Multisite study: Predicting Lewy body disease using skin biopsy α-synuclein seed amplification assays.

Area of Science:

• Neurology
• Biomarker Discovery
• Diagnostic Technologies

Background:

• Alpha-synuclein aggregates are key pathological hallmarks of synucleinopathies like Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB).
• Skin biopsies offer a minimally invasive method to access neural tissue for diagnostic purposes.

Purpose of the Study:

• To evaluate the accuracy of alpha-synuclein seed amplification assays (SAAs) performed on skin biopsies in predicting clinical diagnoses of PD, PDD, and DLB.
• To assess the reliability of SAAs across multiple independent laboratories and assays.

Main Methods:

• Blinded SAAs were conducted on punch biopsies from the posterior neck of subjects diagnosed with PD, PDD, DLB, clinically unaffected individuals, and those at risk for LBD.
• Six separate SAAs were performed across three independent laboratories.
• Agreement between labs and assays was assessed using kappa statistics.

Main Results:

• Pairwise agreement between laboratories and assays ranged from moderate (kappa 0.40–0.68) to excellent (kappa 0.82).
• Sensitivity across assays was 50.0%–61.3%, with specificity ranging from 68.6%–100%.
• High specificities (77.3%–100%) were observed when comparing PD/PDD/DLB patients to unaffected subjects. Post-mortem analysis showed 93% SAA positivity in neocortical LBD stages.

Conclusions:

• Skin biopsy alpha-synuclein SAAs demonstrate potential as a diagnostic biomarker for Lewy body dementias.
• The assay may also serve as a progression biomarker in clinical trials for LBD.
• Further validation is warranted to establish its role in routine clinical practice.