Differential Cellular Mechanisms Underlie Language and Executive Decline in Amyotrophic Lateral Sclerosis

Half of all amyotrophic lateral sclerosis (ALS) patients demonstrate a spectrum of cognitive and behavioral changes over the course of the disease, but the mechanisms underlying this heterogeneity remain unclear. We assemble a high-resolution cellular map of prefrontal cortex regions of the ALS brain by integrating spatial and single-nucleus transcriptomic profiles of a cognitively stratified ALS patient cohort that includes non-neuropathological controls. We find cellular programs characteristic of ALS, including a frequent gliotic response. We also find that executive and language cognitive impairments differ from ALS without cognitive impairment, and from each other, in the extent and pattern of neuronal dysregulation and neuron-glial interactions across different brain regions. These findings reveal a relationship between cognitive phenotype and prefrontal cortex dysfunction in ALS. Single cell multiomic (transcriptomic and ATAC) libraries generated from 48 human donor prefrontal cortex samples (24 from BA44/45 and 24 from BA46), across a range of non-neuropathological sudden-death controls, ALS patients, and ALS patients who exhibit cognitive impairment on a standardized screening exam