Lu, C; (2013) Developing Blood-Based Biomarkers of Disease Progression in Amyotrophic Lateral Sclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder, for which there is no effective treatment. Clinical trials in ALS are hindered by the lack of reliable biomarkers to enable an early diagnosis and monitoring of disease progression. There is therefore an urgent need to develop biomarkers for ALS. In this Thesis, I examined the possibility that plasma Neurofilament levels may be a biomarker of disease progression in mouse models and ALS patients. I first developed an enzyme-linked immunosorbent assay (ELISA) method that overcomes a well-known technical obstacle, the NfH ’Hook Effect’, to enable accurate quantification of plasma Neurofilament Heavy Chain (NfH). Using this ELISA, I next examined the longitudinal changes in plasma NfH levels in SOD1G93A mice that model ALS. I observed a significant increase in plasma NfH levels as disease progressed, which correlated with the decrease in functional and morphological read-outs of neuromuscular function and motor neuron survival. Moreover, treatment of SOD1G93A mice with different disease-modifying agents, Arimoclomol, Cogane and Riluzole, was found to not only ameliorate disease but also reduce plasma NfH levels compared to untreated controls. Plasma NfH levels may therefore be of use in monitoring drug efficacy and disease progression in clinical trials. Examination of plasma NfH levels in an alternative ALS model with a slower disease progression, the SOD1G93Adl mouse, confirmed that plasma NfH levels increase during disease progression in models other than the rapidly progressing SOD1G93A model. The relevance of these findings of increased plasma NfHs in SOD1 mice as a biomarker of disease progression in the human disease were examined in the final Results Chapter using serial samples longitudinally collected from a cohort of 136 ALS patients with follow-up up to three years. To sum up, the results presented in this Thesis detail the investigation of plasma NfH levels as a disease progression marker in SOD1 mice and in ALS patients.

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