Biofluid and neurophysiological biomarkers in amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease, characterized by the progressive degeneration of upper and lower motor neurons. There is an urgent need of biomarkers for a deeper understanding of the disease pathogenesis and for treatments discovery. In this Ph.D. dissertation we aimed to explore the role of some biofluid biomarkers reflecting neurodegeneration, i.e. neurofilament light chain (NfL) and plasma p-tau phosphorylated at residue 181 (p-tau181), as well as others reflecting astrocitopathy (glial fibrillary acidic protein, GFAP). We also investigated the prognostic role of conventional electromyography (EMG) in the bulbar region and the diagnostic value of a new method which estimates the number of motor units (MScanFit MUNE). We confirmed that both cerebrospinal fluid (CSF) and plasma NfL showed a high accuracy in discriminating ALS patients from ALS mimics, and displayed an excellent prognostic value in detecting ALS patients with a faster disease progression and a shorter survival. Plasma p-tau181 values were found increased in ALS patients compared to controls, and resulted highly correlated with clinical and EMG lower motor neuron dysfunction. Furthermore, plasma GFAP increase in ALS was merely driven by amyloid-beta co-pathology and resulted well correlated with the cognitive profile of patients. Exploring neurophysiological biomarkers, we demonstrated an excellent prognostic value of EMG genioglossus involvement, which resulted associated to a worse prognosis even in patients without clinical bulbar signs/symptoms. A comparison between conventional quantitative EMG analysis and the novel MScanFit MUNE method did not reveal a better sensitivity of the second one in detecting abnormalities in the affected muscles. However, motor unit number estimation could be useful for monitoring ALS progression over time. With these studies we produced several pieces of evidence which significantly contribute to this field of research in amyotrophic lateral sclerosis.