- New paper in The Lancet Neurology proposes the first iteration of a research framework for defining and staging Parkinson’s disease (PD) based on biology, rather than clinical symptoms
- The framework defines PD based on the neuronal alpha-synuclein pathology that is a hallmark for the disease, building on the 2023 discovery of a biomarker that detects alpha-synuclein in living people
- Based on this new definition, the paper’s authors propose a staging system — the neuronal alpha-synuclein disease integrated staging system (NSD-ISS) — that promises to be a research accelerator by improving the development of new drugs across the disease continuum, enabling clinical trials for disease prevention and clarifying regulatory review
NEW YORK (January 23, 2024) — Today, an international working group has proposed a new research framework — the neuronal alpha-synuclein disease integrated staging system (NSD-ISS) —that, for the first time, stages Parkinson’s disease (PD) and defines it based on the disease’s underlying biology. The paper, published in The Lancet Neurology, describes the framework, its applications, gaps in knowledge and future plans. The NSD-ISS framework is considered a milestone for the field, and a critical starting point — as more data is developed, its concepts and definitions are expected to evolve.
The foundation of NSD-ISS defines Parkinson’s by the presence of its hallmark pathology, neuronal alpha-synuclein (asyn), that can now be detected by reliable biomarkers, often before symptoms appear. By applying an objective approach to detecting PD and standardizing its tracking on a biological continuum, NSD-ISS represents a major leap into the new and emerging biological era of Parkinson’s science. The new research framework stands to accelerate and increase the success of scientific discovery and therapeutic development at all stages of Parkinson’s. And ultimately, a treatment that targets the biology of the disease — rather than just its symptoms — is the way to reach a cure. (A similar biological framework in Alzheimer’s disease resulted in successful trials and new drug approvals, with the first drugs to slow Alzheimer’s-related cognitive decline appearing in 2022 and 2023.)
This landmark step forward was made possible by the breakthrough discovery of a test — validated in April 2023 by The Michael J. Fox Foundation’s Parkinson’s Progression Markers Initiative — capable of detecting the earliest believed pathology of PD even prior to the onset of any visible symptoms. The test, known as the alpha-synuclein seed amplification assay (αSyn-SAA), detects dysfunctional alpha-synuclein protein, one of the two biological hallmarks of PD alongside dopaminergic transport dysfunction, which can be visualized later in the disease process in the brain using DaTScan. Together, these two hallmarks serve as the basis for the NSD-ISS staging system. Key details include:
- The NSD-ISS integrates two core biomarkers: aggregated asyn (as currently detected by αSyn-SAA) and dopamine dysfunction (as currently measured by DaTScan dopamine transporter imaging in the brain).
- Stages one and two are based on these objective biomarkers, and stages three to six require these biomarkers and progressive motor and other nonmotor symptoms, such as REM sleep-behavior disorder, tremor, severe loss of smell, cognitive impairments and gait and balance problems.
- While disease occurs on a continuum and progression varies from person to person, defining discrete biological stages is critical to provide an objective framework for therapeutic development. Researchers are still investigating and refining the timeline for biological disease progression.
“This new research framework promises to transform clinical trial design as we know it,” said Diane Stephenson, PhD, executive director, Critical Path for Parkinson’s Consortium, Critical Path Institute, and a coauthor on The Lancet Neurology paper. “This is how the field will meaningfully and tangibly achieve smarter and faster drug trials and treatments that can slow or halt disease progression, and perhaps one day, prevent the disease process from occurring altogether.”
Because the framework encompasses clinical syndromes for which dysfunctional asyn is the defining biological hallmark, it applies to — and stands to improve treatment for — both PD and dementia with Lewy Bodies (DLB). The NSD-ISS unifies PD and DLB along the same continuum of progression based on a standardized biological diagnosis.
Framework Developed through Open Multistakeholder Collaboration
There is widespread recognition that to achieve a paradigm shift in how PD is defined and staged, multiple diverse stakeholders need to come together and engage in open and transparent dialogue. As part of the effort, the framework’s international working group hosted a multistakeholder discussion to collect input on the concepts for NSD-ISS from people and families living with PD, neuroscience and clinical leaders, industry experts, federal research funders (i.e., the National Institutes of Health), disease-focused nonprofit organizations and regulatory authorities (i.e., the Food and Drug Administration). A draft manuscript also was posted online for public comment. The process — which engaged more than 550 individuals and organizations from six continents — resulted in a framework informed by collective community input.
“Inviting scientific discourse from a multitude of perspectives is a key principle and a shared value of every organization and individual in the working group effort,” said Sohini Chowdhury, The Michael J. Fox Foundation’s chief program officer and a coauthor on the paper. “This new research framework is the product of a diverse community of contributors, whose inputs have helped to align and harmonize this first meaningful step toward a shared tool for researchers and the biopharma industry.”
NSD-ISS Will Become a Research Accelerator for the Field
The first iteration of the NSD-ISS framework is expected to play a transformative role in guiding development of therapies that affect disease progression by:
- Stimulating new approaches to develop and test therapies targeting relevant biology across the disease continuum, which could lead to precision treatments for people at every stage of disease.
- Enabling clinical trials even prior to symptom onset though biomarker-based disease detection. These trials could ultimately lead to therapies that prevent the onset of clinical symptoms.
- Providing academic researchers, industry investigators and regulators a consistent and uniform definition for each disease stage so that molecular investigations and clinical trial outcomes can be objectively assessed, standardized and compared efficiently.
“Our shared hope is that this new framework will foster innovation in clinical development, making trials more efficient and streamlining regulatory review. In short, the NSD-ISS is a research accelerator. And it is expected to evolve with accumulating scientific knowledge,” said Tanya Simuni, MD, lead author on the paper, professor of neurology and director of the Parkinson’s Disease Movement Disorders Center at Northwestern University. “The success that the Alzheimer’s field has had with its biological framework provides the inspiration and motivation to achieve similar accelerated timelines in Parkinson’s. Ten years from now, we hope we will look back and say this framework was the key that finally opened the door to next-generation treatments in Parkinson’s.”
As Simuni and her coauthors note in The Lancet Neurology paper, the framework offers an actionable proposal to researchers and industry creating a new path for efficient clinical trials, but at present, it is not intended for use in routine clinical care.
The paper includes acknowledgement that data supporting concepts of the NSD-ISS framework have emerged largely 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 PD. ASAP support is enabling a 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. Heralded as “the study that’s changing everything” about how Parkinson’s is diagnosed, managed and treated, PPMI and its data are made possible by the more than 2,000 in-clinic and 40,000 online research volunteers with and without Parkinson’s disease.
“It’s still early, but this framework will have an immediate impact in terms of how we’re designing clinical protocols and optimizing research that can lead to better treatments that patients are waiting for,” said Peter DiBiaso, MHSA, a coauthor on the paper, a drug development professional, and member of MJFF’s Patient Council who was diagnosed with PD at 49. “We know there’s a lot of work to be done, but this is the most important first step the field can take together to rapidly advance breakthroughs for patients and families.”
###
About The Michael J. Fox Foundation for Parkinson’s Research (MJFF)
As the world's largest nonprofit funder of Parkinson's research, The Michael J. Fox Foundation is dedicated to accelerating a cure for Parkinson's disease and improved therapies for those living with the condition today. The Foundation pursues its goals through an aggressively funded, highly targeted research program coupled with active global engagement of scientists, Parkinson's patients, business leaders, clinical trial participants, donors and volunteers. In addition to funding $1.75 billion in research to date, the Foundation has fundamentally altered the trajectory of progress toward a cure. Operating at the hub of worldwide Parkinson's research, the Foundation forges groundbreaking collaborations with industry leaders, academic scientists and government research funders; creates a robust open-access data set and biosample library to speed scientific breakthroughs and treatment with its landmark clinical study, PPMI; increases the flow of participants into Parkinson's disease clinical trials with its online tool, Fox Trial Finder; promotes Parkinson's awareness through high-profile advocacy, events and outreach; and coordinates the grassroots involvement of thousands of Team Fox members around the world. For more information, visit us at www.michaeljfox.org, Facebook or Twitter.
Media Contacts:
Stephanie Blank
FGS Global
stephanie.blank@fgsglobal.com
917-593-2907