen H, Yao C, Postuma RB, et al. Update of the MDS research criteria for prodromal Parkinson's disease. Mov Disord. 2019;34(10):1464-70.
14. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015;30(12):1591-601.
15. Outeiro TF, Alcalay RN, Antonini A, Attems J, Bonifati V, Cardoso F, et al. Defining the Riddle in Order to Solve It: There Is More Than One "Parkinson's Disease". Mov Disord. 2023;38(7):1127-42.