Research Paper Adds Clinical Anchors to Proposed Parkinson’s Staging System

The US Food and Drug Administration (FDA) rounded out Summer 2024 by issuing a "Letter of Support" for use of the synuclein seeding amplification assay (SAA) as a biomarker test in research and clinical trials. In the letter of support, the FDA also called for further exploration of a specific staging framework based on this test, called the Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-ISS). The FDA acknowledged the potential of NSD-ISS as a research tool to classify people with Parkinson's and biologically related disorders in a way that facilitates comparing like-to-like in studies and drug trials.

In September 2024, researchers published a paper in npj Parkinson's Disease proposing specific clinical and functional impairment anchors for NSD-ISS. These anchors move beyond previous, more general categorizations of functional impairment (such as mild, moderate or severe) and offer concrete definitions that cover both motor and non-motor aspects of the disease, including cognition.

The anchors were developed based on analysis of the data from The Michael J. Fox Foundations' flagship Parkinson's Progression Markers Initiative (PPMI) and two recently completed interventional studies, the PASADENA and SPARK studies.

The paper then examines NSD-ISS's performance using these anchors in three major cohorts. The baseline datasets from the three large studies provide critical insights into how individuals with Parkinson's disease can be staged at baseline, using that combination of biological, clinical and functional data.

The new anchors enable application of the staging framework in clinical trials, incorporating a wider range of symptoms experienced in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While the NSD-ISS at launch emphasized biological markers (such as the presence of misfolded alpha-synuclein and dopaminergic dysfunction), this paper focuses on the functional impairment that patients face - particularly in terms of how motor and cognitive impairments influence day-to-day activities. Analysis of the longitudinal changes in NSD-ISS using PPMI and other cohorts is underway.

Why These Clinical Anchors Matter

The proposed clinical anchors provide essential operational anchors to researchers looking to use the staging framework. By establishing operational clinical criteria, the NSD-ISS aims to more precisely stratify patients based on their current level of impairment. This not only sharpens our understanding of the patient population but also makes it possible to predict disease progression with greater accuracy.

The team of researchers behind the paper chose to use anchors from the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) and Montral Cognitive Assessment (MoCA) as commonly used measures that capture a range of symptoms.

The predictive value of this new staging framework will need to be further explored in the longitudinal studies. However, there are immediate and important implications for research. For instance, the study found that individuals in Stage 4 NSD (as defined by both clinical and biological anchors) reached significant disease milestones - such as motor complications or cognitive decline - more quickly than those in earlier stages. This shows how clinical measures of impairment may be better suited for predicting disease trajectory compared to more general benchmarks like time since diagnosis and the Hoehn and Yahr scale.

Implications for Clinical Trials

The introduction of these initial clinical anchors for staging could significantly enhance the design and effectiveness of clinical trials. Trials like SPARK and PASADENA have historically enrolled patients based on time since diagnosis or basic motor assessments. The new NSD-ISS anchors would enable trials to focus on participants whose progression is more predictable based on their precise level of clinical impairment combined with their biology. This reduces variability in patient outcomes and could help trials detect treatment effects more easily.

Dr. Catherine Kopil, PhD, an author of the paper and senior vice president of clinical research at The Michael J. Fox Foundation (MJFF), highlighted the potential of these findings.

"The proposed clinical and functional impairment anchors for NSD-ISS are a key, initial advancement for how we can measure and predict progression in Parkinson's and biologically related disorders," Dr. Kopil says. "This level of specificity will help researchers better design trial and select patients who are most likely to show meaningful results from therapeutic interventions in the near-term while setting a foundation for development of novel, stage-dependent measures in the future."

Moving Forward

The authors of the paper call for further research to validate the proposed clinical and functional anchors in more diverse populations. Understanding the diversity of symptoms within NSD, especially between PD and DLB, will help researchers fine-tune these definitions and improve the staging system even further.

The NSD-ISS framework, bolstered by these clinical anchors, offers an exciting new tool for understanding disease progression and tailoring treatment to meet individual patient needs. It not only facilitates better patient selection for clinical trials but also sharpens our predictions for how the disease will unfold, leading to more effective therapies in the future.

• David Kumbroch

  Senior Science Writer