The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has announced what it says is the ‘most significant breakthrough yet’ in the search for a Parkinson’s biomarker: a biological test for Parkinson’s disease. The test demonstrates high diagnostic accuracy, differentiates molecular subtypes and detects disease in individuals before cardinal movement symptoms arise.
A paper on the test was published in The Lancet Neurology journal by leaders of the Parkinson’s Progression Markers Initiative (PPMI), the Parkinson’s biomarker study sponsored by the MJFF.
The new Parkinson’s test, known as the alpha-synuclein seed amplification assay (αSyn-SAA), heralds the ability for research to define Parkinson’s disease biologically, offering a critical tool for clinical trial design and assessment of treatment effects, and for early detection of disease pathology.
The PPMI authors said the test detects synuclein pathology, one of the two biological hallmarks of Parkinson’s disease (alongside dopaminergic transport dysfunction, which can be visualized using DaTScan). As a result, for the first time since James Parkinson first characterized the disorder in 1817, researchers and clinicians can use biology (as opposed to clinical assessments and patient-reported outcomes) to identify, define and monitor Parkinson’s objectively, based on cellular pathology in the body.
New era in Parkinson’s disease research
“Validation of this biomarker launches a new, biological era in Parkinson’s research,” said Kenneth Marek, PPMI principal investigator, president and senior scientist at the Institute for Neurodegenerative Disorders.
“Using αSyn-SAA, we are already unlocking a new understanding of Parkinson’s, which will transform every aspect of drug development and ultimately clinical care. We will rapidly be in a position to test new therapies in the right populations, target the right therapy to the right patient at the right time, and launch studies of agents with potential to prevent Parkinson’s disease altogether. This is what PPMI was built to do, and we are especially grateful to the thousands of study participants whose contributions have enabled this watershed moment.”
The paper, co-led by Andrew Siderowf, PPMI investigator and director, Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania and Luis Concha, director, research and development at Amprion, outlines αSyn-SAA results from more than 1,100 PPMI participants including individuals with Parkinson’s disease, those with genetic and/or clinical risk factors but not diagnosed with Parkinson’s, and control volunteers.
High sensitivity
The large-scale analysis in PPMI confirms previous reports — including from MJFF-funded work — that αSyn-SAA can distinguish Parkinson’s from control volunteers with a sensitivity of 88% and specificity of 96%.
As an objective and reliable biomarker of Parkinson’s biology, αSyn-SAA will significantly decrease the risk for industry to invest in the development of potential blockbuster therapies, including preventive agents, and increase the speed and efficiency with which these therapies can be developed, tested and brought to market.
Using αSyn-SAA, it will be possible to establish objective endpoints for clinical trials of Parkinson’s treatments, ensure study participants exhibit appropriate pathology, and detect therapy-induced changes in their status. This is already reworking the design of clinical trials and can induce greater pharma and biotech investment in the space — creating more “shots on goal” to benefit people at every stage of disease.
Parkinson’s disease biology subtypes linked to genetic and clinical factors
The authors reported findings related to olfactory deficit, or smell loss (enduring and significant smell loss is a common symptom of Parkinson’s often seen years before a diagnosis) and to carrying a mutation in the Parkinson’s-associated LRRK2 gene.
- The assay accurately diagnosed disease in 99% of people with smell loss and sporadic Parkinson’s (without a known causal genetic mutation).
- The proportion of positive results – at 68% – was lower in people with Parkinson’s and a LRRK2 mutation.
- Positive results were lower in people with sporadic Parkinson’s without olfactory deficit (78%).
- For people with Parkinson’s, a LRRK2 mutation and normal smell ability were even less likely to show positive assay results. This was particularly true among females; only 12.5% of females in this population showed synuclein pathology on the test.
- In people with Parkinson’s enrolled in PPMI who consented to post-mortem examination and who have passed since joining the study, all those with positive assay results showed typical alpha-synuclein aggregation pathology in brain cells; the single such PD participant who did not show positive assay results was a LRRK2 mutation carrier with preserved olfaction.
The researchers said the results suggest that not all cases of clinical Parkinson’s symptoms are associated with the accumulation of alpha-synuclein aggregates as detected by this assay, and that LRRK2 variant carriers, in particular, may not show this pathology.
Parkinson’s disease: New avenues of investigation
This opens new avenues of investigation toward treatments to benefit more people with PD. It will also enable deeper studies of the cellular pathways and cascades occurring in LRRK2-associated Parkinson’s, some of which may be protective against synuclein dysfunction and Parkinson’s toxicity. MJFF said this could lead to breakthroughs to benefit everyone with Parkinson’s, not just those who carry a genetic mutation. Three therapies targeting dysfunction in the LRRK2 pathway are currently in clinical trials.
Parkinson’s disease biomarker test development
The αSyn-SAA was developed when MJFF on-staff neuroscience PhDs approached researchers at University of Texas working on seed amplification assays in Alzheimer’s. The Foundation offered funding to experiment with developing an alpha-synuclein assay using PPMI cerebrospinal fluid samples.
The University of Texas team that developed the assay has launched a biotech company, Amprion, which partnered with PPMI on its analysis of αSyn-SAA. The company has commercialized the assay as the SYNTap test, which is available for order by physicians, for people exhibiting symptoms of Parkinson’s or related disorders.
When the test is positive, a person likely has Parkinson’s or a related disorder of alpha-synuclein, such as dementia with Lewy bodies (DLB) or multiple system atrophy (MSA). The test, on its own, cannot differentiate between these diseases. It also may not be covered by insurance. But, in conjunction with a doctor’s examination, the test might help support a specific diagnosis.
“The Michael J. Fox Foundation has always recognized the indisputable need for biomarkers of Parkinson’s disease, and has relentlessly pursued them as a mission-critical goal,” said Deborah W. Brooks, MJFF’s chief executive officer (and a PPMI control volunteer at the University of Pennsylvania since 2010).
“It would be difficult to overstate the implications of this discovery. With development and scaling, αSyn-SAA can usher in the era of objectively and biologically defining Parkinson’s disease — revolutionizing every aspect of research and care.”
Parkinson’s cure “inevitable”
Michael J. Fox said: “There are many ways I am involved with the work of the Foundation, but I come to this result first and foremost as a Parkinson’s patient. I am deeply moved by this breakthrough and endlessly grateful to the researchers, study participants and funders who have endeavored to bring us this far. When we started PPMI, we weren’t casting about for fish — we were going after a whale. Now, here we are. Together, we are making a cure for Parkinson’s inevitable.”
About PPMI
MJFF launched the Parkinson’s Progression Markers Initiative in 2010 at 18 clinical sites in the U.S. and Europe. A longitudinal observational study, PPMI has built a robust dataset and biosample library, which is shared with the broader research community in real time for ongoing discovery and validation studies. Today, the study has enrolled nearly 2,000 participants and is actively enrolling Parkinson’s patients, at-risk individuals and control volunteers at 51 clinical sites around the globe. Study data are downloaded by researchers worldwide for independent studies on average 2,200 times a day.
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