Editor's Update: This blog explores a publication in Lancet Neurology proposing a new staging system for Neuronal Synuclein Disease (NSD). As part of the ongoing discussion, Lancet Neurology published several letters raising questions about the staging system and definition of NSD. On June 12, 2024, Lancet Neurology assembled those letters along with responses from the researchers behind the original article. Together, the Letters to the Editor and responses illustrate the robust, ongoing conversation surrounding NSD and its accompanying staging system.
A global team of researchers published a paper in The Lancet Neurology in January 2024, conceptualizing a biologic definition as well as a research staging system for “Neuronal alpha-Synuclein Disease” (NSD), which includes Parkinson’s disease (PD).
The researchers propose that the door is open to an era where PD has a biologic definition, as opposed to one based purely on symptoms. The biologic definition, combined with the development of an accompanying framework to stage people with measurable pathology whether or not they have symptoms, can accelerate research by empowering clinical trials to better enroll the right people in the right studies.
The Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-ISS), described in detail below, is expected to evolve as the scientific community gains more data and learnings, becoming a powerful tool in clinical trial design.
The Proposal
Using a biologic definition for staging NSD follows the success of similar strategies in Alzheimer’s and Huntington’s disease, which led to sustained industry investments in therapeutic development and, in the case of Alzheimer’s, approved treatments.
Biologic Definition
The NSD framework builds on the recent research reported in April 2023 by The Michael J. Fox Foundation’s landmark Parkinson’s Progression Markers Initiative, to reliably and objectively detect dysfunctional alpha-synuclein (asyn) in living people for the first time, using a tool called a Seed Amplification Assay (SAA). A person’s SAA status is the first biologic anchor of the proposed NSD definition.
The second core biologic anchor proposed is dopaminergic dysfunction, which can be visualized by targeted brain imaging (DaTScan) and is hypothesized to come later in the disease process. Now having these two objective standards, the multidisciplinary researchers behind the NSD paper (as well as other authors in the same journal) propose the field is prepared to move into a biological era of disease.
Based on biomarkers, NSD allows researchers to define PD in biologic terms, but it also uses a wider umbrella definition to include diseases with similar pathology, like dementia with Lewy bodies. Developing a unifying biological term has the potential to revolutionize trial design, while respecting and preserving the unique identities of patient communities. Further, efforts to assess co-pathologies in individuals defined by NSD and diseases like Alzheimer’s open the door to combination therapies with broad application.
Integrated Staging System
The Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-ISS) relies on the biomarker detected by SAA to categorize the evolution of NSD into progressive stages, integrating the biology with clinical symptoms. The framework as it stands is intended to be part of a dynamic and iterative scientific process.
In the staging system proposal, Stage 0 is defined currently by the presence of pathogenic mutations in the SNCA gene, which are tied to developing NSD. Stage 1 occurs before symptoms begin and is characterized by the detection of pathological neuronal alpha-synuclein (n-asyn) and the imaging of dopaminergic dysfunction. In Stage 2, clinical symptoms are integrated, though they are still subtle, without functional impairment.
Stages 3-6 are defined by the level of functional impairment caused by symptoms.
The majority of individuals receive a clinical PD diagnosis at Stage 3. However, various factors, including the severity of symptoms and access to healthcare, contribute to a broader range of diagnosis timing, with most falling within stages 2 to 4. Emphasizing this variability can be advantageous for clinical trials, as relying solely on time since diagnosis to define 'early PD' can introduce bias unrelated to the disease's natural progression.
The staging system would allow people working on treatments to target specific stages of disease progression in clinical trials, helping compare like to like.
What it means for Researchers
For researchers in the field of Parkinson's and Lewy body diseases, the proposed redefinition of PD and dementia with Lewy Bodies (DLB) as "Neuronal alpha-Synuclein Disease" based on biology is a game-changer.
SAA opened the door to a biological framework for understanding PD; the proposed staging system moves us through the door, while bringing along the lived experience of people with Parkinson’s.
The Biologic Era
For scientists involved in basic or early-stage translational research, a biological definition of NSD offers a unique opportunity to delve into the molecular aspects of PD, such as genetic mutations, inflammation and mitochondrial dysfunction. By identifying biological signals before clinical symptoms are apparent, researchers are given a much longer timeline to track the progression of the disease, while also better understanding its underpinnings.
"Apples to Apples”
Parkinson’s disease is known for being heterogenous, as it does not appear identically in any two people with PD. It’s difficult to compare like to like. This presents a significant challenge for researchers trying to establish controls and understand variables when testing new interventions. Staging NSD aims to compare individuals in similar phases of their disease journey, helping to reduce noise and refine findings.
This helps with comparison, but it also helps with contrast. For example, not all people diagnosed with PD will meet NSD criteria, with approximately 10% being SAA-negative. NSD-ISS presents an opportunity to leverage biologic heterogeneity in trials, driving research to better understand distinct biologic signatures in individuals who have clinical PD symptoms but do not fit the NSD criteria.
What it means for Industry Drug Development
For industry professionals involved in drug development and the pharmaceutical sector, the shift towards a biology-anchored approach to PD and DLB has far-reaching implications, especially for clinical trials.
Objective Evaluation Frameworks
The proposed staging system would serve as a catalyst for research endeavors, providing an objective framework for optimizing target populations and endpoints for clinical trials. Under the staging system, companies putting disease-modifying therapies through clinical trials would be able to compare stage-specific outcomes, leading to more accurate assessments of a potential treatment’s efficacy.
Better Identification of Trial Participants
Industry professionals can design trials that target specific aspects of disease biology and phases of disease progression with confidence that participants in the study have similar, important biological features. Since these trials could now include people who are not symptomatic yet, you can test therapies designed to delay or even prevent onset of clinical symptoms.
What it means for Clinicians
For now, the authors of the paper emphasize that NSD-ISS is a research framework not ready for the clinic, but it’s easy to envision how such a staging system could be integrated into clinical care one day, much like we have seen the updated Alzheimer’s disease framework being adapted for the clinic.
Improved Treatment Paradigms
While the Seed Amplification Assay has shown promise in detecting NSD biology, it's important to acknowledge that there is ongoing research aimed at refining and expanding its accessibility. Currently, it may not be readily ordered by most clinicians due to the invasiveness of the procedure (spinal tap) and perceived lack of immediate clinical value. However, the ongoing efforts to develop non-invasive alternatives, such as a blood test, and to enhance its utility as a prognostic or progression tool through quantitative assays are critical steps in making it more valuable to a broader community.
The Future of Therapeutics
Researchers expect that one day we will see therapies targeted specifically at asyn. At that point, asyn biomarker tests will gain clinical significance, aiding in the identification of patients who should be considered as candidates for treatment as well as potentially measuring success through a quantitative version of the assay. While these developments remain years away, the future on the horizon is starting to come into focus.
The Step Forward
The proposed redefinition of Parkinson's disease and dementia with Lewy bodies as Neuronal alpha-Synuclein Disease based on biology, along with the introduction of the NSD Integrated Staging System, could represent a significant step forward in our understanding and management of these neurodegenerative disorders.
Collaboration within the research community is essential to refine this innovative staging system further. With these advancements, we are closer to improving therapeutic development in PD and DLB cases caused by NSD and ultimately finding a cure for all individuals affected by these diseases.
The paper acknowledges that data supporting concepts of the NSD-ISS framework has largely emerged from the Foundation’s landmark PPMI study. Major funding for PPMI comes from Aligning Science Across Parkinson’s (ASAP) (www.parkinsonsroadmap.org), a coordinated research initiative focused on accelerating the pace of discovery and informing the path to a cure for Parkinson’s disease. ASAP support is enabling the seismic expansion of PPMI to increase recruitment efforts and remote testing for those at-risk for PD as well as expanding assay development efforts to enable breakthroughs such as the alpha-synuclein seed amplification assay. PPMI is additionally funded by a consortium of more than 40 biotech and pharmaceutical firms providing financial and in-kind support, and by tens of thousands of individual donors to The Michael J. Fox Foundation.