Many of you will by now have seen the news of a “biomarker breakthrough” from the Michael J. Fox Foundation late last week, but what does this breakthrough mean for people living with Parkinson’s disease and just how big a step forward is this? The short answer is that the biomarker in question will enable accurate biochemical diagnosis of very early-stage Parkinson’s disease, matching of potential treatments to the individuals most likely to benefit from them, and better tracking of treatment outcomes (improvements with treatment), all of which will aid in getting new beneficial therapies approved for people living with Parkinson’s.
For readers who want to more detail, first, some context. One of the key initiatives launched (in 2010) and funded by The Michael J. Fox Foundation is a study known as the Parkinson’s Progression Markers Initiative (PPMI), which aims to identify and characterize biomarkers (essentially just objective, measurable indicators of biological state, e.g., a molecule present in tissues, blood or other body fluids) associated with the onset and progression of Parkinson’s. Why? Because being able to identify people at the earliest stages of the disease, being able to recognize different subtypes of Parkinson’s based on underlying pathology, and being able to objectively assess the impact of treatments on the levels of such biomarkers, will be a game-changer for clinical trials aimed at getting therapies for Parkinson’s into the clinic by enabling improved trial design, more nuanced recruitment (more targeted and personalized), and shorter timelines to measurable outcomes. With all this in mind, the publication in The Lancet Neurology that came out last week, underlying those press releases, is certainly a significant step forward and one that opens the door for better and earlier diagnosis of Parkinson’s as well as better designed (and more likely to result in success) clinical trials.
Before we dive into the details of the new study it is worth taking a step back to quickly touch on three aspects of the biology of Parkinson’s disease (PD) as it relates to this study. First, a protein called alpha-synuclein, which has an as-yet unclear normal function (it is thought to be involved in mediating communication between neurons), is a key causal factor in the development of Parkinson’s disease. Various known mutations in this protein cause familial forms of Parkinson’s (representing only a small proportion of all PD) and alpha-synuclein has also been shown to be a major component of the Lewy bodies and Lewy neurites that are characteristic pathological hallmarks seen in almost all people with PD. Second, Parkinson’s is one of a number of protein misfolding diseases (many but not all of which are neurodegenerative conditions). In these conditions, a protein (beta-amyloid and tau in Alzheimer’s disease, huntingtin in Huntington’s disease, and alpha-synuclein in PD to give just a few examples) adopts an abnormal shape that makes the proteins more prone to aggregation eventually leading to the appearance of pathological hallmarks like the afore-mentioned Lewy bodies in PD and amyloid plaques in Alzheimer’s, which are seen post-mortem. Third, and related to this last point, misfolded alpha-synuclein can spread between cells and propagate the process of misfolding. This was most famously seen in transplanted grafts of foetal dopamine cells several years after patients had received these grafts. On inspection post-mortem, the transplanted cells showed Lewy pathology, suggesting that the normal alpha-synuclein in the grafted cells began to misfold and aggregate after exposure to misfolded alpha-synuclein in the neighbouring cells of the patient’s brain. It is important to note that it isn’t the large (visible through a microscope) aggregated protein hallmarks that are propagating here, but much smaller soluble forms of misfolded protein made up of perhaps one (monomeric) or only a few (oligomeric) alpha-synuclein protein “units”.
So, keeping all of that in mind, what did the researchers on this most recent study do? They used a method called an alpha-synuclein seed amplification assay (SAA), which has been previously shown to accurately distinguish people with Parkinson’s from those without it, and cerebrospinal fluid (CSF) samples from the large and well-characterized PPMI cohort, to test whether the SAA could detect early-stage PD in those at risk (but not yet diagnosed) and to determine whether there might be differences in SAA results between different subgroups of individuals in the PPMI cohort. The SAA itself is quite simple: the authors mixed alpha-synuclein grown in bacteria in the lab (normal shape) with CSF samples from people in the PPMI cohort, added a dye that emits fluorescence in the presence of aggregated protein, shook the mixture periodically, and measured the emission of fluorescence over a 2.5-hour period. Presence of fluorescence would suggest that misfolded forms of alpha-synuclein in a person’s CSF sample induced misfolding of the normal, lab-grown protein, leading to its aggregation. Samples were then deemed to be either positive (3 of 3 replicates showed fluorescence), negative (0 or 1/3 fluoresced), or inconclusive (2/3 fluoresced). The five subgroups of the PPMI cohort examined were people with Parkinson’s, healthy controls, people with parkinsonism but no signs of dopamine deficiency based on brain scans, people with prodromal disease (people displaying loss of smell and REM sleep behaviour disorder, thought to be at risk of developing PD), and people with gene mutations associated with PD but without any symptoms.
Importantly, the authors not only confirmed that the SAA can distinguish people with Parkinson’s from healthy controls (as previously shown), but they showed that 44 out of 51 (86%) prodromal participants had a positive SAA, suggesting that alpha-synuclein “seeding” occurs prior to onset of PD. The percentage with positive assays was even higher when looking only at those with loss of smell (88.9%) as an early symptom. Among the 390 Parkinson’s cases with loss of smell, the SAA was highly sensitive (detecting 97.2% of cases), suggesting the misfolding of alpha-synuclein is an important disease pathway in those with loss of smell, and that therapies targeting alpha-synuclein might be effective in these individuals (and potentially less effective in almost half of those without loss of smell, as the sensitivity of the assay in PD cases with normal smell was much lower at 63%). Similar mixed results were seen in participants with different gene variants linked to PD (only two of which were studied here): in those with a GBA mutation, the SAA was highly sensitive (95.9%), whereas in those with a LRRK2 mutation, the SAA was less useful as a predictive tool (sensitivity of 67.5%) This suggests that, whereas the former group might benefit from therapies targeting alpha-synuclein, many of the latter group might not (which in turn could result in a negative trial owing to the inclusion of too many participants unlikely to benefit). Very few (8%) of the participants with PD-associated gene variants but no symptoms had a positive SAA.
There is, of course, more work to do. The authors used a cross-sectional study design (meaning they only looked at samples from a single point in time for each subject) and it would be of interest to perform a longitudinal study to determine the timing of SAA positivity relative to onset of non-motor symptoms (like loss of smell and sleep disturbances) and the appearance of dopamine deficiencies on brain scans. It would also be interesting to see what other PD-associated gene variants have a strong link to SAA positivity. Different therapeutic approaches will potentially need to be followed in those with a positive SAA compared with those without it, and additional biomarkers will likely be needed in the latter group. Finally, sampling of CSF is an invasive procedure, and evidence that the SAA could be effectively performed using other sample types (e.g., blood, nasal swabs) is eagerly awaited.
All in all, this study opens the door to better designed clinical trials with a higher chance of success, particularly in those with loss of smell as a prodromal symptom, and those with a GBA gene variant. This demonstration of an objective biochemical marker of Parkinson’s onset and progression will enable targeting of therapies to individuals based on their underlying biology, as well as better tracking of the impact of those therapies on the disease process. Armed with this tool, we enter a new era of clinical trials for PD better geared for success.
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