The following story appeared in our Fall/Winter 2024 edition of The Fox Focus on Parkinson’s newsletter. For this story and more, download the full edition. 

Last year, Parkinson’s researchers hailed the discovery of a biomarker for detecting the disease’s hallmark misfolded alpha-synuclein proteins in spinal fluid from living people. 

This year, they are hopeful for another breakthrough biomarker: an imaging tool that would allow them to see these clumping proteins inside the brains of people living with Parkinson’s disease (PD). Currently these clumps can only be seen at autopsy.  

“There’s been tremendous progress in the past few years that has brought us to a pivotal moment for alpha-synuclein imaging,” said Jamie Eberling, PhD, the head of research resources and long-time imaging lead at The Michael J. Fox Foundation.  

At least six alpha-synuclein tracers recently advanced to testing in human trials, Eberling noted, and the first results from these trials are expected by early 2025. Positive results from any of these trials could deliver the breakthrough alpha-synuclein imaging tool that the Parkinson’s field has long been seeking. 

By revealing in real-time what is happening in the brain in Parkinson’s, alpha-synuclein brain imaging holds “game-changing” potential for expanding disease understanding and drug development, Eberling said. She anticipates that it will be applied almost immediately to help with early diagnosis, shed light on disease progression and monitor treatment response. Alpha-synuclein imaging insights also would help inform and improve disease staging.  

The Promise of PET Imaging  

The alpha-synuclein imaging efforts in human trials all employ positron emission tomography (PET), which uses “tracers” specially designed to interact with a protein target (alpha-synuclein in PD) and reveal information about that protein on 3D scans.  

Use of PET imaging in Alzheimer’s offers perspective on just how much value it could hold for PD: In 2004, researchers developed a tracer for amyloid, a brain clumping protein linked to Alzheimer’s disease. They then applied it to anti-amyloid drug trials — both to enroll target participants and assess how the drugs affected amyloid in the brain. Data from these trials helped lead the way for U.S. Food and Drug Administration approvals of two new therapies: lecanemab in 2023 and donanemab in 2024. 

MJFF invested for well over a decade in finding tracers capable of revealing PD-related alpha-synuclein. Then in 2019, the Foundation launched the three-year, $10-million Ken Griffin Alpha-synuclein Imaging Competition that spurred a scientific race. Funded largely through a leadership gift from Griffin, the Citadel founder and CEO, the competition helped advance alpha-synuclein imaging like never before.  

The three finalists — runners-up AC Immune and Mass General Brigham and winner Merck — are now among six groups known to be testing alpha-synuclein tracers in human trials.  

All six received support from MJFF at some point in the development of their tracers, Eberling said. Most recently, the Foundation provided additional funds to Mass General Brigham through a supplemental grant and to Merck through a new quantitative biomarker initiative. 

Progress on the Path to Imaging 

Alpha-synuclein is a major focus of today’s imaging efforts because of its critical role in PD starting from the earliest stage. But work on imaging biomarkers does not end with alpha-synuclein PET scans. MJFF recently launched an imaging consortium to bring together industry partners in sharing progress toward a range of better imaging tools for PD, including tracers to visualize inflammation and synaptic functioning. MJFF-backed researchers also are working to optimize dopamine imaging — currently possible with PET and dopamine transporter scan (DaTscan), which uses another imaging technology called single photon emission computed tomography (SPECT).  

“To see where we are today is just astonishing,” said Eberling, highlighting a recent milestone report from AC Immune in Nature Communications showing definitively that alpha-synuclein imaging is achievable.  “The field is energized for what’s to come: a day when we can clearly measure, quantify and visualize brain pathology in PD. When that day comes, it will fully transform what’s possible in drug development.”