New publication in The Lancet Neurology confirms that a key pathology of Parkinson’s disease can now be identified by analysing the spinal fluid of living patients
The test, validated as the gold standard within the Parkinson’s Progression Markers Initiative, shows a sensitivity of more than 90 % in people with typical Parkinson’s pathology and is often positive even before the onset of symptoms.
The results show differences in subtypes of the disease and in people with Parkinson’s risk factors and provide a new tool for precision medicine approaches, earlier interventions and better planning of clinical trials.
Michael J. Fox is “deeply moved by the breakthrough”, “as it makes the cure for Parkinson’s inevitable”
Parkinson’s Progression Markers Initiative (PPMI)
A groundbreaking paper published today in The Lancet Neurology by the leaders of the Parkinson’s Progression Markers Initiative (PPMI), the Parkinson’s biomarker study funded by the Michael J. Fox Foundation for Parkinson’s Research (MJFF), confirms the most significant breakthrough to date in the search for a Parkinson’s disease biomarker: a biological test for Parkinson’s disease that has high diagnostic accuracy, differentiates molecular subtypes and detects the disease in individuals before cardinal movement symptoms appear.
The new test, called the Alpha-Synuclein Seed Amplification Assay (αSyn-SAA), represents a revolutionary way for researchers to biologically define Parkinson’s disease and provides an important tool for planning clinical trials and evaluating treatment effects, as well as for early detection of disease pathology.
As the PPMI authors 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 visualised with DaTScan). Thus, for the first time since James Parkinson first described the disease in 1817, researchers and clinicians can use biology (as opposed to clinical judgement and patient-reported outcomes) to objectively identify, define and monitor Parkinson’s based on cellular pathology in the living body.
New biological era in Parkinson’s research
“The validation of this biomarker heralds a new, biological era in Parkinson’s research,” said Kenneth Marek, M.D., PPMI principal investigator and president and chief scientist at the Institute for Neurodegenerative Disorders. “With the help of αSyn-SAA, we can already gain new insights into Parkinson’s disease that will transform every aspect of drug development and ultimately clinical care. We will quickly be able to test new therapies in the right populations, target the right therapy to the right patient at the right time, and start trials with compounds that have the potential to prevent Parkinson’s disease altogether. This is what PPMI was created for, and we are especially grateful to the thousands of trial participants whose contributions have made this turning point possible.”
Study involving 1,100 participants
The study led by Andrew Siderowf, M.D., a PPMI researcher and Director of the Centre for Parkinson’s Disease and Movement Disorders at the University of Pennsylvania, and Luis Concha, Ph.D., Director of Research and Development at Amprion, describes the αSyn-SAA results from more than 1,100 PPMI participants, including people with Parkinson’s disease, people with genetic and/or clinical risk factors who have not, however, been diagnosed with Parkinson’s disease, and control subjects. The large-scale analysis in the PPMI confirms previous reports – including those from MJFF-funded research – that αSyn-SAA can distinguish Parkinson’s patients from control subjects with a remarkably robust sensitivity of 88 per cent and a specificity of 96 per cent.
As an objective and reliable biomarker of Parkinson’s disease biology, αSyn-SAA will significantly reduce the risk for the industry of investing 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, it will be possible to establish objective endpoints for clinical trials for the treatment of Parkinson’s disease, ensure that trial participants have the appropriate pathology, and detect treatment-related changes in their condition. This is already leading to a redesign of clinical trials and may result in increased investment by pharmaceutical and biotech companies in this field, enabling more ‘shots on goal’ that will benefit people at every stage of the disease.
Subtypes of Parkinson’s disease are linked to genetic and clinical factors
The authors reported findings relating to olfactory deficits or loss of smell (persistent and significant loss of smell is a common symptom of Parkinson’s disease, often occurring years before diagnosis) and the presence of a mutation in the Parkinson’s-associated LRRK2 gene:
The assay accurately diagnosed the disease in 99 per cent (274 out of 278) of people with loss of smell and sporadic Parkinson’s disease (without a known causative genetic mutation).
The proportion of positive results was lower in people with Parkinson’s disease and an LRRK2 mutation [68 per cent (83 out of 123)].
Positive results were also lower in people with sporadic Parkinson’s disease without a loss of smell (78 per cent).
People with Parkinson’s disease, an LRRK2 mutation and normal sense of smell were even less likely to show positive test results. This was particularly true for women; only 12.5 per cent of women in this group (three out of 24) showed synuclein pathology in the test.
Among people with Parkinson’s disease who were enrolled in the PPMI, had consented to a post-mortem examination, and had died since the start of the study, all those with positive test results (14) showed typical alpha-synuclein aggregation pathology in brain cells; the only one of these PD participants who did not show positive test results was a LRRK2 mutation carrier who had retained their sense of smell.
Accumulation of alpha-synuclein aggregates
These findings 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, in particular, carriers of the LRRK2 variant may not exhibit this pathology. This insight opens up new avenues for research into treatments that could benefit more people with Parkinson’s. Furthermore, it will enable a more detailed investigation of the cellular signalling pathways and cascades that occur in LRRK2-associated Parkinson’s disease, some of which may protect against synuclein dysfunction and Parkinson’s toxicity. This could lead to breakthroughs that benefit all people with Parkinson’s, not just those who carry a gene mutation. (Three therapies targeting dysfunction in the LRRK2 signalling pathway are currently in clinical trials).
New evidence that biological changes in synuclein precede both symptoms and dopamine dysfunction paves the way for the first prevention studies. The αSyn-SAA has also been validated in individuals participating in the PPMI who have not been diagnosed with Parkinson’s disease but who are aged 60 or over and who, due to genetic mutations, loss of smell or a diagnosed REM sleep behaviour disorder (RBD), have an increased relative risk of developing Parkinson’s disease. (RBD is a sleep disorder in which dreams are acted out through hitting, pushing or kicking, and is associated with a significant risk of developing Parkinson’s disease or a similar neurodegenerative disorder). PPMI resumed recruitment in 2020 and is in the process of establishing a longitudinal cohort of 2,000 such at-risk individuals.
Screening of people at risk
Most people with olfactory disorders [88 per cent (16 out of 18)] or RBD [84 per cent (28 out of 33)] tested positive.
The authors also compared the results with dopamine transporter (DAT) brain imaging scans, a tool for assessing dysfunction of the dopamine transporter system and thus Parkinson’s pathology, including in at-risk individuals. Only around 30 per cent of at-risk individuals with a positive result on the seed amplification test also had significant dopamine loss.
This finding suggests that synuclein pathology could be detected earlier with this test than the dopamine dysfunction identified by DAT imaging, thereby extending the window of opportunity in which preventive therapies can be administered. In contrast, among undiagnosed but at-risk carriers of an LRRK2 or GBA mutation (the most common known genetic link to Parkinson’s disease), the probability of a positive test result was lower: 8.8 per cent (14 out of 159) and 7.3 per cent (11 out of 151), respectively.
This finding suggests that RBD and the olfactory deficit occur closer to the onset of Parkinson’s motor symptoms.
It also suggests that alpha-synuclein aggregation in the cerebrospinal fluid is not a lifelong feature, but is acquired as part of a biological disease process that ultimately leads to symptoms. By using this knowledge to intervene in this process, drug manufacturers hope to make Parkinson’s disease a preventable condition.
A Parkinson’s biomarker test is available for diagnostic assessment
The αSyn-SAA test was developed when MJFF doctoral students specialising in neuroscience approached researchers at the University of Texas who were working on seed amplification tests for Alzheimer’s disease. The foundation offered funding to experiment with the development of an alpha-synuclein test using PPMI cerebrospinal fluid samples.
The University of Texas team that developed the test has since founded the biotech company Amprion, which collaborated with the PPMI on the analysis of αSyn-SAA. The company has marketed the test as the SYNTap® test, which can be ordered by doctors for people with symptoms of Parkinson’s disease or related conditions. If the test is positive, Parkinson’s disease or a related alpha-synuclein disorder, such as Lewy body dementia (DLB) or multiple system atrophy (MSA), is likely present. The test alone cannot distinguish between these conditions. The costs are also not covered by insurance. However, when used in conjunction with a medical examination, the test can help to establish a specific diagnosis.
“The Michael J. Fox Foundation has always recognised the undeniable need for biomarkers for Parkinson’s disease and has pursued this tirelessly as a key objective,” said Deborah W. Brooks, Executive Director of the MJFF (and a volunteer PPMI control subject at the University of Pennsylvania since 2010). “It would be difficult to overstate the significance of this discovery. With development and scaling, αSyn-SAA could herald the era of an objective and biological definition of Parkinson’s disease, thereby revolutionising every aspect of research and treatment.”
Michael J. Fox said: “I am committed to the Foundation’s work in many ways, but I come to this conclusion first and foremost as a person living with Parkinson’s. I am deeply moved by this breakthrough and infinitely grateful to the researchers, study participants and donors who have worked so hard to bring us this far. When we started PPMI, we weren’t fishing for small fry – we were hunting for a whale. Now we’re here. Together, we are making a cure for Parkinson’s inevitable.”
PPMI: The study that is changing so much
MJFF launched the Parkinson’s Progression Markers Initiative (www.ppmi-info.org, michaeljfox.org/ppmi) in 2010 at 18 clinical sites across the United States and Europe, thanks to a donation from the late Mrs Lily Safra, a visionary friend, partner and board member of MJFF. As a long-term observational study, PPMI has built the most robust dataset and the most extensive library of biosamples ever assembled in Parkinson’s research, and is made available to the wider research community in real time for ongoing discovery and validation studies. To date, nearly 2,000 participants have been enrolled in the study, and Parkinson’s patients, at-risk individuals and volunteer controls continue to be recruited at 51 clinical centres around the world. The study data is downloaded by researchers worldwide an average of 2,200 times a day for independent studies.
With the publication of αSyn-SAA, the Michael J. Fox Foundation announced that the slogan for the PPMI study had changed from “The Study that Could Change Everything” – in terms of how Parkinson’s disease is diagnosed, managed and treated – to “The Study that’s Changing Everything”.
The primary 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 paving the way for a cure for Parkinson’s disease. ASAP support enables the seismic expansion of PPMI to intensify recruitment efforts and remote testing for people at risk of Parkinson’s, as well as the expansion of assay development to enable breakthroughs such as αSyn-SAA. This infrastructure provides a ready-made 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 further funded by a consortium of more than 40 biotech and pharmaceutical companies providing financial support and in-kind contributions, as well as by tens of thousands of individual donors to the Michael J. Fox Foundation.
About the Michael J. Fox Foundation for Parkinson’s Research (MJFF)
As the world’s largest non-profit funder of Parkinson’s research, the Michael J. Fox Foundation is committed to finding a cure for Parkinson’s disease and developing better treatments for those affected. For further information, please visit www.michaeljfox.org, Facebook, Twitter and LinkedIn.
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