Science made a huge step-forward in the world of neurological diseases. It is the first profound discovery in Parkinson’s disease.
A landmark paper published today in The Lancet Neurology journal by leaders of the Parkinson’s Progression Markers Initiative (PPMI), the gold-standard Parkinson’s biomarker study sponsored by The Michael J. Fox Foundation for Parkinson’s Research (MJFF), confirms the most significant breakthrough yet in the search for a Parkinson’s biomarker: a biological test for Parkinson’s disease that demonstrates high diagnostic accuracy, differentiates molecular subtypes and detects disease in individuals before cardinal movement symptoms arise.
The new test, known as the alpha-synuclein seed amplification assay (αSyn-SAA), heralds the revolutionary 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.
As authors from PPMI detail in The Lancet Neurology, 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 (vs. clinical assessments and patient-reported outcomes) to identify, define and monitor Parkinson’s objectively, based on cellular pathology in the living body.
“Validation of this biomarker launches a new, biological era in Parkinson’s research,” said Kenneth Marek, MD, PPMI Principal Investigator and president and senior scientist at the Institute for Neurodegenerative Disorders. “Using αSyn-SAA, we are already unlocking 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, MD, PPMI Investigator and Director, Parkinson Disease and Movement Disorders Center at the University of Pennsylvania and Luis Concha, PhD, 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. 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 stunningly robust sensitivity of 88 percent and specificity of 96 percent.
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. With αSyn-SAA in hand, 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 already is 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.
Subtypes of Parkinson’s Biology 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 percent (274 of 278) of people with smell loss and sporadic Parkinson’s (without a known causal genetic mutation).
- The proportion of positive results was lower in people with Parkinson’s and a LRRK2 mutation [68 percent (83 of 123)].
- Positive results also were lower in people with sporadic Parkinson’s without olfactory deficit (78 percent).
- 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 percent of females in this population (three of 24) 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 (14) 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.
These 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. This insight opens new avenues of investigation toward treatments to benefit more people with PD. It also will 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. 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.)
New Evidence that Biological Changes in Synuclein Predate Both Symptoms and Dopamine Dysfunction, Setting Stage for First Prevention Trials
The αSyn-SAA also has been validated in individuals enrolled in PPMI who have not been diagnosed with Parkinson’s, but are age 60 or older and living with increased relative risk of developing Parkinson’s due to genetic mutations, smell loss, or diagnosed REM sleep behavior disorder (RBD). (RBD is a sleep disorder of acting out dreams by hitting, punching or kicking, and is tied to significant risk of developing Parkinson’s or a similar neurodegenerative disease.) PPMI reopened enrollment in 2020 and is building a longitudinal cohort of 2000 such at-risk individuals.
- Most people with olfactory deficit [88 percent (16 of 18)] or RBD [84 percent (28 of 33)] showed positive assay results.
- The authors also compared results to dopamine transporter (DAT) brain imaging scans, a tool for assessing dopamine transporter system dysfunction and thereby Parkinson’s pathology, including in at-risk individuals. Only about 30 percent of at-risk individuals with a positive seed amplification assay result also had significant dopamine loss.
- This finding suggests that synuclein pathology could be detectable by this assay earlier than dopamine dysfunction is seen with DAT imaging, extending the window in which it may be possible to intervene with preventive therapies.
- On the other hand, undiagnosed but at-risk carriers of a LRRK2 or GBA mutation (the most common known genetic link to Parkinson’s disease) were less likely to show positive assay results: 8.8 percent (14 of 159) and 7.3 percent (11 of 151) respectively.
- This finding suggests that RBD and olfactory deficit arise closer to onset of Parkinson’s movement symptoms.
- It also suggests that alpha-synuclein aggregation in spinal fluid is not a life-long trait but rather acquired as part of a disease biology process that ultimately gives rise to symptoms. By exploiting this understanding to intervene in this process, drugmakers hope to make Parkinson’s a preventable condition.
Biomarker Test Available for Diagnostic Assessment
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 since launched biotech 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.”
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.”
PPMI: The Study that’s Changing Everything
MJFF launched the Parkinson’s Progression Markers Initiative (www.ppmi-info.org, michaeljfox.org/ppmi) in 2010 at 18 clinical sites in the United States and Europe with a lead gift from the late Mrs. Lily Safra, a visionary friend, partner, and board member of MJFF. A longitudinal observational study, PPMI has built the most robust dataset and biosample library ever assembled in Parkinson’s research, which is shared with the broader research community in real time for ongoing discovery and validation studies. Today the study has enrolled nearly 2000 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 2200 times a day.
With the publication of αSyn-SAA, The Michael J. Fox Foundation announced that the tagline of the PPMI study will change from “The Study that Could Change Everything” about how Parkinson’s disease is diagnosed, managed and treated to “The Study that’s Changing Everything.”
Major funding for PPMI comes from Aligning Science Across Parkinson’s (ASAP) (www.parkinsonsroadmap.org), a coordinated research initiative focused on accelerating the pace of discovery and informing the path to a cure for Parkinson’s disease. ASAP support is enabling the seismic expansion of PPMI to increase recruitment efforts and remote testing for those at-risk for PD as well as expanding assay development efforts to enable breakthroughs such as αSyn-SAA. This infrastructure provides a ready platform for future discoveries.
In addition to ASAP, PPMI is supported by the Edmond J. Safra Foundation, the Farmer Family Foundation and Connie and Steve Ballmer. The study 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.