Penn and Michael J. Fox Foundation ID Breakthrough Biomarker in Parkinson’s Disease
By Mark Terry
April 17, 2023
Researchers with the University of Pennsylvania Perelman School of Medicine and others, with funding from the Michael J. Fox Foundation for Parkinson’s Research, identified a biomarker that shows promise for early detection of Parkinson’s Disease. The research was published in The Lancet Neurology.
Co-lead author, Andrew Siderowf, of Penn’s Perelman School of Medicine and the Parkinson Progression Marker Initiative (PPMI), said in a press statement, “Recognizing heterogeneity in underlying pathology among patients with Parkinson’s disease has been a major challenge. Identifying an effective biomarker for Parkinson’s disease pathology could have profound implications for the way we treat the condition, potentially making it possible to diagnose people earlier, identify the best treatments for different subsets of patients, and speed up clinical trials.”
The study analyzed 1,123 participants enrolled between July 7, 2010, and July 4, 2019. Of them, 545 had Parkinson’s disease, 163 were healthy controls, 54 had scans showing no dopaminergic deficit, and 51 were prodromal. Another 310 were non-manifesting carriers. The study found that alpha-synuclein seed amplification assays (SAAs) had the potential to tell the difference between Parkinson’s patients and healthy controls.
“This study represents the largest analysis so far of the alpha-synuclein SAA for the biochemical diagnosis of Parkinson’s disease,” the authors wrote. “Our results show that the assay classifies people with Parkinson’s disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis.”
The PPMI is funded by the Michael J. Fox Foundation and includes a consortium of more than 40 private and philanthropic partners, including, but not limited to AbbVie, Avid Radiopharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Denali, Edmond J. Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline and many others. The PPMI, launched in 2010, is now a $500 million effort in partnership with the Aligning Science Across Parkinson’s initiative.
In an article published in STAT penned by Michael J. Fox, Fox said, “The foundation has pounded the pavement to secure every donor, involve every company with a Parkinson’s program, enroll every participant, bring every site online. And now that the study has done precisely what it was built to do — significantly accelerating the validation of a promising biomarker in more than 1,100 Parkinson’s patients, controls and at-risk individuals over the course of less than a year — we are reminded anew how completely worthwhile this work has been.”
Fox added, “…I come to this breakthrough first and foremost as a patient. As someone who has Parkinson’s, up until now, I think I could be forgiven for feeling a little left behind in biology’s century. Going all the way back to 1817, when James Parkinson first described the disease in the scientific literature, it’s been a clinically defined condition. You knew you had it because it was your doctor’s opinion that you had it, after giving you a once-over and deciding where you fell from one to five on a rating scale.”
In 2011, a molecular neuroimaging technique of the dopamine transporter became the first imaging biomarker for the disease.
This new SAA has the potential to be a reliable test for Parkinson’s disease based on samples of cerebrospinal fluid and potentially blood. The technique amplifies minuscule amounts of misfolded aggregates of alpha-synuclein to a point where they can be detected using standard lab techniques. The study confirmed Parkinson’s disease diagnoses in 88% of participants, matching a combination of sporadic and genetic cases. In sporadic cases, there are no known genetic causes. Of them, 93% had a positive AAS result. In people with a genetic form of Parkinson’s, 96% with the GBA variant had a positive SAA compared to 68% with LRRK2 genetic Parkinson’s.
The authors wrote, “Most prodromal participants had alphaSyn-SAA results, indicating they had alpha-synuclein aggregates despite not yet being diagnosed with Parkinson’s disease. Among those recruited based on their loss of smell, 89% (16/18) had positive alphaSYN-SAA results. Similarly, in people with REM sleep behavior disorder, a sleep disturbance that is known to be a precursor to Parkinson’s disease, positive alphaSyn-SAA results were present in 85% (28/33) of cases.”
In people who carried LRRK2 or GBA variant but had no Parkinson’s disease diagnosis or prodromal symptoms, who are dubbed non-manifesting carriers (NMCs), 9% and 7%, respectively, had positive alphaSyn-SAA results. Most prodromal participants and NMCs with alphaSyYn-SAA positive results had brain scans that did not demonstrate a drop in dopamine-producing nerve cells, a molecular imaging biomarker present before diagnosis.
The authors wrote, “This result suggests build-up of alpha-synuclein aggregates may be a very early indicator of disease onset.”
Tanya Simuni of Northwestern University, one of the study authors, noted, “While loss of smell appears to be a strong predictor of Parkinson’s disease, it’s important to note that this study identified individuals with positive alphaSyn-SAA results, but who had not yet lost their sense of smell, indicating that alpha-synuclein pathology may be present even before there is a measurable loss of sense of smell.”
The authors of the study acknowledge its limitations. They note that more samples would improve analyses by helping alleviate several factors, such as skewed data and low sample numbers for some participant groups.
In a linked Comment, Daniela Berg and Christine Klein, of University Hospital Schleswig-Holstein, Germany, pointed out that, “Siderowf and colleagues showed that people with prodromal Parkinson’s disease and non-manifesting mutation carriers had abnormal alpha-synuclein aggregation before any other detectable clinical or biomarker changes, a finding that lays the foundation for a biological diagnosis of Parkinson’s disease… Although the blood-based method needs to be further elaborated for scalability, alphaSyn-SAA is a game-changer in Parkinson’s disease diagnostics, research, and treatment trials.”
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Mark Terry is a freelance writer, editor, novelist and ghostwriter. He holds a degree in microbiology & public health and spent 18 years in infectious disease research and clinical and research genetics prior to his transition to a writing career. His areas of expertise include biotechnology, pharma, clinical diagnostics, and medical practice management. He has written literally thousands of articles, as well as market research reports, white papers, more than 20 books, and many other written materials. He currently lives in Michigan with his family.
