Towards quantifying axonal injury in blood samples of patients affected by multiple sclerosis

Barro, Christian. Towards quantifying axonal injury in blood samples of patients affected by multiple sclerosis. 2019, Doctoral Thesis, University of Basel, Faculty of Medicine.


Official URL: http://edoc.unibas.ch/diss/DissB_13241

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Background. Neuro-axonal injury is a hallmark of the underlying pathological processes in neurodegenerative disorders. Reliable quantification and longitudinal follow-up of such damage via a biofluid marker would be a highly relevant adjunctive tool in the treatment workup for patients with multiple sclerosis (MS). The neurofilament proteins have emerged as the first biomarker bearing promise for a clinical application beyond a research tool. For the first time a biomarker specifically indicative of neuronal damage can be quantified in an easily accessible fluid source, i.e. in serum or plasma. Second (Enzyme-linked immunosorbent assays (ELISA)) and third generation (electrochemiluminescence based (ECL) assays) measuring systems lacked sufficient sensitivity to reliably measure neurofilaments throughout the range of concentrations found in blood samples, and specifically failed to define normal levels. The single molecule array system (SIMOA) marks a qualitative technological advancement as it provides the sensitivity to quantify physiologic neurofilament levels. This has paved the way to investigate neurofilaments in a range of neurological disorders, and specifically in diseases with smoldering course of neurodegeneration.
Objective. We aimed to develop and validate a highly sensitive SIMOA assay for the neurofilament light chain (NfL). Using this assay, we investigated blood-based neurofilament light chain (NfL) as fluid biomarker of disease activity, treatment response, and as a predictor of the long-term course of disability and morphological features of neurodegeneration in MS.
Further, we are evaluating in a third work stream the validity of NfL as a tool to detect suboptimal treatment with current standard MS therapies.
Methods. In the first study, we quantified serum NfL (sNfL) in two independent MS patient cohorts: (i) in a cross-sectional cohort (142 patients) NfL in serum and CSF was correlated with magnetic resonance imaging (MRI) data, ii) in a longitudinal cohort (246 patients) from the Swiss MS Cohort study (SMSC) NfL levels in two samples post-switch to a new disease modifying treatment were compared to pre-switch levels and with those from 254 healthy controls from the Genome-Wide Association Study of Multiple Sclerosis (GeneMSA).
In the second study, we quantified yearly serum sNfL in 259 MS patients followed up in the GeneMSA study for up to 10 years and 259 healthy controls who had also a one year follow up blood sampling.
Results and interpretation. NfL levels in CSF and blood were highly correlated, thus supporting the concept that serum is a valid biofluid source to determine accurately neuronal damage within the central nervous system compartment. sNfL levels were higher in relapsing and progressive forms of MS, compared to healthy controls and were associated with current clinical and MRI disease activity. Finally, sNfL levels independently predicted future disability worsening, and cranial and spinal cord volume loss.
Conclusion. Our data demonstrate that NfL can be reliably quantified in peripheral blood and CSF. Levels are associated with a) concurrent clinical and MRI measures of acute and chronic disease activity, b) response to DMT and c) long-term course of disability. This supports the potential of sNfL to become the first precision medicine tool to monitor subclinical disease activity and suboptimal treatment response.
Advisors:Kuhle, Jens and Kappos, Ludwig and Schippling, Sven
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Neurologie > Neuroimmunologie (Kappos)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Neurologie > Neuroimmunologie (Kappos)
UniBasel Contributors:Kappos, Ludwig
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13241
Thesis status:Complete
Number of Pages:1 Online-Ressource (vii, 69 Seiten)
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Last Modified:03 Sep 2019 04:30
Deposited On:02 Sep 2019 13:12

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