There is a proposal from an international alliance of patients, researchers, and industry leaders, led by the Michael J. Fox Foundation for Parkinson’s Research (MJFF), for defining and staging Parkinson’s disease. This proposal is based on the underlying biology rather than on the hallmark disease symptoms.
This approach, called the neuronal alpha-synuclein disease integrated staging system (NSD-ISS), could also be applicable for other diseases characterized by abnormal accumulation of the alpha-synuclein protein, such as Lewy body dementia. With biomarker advancements enabling precise detection of pathological alpha-synuclein, the scientists recommend redefining Parkinson’s disease and dementia with Lewy bodies as neuronal alpha-synuclein disease instead of clinical syndromes.
The scientists believe that once refined, the NSD-ISS will provide a standardized, shared tool for researchers and industry, ultimately accelerating therapy development and facilitating clinical trials for disease prevention.
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Diane Stephenson, PhD, the executive director of the Critical Path for Parkinson’s Consortium at the Critical Path Institute and a study author, stated in a press release from the MJFF, which supported the work, that this new research framework has the potential to revolutionize clinical trial design.
The framework was presented in “A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research,” a position paper published in The Lancet Neurology. In the early stages of Parkinson’s disease, a toxic version of the alpha-synuclein protein accumulates in neurons, causing protein clumps that lead to the death and dysfunction of dopamine-producing neurons in the brain.
Despite these known biological underpinnings, Parkinson’s and its stages are currently defined by clinical presentation, such as the presence of motor symptoms, due to the lack of a reliable method to measure the presence of abnormal alpha-synuclein in the nervous system of living individuals until recently.
The MJFF validated the alpha-synuclein seed amplification assay (aSyn-SAA) last year, a test capable of accurately detecting the toxic protein in the cerebrospinal fluid of patients. With this advancement, there are calls for a more objective determination of Parkinson’s and its stages based on biological markers like alpha-synuclein and dopamine loss.
Development of the proposal involved experts, including patients, from six continents
MJFF organized an international working group consisting of neuroscientists, clinical experts, industry sponsors, nonprofit organizations, regulatory authorities, and patient representatives, totaling more than 550 individuals and organizations from six continents.
The resulting proposed NSD-ISS system is based on disease stages ranging from zero to six. According to NSD-ISS guidelines, the earliest disease stages (0-1) involve aggregated alpha-synuclein detected by the aSyn-SAA test, followed by problems in dopaminergic neurons measured via an imaging test called DaTScan. As the disease progresses, patients develop motor and nonmotor symptoms leading to progressively worsening functional impairments. By stage 6, patients cannot perform daily activities independently.
Experts believe that a consistent definition of Parkinson’s stages will enable an objective assessment and comparison of lab research and clinical trial designs, and outcomes, thus aiding in the development of therapies for patients at every stage of the disease.
Tanya Simuni, MD, a professor of neurology and director of the Parkinson’s Disease Movement Disorders Center at Northwestern University, who led the study, expressed hope that the NSD-ISS will lead to innovation in clinical development, streamlining regulatory review and making trials more efficient. The NSD-ISS is considered a research accelerator and is expected to evolve, possibly opening the door to next-generation treatments in Parkinson’s in the years to come.
This version of the NSD-ISS framework is intended solely for research purposes, not for routine clinical care. The scientists have urged the research community to collaborate in providing data for its full testing. Data used to develop the framework largely came from MJFF’s Parkinson’s Progression Markers Initiative (PPMI), a study that was also utilized for developing the aSyn-SAA test, and is supported by Aligning Science Across Parkinson’s, biotech and pharmaceutical companies, and individual donors.
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