Clinical Alpha-Synuclein Biomarker Urgently Needed!
This is a pivotal moment in PD research and therapy, as while we have had good evidence for accumulation of aggregated alpha-synuclein as the central molecular event since 1997, only within the last few years has there been a promising therapeutic approach based on this knowledge.
The accumulating results of monoclonal antibody trials for Alzheimer’s disease (AD), culminating in the recent US FDA approval of aducanamab, have clearly shown that the brain levels of another aggregated protein, Abeta, that plays an analogous role to alpha-synuclein in AD, can be brought down with these agents. While their benefit to clinical function is still being debated and will likely become clearer in the next few years, the anti-Abeta monoclonals are clearly addressing the Abeta “overload”. Anti-synuclein monoclonal antibody trials are several years behind those for AD but I am optimistic that one more monoclonals or other drugs in development will ultimately be able to repeat the success of the anti-Abeta monoclonals.
What worries me more is that our ability to detect alpha-synuclein in the brain, and to thereby identify the most appropriate clinical trial subjects and measure the effects of a drug, lag far behind the AD situation. For more than 10 years now we have had PET scans and CSF tests that are able to tell us which subjects have worrisome levels of Abeta in their brains, even before they show any symptoms of AD. Measuring these brain levels at the beginning and end of a clinical trial tell us whether the drug “worked” and lowered the levels. There have been no such methods deployed in PD clinical trials yet. We have to rely only on the decades-long clinical diagnostic methods, which are only 50-70% accurate in the first few years of symptomatic PD, and so many subjects included in PD trials have not actually had PD but another form of parkinsonism, most often progressive supranuclear palsy or corticobasal degeneration, which are caused by accumulation of a completely different protein, tau. Anti-synuclein agents are unlikely to work on a tau disease.
This is why I have devoted most of my career to first showing the clinical diagnostic inaccuracies for both AD and PD, and then helping to validate new, protein-based clinical diagnostic methods for both. As mentioned, this goal has now largely been achieved for AD but not quite yet for PD. As mentioned in my presentation, I believe that alpha-synuclein RT-QuIC assays, of CSF, or of skin biopsies, might be the current best hope for a quantifiable and accurate alpha-synuclein diagnostic but there is also a lot of current work going on towards a PET scan as well. I will continue to work hard towards bringing these methods into future PD trials.
Thomas G Beach, MD, PhD was a speaker at the WPC Virtual Congress where he presented on Peripheral biopsies for diagnosis and progression tracking of PD. He is currently working at the Banner Sun Health Research Institute.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®