NeuroVoices: Tanya Simuni, MD, FAAN, on Using the Neuronal Synuclein Disease Integrated Staging System Framework to Advance Parkinson Disease Staging

Tanya Simuni, MD, FAAN

(Credit: Northwestern University Feinberg School of Medicine)

The neuronal α-synuclein disease (NSD) biological definition and integrated staging system (NSD-ISS), introduced in 2024, may offer a research framework to identify individuals with Lewy body pathology and categorize them based on biological markers and functional impairment. Using data from the PPMI (NCT01141023), PASADENA (NCT03100149), and SPARK (NCT03318523) studies, researchers applied biologic and clinical criteria to stage individuals diagnosed with Parkinson disease (PD), those in the prodromal phase (S+), and healthy controls in a recent study published in NPJ Parkinson’s Disease.^1,2 Among 1741 participants with seed amplification assay (SAA) data, 1030 (59%) were S+, aligning with the NSD definition. In the sporadic PD cases, 93% met NSD criteria, with 25% in Stage 2B, 63% in Stage 3, and 9% in Stage 4.

Conducted by coauthor Tanya Simuni, MD, FAAN, professor of neurology at Northwestern University Feinberg School of Medicine, and colleagues, this analysis demonstrated a clear correlation between baseline staging and the time to clinically meaningful disease progression. The median time to progression was 8.3 years for Stage 2B, 5.9 years for Stage 3, and 2.4 years for Stage 4, underscoring the heterogeneity among individuals currently classified as early PD. These findings suggest that NSD-ISS could improve the ability to predict disease trajectory, enabling more precise staging of patients. However, further longitudinal research may be needed to validate these staging anchors and refine their clinical and research applications.

In a new iteration of NeuroVoices, Simuni expanded on the implications of NSD-ISS as a research-driven framework. She emphasized its potential to biologically define PD through synuclein pathology, dopaminergic dysfunction, and genetic markers, potentially offering a more refined alternative to traditional clinical models. By identifying individuals earlier in the disease course and improving patient selection for clinical trials, she noted that the NSD-ISS could represent a crucial step toward advancing personalized therapeutic approaches in neurodegenerative diseases. Although still in the research phase, she underscored that this framework could lay the groundwork for more targeted and effective treatments in the future.

NeurologyLive: How does the NSD-ISS improve upon existing staging models for Lewy body pathology, particularly in differentiating early Parkinson disease subgroups?

Tanya Simuni, MD, FAAN: This is the new biological research—and I underscore research—definition of the disease that we have introduced to increase the accuracy and reduce the heterogeneity of the population that currently carries the clinical diagnosis of PD. The staging system builds on this definition to provide a framework to recruit into clinical trials individuals who are biologically and clinically more homogeneous.

Now, to address your direct question, the existing staging system for Lewy body pathology is a neuropathological staging system. It is extremely informative for postmortem diagnosis and understanding of disease biology, but not for living individuals. The only staging system we currently have in PD is the Hoehn and Yahr staging, which was introduced more than 50 years ago. It is very useful in the clinic, but it categorizes patients broadly—essentially, whether someone has symptoms on one side of the body, on both sides, or has balance problems. These are broad categories, and someone can remain in a stage for 10 years or more.

So why do we need biological staging for therapeutic trials? I think the Alzheimer field is a perfect example. They have been trying to develop amyloid-targeting therapeutics for over 30 years, and while multiple factors contributed to their recent success, a key factor was recruiting individuals who, based on biomarkers, were confirmed to have amyloid pathology. That speaks for itself.

What were the key biological and clinical data points that informed the development of the NSD-ISS, and how did they influence staging decisions?

Just to remind everyone, the definitive diagnosis of PD or dementia with Lewy bodies is made by a pathologist based on the recognition of Lewy bodies and neurodegeneration. The transformative milestone that allowed us to postulate a biological definition in living people was the development of a biomarker for synuclein pathology.

Currently, there are 2 biomarkers in the field. The one we anchor to is the cerebrospinal fluid SAA. Another promising biomarker is the skin synuclein test, which has shown very high sensitivity and specificity but still needs to be tested in earlier populations. Because we define the disease by synuclein pathology, we need a way to measure that pathology in living individuals.

Additionally, as a correlate to how pathologists make the diagnosis, we measure dopaminergic dysfunction. The validated, partially available measure for this today is dopamine transporter uptake using single-photon-emission computed tomography imaging.

These 2 core biomarkers—synuclein pathology and dopaminergic dysfunction—are combined with genetic characterization in applicable individuals. These 3 pillars of biological characterization—genetics, synuclein pathology, and dopaminergic dysfunction—form the foundation of the NSD-ISS.

In this research framework, a person who has synuclein pathology is defined as having NSD. This means that a person can have the disease even if they have no symptoms. The objective is to identify individuals at risk as early as possible. However, more work is needed to improve risk prediction. Today, there are likely many people with synuclein pathology who may never develop clinical manifestations. Unless we identify them, we won't be able to establish a framework to understand predictive biomarker patterns and timelines for disease progression.

Given the baseline heterogeneity in early PD, what are the implications of NSD-ISS staging for patient selection in clinical trials and personalized treatment approaches?

It all comes down to reliability in study outcomes. To achieve this, we need to reduce population heterogeneity and match treatments to an individual's underlying biology. Our framework certainly reduces heterogeneity—though this is just the start.

In a recent paper we published, with Tien Dam, MD, as the first author, we demonstrated that when we applied our staging anchors to 3 independent cohorts—including the seminal observational study PPMI and 2 large phase 2 trials testing α-synuclein-targeting monoclonal antibodies—individuals recruited under the broad label of "early PD" were actually spread across at least three different stages. This demonstrates that we can improve patient selection.

Not only have we shown this, but we also found that progression trajectories varied significantly by stage. The higher the stage, the more functional impairment and the faster the progression. Depending on the study design, researchers may want to recruit individuals who progress faster or slower, depending on the therapeutic strategy.

That said, we are not claiming this is the definitive model. This is just the beginning. Neurodegenerative diseases are extremely complex, and even the best biomarkers cannot fully address the heterogeneity. While 90% of individuals with PD have neuronal synuclein disease, they still progress and behave differently. We need to understand additional factors—comorbid pathologies, underlying neurodegenerative mechanisms, and resilience factors.

For example, many individuals with PD also have Alzheimer pathology. What impact does that have? There is also significant scientific discussion about resilience—why some individuals with the same pathology remain stable while others decline rapidly.

So, while this framework is a significant advancement over current staging models, it also sets scientific priorities for future iterations. We will need to expand biomarker characterization beyond the core biomarkers. Reflecting on Alzheimer disease, just last year, the field revised its diagnostic and staging criteria to incorporate copathology, vascular measures, and inflammation markers. These are all important steps toward truly personalized therapeutics.

What are the next steps for validating the NSD-ISS anchors in longitudinal cohorts, and what challenges do you anticipate in its broader clinical application?

I think you started answering your own question—we need to apply the diagnostic and staging criteria to multiple cohorts. To do that, these cohorts must include biological anchors, and a lot of work is underway to make that possible.

I want to emphasize again: this is a research framework. It is not yet ready for clinical use.

To validate it more broadly, we need longitudinal cohorts. We also need biomarkers that are more readily available. Right now, our key biomarkers are based on cerebrospinal fluid. Ideally, we would follow the path of Alzheimer research, where blood-based biomarkers are now emerging. This is a challenge in synuclein diseases because there is simply less synuclein protein in the blood compared to amyloid or tau. However, research is ongoing, and we are optimistic that more accessible biomarkers will become available.

In the meantime, the global neurology community needs to be educated on the tremendous advancements in our ability to assess disease biology in living individuals. Clinicians will still diagnose PD or dementia with Lewy bodies in the traditional way, but we need to start thinking biologically. That shift is essential for moving the field forward.

Transcript edited for clarity. Click here to view more NeuroVoices.

REFERENCES
1. Dam T, Pagano G, Brumm MC, et al. Neuronal alpha-Synuclein Disease integrated staging system performance in PPMI, PASADENA, and SPARK baseline cohorts. NPJ Parkinsons Dis. 2024;10(1):178. Published 2024 Sep 27. doi:10.1038/s41531-024-00789-w
2. Rohman M. Improving Diagnosis and Tracking of Neurodegenerative Diseases. News Release. Northwestern Medicine. Published November 22, 2024. Accessed March 11, 2025. https://news.feinberg.northwestern.edu/2024/11/22/improving-diagnosis-and-tracking-of-neurodegenerative-diseases/