Framework for Parkinson’s stages, based on disease biology, proposed
Fox Foundation-led effort to move beyond symptoms in research, clinical trials
Led by the Michael J. Fox Foundation for Parkinson’s Research (MJFF), an international group of patients, researchers, and industry leaders has proposed a framework for defining and staging Parkinson’s disease based on its underlying biology rather than by hallmark disease symptoms.
Called the neuronal alpha-synuclein disease integrated staging system (NSD-ISS), the proposed framework also would be relevant for other diseases marked by abnormal accumulation of the alpha-synuclein protein, such as Lewy body dementia.
“We propose that, given biomarker advances enabling accurate detection of pathological [alpha]-synuclein (ie, misfolded and aggregated) … it is time to redefine Parkinson’s disease and dementia with Lewy bodies as neuronal [alpha]-synuclein disease rather than as clinical syndromes,” the scientists wrote.
Although still being refined, scientists believe that by offering a standardized, shared tool for use by researchers and industry, the NSD-ISS ultimately could speed therapy development and facilitate clinical trials for disease prevention.
Advances in biomarker tests support new view of Parkinson’s stages
“This new research framework promises to transform clinical trial design as we know it,” Diane Stephenson, PhD, executive director of the Critical Path for Parkinson’s Consortium at the Critical Path Institute and a study author, said in a press release from the MJFF, which supported the work.
“This is how the field will meaningfully and tangibly achieve smarter and faster drug trials and treatments that can slow or halt disease progression,” Stephenson added.
The framework was described in the position paper, “A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research,” published in The Lancet Neurology.
In the earliest stages of Parkinson’s disease, a misfolded and toxic version of the alpha-synuclein protein accumulates in nerve cells (neurons). These protein clumps, or aggregates, start to form years before symptoms are evident.
Over time, they drive the death and dysfunction of neurons that produce dopamine, an important brain signaling molecule.
Despite these known biological underpinnings, Parkinson’s and its stages currently are defined by clinical presentation, such as the presence of motor symptoms. That’s in part because until recently, there was no reliable way to measure the presence of abnormal alpha-synuclein in a living person’s nervous system.
Last year, the MJFF validated the alpha-synuclein seed amplification assay (aSyn-SAA), a test that accurately detects the toxic protein in the cerebrospinal fluid — the fluid that surrounds the brain and spinal cord — in patients, including those without overt motor symptoms.
With this advancement, scientists have started calling for a more objective way of defining Parkinson’s and its stages based on biological markers such as alpha-synuclein and dopamine loss.
Proposal work of experts, including patients, across six continents
MJFF responded by coordinating an international working group to develop a framework for biological disease staging. This group included neuroscientists and other clinical experts, industry sponsors, nonprofit organizations, regulatory authorities, and patient representatives — in total, more than 550 people and organizations across six continents
The result is the proposed NSD-ISS system, based on disease stages that range from zero to six.
Briefly, NSD-ISS guidelines indicate that, for most patients, the earliest disease stages (0-1) are characterized by the presence of aggregated alpha-synuclein, as assessed by the aSyn-SAA test, followed by problems in dopaminergic neurons, measured via an imaging test called DaTScan.
In later stages, patients begin to develop motor and nonmotor disease symptoms that contribute to progressively worsening functional impairments. By stage 6, patients are experiencing severe impairments and are no longer independent in daily life activities.
Experts believe that a uniform definition of Parkinson’s stages will allow for a more objective assessment and comparison of lab research and clinical trial designs, and trial outcomes, helping in the development of therapies for patients at every stage of the disease.
“Our shared hope is that this new framework will foster innovation in clinical development, making trials more efficient and streamlining regulatory review,” said Tanya Simuni, MD, a professor of neurology, director of the Parkinson’s Disease Movement Disorders Center at Northwestern University, and the study’s lead author.
“In short, the NSD-ISS is a research accelerator. And it is expected to evolve. … 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,” Simuni added.
As this is an initial version, the NSD-ISS framework “is intended for research use only,” not routine clinical care, the scientists wrote.
They urged the research community to work together in providing data that would enable it being fully tested.
Data used to develop the framework largely came from MJFF’s Parkinson’s Progression Markers Initiative (PPMI), a large international study that was also used to develop the aSyn-SAA test. PPMI is supported by Aligning Science Across Parkinson’s, dozens of biotech and pharmaceutical companies, and thousands of individual donors.