Diffusion network model analysis of multimodal neuroimaging reveals differential patterns of brain disease propagation in four subgroups of ALS patients.

Four different subtypes of amyotrophic lateral sclerosis (ALS) were identified based on their clinical and magnetic resonance imaging (MRI) findings, including: (a) classic ALS (ALS-Cl) (b) upper motor neuron (UMN)-predominant ALS with corticospinal tract (CST) hyperintensity (ALS-CST+), (c) UMN-predominant ALS without CST hyperintensity (ALS-CST–), and (d) ALS with frontotemporal dementia (ALS-FTD). These phenotypes also showed differences in symptom duration, disease progression rate, revised ALS functional rating scale score and El Escorial score.Network diffusion model (NDM) is a computational approach that can identify disease epicenters based on brain gray matter (GM) atrophy and white matter (WM) structural connectome from cross-sectional MRI. Although previous NDM MRI studies have considered ALS patients as a single group, we examined whether the above-mentioned phenotypes display subgroup-specific site of disease onset, and whether the latter differs between positron emission tomography -revealed hypo- and hypermetabolic brain regions in ALS-FTD patients. Clinical evaluation and cross-sectional MRI of 83 patients with differing presentations of ALS were assigned into one of four subgroups, and NDM applied to the data.Both ALS-CST + and ALS-CST– subgroups showed the putamen as epicenter for GM atrophy and superior frontal gyrus (orbital part) as epicenter for WM disconnection. The ALS-Cl subgroup also showed the putamen as epicenter for GM degeneration but the inferior parietal gyrus (excluding supramarginal and angular gyri) for WM disconnection, the latter overlapping with ALS-FTD patients. However, epicenters for structural and functional GM degeneration in the ALS-FTD subgroup were different. These results suggest differential patterns of GM and WM degeneration onset between the four ALS subgroups.