Amyotrophic Lateral Sclerosis (ALS) is a terminal neurodegeneration of the motor neurons leading to progressive loss of movement and death within 3 years. A crucial challenge in finding effective therapeutics is the lack of biomarkers for early diagnosis and stratification of patients for increased likelihood of response to drugs in clinical trials. While wet neurofilament-based biomarkers are promising for diagnosis, they are of limited use for patient stratification and tracking the prognosis of specific pathologies in affected neural circuits. We have recently shown that non-invasive neuroelectric biomarkers based on electroencephalography, electromyography and transcranial magnetic stimulation provide an exhaustive array of network-specific measures of dysfunction in ALS and identify previously unrecognised subphenotypes of ALS. The overarching aim of this proposal is to refine these neurophysiological biomarkers, and to link the findings with specific neural circuits that provide maximum discriminatory power and strongest cluster separation for phenotyping and practical implementation in clinical trials. We hypothesise that a small subset of network-specific biomarkers selected from an array of non-invasive, inexpensive neurophysiological methods can mark the onset and the subphenotype of the disease. For this purpose, we extend our experimental studies to determine the measures that are most suitable for discrimination and clustering, and to introduce novel experimental and analytical components to refine the network-based biomarkers. We will compare and aggregate our array of improved neuroelectric biomarkers across experimental modalities to find the subset with maximum diagnostic discrimination and cluster separation. These biomarkers will be used for early implementation within clinical settings. These cost-effective biomarkers are therefore expected to streamline the early diagnosis, stratification, and early enrolment of patients to future clinical trials and eventually enable treatments for ALS to be applied at an earlier disease stage.
