Taking another major step into the new biological era of Parkinson’s disease (PD), an international team of patient, research and industry leaders has proposed the first iteration of a research framework for staging and defining PD based on its underlying biology.
Published in the January issue of The Lancet Neurology, the new research tool uses biomarkers that can detect Parkinson’s objectively in a living body — a significant paradigm shift after nearly two centuries of relying on outward, primarily movement-based symptoms for its detection. This new biological framework for PD is expected to have an immediate impact on research, speeding clinical trials and increasing the success of scientific discovery. And ultimately, a treatment targeting the biology of the disease — rather than just its symptoms — is the path to a cure.
The framework defines PD by the presence of alpha-synuclein (aSyn), the protein that misfolds, clumps and damages the brain over the course of the disease. The ability to define PD based on this underlying biology was made possible by a new biomarker — called the aSyn-seeding amplification assay (SAA) — that can detect aSyn in the spinal fluid of living people even prior to the onset of visible symptoms. The biomarker was validated in April 2023 by The Michael J. Fox Foundation’s Parkinson’s Progression Markers Initiative (PPMI) and has set about a sea change in how we think about the disease.
The framework then describes a system for staging the disease that accounts for Parkinson’s risk, diagnosis, and functional impairment ranging from slight to severe. An individual’s stage is premised on their personal biological profile, including their genetic risk factors and the presence or absence of aSyn in cerebral spinal fluid as well as dopamine degeneration in the brain.
The takeaway: This new tool is a research accelerator
The framework, which is referred to as the neuronal alpha-synuclein disease integrated staging system (NSD-ISS), is the first biological staging system for PD. With it, biopharma companies can more efficiently test novel therapies in individuals who have the targeted disease biology, and regulators can better assess the impact of these therapies on disease progression. In this way, the NSD-ISS is expected to help accelerate the success of scientific discovery and therapeutic development, and pave the way for precision medicine approaches for all stages of PD.
A similar biological framework in Alzheimer’s disease led to successful trials and new drug approvals, with the first drugs to slow Alzheimer’s-related cognitive decline appearing in 2022 and 2023. “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,” said Tanya Simuni, MD, lead author on The Lancet Neurology paper, associate professor of neurology and director of the Parkinson’s Disease Movement Disorders Center at Northwestern University. “Ten years from now, we hope we will look back and say this framework was the key that opened the door to next-generation treatments in Parkinson’s.”
The staging system will be applied immediately in research, where it is expected to quickly enable novel insights and disease measures. But while the NSD-ISS represents a critical milestone in the field — one that integrates input from hundreds of neuroscience and clinical leaders, industry experts, federal research funders (i.e., the National Institutes of Health), disease-focused nonprofit organizations, regulatory authorities (i.e., the Food and Drug Administration) and people and families living with PD — it is just a starting point and its concepts and definitions are expected to evolve. One day, after researchers learn more about the biology of PD and how and when it changes as the disease progresses, the framework and its biomarkers can become a routine part of practice that helps direct personalized treatment. For now, it is not intended for use in routine clinical care. (Read more in the latest edition of the Fox Focus on Parkinson’s.)
“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, 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.”
The 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), a coordinated research initiative focused on accelerating the pace of discovery and informing the path to a cure for PD. 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.