Traditionally, a diagnosis of Parkinson’s Disease relies on a clinical assessment by a doctor based on established clinical criteria. The clinical presentation of Parkinson’s often manifests late in disease progression. By this point, it is believed that significant underlying pathological biological processes and/or neurodegeneration have occurred.  

In the dynamic landscape of Parkinson’s research, two groundbreaking papers published in The Lancet Neurology have provided an important shift in the field’s understanding of Parkinson’s from a clinical perspective to a biological perspective. This means that we are now given a clearer window into the processes taking place from the very first stages of the disease, even well before the disease is clinically apparent. The NSD-ISS paper by Simuni and colleagues, titled A biological definition of neuronal a-synuclein disease: towards an integrated staging system and the SynNeurGe paper from Höglinger and colleagues, titled A biological classification of Parkinson’s disease: the SynNeurGe research diagnostic criteria, mark a transformative shift in how we are defining Parkinson’s. These papers are a result of collaborative international efforts and the contribution of both new scientific techniques and data contributed by patients.  

Understanding NSD-ISS and « SynNeurGe » in Parkinson’s 

Developing effective treatments for Parkinson’s disease is challenging due to its multifaceted nature and variability from person to person. Various forms of the disease are influenced by genetics, environmental factors, and more recently understood variations in biological processes, leading to a wide range of presentations. Additionally, the current diagnosis of Parkinson’s often occurs late, after the disease may have been present in the brain for a decade or more.

Published in The Lancet Neurology, scientists in both papers argue that the complexity of Parkinson’s demands a new approach to classifying individuals based on various biological markers. This not only helps to advance further research into the disease but can also have important implications in how patients are enrolled and studied in clinical trials for therapies and, further down the road, disease management. 

Each paper relies on the use of relatively new techniques, including the alpha-synuclein seed amplification assay and dopamine neuroimaging. These techniques have undergone significant validation to show their effectiveness as early biomarkers for Parkinson’s disease, both independently and through larger studies, including in the Parkinson’s Progressive Marker Initiative (PPMI) and Dementia with Lewy Bodies (DLB) Consortium. Both papers compiled these known biomarkers (alpha-synuclein aggregation, neurodegeneration and genetic background) to highlight how they contribute to disease and disease progression. Both also acknowledge the well-known clinical symptoms of the disease but note that they typically manifest after these biomarkers are able to be detected. These researchers propose the use of these models in identifying subsets of patients for more targeted research studies. With further validation, these models could be used for more targeted clinical trial recruitment, therapeutics designed for specific disease sub-groups and modeling disease progression. 

The SynNeurGe paper proposes a new classification framework based on the biological underpinnings of disease. Using these three components (outlined below), in addition to any clinical manifestations of disease, will help determine how someone is categorized for research purposes. 

1. « Syn » – alpha-synuclein, this component measures whether a patient sample has aggregated alpha-synuclein. This test uses an alpha-synuclein seed amplification assay from a cerebrospinal fluid (collected via spinal tap) sample, or other validated samples for the seed amplification assay.  
2. « Neur » – neurodegeneration, this component measures whether a patient has detectable neurodegeneration. 
3. « Ge » – genetics, this component measures whether a patient has a genetic cause or susceptibility associated with Parkinson’s disease.

In this model, a person is categorized based on their positive or negative results in the three components and are assigned a distinct disease title. This classification aids in refining research-related studies, including therapeutic development and clinical trials. For instance, one diagnosed with Parkinson’s disease could be categorized as being “Syn” positive and “Neur + Ge” negative, which they call ‘Sporadic Parkinson’s type synucleinopathy’, while another diagnosed with Parkinson’s disease could be categorized as “Syn + Neur” positive but “Ge” negative, which they call ‘Sporadic Parkinson’s disease.’ Despite both individuals having Parkinson’s disease, but they would be viewed differently for research purposes, allowing for a more targeted approach in studying the disease. This will have downstream effects on therapeutic development as researchers will have a better ability to target specific subsets of disease, which will have better translation from the laboratory to patients. 

The NSD-ISS paper introduces a similar classification framework as a basis for their proposed disease staging framework that includes: 

• Classification framework: 

1. S: alpha-synuclein, this component measures whether a patient sample has aggregated alpha-synuclein. This test uses an alpha-synuclein seed amplification assay from a cerebrospinal fluid (spinal tap) sample.    
2. D: dopamine neuron degeneration, this component measures whether a patient has detectable dopaminergic neurodegeneration. 
3. G: genetics, this component measures whether a person has a variant within the SNCA gene (encoding alpha-synuclein) and further categorizes based on genetic risk scores 

• Staging framework: 

1. Stage 0: A person has a known genetic cause of “Neuronal Synuclein Disease”, specifically a fully penetrant pathological variant in the SNCA gene. 
2. Stage 1: A person would fall into stage 1 if they have positive biomarker evidence of alpha-synuclein alone (stage 1A) or alpha-synuclein with dopaminergic neuron degeneration (stage 1B) without clinical symptoms of disease. 
3. Stage 2: A person has the characteristics of stage 1 plus mild clinical symptoms, but without functional impairment. 
4. Stage 3-6: These stages mark the traditional progression of clinical symptoms from slight, mild, moderate, to severe. 

This introduces a new naming system for Parkinson’s disease and demential with Lewy Bodies (DLB) – Neuronal alpha-Synuclein Disease – to better reflect the underlying biology of the disease, which is based on the presence of pathological neuronal alpha-synuclein. Additionally, they propose a staging framework that builds upon the traditional framework for clinical manifestations of disease, integrating newly validated biomarkers for earlier stages of disease. The aim of this new staging system is to provide clarity on disease progression before functional impairment occurs, aiding researchers in defining disease stages for therapeutic targeting and clinical trial recruitment. It’s important to note that this staging system does not currently replace the Parkinson’s disease staging system (ex. MDS-UPDRS), as individuals already diagnosed with Parkinson’s disease are likely to be in Stage 3 or above. This proposal is primarily for research purposes. The significance of this classification lies in targeting the earlier stages of disease to delay (or prevent) symptom onset. By categorizing stages based on the molecular signatures of disease, researchers will have more success in targeting these aspects of disease – ex. pathological alpha-synuclein and neurodegeneration in stages 1 and 2, or clinical symptoms in stages 3-6. 

What we can take from these papers is twofold: 1) understanding the disease from a biological standpoint is crucial for conducting research to achieve better outcomes for patients, and 2) collaborative efforts to further validate and develop new metrics for detecting and measuring the disease are vital for meaningful research discoveries that will benefit patients. Although these models were developed independently, both groups highlight similar metrics to address the broad spectrum of disease and disease progression based on a new biological definition of disease. However, these proposed definitions and stages of disease are currently for research purposes only – further research is needed to operationalize these frameworks effectively and translate them into clinical practice.  

Future directions for research 

Researchers are encouraged to contribute to further discovery and validation of techniques to refine the proposed redefinition of disease states and staging. They are working to improve the accuracy and sensitivity of tests measuring misfolded alpha-synuclein to make patient samples easier to obtain. The SynNeurGe paper suggests some of these developing techniques to detect misfolded alpha-synuclein from skin and blood plasma, however additional work is needed to ensure their validity as biomarkers. The ultimate goal is to redefine Parkinson’s through a different biological lens, emphasizing aSyn pathology and neurodegeneration for improved research outcomes and measurability. 

Insights empowering patients, families and the community 

The introduction of the NSD-ISS and SynNeurGe biomarker models represents a significant step forward in Parkinson’s disease research, with far-reaching implications for patients and their families. These models offer a more comprehensive understanding of the disease, allowing for earlier detection and more precise classification of patients based on their individual biological markers. 

For patients, this could mean a more personalized approach to diagnosis and treatment. Rather than relying solely on clinical symptoms, healthcare providers will eventually be able to utilize biological markers to assess disease progression and tailor treatment plans accordingly and accurately. This shift towards precision medicine holds promise for improving patient outcomes and quality of life. 

The NSD-ISS and SynNeurGe models have the potential to offer patients valuable information about where they fit within the Parkinson’s disease spectrum. Categorizing individuals based on their biomarker profiles, patients can gain insight into their disease stage and prognosis, empowering them to make informed decisions about their care. As research continues to evolve and new biomarkers are identified, patients can look forward to even greater precision and efficacy in Parkinson’s care.  

This targeted approach focuses on patients with shared biological characteristics, enhancing the success of drug development efforts and bringing us closer to the long-awaited goal of providing personalized care for individuals with Parkinson’s disease, guided by biological classification. 

Parkinson Canada’s involvement in the space 

As part of our expanding research initiatives, Parkinson Canada is dedicated to supporting projects aimed at unravelling the biological complexities of Parkinson’s disease. We are proud to sponsor various studies focused on elucidating the role of alpha-synuclein in disease advancement.  

Notably, we played a crucial role in co-sponsoring a landmark event—the PD Staging Roundtable on April 13, 2023, in Washington, DC. This roundtable convened experts who had crafted an initial blueprint for an integrated biological and clinical staging system applicable to PD, DLB, and related disorders. It also brought together specialists with complementary classification systems alongside stakeholders from diverse sectors with a vested interest. Our collaboration served as a catalyst for these papers, propelling a transformative shift in how we conceptualize Parkinson’s disease. By facilitating dialogue between these groups, we fostered collaboration and facilitated the exchange of knowledge. This meeting not only highlighted the similarities and differences in their approaches but also paved the way for future collaborative endeavours. 

Also, in the 2023-2025 cycle, we funded PhD Student Nathan Karpilovsky from McGill University, whose project titled “Genetic Modulators of alpha-synuclein Propagation in Parkinson’s Disease: a Genome-Wide CRISPR Approach” began to uncover the genes that may be involved in the accumulation of α-syn aggregates by healthy neurons and other relevant cell types. Additionally, within the same cycle we funded a Pilot Project Grant awarded to Professor Martin Ingelsson from the University Health Network titled “Strain-specific alpha-synuclein immunotherapy for Parkinson’s disease,” which employed cutting-edge techniques to investigate different properties of alpha-synuclein from the Parkinson brain and identify the most harmful species with the goal of delaying the alpha-synuclein pathogenic effects. 

Our funded researchers, along with the novel redefinition of Parkinson’s disease through a biological lens will no doubt prompt further discoveries within this space. 

Karen Lee, President, and CEO at Parkinson Canada, emphasizes the transformative impact of this new biological lens on Parkinson’s research and clinical trials: “Reshaping how we think about Parkinson’s in this new biological lens has the potential to change the landscape of research and clinical trials, leading to better research outcomes. We must strive to improve our detection methods to increase accuracy and sensitivity of these early biomarkers. Ultimately, these newly proposed models of Parkinson’s will help push the field to develop better therapeutics based on the molecular signature of disease.” 

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