Abstract
The lack of biomarkers for an early diagnosis of neurodegenerative disorders (NDs) has hampered the development of therapeutics whose effect would be enhanced by a timely intervention. Neurofilaments light chain (Nf-L), an integral part of the axonal structure, has emerged as a robust fluid biomarker for fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). To facilitate large-scale studies into early-stage neurodegeneration, reduce costs of samples collection/processing and cold-chain storage, we describe the measurement of Nf-L in blood fractions obtained from dry blood spots (DBS) and dry plasma spots (DPS), two filter paper-based remote blood collection tools. To test the feasibility of using this approach, Nf-L analysis in DBS/DPS is compared to that in plasma obtained from the same blood sample, looking at Nf-L discriminatory power in the clinical stratification of ALS compared to healthy controls. With the best pre-analytical treatment for total protein recovery and using highly sensitive immunoassays, we report the detection of different Nf-L levels in DBS elute compared to reference plasma and DPS from the same blood samples. However, Nf-L measurement in DBS elutes provides a very good discrimination of ALS from healthy controls which is comparable to that obtained using plasma Nf-L assays. With the available immunodetection methods, we show that Nf-L measurement based on DPS microsampling is similar to that in plasma. The filter-paper biophysical characteristics and the interference of high haemoglobin concentration released by erythrocyte lysis is likely to perturb Nf-L detection in DBS elute. Further studies into DBS-based Nf-L detection and its analytical optimization are needed to make this method suitable for routine Nf-L blood analyses in neurodegeneration.
Highlights
The lack of biomarkers for an early diagnosis of neurodegenerative disorders (NDs) has hampered the development of therapeutics whose effect would be enhanced by a timely intervention
Taking advantage of red cells, plasma and dry blood spots (DBS) extracted from the same blood samples from healthy controls and patients with amyotrophic lateral sclerosis (ALS), a clinically heterogeneous and invariably fatal neurodegenerative disorder, we have looked at whether DBS-based Neurofilaments light chain (Nf-L) measurements maintain the same discriminatory power reported using plasma assays where Nf-L differentiates healthy from affected individuals as well as fast versus slow progressing ALS patients
Demographic and clinical characteristics are reported in Table 1. 30 ml blood was drawn by venepuncture from each participant to obtain plasma and serum and between 0.7 to 1 ml was spotted on to 2 protein saver cards (PSC), one stored at room temperature and one at −80 °C
Summary
The lack of biomarkers for an early diagnosis of neurodegenerative disorders (NDs) has hampered the development of therapeutics whose effect would be enhanced by a timely intervention. The development of tools for early diagnosis allowing timely therapeutic interventions is one of the responses to this problem[2] To this end, it is important to acquire measurable, cost-effective and sensitive biomarkers of axonal loss, the process underpinning neurodegeneration, which can be used as surrogate markers of treatment response in clinical trials. As serial lumbar punctures to procure CSF for biomarkers analysis may be impractical in advanced and uncooperative patients and disease monitoring by structural and functional brain imaging is expensive and logistically complex[7], blood may represent the ideal source to track any meaningful disease signal of neurodegeneration cost-effectively in large biomarkers studies and clinical trials Both light and heavy neurofilament chain (Nf-L; Nf-H) measurement in blood is possible thanks to highly sensitive immunodetection platforms like Meso.
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