Objective: To demonstrate the usefulness of measuring the concentration of neurofilament light chain (NfL) in blood using Single Molecule Array matrix (SiMoA, Quanterix) as a biological correlate of neurodegeneration E46K-SNCA mutation carriers.

Background: Symptomatic carriers of the E46K-SNCA mutation represent a highly penetrating and clinically aggressive genetic model of pure Lewy body disease (LBD) with accelerated neurodegeneration. Two out of 8 known E46K-SNCA mutation carriers are currently free of disease, and 1 has recently been diagnosed with Parkinson’s disease (PD). The study of biological samples of this family and its correlation with the clinical tests offers a unique opportunity to validate phenoconversion and disease progression monitoring biomarkers, not only in carriers, but also in PD patients whose prognosis is uncertain.

Method: Serum NfL levels were analyzed with SiMoA and HD-1 platform in 8 carriers of E46K-SNCA mutation (2 young non-demented symptomatic, 1 elder non-demented symptomatic, 3 demented symptomatic and 2 asymptomatic) and 8 age (± 2 years) and sex-matched controls. We also analyzed CSF of E46K-SNCA carriers using SiMoA. Cognitive impairment was measured with Montreal Cognitive Assessment and motor disability with part 3 of Unified Parkinson’s Disease Rating Scale (UPDRS III).

Results: Serum and CSF NfL levels were highly correlated (Pearson’s r=0.87, p = 0.0047). The serum NfL levels of young symptomatic carriers were comparable to age-matched controls. NfL serum levels of elder symptomatic carriers were increased, and differences were significant between demented symptomatic carriers compared to age and sex-matched controls (p=0.035). Indeed, correlation analyses showed that serum NfL levels were highly correlated with cognitive deterioration in E46K-SNCA mutation carriers (r = -0.89, p=0.003), but not in controls. The correlation with motor impairment was also significant (r = 0.88, p=0.021). The median NfL increased from 9.97 pg/ml to 12.19 pg/ml within one year of follow-up.

Conclusion: These preliminary results support the idea that the proposed molecular biomarker is adequate to identify patients with increased brain damage and clinical disability.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neurofilament-light-chain-serum-levels-in-e46k-snca-mutation-carriers/