To determine (1) which, if any of the cALS, ALS-CST+, ALS-CST–, or ALS-FTD patient subgroups share regional WM abnormalities, and (2) whether ALS and ALS-FTD are on a continuum.

Four subgroups of ALS patients were identified by clinical assessment and routine neuroimaging assessment: (1) classic ALS (cALS) with upper motor neuron (UMN) and lower motor neuron (LMN) signs, (2) upper motor neuron-(UMN-) predominant ALS with hyperintensity of the corticospinal tract (ALS-CST+), (3) UMN-predominant ALS without CST hyperintensity (ALS-CST–), and (4) ALS with frontotemporal lobe dementia (ALS-FTD). Some^1,2 but not all^3,4 studies have shown ALS and ALS-FTD to be on a continuum.

An exploratory whole brain white matter (WM) network analysis was performed using graph theory approach. Diffusion tensor MRI data were obtained for 83 ALS patients (cALS n=25, ALS-CST+ n=19, ALS-CST– n=24, ALS-FTD n=15) and 14 neurologic controls.

Brain regions showing significant differences in degree (WM network) measures between ALS patients with or without FTD and neurologic controls included: prefrontal, motor, extra motor, subcortical and cerebellar regions. WM networks affected by ALS degeneration were noticeably different between cALS, ALS-CST+, ALS-CST–, and ALS-FTD groups, although with some overlaps, particularly in ALS-CST+ and ALS-FTD groups.

Of the few brain regions sharing WM abnormalities between patient groups: (1) more were found in the cerebellum than in the forebrain of those with cALS, ALS-CST+, or ALS-CST–; (2) only three occurred in all four groups, including ALS-FTD patients. Despite some overlap, distinct regional involvement in cALS, ALS-CST+, ALS-CST–, and ALS-FTD patients does not support a continuum between the subgroups and suggests differential patterns of WM neurodegeneration between these ALS phenotypes.