An international team of patient, research and industry leaders, including Shake It Up Australia, have collaborated to propose the first iteration of a new research framework – the neuronal alpha-synuclein disease integrated staging system (NSD-ISS). The NSD-ISS, for the first time, stages Parkinson’s disease (PD) and defines it based on the disease’s underlying biology.
Published in the January issue of The Lancet Neurology, the new research tool uses biomarkers that can detect Parkinson’s in an individual living with the disease. This is a significant change after nearly two centuries of relying on outward, primarily movement-based symptoms to detect PD. The new framework is expected to have an immediate impact on research, speeding clinical trials and increasing the success of scientific discovery. The Michael J. Fox Foundation for Parkinson’s Research (MJFF ) highlights that ultimately, a treatment targeting the biology of the disease — rather than just its symptoms — is the path to a cure.
What does the staging framework do?
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 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 – co-funded by Shake It Up here in Australia back in 2011 – and has transformed 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 framework proposes how two new tests can be used in clinical trials of new treatments for Parkinson’s to monitor progression of the disease. The tests have been chosen because they can be used to identify key biological features of Parkinson’s. Parkinson’s UK describes these tests as:
- a new test that can identify misfolded alpha-synuclein, a protein that is a feature of Parkinson’s, in fluid taken from the spine via a lumbar puncture
- a brain scan called a DaTSCAN that can tell if there is a lack of dopamine, the chemical that decreases over time in Parkinson’s, inside the brain.
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 finally opened the door to next-generation treatments in Parkinson’s.”
How will the biological staging system be used?
The first iteration of the NSD-ISS framework is expected to transform the development of new Parkinson’s therapies by:
- Stimulating new approaches to develop and test therapies targeting relevant biology, which could lead to precision treatments for people at every stage of disease.
- Enabling clinical trials even prior to symptom onset. These trials could lead to therapies that prevent the onset of clinical symptoms.
- Providing scientists and regulators a consistent and uniform definition for each disease stage.
But while the NSD-ISS represents a critical milestone in the field, it is just a starting point. Its concepts and definitions are expected to evolve. MJFF notes that 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 personalised treatment. For now, it is not intended for use in routine clinical care.
“This new staging system for Parkinson’s is a crucial step forward to make clinical trials more precise, and to eventually improve the development of new therapies and treatments for people living with Parkinson’s, who have vastly different symptoms at different stages of the disease”, said Shake It Up Australia CEO Vicki Miller. “The global collaboration that led to this framework is just the first step of an exciting new biological era in Parkinson’s research that will bring us ever closer to slowing and stopping the progression of the disease while in pursuit of the ultimate goal: a cure.”
