Differential Cellular Mechanisms Underlie Language and Executive Decline in Amyotrophic Lateral Sclerosis [Visium spatial transcriptomics]

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. Overall design: 246 10x Visium spatial transcriptomic libraries generated from 64 human donor prefrontal cortex samples (BA44/45 and BA46), across a range of non-neuropathological sudden-death controls, ALS patients, and ALS patients who exhibit cognitive impairment on a standardized screening exam