Today researchers from the Parkinson's Progression Markers Initiative (PPMI) -- a landmark study to find measures of Parkinson's disease sponsored by The Michael J. Fox Foundation (MJFF) -- published the first results looking at protein levels in spinal fluid in a large, longitudinal cohort. They analyzed cerebrospinal fluid (CSF) from 173 people recently diagnosed with Parkinson's and 112 control volunteers collected at baseline (when they joined PPMI) and six- and 12-month follow-up.
The findings, published in the journal Neurology, show levels of alpha-synuclein, amyloid-beta 1-42 and tau (total and phosphorylated forms) are lower in CSF of people with Parkinson's disease (PD) but remain stable over the year.
"These CSF biomarkers do not mirror disease progression ... Whether these CSF biomarkers change over a longer time course, during more advanced stages of PD, or in relation to, for example, blood-brain barrier changes, can be reassessed once further PPMI biomarker analyses are conducted," wrote the authors.
Interestingly, they found CSF alpha-synuclein levels at 12 months were lower in people with PD treated with dopamine replacement therapy, especially dopamine agonists.
We spoke with lead author Brit Mollenhauer, MD, assistant professor at University Medical Center of Goettingen in Germany and co-chair of the PPMI bioanalytics core, about the findings.
What is the significance of this analysis?
The novelty is (i) that it is the largest longitudinal cohort where we looked at these proteins over time and (ii) that the cohort is really well characterized. We did not find a lot of change in the core protein in the first 12 months of disease, but this is important information for biomarker studies and clinical trials. CSF protein levels may show target engagement in therapies against alpha-synuclein, for example. Maybe it's a good thing that levels are stable, and we can see if we decrease alpha-synuclein in the CSF with treatments.
Why do we look at alpha-synuclein in spinal fluid?
Alpha-synuclein aggregates in certain areas in the brain in Parkinson's disease, and we believe, because of the aggregation, neurons lose function and cause symptoms. We don't have a tool to image the living brain and see these alpha-synuclein aggregates -- there are groups working on that. Cerebrospinal fluid, like the brain, is part of the central nervous system, so we look for biomarkers in these fluids.
Why do you think protein levels are lower in CSF in PD?
It's probably trapped in the cells, and therefore there is an extracellular decrease. But there are so many questions; it's not proven yet. It could also be there are people who just express the protein on a lower level and they just get Parkinson's disease. We don't know.
Why do we look at Alzheimer's proteins tau and amyloid-beta in people with Parkinson's?
Mainly because there are tests available to measure those in spinal fluid. Also we know there is a lot of Alzheimer's pathology in Parkinson's disease patients and some people with PD have cognitive impairment or dementia.
What do you make of the dopamine therapy association?
We were surprised, but I think for now it has to be taken carefully. We don't know if this holds true in the next analysis. I would tell any patient this should not influence their decision to take dopamine replacement therapy, which can help treat symptoms and significantly improve quality of life.
What do you think these findings mean for the use of CSF biomarkers?
It means we need better and more accurate biomarkers to mimic the progression of disease at the same time as the clinical symptoms progress.
Maybe total alpha-synuclein is not the best measure; maybe this is just too unspecific. Maybe phosphorylated alpha-synuclein may be different or truncations of alpha-synuclein or even completely different proteins or other biomarkers that we don't even know of yet.
What are the next steps?
We are continuing to look at these protein levels over time and in more PPMI participants. At The Michael J. Fox Foundation's Parkinson's Disease Therapeutics Conference on October 30 I will present data looking at alpha-synuclein CSF levels over three years, including from the prodromal cohort: people with Parkinson's risk factors but not diagnosis.
And I put a lot of hope in more specific alpha-synuclein markers. Our MJFF-led consortium is working to identify these different forms of the protein and create tests to measure them.
PPMI is looking at different biochemical biomarkers, too. And we have a project, with MJFF funding, looking at different markers in 500 people from our hospital here. If we have positive findings, we'll go to PPMI to validate.
The clinical trials that need these progression markers rely on several sites, so a biomarker needs to be so robust that it overcomes certain differences in handling from different sites. The PPMI model of many sites helps us test the integrity of these potential biomarkers.
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