An alpha-synuclein seed amplification assay (αSyn-SAA) accurately identifies people with Parkinson’s disease (PD), as well as those at risk for PD and those with early, prodromal symptoms, and provides information on molecular subtypes, new research indicates.
“Identifying an effective biomarker for Parkinson’s disease pathology could have profound implications for the way we treat the condition, potentially making it possible to diagnose people earlier, identify the best treatments for different subsets of patients, and speed up clinical trials,” the study’s co-lead author Andrew Siderowf, MD, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, said in a news release.
“Our findings suggest that the αSyn-SAA technique is highly accurate at detecting the biomarker for Parkinson’s disease regardless of the clinical features, making it possible to accurately diagnose the disease in patients at early stages,” added co-lead author Luis Concha-Marambio, PhD, director of research and development at Amprion, San Diego, California.
The study was published online April 12 in Lancet Neurology.
“New Era“ in Parkinson‘s
The researchers assessed the usefulness of αSyn-SAA in a cross-sectional analysis of 1123 participants in the Parkinson’s Progression Markers Initiative (PPMI) cohort from 33 participating academic neurology outpatient practices in 12 countries.
The cohort included individuals with sporadic PD from LRRK2 or GBA variants, healthy controls, individuals with clinical syndromes prodromal to PD (rapid eye movement sleep behavior disorder [RBD] or hyposmia), and nonmanifesting carriers of LRRK2 and GBA variants. Cerebrospinal fluid (CSF) samples from each participant were analyzed using αSyn-SAA.
Overall, αSyn-SAA differentiated PD from healthy controls with 87.7% sensitivity and 96.3% specificity.
Sensitivity of the assay varied across subgroups based on genetic and clinical features.
Among genetic PD subgroups, sensitivity was highest for GBA PD (95.9%), followed by sporadic PD (93.3%), and lowest for LRRK2 PD (67.5%).
Among clinical features, hyposmia was the most robust predictor of a positive assay result.
Among all PD cases with hyposmia, the sensitivity of the assay was 97.2%, compared with 63.0% for PD without olfactory dysfunction.
Combining genetic and clinical features, the sensitivity of positive αSyn-SAA in sporadic PD with olfactory deficit was 98.6%, compared with 78.3% in sporadic PD without hyposmia.
Most prodromal participants (86%) with RBD and hyposmia had positive αSyn-SAA results, indicating they had α-synuclein aggregates despite not yet being diagnosed with PD.
Among those recruited based on their loss of smell, 89% (16 of 18 participants) had positive αSyn-SAA results. Similarly, in those with RBD, positive αSyn-SAA results were present in 85% of cases (28 of 33). No other clinical features were associated with a positive αSyn-SAA result.
In participants who carried LRRK2 or GBA variants but had no PD diagnosis or prodromal symptoms (nonmanifesting carriers), 9% (14 of 159) and 7% (11 of 151), respectively, had positive αSyn-SAA results.
To date, this is the largest analysis of α-Syn-SAA for the biochemical diagnosis of PD, the researchers say.
The results show that the assay classifies people with PD with “high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis,” they write.
“These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson’s disease and to establish biomarker-defined at-risk cohorts,” they add.
Amprion has commercialized the assay (SYNTap test), which can be ordered online.
“Seminal Development”
The authors of an accompanying editorial note the study “lays the foundation for a biological diagnosis” of PD.
“We have entered a new era of biomarker and treatment development for Parkinson’s disease. The possibility of detecting a misfolded α-synuclein, the pathological hallmark of Parkinson’s disease, by employing an SSA, is a seminal development,” write Daniela Berg, MD, PhD, and Christine Klein, MD, with University Hospital Schleswig-Holstein, Germany.
“However, to fully leverage the enormous potential of the α-synuclein seed amplification, the test would have to be performed in blood rather than the CSF, a less invasive approach that has proven to be viable,” they add.
“Although the blood-based method needs to be further elaborated for scalability, α-synuclein SAA is a game changer in Parkinson’s disease diagnostics, research, and treatment trials,” they conclude.
The study was funded by The Michael J. Fox Foundation for Parkinson‘s Research and a consortium of more than 40 private and philanthropic partners. Siderowf has declared consulting for Merck, Parkinson Study Group, and receiving honoraria from Bial. A full list of author disclosures is available with the original article. Berg and Klein have reported no relevant financial relationships.
Lancet Neurol. Published online April 12, 2023. Abstract, Editorial
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