Objective: Amyotrophic Lateral Sclerosis (ALS) is a disease of unknown cause characterized by progressive loss of upper motor neurones (UMN) and lower motor neurones (LMN). For patients with ALS there is no effective method of assessing disease progression and a biomarker is especially required for assessing potential therapies.
Methods: We have developed new methods of assessing UMN and LMN involvement using a practical method of Bayesian motor unit number estimate (MUNE) and diffusion tractography (DT) using a High Angular Resolution Diffusion Imaging (HARDI) scan. Serial studies performed in a cohort of ALS subjects with different clinical phenotypes. Results: To assess loss of LMN, we performed serial recordings of MUNE in 15 ALS subjects on a more than 5 occasions (mean=9) over 12–40 months. In all subjects, there was a progressive decline in the number of motor units over time. The rate of fall more closely approximated an exponential loss than a linear change. In a subgroup of patients, the loss of motor units showed an exponential decline with different half-lives in different nerves. We also detected changes in distribution of motor unit sizes over time. To assess UMN, using DT, we found a reduction in intrahemispheric connectivity within the corticospinal tracts linking primary motor and other regions, within the brainstem, and notably the left precentral gyrus related to handedness, compared to controls.
Conclusion: Our novel methods, Bayesian MUNE and DT using HARDI appear sensitive to the disease process and are potential biomarkers of disease progression in ALS.