α-synuclein seed amplification potential for early Parkinson’s disease diagnosis

medwireNews: An assay for identifying the build-up of the misfolded α-synuclein protein in cerebrospinal fluid (CSF) could enhance the detection of Parkinson’s disease in the early stages before the onset of motor symptoms, suggests research.

Emerging evidence has shown the potential of α-synuclein seed amplification assays (SAAs) to differentiate between people with and without Parkinson’s disease. The latest findings support this evidence and go further to suggest that a positive assay result can also detect prodromal individuals and those at genetic risk.

“Our findings suggest that the α-synuclein 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”, explained co-lead author Luis Concha-Marambio (Research and Development Unit, Amprion, San Diego, California, USA) in a press release.

“Moreover, our results indicate that misfolded α-synuclein is detectable before dopaminergic damage in the brain is about to be observed by imaging, suggesting ubiquitous spread of these misfolded proteins before substantial neuronal damage has occurred.”

Concha, fellow co-author Andrew Siderowf (University of Pennsylvania Perelman School of Medicine, Philadelphia, USA) and team conducted a cross-sectional analysis of CSF assessments carried out at enrolment on 1123 participants of the Parkinson’s Progression Markers Initiative cohort.

The group included 545 patients with Parkinson’s disease (sporadic and genetic cases), 163 healthy individuals, 54 individuals with parkinsonism but without evidence of dopaminergic deficit, 51 prodromal individuals with non-motor symptoms – rapid eye movement sleep behaviour disorder (RBD) or hyposmia – and 310 at-risk individuals with genetic variants associated with Parkinson’s disease (GBA or LRRK2).

The α-synuclein SAA was “highly accurate” at identifying Parkinson’s disease, report the researchers, with a sensitivity of 87.7%, while a negative test correctly identified 96.3% of those without the condition. The accuracy varied among the subgroups according to genetic and clinical characteristics, they note.

Among Parkinson’s disease patients with hyposmia, 97.2% tested positive on the assay, compared with 63.0% of those without. And this increased to 98.6% among those with hyposmia who had sporadic Parkinson’s disease, compared with a 78.3% rate among those with sporadic Parkinson’s disease without hyposmia.

The assay was more sensitive for detecting Parkinson’s disease among patients with GBA than LRRK2 mutations, with 95.9% versus 67.5% testing positive, and the lowest sensitivity of 34.7% occurred among LRRK2 carriers without hyposmia. Further variation in α-synuclein SAA was seen among LRRK2 carriers according to sex, age and motor performance.

The investigators comment that 15 participants with a clinical diagnosis of Parkinson’s disease had autopsy data available, 14 of whom were α-synuclein SAA positive and had typical pathological findings for the disease. The only participant testing negative had been normosmic and carried the LRRK2 variant.

Assay results among the prodromal individuals showed a positive rate of 86.3% and in 29.6% of these dopamine transporter imaging was in the normal range.

Therefore, “[o]ur results provide biomarker support for a long-term prodromal period,” say the researchers, “whereby there might be a long-term period in which abnormalities in α-synuclein SAA are present before changes appear in physiological markers.”

Among at-risk individuals, 8.1% tested positive for α-synuclein SAA, “suggesting that the presence of synuclein aggregates in the CSF is not a lifelong trait but rather acquired at some point close to disease onset”, say the authors in The Lancet Neurology.

Commentating on the findings, Daniela Berg (University Hospital Schleswig-Holstein, Kiel, Germany) and Christine Klein (University Hospital Schleswig-Holstein, Lϋbeck, Germany) say that “studying genetic forms of Parkinson’s disease with [α-synuclein SAA] will not only advance pathophysiological understanding of the disease and its genetic subtypes, but also aid in prioritising participants for gene-targeted or pathophysiology-targeted clinical trials.”

They believe that “α-synuclein SAA is a game-changer in Parkinson’s disease diagnostics, research, and treatment trials.”

However, the commentators add that “to fully leverage the enormous potential of the [α-synuclein SAA], the test would have to be performed in blood rather than the CSF, a less invasive approach that has proven to be viable.”

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Lancet Neurol 2023; 22: 369–371, 407–417

Article: https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00109-6/fulltext

Commentary: https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00124-2/fulltext