NeuralCipher Research overview
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Abstract Background Multiple system atrophy (MSA) is a devastating synucleinopathy with a clinical presentation that often overlaps with Parkinson's disease (PD), leading to diagnostic challenges. Although the ultrasensitive real-time quaking-induced conversion (RT-QuIC) assay for α-synuclein (αSyn) is promising, its sensitivity when applied to cerebrospinal fluid (CSF) for diagnosing MSA remains suboptimal, and CSF collection is invasive. We hypothesize that the less-invasive erythrocyte sample, which contains over 99% of blood αSyn, harbors prion-like αSyn-seeding activity, thereby offering a potential diagnostic biomarker for MSA. Methods We developed and applied two complementary real-time quaking-induced conversion (RT-QuIC) assays to detect αSyn-seeding activity in plasma and erythrocytes from clinically-established patients with MSA and PD, and healthy controls. The RT-QuIC end-products were characterized using proteinase K (PK) digestion, filter-trap assays (FTA), sucrose gradient ultracentrifugation, and transmission electron microscopy (TEM). Diagnostic performance was evaluated via receiver operating characteristic (ROC) analysis, and correlations with clinical scales were assessed. Results The plasma RT-QuIC assay demonstrated high specificity (91.3%) but moderate sensitivity (61.4%) for MSA, while the erythrocyte assay showed a sensitivity of 70.0% for MSA and 70.6% for PD with a specificity of 85.7%. Combining both assays yielded a synergistic improvement, achieving an area under the curve (AUC) of 0.93 for MSA. Physicochemical characterization confirmed the bona fide generation of PK-resistant, fibrillar αSyn aggregates in positive reactions. Notably, plasma seeding activity correlated significantly with motor severity (UMSARS), autonomic dysfunction (SCOPA-AUT), and neuropsychological burden (PHQ-9, GAD-7) in MSA patients, whereas erythrocyte seeding activity did not. Conclusions This study is the first to establish erythrocytes as a robust, accessible matrix for detecting αSyn-seeding activity in MSA and PD. A combined blood-based approach using both plasma and erythrocytes significantly enhances diagnostic accuracy, potentially rivaling CSF-based assays. This dual-assay strategy represents a transformative, minimally invasive tool for the differential diagnosis and clinical management of synucleinopathies.
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