What is coming in 2024 for Parkinson's Biological Definitions, Staging and Classification?
By Michael S Okun
One of the big stories of 2023 in Parkinson’s disease was the emergence of a ‘seeding assay’ as a potential biomarker for Parkinson’s disease. We keep hearing over and over about a ‘Parkinson’s breakthrough.’ I prefer to think of the current moment in Parkinson’s history as an ‘inflection point,’ rather than a breakthrough. As a collective group of stakeholders, we are now moving with purpose toward biological definitions, staging and classifications for Parkinson’s disease. There remains a lot to ‘unpack,’ so in this month’s blog, I will explain where we are, and where we may be headed in 2024. I will review the new ‘Statement of the Movement Disorders Society on Biological Definition, Staging, and Classification of Parkinson's Disease.’ I will dispel the myth that there is ‘only one potential biomarker for Parkinson’s disease?’ I will attempt to explain the differences in core definitions of Parkinson’s disease, staging, classification and rating scales. Finally, I will discuss the importance of not rushing the process and I will argue for the importance of stakeholders and harmonization.
Standke and Kraus do a wonderful job reviewing seed amplification assays and also in discussing next steps for this approach: https://link.springer.com/article/10.1007/s00441-022-03595-z
Cardosa and colleagues published this paper in Movement Disorders which was the product of a recent meeting on the topic in 2023. ‘Statement of the Movement Disorders Society on Biological Definition, Staging, and Classification of Parkinson's Disease.’
Is there ‘only’ one biomarker for Parkinson’s disease?
A great starting point to explore this question of ‘one’ biomarker is actually another question, ‘what is a biomarker?’
Strimbu tackled this question in a recent 2011 paper.
“The term “biomarker”, a portmanteau of “biological marker”, refers to a broad subcategory of medical signs – that is, objective indications of medical state observed from outside the patient – which can be measured accurately and reproducibly. Medical signs stand in contrast to medical symptoms, which are limited to those indications of health or illness perceived by patients themselves. There are several more precise definitions of biomarkers in the literature, and they fortunately overlap considerably.”
Is it possible for a disease (like Parkinson’s) to have only a single biomarker? Technically, it is possible, however in reality there will be MANY potential biomarkers for most diseases. I think we should therefore be cautious to state ‘we have found the biomarker.’
Where was the notion of disease staging born?
The TMN staging system is a cornerstone of cancer and we can learn from their experience. This is a nice picture from: https://www.icliniq.com/articles/cancer/cancer-staging
The staging of medical diseases has been around for decades, however most experts concede that the field of cancer pioneered these methods.
Why would we desire ‘staging a disease?’ I love the comment in the Cardosa paper, that it ‘facilitates unequivocal allocation of individuals into groups of shared biomedical characteristics along a specific disease trajectory.'
In cancer we have the TNM classification: a primary Tumor, Nodes, and Metastasis (TNM). Pay attention: In cancer, the person’s symptoms are not part of this classical staging system. This may be different in Parkinson’s? We will wait and see.
Alzheimer's disease has recently developed a similar classification called ATN. A: amyloid, T: tau, and N: neurodegeneration.
Will Parkinson’s disease be next? My guess is that in Parkinson’s disease, these concepts will slowly evolve over the next 3-5 years.
The ATN classification for Alzheimer’s and related diseases can serve as a model for Parkinson’s. This is a nice picture by Mankhong and colleagues in https://www.mdpi.com/2227-9059/10/4/850
Definitions of Disease, Staging, Classification and Rating Scales
Have you ever experienced an ‘aha’ moment when you realized that all the people around you were vigorously debating a topic, only to discover they were not even talking about the same thing? Well, welcome to what is going on in the Parkinson’s disease field. Here are some useful definitions you can always fall back on.
Staging: This system is interested in the natural history of a disease. It may help with prediction of disease milestones. Staging can also be used to place folks into different groups, especially for clinical trials.
Disease: ‘A deviation or disorder in the normal functioning of a living organism, resulting in specific symptoms, physiological abnormalities, or pathological changes.’
Disease classification: Categorization and organization of diseases based on set criteria.
Disease staging: Categorizing by the extent of disease progression. Stages can be further defined using either biomarkers or using a person’s symptoms.
Rating scale: A standardized measure to quantify symptoms, function, or disease severity.
Cardosa and colleagues offered a great summary comparing the different systems and terms. This table in my mind is ‘ground zero’ for anyone trying to understand this topic. It appeared in this publication: https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29683
What does the biological definition of Parkinson’s disease actually mean?
Can we measure ‘neurodegeneration’ both anatomically and biologically? The answer is ‘sort of.’
We are pretty good at bedside examinations and awarding numbers on paper ‘scales’ as a method to rate specific symptoms. In Parkinson’s disease these scores on the rating scales are frequently like golf— lower numbers are better (translating to less disease).
We have yet to agree on a biological definition for Parkinson’s disease. In 2023 scientists and clinicians began more seriously considering ‘α-Synuclein (α-syn) aggregation’ as a possible biological event; this could be a candidate for contribution to the ‘biological definition’ of Parkinson’s disease.
The 2023 buzz has been all about a seed amplification assay (SAA) test. It is important to recognize that not all scientists agree that the SAA will be adequate, as the test must biologically define Parkinson’s disease.
What biologicals (fluids, tissue) can possibly be used to detect Parkinson’s disease
Shama and colleagues review the vast number of fluids and tissues which may be potentially used for biomarkers in this publication: https://www.researchgate.net/publication/372760013
So far, the α-synuclein seeding has been found most reliable in spinal fluid; however blood, saliva and skin are catching up and could provide a more practical solution; especially in low income and developing countries.
There is an important limitation to all of these tests, regardless of the source of the biological (spinal fluid, blood, skin, etc.). Seeding may not actually reflect aggregation of α-synuclein in the brain. Many experts are concerned that the actual contribution of α-synuclein to Parkinson’s disease is variable; in other words it may vary from one individual to another.
Does the seeding assay pick up the genetic forms of Parkinson’s disease?
Love this article by Andy Singleton and colleagues who trace the genetics of Parkinson’s disease over time: https://www.sciencedirect.com/science/article/pii/S0969996120300577
The leucine-rich repeat kinase 2 (LRRK2) gene, the Parkin (PRKN) gene, and possibly other genes may or may not be picked up by the seeding assay. It is important to remember that Parkinson’s is not one disease and that α-synuclein can be absent in the brain tissue; as has been shown in a large number of post-mortem cases of ‘genetic Parkinson’s disease.’ One large conundrum— the finding that α-synuclein seeding is commonly absent in LRRK2 Parkinson’s disease.
Which comes first, establishing the biological definition or disease classification?
I would look to history to answer this important question. Scientists and clinicians in the Alzheimer’s field established the biological definition first.
Do we need a staging system for Parkinson’s disease?
The short answer is yes. A staging system could possibly address disease progression and function.
One area that is lacking among clinicians taking care of persons with Parkinson’s would be a quick communication tool to facilitate a common language ; one which expresses the status of Parkinson’s disease for any given person. Will one staging system be able to pull off this need? Probably not.
A staging system will have a positive impact on the development of disease-modifying treatments and will contribute meaningfully to producing high quality clinical trials.
Everyone uses the old-fashioned Hoehn and Yahr Staging system for Parkinson’s disease. Why abandon it?
There are lots of pictures in the literature of the Hoehn and Yahr Parkinson’s staging system. Here is one illustrative version at: https://physioed.com/the-five-stages-of-parkinsons-disease/ Remember the 0.5 versions are not validated (1.5, 2.5, 3.5, etc.).
The Hoehn and Yahr (H&Y) Parkinson’s staging scale has been used as a research tool for many years and although not an ideal clinical staging tool, many clinicians us it because it is simple and practical.
It is a simple 1-5 scale and addresses unilateral vs. bilateral disease, disability level, and balance.
Why abandon it? It is not ‘anchored on a biological or pathological basis.’ Also most experts do not believe we should even refer to the Hoehn and Yahr as a staging system.
One ‘shocker’ as Cardosa and colleagues point out is that the Hoehn and Yahr is used as ‘international currency’ in Parkinson’s and is currently the preferred globally used tool.
What are the weaknesses of the Hoehn and Yahr?
It does not account for motor and non-motor symptoms.
It does not capture the overall functional status.
There is no ‘prodromal’ measure the Hoehn and Yahr scale (picking up the early symptoms)
The commonly used versions of the Hoehn and Yahr using 0.5 designations (e.g. H&Y 2.5) have not been validated.
Where are we going in 2024 and beyond?
First, we will bear witness to multiple clinical-research groups and stakeholders ‘dialoguing and debating’ the biological classification. We should welcome this sometimes heated discussion as ‘critically important.’
There will be definitely be more discussion on two proposed schemes:
Höglinger, Adler, Lang and colleagues have proposed a research based biological classification called the SynNeurGe. It is simple: 1- presence/absence of synuclein or a positive seeding assay; 2- evidence of underlying neurodegeneration which is referred to as Neur (not limited to DaT scan, can be other images), and 3- potential presence of gene variants Ge. Experts have argued that this may be more of a classification system vs a biological definition, though there is definitely overlap.
This is part of the preprint proposal for a staging system by Höglinger, Adler, Lang and colleagues. https://www.preprints.org/manuscript/202304.0108/v1
Chahine, Marek, Simuni and colleagues have proposed reimagining Parkinson’s (more broadly) as neuronal synuclein disease or NSD. These authors would include all those folks with both a positive seeding assay and a positive DaT scan. This definition would broaden to include Lewy body dementia, isolated rapid eye movement (REM) sleep behavior disorder (RBD), and asymptomatic individuals. This scheme would not include MSA. Overall the authors propose a staging system using the CSF seeding assay, genetics, and dopamine dysfunction determined by DaT and symptoms.
This is an example of the Chahine, Simuni, Marek and colleagues proposed system in their recent paper: https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd225111
We can bet there will be more proposals and more hybrid changes on existing proposals in 2024.
All of stakeholders will in 2024 and beyond collectively be challenged to develop a biological definition that predicts progression and could be plugged into a staging system. In my view, we are not there yet. The clinicians and scientists must come to terms with the failure of the seeding assay to pick up all cases, and especially the genetic forms of Parkinson’s. Further, whatever system is adopted, we will be stuck with it for a long time (as evidenced by the Hoehn and Yahr); so we should take our time and get it right.
The 'race is on' for a biological definition, disease staging and a classification for Parkinson's disease. All stakeholders should be actively involved and at the table: clinicians, basic science researchers, persons living with Parkinson’s, regulatory agencies, insurance providers, governments, and pharmaceutical/ device companies.
Developing a biological diagnostic criteria and staging/classification for Parkinson's will take time and rigor. We should not rush or race. We should slow down and get it right— in 2024 and beyond. Finishing first place in this quest is not important. It took time in Alzheimer's and in cancer, and my guess is that we still conservatively have 3-5 years left to go. Whatever the product, it needs to stick, as it has the potential to drive both innovation and care. I applaud the competing groups for stepping out of the shadows and engaging in ‘spirited debate.’
It is not easy to harmonize thought, however we must persist in our effort(s). Persons with Parkinson’s disease must be present for these dialogues in order to drive the necessary foundational principles and to be sure we achieve a meaningful product.
We have one more important task for 2024 and beyond— educating persons with Parkinson’s, families, clinicians and the public. It is our duty to explain the differences between core definitions of disease, a biological definition, staging, classification and rating scales. It is our obligation to listen and to integrate feedback. We need to consider the following questions:
Are we trying to use the product to communicate with persons with disease?
Are we using the product as a tool to communicate between doctors and clinicians?
Are we attempting to use the product to improve clinical trials?
Are we developing a tool for a diagnostic test or are we measuring disease progression?
Are all the stakeholders at the table?
Have we asked ourselves the question ‘what do we want?’ A biological definition, a staging system, a classification scheme or something else? Why do we want it?
The bottom line is that a ‘big reward’ is on the horizon if we can harmonize our outputs on the biological definition, classification and staging system(s) for Parkinson’s disease.
Special Acknowledgement:
I am grateful to the International Parkinson’s Disease and Movement Disorders Society for inviting me to be a participant in the Atlanta meeting (2023), which ultimately yielded the publication: ‘Statement of the Movement Disorders Society on Biological Definition, Staging, and Classification of Parkinson's Disease.’ I learned much of what I have shared in this blog post directly from my colleagues; I want to be sure they are appropriately acknowledged as the ‘true experts.’ I am grateful that many of the competing groups who attended the Atlanta meeting participated in the spirited discussion and debate. I am appreciative of Cliff Jack for educating me about the decade plus (and similar) journey in Alzheimer’s disease which also focused on biological definitions, classifications and staging. I have provided in the references below several papers which helped me to formulate my thoughts on this tricky topic. There are many more papers out there, and I encourage you to seek these out and and to read as many as you can.
Dr. Michael Okun is the author of this piece and is a co-editor of the parkinsonsecrets.com blog. Dr. Okun co-edits with Dr. Indu Subramanian from UCLA and the VA.
Jonny Acheson is the parkinsonsecrets.com website artist and also a physician, advocate and PWP.
Selected references used to formulate thoughts for this blog post:
Cardoso F, Goetz CG, Mestre TA, Sampaio C, Adler CH, Berg D, Bloem BR, Burn DJ, Fitts MS, Gasser T, Klein C, de Tijssen MAJ, Lang AE, Lim SY, Litvan I, Meissner WG, Mollenhauer B, Okubadejo N, Okun MS, Postuma RB, Svenningsson P, Tan LCS, Tsunemi T, Wahlstrom-Helgren S, Gershanik OS, Fung VSC, Trenkwalder C. A Statement of the MDS on Biological Definition, Staging, and Classification of Parkinson's Disease. Mov Disord. 2023 Dec 13. doi: 10.1002/mds.29683. Epub ahead of print. PMID: 38093469.
Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS. 2010 Nov;5(6):463-6. doi: 10.1097/COH.0b013e32833ed177. PMID: 20978388; PMCID: PMC3078627.
Wood, H. A new biological classification classification for Parkinson disease. Nature Reviews Neurology Volume 19, page 711, 2023.
Lang AE and colleagues. Plenary lecture at the XXVI World Congress of Neurology WCN; Montreal, Canada, 15–19 October 2023.
Siderowf A, Concha-Marambio L, Lafontant DE, Farris CM, Ma Y, Urenia PA, Nguyen H, Alcalay RN, Chahine LM, Foroud T, Galasko D, Kieburtz K, Merchant K, Mollenhauer B, Poston KL, Seibyl J, Simuni T, Tanner CM, Weintraub D, Videnovic A, Choi SH, Kurth R, Caspell-Garcia C, Coffey CS, Frasier M, Oliveira LMA, Hutten SJ, Sherer T, Marek K, Soto C; Parkinson's Progression Markers Initiative. Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 2023 May;22(5):407-417. doi: 10.1016/S1474-4422(23)00109-6. PMID: 37059509; PMCID: PMC10627170.
Chahine LM, Merchant K, Siderowf A, Sherer T, Tanner C, Marek K, Simuni T. Proposal for a Biologic Staging System of Parkinson's Disease. J Parkinsons Dis. 2023;13(3):297-309. doi: 10.3233/JPD-225111. PMID: 37066922; PMCID: PMC10200239.
Yan S, Jiang C, Janzen A, Barber TR, Seger A, Sommerauer M, Davis JJ, Marek K, Hu MT, Oertel WH, Tofaris GK. Neuronally Derived Extracellular Vesicle α-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease. JAMA Neurol. 2023 Dec 4:e234398. doi: 10.1001/jamaneurol.2023.4398. Epub ahead of print. PMID: 38048087; PMCID: PMC10696516.
Qi R, Sammler E, Gonzalez-Hunt CP, Barraza I, Pena N, Rouanet JP, Naaldijk Y, Goodson S, Fuzzati M, Blandini F, Erickson KI, Weinstein AM, Lutz MW, Kwok JB, Halliday GM, Dzamko N, Padmanabhan S, Alcalay RN, Waters C, Hogarth P, Simuni T, Smith D, Marras C, Tonelli F, Alessi DR, West AB, Shiva S, Hilfiker S, Sanders LH. A blood-based marker of mitochondrial DNA damage in Parkinson's disease. Sci Transl Med. 2023 Aug 30;15(711):eabo1557. doi: 10.1126/scitranslmed.abo1557. Epub 2023 Aug 30. PMID: 37647388.
Okuzumi A, Hatano T, Matsumoto G, Nojiri S, Ueno SI, Imamichi-Tatano Y, Kimura H, Kakuta S, Kondo A, Fukuhara T, Li Y, Funayama M, Saiki S, Taniguchi D, Tsunemi T, McIntyre D, Gérardy JJ, Mittelbronn M, Kruger R, Uchiyama Y, Nukina N, Hattori N. Propagative α-synuclein seeds as serum biomarkers for synucleinopathies. Nat Med. 2023 Jun;29(6):1448-1455. doi: 10.1038/s41591-023-02358-9. Epub 2023 May 29. PMID: 37248302; PMCID: PMC10287557.
Beach TG, Adler CH, Shill HA, Zhang N, Driver-Dunckley ED, Mehta SH, Serrano GE. Accuracy of the Early Diagnosis of Parkinson's Disease. Mov Disord. 2023 Aug;38(8):1573-1574. doi: 10.1002/mds.29556. PMID: 37565398; PMCID: PMC10662959.
Concha-Marambio L, Pritzkow S, Shahnawaz M, Farris CM, Soto C. Seed amplification assay for the detection of pathologic alpha-synuclein aggregates in cerebrospinal fluid. Nat Protoc. 2023 Apr;18(4):1179-1196. doi: 10.1038/s41596-022-00787-3. Epub 2023 Jan 18. PMID: 36653527; PMCID: PMC10561622.
Höglinger, G.U.; Adler, C.H.; Berg, D.; Klein, C.; Outeiro, T.F.; Poewe, W.; Postuma, R.; Stoessl, J.; Lang, A.E. Towards a Biological Definition of Parkinson’s Disease. Preprints 2023, 2023040108. https://doi.org/10.20944/preprints202304.0108.v1