Unbiased MRI analyses identify micropathologic differences between upper motor neuron-predominant ALS phenotypes

Amyotrophic lateral sclerosis (ALS) is an incurable and progressively fatal neurodegenerative disease that manifests with distinct clinical phenotypes, which are seen in neuroimaging, and clinical studies. T2- and proton density (PD)-weighted magnetic resonance imaging (MRI) displays hyperintense signal along the corticospinal tract (CST) in some ALS patients with upper motor neuron (UMN)-predominant signs. These patients tend to be younger and have significantly faster disease progression. We hypothesize that such ALS patients with CST hyperintensity (ALS-CST+) comprise a clinical subtype distinct from other ALS subtypes, namely patients with UMN-predominant ALS without CST hyperintensity, classic ALS, and ALS with frontotemporal dementia (FTD). Novel approaches such as fractal dimension analysis on conventional MRI (cMRI) and advanced MR techniques such as diffusion tensor imaging (DTI) reveal significant differences between ALS-CST+ and the aforementioned ALS subtypes. Our unbiased neuroimaging studies demonstrate that the ALS-CST+ group, which can be initially identified by T2-, PD-, and FLAIR-weighted cMRI, is distinctive and distinguishable from other ALS subtypes with possible differences in disease pathogenesis.