International Parkinson and Movement Disorder Society Viewpoint on Biological Frameworks of Parkinson's Disease: Current Status and Future Directions

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder that, in the majority of patients, is associated with intraneuronal inclusions of aggregated fibrillar forms of α-synuclein, termed Lewy pathology. Although many questions regarding the link between α-synuclein and neurodegeneration in PD remain unanswered,¹ data generally indicate that α-synuclein aggregation can be accompanied by a decline in the health and function of neurons. Further, multiple lines of evidence support the hypothesis that Lewy pathology can occur before motor symptoms in PD and may spread across the neuroaxis via a prion-like mechanism.^2-5 Based on these pathobiological underpinnings of the disease, two novel frameworks regarding PD ontology were published in early 2024: Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS)⁶ and Synucleinopathy-Neurodegeneration-Genetic research diagnostic criteria for PD (SynNeurGe).⁷ Both propose a new research definition of PD that, unlike prior definitions of the disease, from James Parkinson's initial description to the International Parkinson and Movement Disorders Society (MDS) diagnostic criteria for PD,⁸ are not anchored to the presence of the clinical syndrome of motor parkinsonism (ie, bradykinesia, rigidity, rest tremor). Instead, these two frameworks propose to redefine PD based on biological markers that can occur in the absence of signs or symptoms currently required for a clinical diagnosis of PD.

Many in the field view this as an opportune time to introduce such a paradigm shift, given recent advances in the development of high-performance biomarkers of disease-associated α-synuclein aggregates, particularly α-synuclein seed amplification assays (SAA) and α-synuclein immunostaining using skin biopsies. Relying on these biomarkers, NSD-ISS and SynNeurGe define α-synuclein biomarker positivity alone as the earliest time point of disease detection (with exceptions made only for disease associated with pathogenic/risk gene variants). Both frameworks therefore do not make a distinction between prodromal and manifest PD (ie, presence of disease before versus after fulfilling current clinical diagnostic criteria, respectively). Further, they integrate PD and dementia with Lewy bodies (DLB) into a unified entity based on their shared association with Lewy pathology.

These proposed frameworks offer opportunities to propel scientific inquiry and development of therapies targeting α-synuclein-related pathology in its early stages. Nevertheless, they pose several challenges and considerations. The MDS, which serves as a voice for the international community of PD care providers and researchers, previously provided a statement outlining the foundational principles for the development of a biological definition and any classification or staging system for PD.⁹ The current viewpoint was prepared as a more focused MDS response to the specific proposals. The authors of the current statement were invited by the MDS president and president-elect based on their positions as current officers, cochairs of the Scientific Issues Committee, and cochairs of the Cognition and Lewy Bodies Study Group of the MDS to represent the clinical and scientific membership. This statement will outline important issues to be considered by the community: (1) challenges posed by two similar but separate frameworks, (2) limitations of defining disease based on α-synuclein, (3) implications of unifying PD and DLB, (4) considerations for the global PD community, and (5) recommendations for the way forward.

The NSD-ISS framework is based on three anchors: (1) pathological neuronal α-synuclein species (S), which is exclusively determined by cerebrospinal fluid (CSF) α-synuclein SAA; (2) dopaminergic dysfunction (D), which is determined as valid only for quantitative dopamine transporter (DaT) SPECT using ioflupane; and (3) genetic status (G), which is confined to fully penetrant SNCA variants. To these, the degree of functional impairment caused by clinical symptoms and signs is added, leading to a staging system, which ranges from 0 (pathogenic SNCA variant) without any of the other anchors to 6 (both “S+” and “D+” with severe functional impairment). New nomenclature is proposed to encompass prodromal and manifest PD and DLB as “neuronal synuclein disease,” or “NSD.”

The SynNeurGe framework uses a three-component classification system: (1) synucleinopathy (Syn), which can be detected by CSF or skin α-synuclein SAA or α-synuclein immunostaining of skin biopsies; (2) neurodegeneration (Neur), which includes not only dopaminergic brain imaging but also metabolic brain imaging and sympathetic cardiac imaging; and (3) genetics (Ge), which is not restricted to SNCA variants but includes both fully and partially penetrant pathogenic gene variants and allows for “Syn-” genetic subtypes. For components Syn and Neur, exclusion criteria are also proposed to help rule out multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome. New nomenclature is proposed to encompass prodromal and manifest PD and DLB as “Parkinson's type synucleinopathy.” A formal staging system is not suggested.

Fundamentally, the key concept proposed by the NSD-ISS and SynNeurGe frameworks is essentially the same: redefining PD/DLB based on in vivo evidence of α-synuclein aggregation, neurodegeneration, and genetic variants. However, each will need to demonstrate that its proposed scheme meets or preferably exceeds current sensitivity and specificity standards, while maintaining the ability to capture the wide array of clinical presentations and heterogeneous disease trajectories, which will require the leveraging of large datasets. Each framework is also expected to require multiple iterations as our understanding of PD pathobiology and biomarker development evolves. Therefore, the presence of two similar but separate frameworks that both require validation and ongoing redevelopment could result in duplication of efforts and inefficient use of finite resources (eg, research participants, biospecimens, funding). Furthermore, with two separate frameworks available for use by researchers, there may be challenges in comparing, interpreting, or consolidating the findings from studies that do not use the same framework. Thus, there would be significant value in a singular framework that aligns the research community.

An important consideration regarding both frameworks is the possibility of narrowing our focus prematurely by confining our attention to α-synuclein. Lewy pathology is a feature of not just PD but also DLB, and it may be seen in MSA¹⁰ and Alzheimer's disease (AD).^{10, 11} Among people with PD, Lewy pathology is present in most brains, but it is not found in all. PD associated with PRKN or LRRK2 gene variants can present with typical clinical parkinsonism in the absence of Lewy pathology.^{12, 13} Furthermore, autopsy studies of people diagnosed with sporadic PD report up to 15% of cases without Lewy pathology (after excluding those with neuropathological features of MSA or PSP).^14-16 The largest PD cohort examined to date (n = 545) using CSF α-synuclein SAA found that 12.3% of the total cohort were negative (ie, had samples without evidence of synuclein seeding [SWESS])¹⁷; more than half of those who were SAA negative had sporadic PD.¹⁸ A recent examination of CSF α-synuclein SAA in a large cohort of people with clinically diagnosed DLB (n = 191) found that 28.3% had SWESS.¹⁹ Thus, we caution against the exclusion of these people who would currently be diagnosed with sporadic PD or DLB but have SWESS from the new biological frameworks. Doing so might prematurely limit exploration of PD/DLB pathobiology distinct from α-synuclein-mediated mechanisms. Further, using SAA to determine enrollment in clinical trials for disease-modifying therapies should be carefully considered based on the specific molecular pathway targeted by the therapeutic being tested. For example, exclusion of people with SWESS may be appropriate if the presumptive disease-modifying therapy aims to affect α-synuclein (directly or indirectly) but not if intended to target LRRK2 or mitochondrial dysfunction unrelated to α-synuclein.

Furthermore, PD is not only a synucleinopathy but a disease with multiple underlying pathologies. Amyloid-β plaques, tau-containing neurofibrillary tangles, and even TDP-43 protein inclusions occur within the nigrostriatal system and other brain regions in PD.²⁰ Co-pathologies have been increasingly recognized as the rule in PD and not the exception, with brains exhibiting three different co-pathologies on average.²¹ These co-pathologies may contribute to the neurodegenerative process; for example, nigral tau alone is associated with nigrostriatal degeneration to a similar degree seen with α-synuclein and tau.²² Additionally, inflammatory responses manifested by glial reactivity, T-cell infiltration, and increased expression of inflammatory cytokines, plus other toxic mediators derived from activated glial cells, are currently recognized as prominent drivers of PD pathology.²³ Co-pathology, particularly AD-related pathology, is also prevalent in DLB, affecting approximately 50% to 70% of cases, and also PD with dementia, affecting at least 33%.^24-26 The presence of AD-related co-pathology influences the phenotype of DLB, leading to accelerated decline, increased institutionalization, and mortality, and potentially interacts synergistically with α-synuclein pathology in PD and DLB at the molecular level.^{24, 27} Thus, it is premature to focus attention on α-synuclein to the exclusion of other potentially significant pathological processes. Expanding the proposed α-synuclein-based frameworks to incorporate co-pathologies, similar to the National Institute on Aging and Alzheimer's Association revised criteria for AD,²⁸ would enhance understanding of their impact on PD and DLB as well as facilitate a more refined precision medicine approach.

Nomenclature of a disease is fundamental to its taxonomy and is crucial for standardized healthcare practice, research endeavors, and public health initiatives. Relative to PD, DLB has gained formal recognition as a distinct diagnostic entity more recently; for example, in international diagnostic classification manuals, including the World Health Organization's 11th International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders 5. This has significantly increased awareness of DLB and led to increased research efforts, funding, and clinical trial activity specific to DLB. Successive iterations of international consensus criteria have improved its diagnosis and management.²⁹ If DLB is subsumed under the disease construct of either NSD or Parkinson's type synucleinopathy, there is a risk that the unification of PD and DLB will diminish the substantial progress achieved in understanding the clinical phenotypes, disease mechanisms, and pathobiology of DLB, especially as an under-recognized and under-diagnosed condition. Collaboration across PD and DLB clinical, research, and advocacy communities will be essential in addressing these nomenclature challenges.

The NSD-ISS framework focuses on neurodegeneration of the nigrostriatal dopaminergic system, but substantia nigra neuronal loss is not a neuropathological requirement for DLB. Indeed, up to 20% of autopsy-confirmed DLB cases do not exhibit dopaminergic deficits on DaT imaging.³⁰ Furthermore, DaT imaging in prodromal stages of DLB, specifically in mild cognitive impairment related to Lewy body disease (MCI-LB), has been reported to be abnormal in only 61% of probable MCI-LB and 40% of possible MCI-LB cases.³¹ A DLB-related glucose metabolic pattern with fluorodeoxyglucose positron emission tomography (FDG-PET) that overlaps with the pattern observed in PD has been identified³²; however, its occurrence in MCI-LB has not yet been reported. The NSD-ISS framework from stage 2B onward (stages that will likely include individuals meeting criteria for dementia) mandates evidence of dopaminergic deficits as measured on DaT imaging. The SynNeurGe classification also focuses on dopaminergic deficits (measured directly by dopaminergic imaging, such as DaT imaging, or by FDG-PET imaging of glucose metabolic networks indirectly related to nigrostriatal dopaminergic neuron loss), but also includes cardiac metaiodobenzylguanidine SPECT to measure cardiac sympathetic denervation, which has diagnostic applicability in DLB.³³ Importantly, the emphasis of both frameworks requiring dopaminergic deficits may exclude from clinical trials and other research a significant subgroup of prodromal and manifest DLB patients in whom motor symptoms and dopaminergic deficits may not be prominent.

Nondopaminergic neurotransmitter system deficits, particularly in the cholinergic system,³⁴ are relevant across the clinical phenotypes of PD and DLB, even in the prodromal phase. These other neurotransmitter systems are not included in the NSD-ISS framework. Although the SynNeurGe group recognizes the importance of nondopaminergic systems, they are not included in their classification framework due to insufficient validated evidence for nondopaminergic molecular imaging in PD. Nonetheless, deficits in these systems may be associated with distinct phenotypes and different neurodegenerative trajectories in clinically defined PD and DLB. Further research is necessary to ensure that nondopaminergic systems are considered within biological frameworks and assessed using validated biomarkers.

Extensive work has been directed toward delineating boundaries of cognitive and functional standpoints from the transitions of MCI (MCI-LB and PD-MCI) to dementia (DLB and PDD, respectively).^{29, 35-37} Challenges have included determining what contributes to functional impairment (ie, cognitive versus motor dysfunction), and this will be an issue to consider in the proposed biological frameworks. The SynNeurGe classification is currently agnostic to definitions of dementia or functional impairment incorporating a “C+” state that encompasses all clinical disease stages, although acknowledging the need for future iterations to incorporate some form of functional stratification and its impact on daily activities. In contrast, the NSD-ISS framework integrates the severity of functional impairment into its staging methodology, albeit without direct mapping to established criteria used to define MCI or dementia. Alignment of definitions used in the biological frameworks and existing MCI and dementia criteria would enhance the application of these frameworks across disease cohorts and the harmonization of research efforts.

The MDS represents over 150 countries, with a membership of over 10,000 clinicians and scientists worldwide who are interested in the care of people with PD and other movement disorders. In 2018, PD was estimated to affect 8.5 million people globally,³⁸ and in coming decades, prevalence is predicted to grow substantially. Because PD is a global disease, the inclusion of diverse populations will be imperative to validate biological frameworks which, hitherto, have been based primarily on data from people of European descent (eg, SAA and genetics). For many MDS members and their patients, diagnosis remains grounded on clinical features, in the absence of access to complex or expensive diagnostic tests. The biomarker field is moving at a quickened pace, with blood-based α-synuclein testing and “omics”-based approaches under current evaluation. Some of these tests may be more accessible and thus better suited to use over a wider geography and could also offer the possibility of quantification of disease-associated α-synuclein, which is currently lacking for CSF-based SAA and skin immunostaining. Both proposed frameworks acknowledge future availability of new biomarkers and thus the importance of being adaptable to change.

Taking an example from outside the field of movement disorders, the most recent comprehensive 2017 position paper of the International League Against Epilepsy on the classification of epilepsies states that “as a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world.”³⁹ Similarly, it is crucial that any revisions to the research definition, classification, or staging of PD are suitable for broad use and adaptable or available to the majority of patients globally.

The MDS recognizes the NSD-ISS and SynNeurGe groups for applying recent advances in understanding PD pathobiology and biomarker development to bring us to a starting point for creating biological frameworks of PD. The enthusiasm for early disease detection to facilitate the development of disease-modifying therapies and ultimately the deployment of precision therapies is warranted. However, our knowledge of the pathobiology of PD and related Lewy body diseases, including DLB, remains incomplete and is evolving rapidly. As the authors of both proposed frameworks recognize, neither proposal is definitive. Thus, there is a need for an adaptable and responsive framework to harmonize existing and future clinical and scientific thought and discovery.

As an international organization representing the clinical and scientific community, the MDS intends to convene and foster collaborative efforts to progress this topic. These collaborations will ideally include key stakeholders such as clinicians and researchers, including the proponents of the NSD-ISS and SynNeurGe proposals, people living with PD or DLB, funding organizations, and industry sponsors. The objective will be to further refine, develop, and validate biological definitions of PD that are “fit for purpose,” depending on the clinical, research, resource, and geographical scenarios.

(1) Research project: A. Conception, B. Organization, C. Execution. (2) Manuscript: A. Writing of first draft, B. Review and critique.

L.V.K.: 1A, 1B, 1C, 2A, 2B

D.B.: 1A, 1B, 1C, 2A, 2B

J.H.K.: 1A, 1B, 1C, 2A, 2B

K.M.S.: 1A, 1B, 1C, 2A, 2B

J.-P.T.: 1A, 1B, 1C, 2A, 2B

F.C.: 2B

J.G.G.: 2B

B.J.: 2B

W.G.M.: 2B

M.A.J.T.: 2B

D.J.B.: 1A, 1B, 1C, 2A, 2B

V.S.C.F.: 1A, 1B, 1C, 2A, 2B

L.V.K. holds the Wolfond-Krembil Chair in Parkinson's Disease Research. In the past year, L.V.K. has received research support from the Canadian Institutes of Health Research (CIHR), Cure Parkinson's, Krembil Foundation, Michael J. Fox Foundation for Parkinson's Research (MJFF), Natural Sciences and Engineering Research Council of Canada (NSERC), and Parkinson Canada; served as a consultant for Cure Ventures, Ipsen, Knight Therapeutics, Right Brain Bio, and UCB; and received honoraria from the Canadian Movement Disorders Society (CMDS), Critical Path for Parkinson's (CPP), International Parkinson and Movement Disorder Society (MDS), and IOS Press/Sage Publications.

D.B.

J.H.K. receives a grant from ASAP/MJFF on co-pathologies in Parkinson's disease. This is the only potential conflict of interest related to this article. In the past 12 months, J.H.K. has received honoraria from Inhibikase Inc., Amydis Inc., Eventumtx, and the NIH and receives funding from the NIH and The Michael J. Fox Foundation. J.H.K. is a founding scientist with financial interest in Kenai Therapeutics. K.M.S. receives funding for Parkison's disease clinical trials from Inhibikase and Sun Pharma. J.-P.T. is funded and supported by the Newcastle NIHR Biomedical Research Centre. J.-P.T. has received educational grants from GE Healthcare and speaker fees. He has also received speaker fees from Bial and consultant fees from EIP Pharma/Cervomed and Eisai. These have no bearing on the current manuscript. F.C.: organization relationships: member of the Brazilian Academy of Neurology and the American Academy of Neurology. J.G.: grants/research support: Acadia, Lewy Body Dementia Association, The Michael J. Fox Foundation. Honoraria: International Parkinson Disease and Movement Disorders Society, Parkinson's Foundation, and Parkinson Study Group. Consulting: Acadia, EIP Pharma (Data Safety Monitoring Board member), KeifeRx, InMuneBio, PaxMedica, Roche, and Sage. B.J.: Research grant: Peptron, AbbVie Korea, Zemvax, and Kael. Expert panel: AspenNeuroscience. W.G.M.: outside the manuscript, W.G.M. has received consultancy fees from Lundbeck, Takeda, Alterity, Inhibikase, and GE. M.A.J.T. reports grants from the Netherlands Organisation for Health Research and Development Domain: NWO-TTW (2022-9), ZonMW Topsubsidie (91218013), and ZonMW Program Translational Research (40-44600-98-323). She also received two European Fund for Regional Development from the European Union (01492947 and DIMATIO) (EFRO-0059) and a European Joint Programme on Rare Diseases (EJP RD) Networking Support Scheme. She received a grant from the Health Holland and the PPP allowance program (PPP-2023-00) and furthermore from the province of Friesland, the Stichting Wetenschapsfonds Dystonie, and unrestricted grants from Ipsen, Actelion and Merz, STIL, AbbVie, and Teva. D.J.B.: no COI. Organization relationships: director, Newcastle Health Innovation Partners (NIHR/NHS-E Academic Health Sciences Center). Royalty: Henry Stewart, Oxford University Press. Employment/owner: full-time employee of Newcastle University. D.J.B. has no other paid employment or source of additional income. V.S.C.F. receives a salary from NSW Health, has received unrestricted research grants from The Michael J. Fox Foundation, AbbVie, and Merz, and receives royalties from Health Press Ltd and Taylor and Francis Group LLC.