Good News About Bad Seeds
There has been a lot of talk recently about “seeds” and “seeding assays” in Parkinson disease. What does this mean, and how important are seeds in PD?
Much of the interest in seeds has been driven by the recent publication from the Michael J. Fox Foundation Parkinson Progression Marker Initiative (PPMI) study. This is an effort that has been going on for more than 10 years and has involved more than 2000 research participants. The goal of PPMI has been to find “biomarkers” – tests that could detect the presence of PD and perhaps even measure how the disease is progressing. A lot of different types of tests have been looked at – blood tests, urine tests, spinal fluid tests, and various brain scans. The first real “win” from PPMI is the synuclein “seeding amplification assay” (SAA). This is described in a recent publication in Lancet Neurology (https://pubmed.ncbi.nlm.nih.gov/37059509/).
At present, an SAA test is done on spinal fluid, obtained by lumbar puncture. An amplification method is used to look for the presence of “seeding activity” – misfolded forms of the protein alpha-synuclein which can induce more molecules of alpha-synuclein to misfold. In the PPMI participants described in the Lancet Neurology paper, this test is remarkably accurate: 87% of the patients with a diagnosis of PD were positive, and only about 4% of controls without PD tested positive. More interesting was that the SAA test seems to be able to detect the Parkinson disease process before movement symptoms appear – in participants with strong risk factors for PD, either REM Behavior Disorder (RBD), a sleep disorder, or anosmia, the loss of the sense of smell, 86% were positive for SAA. Some groups of people with PD symptoms do, however, seem to have negative SAA tests more frequently. These include people with mutations in the genes for LRRK2 or GBA, suggesting that there may be some subgroups where the biology of PD is different.
Like most scientific advances, this one has a backstory. The idea that a protein can misfold and lead to misfolding that spreads across the brain emerged from the study of rare brain diseases called “prion disorders.” The term “prion” was coined by Dr. Stanley Prusiner who received the Nobel Prize for this discovery in 1997. At about the same time, the protein alpha-synuclein was linked to PD, through genetic studies of families living in southern Italy and Greece (the Contursi Kindred). Soon, it became clear that alpha-synuclein has a central role in PD, and is the main component of the “Lewy bodies” that can be seen in the brain in PD. The idea that alpha- synuclein might have prion-like behavior emerged from the work of Heiko and Eva Braak, neuropathologists who observed that the changes in PD brain suggested that the disease was spreading from one neuron to another. This idea really took off after work in the laboratory of John Trojanowski and Virginia Lee at the University of Pennsylvania showed that spreading of abnormal alpha-synuclein could be observed directly in neurons. Laura Volpicelli-Daley led an important study showing spread of abnormal synuclein in neurons in culture (https://pubmed.ncbi.nlm.nih.gov/21982369/), and Kelvin Luk followed this with a study showing spread in living mice (https://pubmed.ncbi.nlm.nih.gov/23161999/). The SAA lets us look for this same kind of abnormal synuclein biology in living people.
How is the SAA test useful? Most people with the typical symptoms of PD can expect their SAA test to be positive, and at least right now, this information would not help much – the treatment today would be the same, whether the SAA is positive or negative. The SAA, at least with current technology, does not seem to tell us anything about how severe the PD is, or how it will progress. In short, I don’t think there is any need to be testing SAA as part of clinical care right now.
I do think the SAA will be very valuable in clinical research studies, as we will want to identify the participants who are SAA negative with the expectation that they may respond differently to experimental treatments. SAA will also be used in situations where symptoms like RBD or anosmia raise questions about the possibility of future PD – but here we need to be careful, the SAA test is new, and we really don’t know much about how reliably it predicts future PD symptoms. There is also work going on to adapt the SAA so it can be used on other kinds of samples that do not require a lumbar puncture – skin biopsies, blood, maybe even saliva.
Since the SAA shows that abnormal synuclein is present in most people with PD, should we be trying to develop a treatment to remove this abnormal protein? Tests of this idea are already underway. The first two studies of antibody methods to remove abnormal synuclein did not show much success after the first year (discussed by Drs. Jensen, Schlossmacher and Leonidas in (https://pubmed.ncbi.nlm.nih.gov/36645106/). There are more efforts underway, and the availability of the SAA test is certain to fuel these efforts further. One can envision a future where we might be able to test for PD before symptoms appear and start a treatment to halt progression – a strategy to prevent the disease entirely.
In the end, it appears that we have good news about bad seeds. Good news, because the development of the SAA test gives us an important new insight into the biology of PD, a way to distinguish PD associated with the “bad” seeding activity of alpha-synuclein from other possible causes of PD, and points the way to improving both diagnosis and treatment of PD.
David G. Standaert, MD, PhD is the John N. Whitaker Professor and Chair of Neurology, Heersink School of Medicine, University of Alabama at Birmingham. He is a member of the WPC Program Committee, and will be speaking on “How can we track PD using blood and tissue-based biomarkers?” View the Scientific Program here.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®