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Parkinson's Biomarker Shows High Accuracy

<ѻý class="mpt-content-deck">— Assay identifies hallmark protein and could help diagnose people earlier
MedpageToday
A photo of blue rubber gloved hands holding an assay plate.

An alpha-synuclein seed amplification assay (SAA) accurately detected Parkinson's disease in cerebrospinal fluid (CSF) and identified people with early, non-motor symptoms prior to diagnosis, cross-sectional data from the Parkinson's Progression Markers Initiative () showed.

Sensitivity for Parkinson's disease overall was 87.7% and specificity for healthy controls was 96.3%, reported Andrew Siderowf, MD, of the University of Pennsylvania in Philadelphia, and colleagues in .

Among people with sporadic Parkinson's disease, the assay showed 93.3% sensitivity. For sporadic Parkinson's disease with the typical olfactory deficit, sensitivity was 98.6%.

However, results varied for genetic forms of Parkinson's disease, with 95.9% sensitivity for GBA mutation carriers and 67.5% sensitivity for those with LRRK2. Some differences also were seen based on age and sex.

Misfolded alpha-synuclein protein aggregates in the brain are a hallmark of Parkinson's disease. Earlier studies have shown that an alpha-synuclein SAA could from those without the disease, but before this study, no large-scale analysis addressing the heterogeneity of the disease had been conducted.

"Recognizing heterogeneity in underlying pathology among patients with Parkinson's disease has been a major challenge," Siderowf said in a statement.

"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," he added.

The 1,123 participants in the study included 545 people with Parkinson's (373 with sporadic disease, 123 with a LRRK2 variant, and 49 with a GBA variant), 51 people with prodromal Parkinson's (18 with hyposmia and 33 with REM sleep behavior disorder), 310 asymptomatic carriers of Parkinson's-associated genes, 54 people with parkinsonism who had scans without evidence of dopamine deficiency, and 163 healthy controls. Study participants were recruited between July 2010 and July 2019 and came from 33 participating academic neurology outpatient practices worldwide.

Overall, 86% of prodromal participants had positive assay results (44 of 51 people, including 16 of 18 with hyposmia and 28 of 33 with REM sleep behavior disorder). Of 310 asymptomatic carriers of Parkinson's-associated genes, 8% (9% with LRRK2 and 7% with GBA) were positive.

The clinical feature that most strongly predicted a positive result was loss of smell. Among participants with Parkinson's disease who had hyposmia, 97.2% had a positive assay result compared with 63.0% of those whose sense of smell was unchanged.

"While loss of smell appears to be a strong predictor of Parkinson's disease, it's important to note that this study identified individuals with positive alpha-synuclein SAA results but who had not yet lost their sense of smell, indicating that alpha-synuclein pathology may be present even before there is a measurable loss of sense of smell," observed co-author Tanya Simuni, MD, of Northwestern University in Chicago.

"Our study looked at patients at a fixed point in time only, and further research is needed to find out how patients' sense of smell may change over time, and how this relates to the build-up of alpha-synuclein aggregates in the brain," she added.

The findings confirm the high sensitivity and specificity of the alpha-synuclein SAA assay in distinguishing Parkinson's from healthy controls, noted Daniela Berg, MD, and Christine Klein, MD, both of University Hospital Schleswig-Holstein in Germany, in an .

"However, the study reaches well beyond this mere confirmation," they wrote. "Siderowf and colleagues showed that people with prodromal Parkinson's disease and non-manifesting mutation carriers had abnormal alpha-synuclein aggregation before any other detectable clinical or biomarker changes, a finding that lays the foundation for a biological diagnosis of Parkinson's disease, , for which use of the ATN [amyloid, tau, and neurodegeneration] criteria can establish a diagnosis before the detection of any cognitive impairment."

"This framework shift in diagnosis changes the possibility of therapeutic intervention to an early point in disease development," Berg and Klein added. "Moreover, because non-motor symptoms might indicate differential starting points of the neurodegenerative process, future subtype-specific interventions could be possible."

To leverage the potential of alpha-synuclein seed amplification, the test will need to be performed in blood rather than CSF, a less invasive approach that is viable, the editorialists pointed out. "Although the blood-based method needs to be further elaborated for scalability, alpha-synuclein SAA is a game-changer in Parkinson's disease diagnostics, research, and treatment trials," they wrote.

The study had several limitations, Siderowf and co-authors acknowledged. Some participant groups had low sample sizes, and the analysis was cross-sectional, not longitudinal.

  • Judy George covers neurology and neuroscience news for ѻý, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more.

Disclosures

The study was funded by the Michael J. Fox Foundation for Parkinson's Research and a consortium of 40 private and philanthropic partners.

Siderowf reported consultancy for Merck and the Parkinson Study Group and honoraria from Bial. Co-authors reported numerous relationships with industry and nonprofit groups. Some co-authors were employees of Amprion, owned stock in the company, or will receive royalties from Amprion's seed amplification assay.

Berg and Klein reported no competing interests.

Primary Source

Lancet Neurology

Siderowf A, et al "Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study" Lancet Neurol 2023; DOI: 10.1016/S1474-4422(23)00109-6.

Secondary Source

Lancet Neurology

Berg D, Klein C "α-synuclein seed amplification and its uses in Parkinson's disease" Lancet Neurol 2023; DOI: 10.1016/S1474-4422(23)00124-2.