Abstract
Alpha-synuclein is a normal protein, but misfolded forms in the cerebrospinal fluid can be detected using the alpha-synuclein seed amplification assay (αSyn-SAA), a potential biomarker for Parkinson's disease (PD). Some experts consider this assay a ‘game changer’ for redefining and reclassifying PD. In this article, we, three individuals with PD, share our perspective on the suitability of αSyn-SAA as the basis for a new classification and staging system for PD. We also discuss other biomarkers and their relevance to those with PD, drawing on our research and the scientific background of two authors. We aim to clarify complex media reports and study findings for the PD community. We argue that while αSyn-SAA can identify the presence of pathology, it cannot explain the underlying cause for such pathology or predict the progression of PD. Given the varied biological pathways leading to PD, using αSyn-SAA as a unified biological definition for a new classification system is premature. Further research is needed before it can serve as the foundation for defining and staging Parkinson's disease. Although αSyn-SAA has its place, like the DAT scan, it should be seen as a tool for confirming diagnoses rather than defining them.
Introduction
Parkinson's disease (PD) patients are increasingly aware of and optimistic about the potential of biomarkers for improving disease management. Patients view biomarkers as a means that could result in an earlier diagnosis, improve monitoring of disease progression, and potentially result in more personalized treatment strategies. We feel there is a growing sense of hope within the PD community that this field of research will support the development of disease-modifying interventions that will positively impact disease progression and hence the quality of life. Alpha-synuclein is viewed as a biomarker candidate for PD because it can detect clumps of the protein alpha-synuclein in cerebrospinal fluid (CSF), a possible indicator of PD.
Recent developments and the surge in biomarker research
Because PD is currently a clinically based diagnosis, 1 experts are increasingly collaborating and adopting integrative approaches in their effort to define a more accurate means of diagnosing PD via biomarkers, genetic results, and other clinical factors. Standardizing and validating biomarker assays are crucial to ensure their accuracy and reproducibility across different settings. An important goal should be the integration of biomarker-based diagnostics into routine care. Integration will necessitate cooperation between researchers, healthcare providers, regulators, and patient advocacy groups which will in turn enhance PD diagnosis and ultimately improve patient outcomes.
The US National Institute of Neurological Disorders and Stroke (NINDS) supports further efforts to identify biomarkers to aid in diagnosing PD and research to understand disease processes and develop new treatments through the Parkinson's disease biomarker program (PDBP) and other programs. In addition, NINDS is driving the discovery of new biomarkers for PD through the Accelerating Medicines Partnership® for PD (AMP PD) program. This public-private partnership is a collaboration between the National Institutes for Health, the Food and Drug Administration, non-profit organizations, and industry. The partnership is focused on conducting large-scale biomarker discovery using whole genome sequencing and gene and protein expression analyses on a vast dataset from patient cohorts made available through a centralized web portal.
From a global perspective, the AMP PD program has partnered with the Global Parkinson's Genetics Program (GP2) to bring GP2's genotyping data from 150,000 + international patients onto the AMP PD platform and provide a one-stop, cloud-based computing shop for PD data.
Other noteworthy events and activities include but are not limited to:
In May 2024, the Michael J. Fox Foundation awarded $9.75 million to five research teams to develop quantitative biomarkers for PD. These biomarkers will measure and track the progression of PD through biology and could be ready for use in drug trials within two to three years.
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A blood biomarker panel that includes eight proteins may be able to predict PD years in advance. The panel was able to identify 100% of patients with PD and predict with 79% accuracy which patients with isolated REM sleep disorder would convert to PD up to seven years before the onset of motor symptoms.
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Northwestern Medicine investigators have discovered novel DNA methylation patterns in the blood of patients with PD. The study demonstrates the potential of utilizing DNA methylation as a biomarker and diagnostic tool for identifying disease risk in patients.
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Indeed, the value of biomarkers for PD has been greeted with great enthusiasm by members of the PD community—patients, scientists, and healthcare providers alike—and for good reasons. These include their potential utility for confirmation of diagnosis or early diagnosis; stratification and characterization of research participants; and if quantitative in the future, may chart progression of the disease and response to potentially disease-modifying treatments.
What is the alpha-synuclein seed amplification assay and what can it do?
The biomarker receiving the greatest attention has been the alpha-synuclein seed amplification assay (αSyn-SAA) shown to be capable of identifying misfolded alpha-synuclein in cerebrospinal fluid with high accuracy. Alpha-synuclein is a protein, and it is present in a misfolded form in >90% of persons with PD (PwP). 5 A positive αSyn-SAA result supports but does not replace a clinical diagnosis of PD. The test is positive in most people who have been diagnosed with PD and is similar to or even more sensitive than the DATscan (an imaging test that reflects dopamine turnover in the brain). It does not provide information on PD biology, clinical subtyping, staging, or pathogenesis.
Thus, while it is well understood that each PwP has a different biological pathway (or pathology) to PD and its progression, it follows that a single assay cannot serve as the foundation of a biological classification system for all PwP. Such a biological definition of PD undermines our fundamental understanding that each patient has their own unique path to PD. The assay can tell us that there is involvement of alpha-synuclein, but it can’t distinguish individual phenotypes.
When the α-syn SAA biomarker was introduced to the public, there was much to learn yet regarding its potential to serve as a unifying platform for the classification and staging of PD. Highly respected organizations welcomed the news of a promising assay as reported by a group of experts. With good intention, Michael J. Fox, is quoted as saying
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: “I’m moved, humbled, and blown away by this breakthrough, which is already transforming research and care, with enormous opportunity to grow from here.”
The problem with focusing on αSyn-SAA
Leading experts have called for caution in prematurely implementing a new biological definition for PD,
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and the knowledge gaps regarding αSyn-SAA are an important reason for this. While αSyn-SAA can provide qualitative information as to the existence of clumped αSyn-SAA protein, it cannot tell us anything about the individual's PD biology. In fact, much is unknown of PD's biology. Thus, before adopting αSyn-SAA as a foundational biomarker for PD classification and staging, its validity and utility throughout the course of the disease must be established. As stated by the International Parkinson and Movement Disorder Society (MDS)
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: “…MDS recognizes the value and efforts of current proposals for a biological diagnosis and staging or classification systems in PD… at the present time such an approach needs to be validated in terms of the biological basis as well as the ability to correlate with progression of the disease and the experience of individuals with clinically defined PD ….”
What biomarkers can and cannot do
It is important that the PwP audience understand that biomarkers in general, and αSyn- SAA, specifically, are simply diagnostic tools, not treatments. That said, they do, however, play a role in clinical research directed toward finding treatments. The availability of biomarker testing raises ethical and practical considerations for those considering the testing. Pre-test counseling is essential to prepare individuals for the implications of the results.
An individual may receive a positive alpha-synuclein test result when they in fact, do not have PD. Alternatively, the same can happen where a negative test result occurs with an individual who does in fact have PD. There are also exceptions from the norm whereby those with PD-associated LRRK2 genetic variant have a lower chance of a positive alpha-synuclein test. 9 In the absence of a genetic variant, it is unclear what a negative test would mean, highlighting the need for additional testing and evaluation.
At present, PD is diagnosed primarily by clinical observation, occasionally with a DATScan to affirm the reduction in dopaminergic neurons, and thus support diagnosis. Diagnostic misclassification based on clinical observation alone is common with error rates ranging from 15% to 24% in different series. 10
An important application of biomarkers will be to add certainty to the diagnosis of PD. For example, what may initially appear to be PD, may turn out to be one of the more complex atypical parkinsonian syndromes such as MSA. If biomarkers can be incorporated into the diagnostic process to effectively minimize uncertainty, that will be an important achievement. As three PwP we have an appreciation of how uncertainty can add to the stress and anxiety of diagnosis, worsening the experience. 11
Prodromal PD
At present, there are two approaches to identifying individuals with a high likelihood of developing prodromal PD. The first approach uses multifactorial screening algorithms that assess overall PD risk. The second approach targets specific risk markers, such as hyposmia and rapid eye movement sleep behavior disorder. An additional test that identifies individuals with genetic markers for monogenic forms of PD may also be used. 12 An additional well-validated biomarker would be helpful.
Considerations for the path forward
While collaboration, standardization, and the adoption of an integrative approach is favorable and may well encourage other clinicians to follow suit, we must not lose sight that there are yet too many questions outstanding to move forward with confidence with a new classification system with αSyn-SAA as the centerpiece.
Continued research regarding biological criteria in support of the diagnosis of PD will hopefully enhance our understanding of the condition; the αSyn-SAA assay will be a useful starting point for this with the potential for contribution from other biomarkers if and when these become available.
We believe the development of biological criteria will ultimately be an important advance in the understanding of PD and related disorders but caution that much work still needs to be done.
Even if a highly accurate and validated set of criteria are developed, there are still likely pros and cons. These might be influenced by the context in which they are undertaken. For example, in a person with a clearly established diagnosis of PD including a good response to L-dopa, there may be no reason to undertake testing. The biggest area of contention is likely to be for individuals who are at risk for PD but have no symptoms. They might have the most potential benefit but also be vulnerable to the most harm from inaccurate diagnostic or prognostic attribution.
A look to the future
Genetic testing is expected to play an increasingly important role in PD diagnosis and treatment in the future. It can help identify biological pathways that cause PD, which can lead to better treatments and care as well as identifying PwP that qualify for certain clinical trials. The Parkinson's Foundation plans to provide genetic testing and genetic counseling at no cost to people with PD through its PD GENEration program. 13
Genetic testing may potentially assume a greater role, particularly if therapies such as anti-sense oligonucleotides prove beneficial. This technology has the potential to create personalized treatments based on the identification of individual genetic defects.
Conclusion
We believe the recent advances in biomarkers and the positive moves to modernize and streamline the overall diagnostic scheme for PD are promising.
While the speed of recent advances in biomarkers and classification is encouraging, there remains much to learn. Hopefully, the proposed new definitions and classification system will streamline research and ultimately lead to new beneficial therapies.
Our dream is for an evidence-based, pragmatic classification scheme supported by reliable, and affordable biomarkers, to be developed around the same time as soon to be completed clinical trials reveal positive results. That really would be a cause for celebration for everyone affected by PD.
We believe a coordinated, international, multi-disciplinary action plan, with input from PwP and utilizing artificial intelligence will be required to accomplish this. It will require proper financial support with backing from investors and politicians. We as patients are prepared to push and help with participation, but we need scientists, politicians, and investors to make a real victory occur as soon as possible. We will gather more ideas on such a plan and report back to PwP, clinicians and researchers with concrete proposals to make this possible.
Footnotes
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: David Blacker is a member of the Editorial Board of this Journal but was not involved in the peer review process of this article nor had access to any information regarding its peer review. The remaining authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.