New research confirms a key disease pathology identified through examining spinal fluid in patients with Parkinson disease.
In a newly published cross-sectional study in The Lancet Neurology, sponsored by The Michael J. Fox Foundation for Parkinson’s Research (MJFF), use of an alpha-synuclein seed amplification assay (αSyn-SAA) technique showed high diagnostic accuracy of Parkinson disease (PD), distinguished molecular subtypes, and detected the disease before primary symptoms.1
In total, data on αSyn-SAA was collected from 1123 participants from the Parkinson’s Progression Markers Initiative (PPMI) cohort, including patients with a diagnosis of PD and at-risk patients with gene variants (GBA and LRRK2) linked to the disease. In the large-scale analysis, αSyn-SAA was shown to differentiate PD from controls with a sensitivity of 88% and specificity of 96%.
"I think that the ability to diagnose people based on underlying biology rather than clinical syndrome is going to have a major effect on current and ongoing research. Patients in clinical trials can be slotted into the trials that are the best fit for them. Also patients that wouldn't necessarily respond to a new treatment could be removed those trials so that you'd have a better chance of seeing the effect of a new therapeutic if one really is there," coauthor Andrew Siderowf, MD told NeurologyLive®. "I think we don't recognize that this also plays a role in studies looking at the etiology of Parkinson's disease. For example, genetic studies, and size environmental risk factors often include patients who we would think have Parkinson based on clinical features, but really don't have the underlying biology. So, you can sharpen that scalpel quite a lot. By using a biologically base classification for putting people in genetic studies."
The research was co-led by authors Siderowf, PPMI investigator and director, PD and Movement Disorders Center at the University of Pennsylvania, and Luis Concha, PhD, director, research and development at Amprion. In the study, samples of cerebrospinal fluid surrounding the brain and spinal cord were analyzed from each participant using αSyn-SAA.
Approximately 93% of patients with no known genetic cause had a positive αSyn-SAA result. Results varied for patients with genetic forms of PD, with 96% having the GBA variant and a positive αSyn-SAA result, compared with 68% of patients with LRRK2. Most prodromal patients had positive αSyn-SAA results, suggesting they had α-synuclein aggregates despite no PD diagnosis. Fifty-five percent of women with PD with the LRRK2 variant had a positive αSyn-SAA result compared with 72% of men with PD who had the same the variant. Patients with the LRRK2 variant and a negative αSyn-SAA result tended to be older compared with than those with positive αSyn-SAA results.
"In environmental studies, I think that this will potentially allow us to identify new genes and new environmental risk factors, which we've been missing because we can't put patients in the right grouping quite as well. I think those are really important research implications. I think that the other thing is trials that could potentially prevent Parkinson rather than just treating the sounds like sort of 'pie in the sky' but we do this in a lot of other disorders. It's not inconceivable at all that we'll be doing it before long at least in terms of experimental therapeutics for Parkinson," Siderowf told.
Loss of sense of smell was the most strongly predicted clinical feature of a positive αSyn-SAA result. Among all participants with PD who had loss of smell, 97% had positive αSyn-SAA compared with 63% of patients whose sense of smell was unchanged. Also, in patients with REM sleep behavior disorder, positive αSyn-SAA results were present in 85% (28 out of 33 patients) of participants. There were no other clinical features associated with a positive αSyn-SAA result.
"I think it's helpful with everything that we're talking about to just take a step back and talk about how we diagnose Parkinson today, and that is clinically. It's what is called a clinical diagnosis and that's because we haven't had objective measures or tests that on their own that can diagnose Parkinson. The diagnosis relies on the motor symptoms of Parkinson and on an expert physician, a movement disorder specialist, who has expertise in Parkinson on identifying those cardinal motor symptoms. Only then can we make the diagnosis of Parkinson but as you know and heard, Parkinson is coming on much earlier than that," Rachel Dolhun, MD, vice president of medical communications at The Michael J. Fox Foundation told NeurologyLive®.
Patients who carried the LRRK2 or GBA variants but had no PD diagnosis or prodromal symptoms, nonmanifesting carriers (NMCs), had positive αSyn-SAA results (LRRK2, 9% [14 out of 159 patients]; GBA, 7% [11 out of 151 patients]). Most prodromal participants and NMCs with positive αSyn-SAA had brain scans that did not show a decline in the expected number of dopamine-producing nerve cells, suggesting buildup of α-synuclein aggregates could be an early mark of disease onset.
As for the study limitations, authors noted that larger samples would improve analyses and thus overcome factors such as skewed data and small number samples for some participant groups. Additionally, the availability of samples gathered over time would allow future research to assess the changes over specific time periods of the disease. Authors also noted more long-term studies are needed to further explore the differences in αSyn-SAA results between patients with different genetic forms of PD.
"Now we've started to see through research, validated in PPMI, that symptoms like REM sleep behavior disorder, acting out your dreams, losing your sense of smell, are some of the earliest potential signs of Parkinson. We've seen in this study that the αSyn-SAA test is positive in most of those people," Dolhun told. "This is our first indication that there is potential to diagnose Parkinson to change the way that we diagnose the disease, identify the biological processes happening and diagnose much earlier. Now all that being said, this test does not replace a Parkinson diagnosis as we know it today, it does not replace a clinician expert diagnosis, but it has the potential."