Cortical Motor Hierarchy Disruption Is Associated With Functional Status in Early Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterised by progressive muscle wasting and functional decline. Although cortical motor network disruption is a hallmark of ALS, the large-scale functional hierarchy alterations and their underlying molecular mechanisms in the early stage of the disease (ALS-ES) remain poorly understood. We aimed to characterise cortical gradient changes in early-stage ALS and to examine their neurochemical and transcriptomic correlates, as well as their cross-sectional associations with clinical functional status.

We recruited 97 patients with early-stage ALS, all at King's stage 1 and 94 healthy controls with comparable age and sex distributions. The ALS-ES group included 65 women and had a median ALSFRS-R score of 40 (IQR, 37-44). Resting-state fMRI was used to construct the principal functional gradient. We integrated neurochemical maps of 19 neurotransmitter receptors/transporters, and transcriptomic data from the Allen Human Brain Atlas. Partial least squares (PLS) regression and cell-type enrichment analysis were employed to identify molecular correlates of gradient alterations.

Compared with HCs, ALS-ES patients exhibited a significant spatial contraction of the principal gradient. Specifically, gradient values significantly increased in the somatomotor network (SMN; t = 3.670, p_FDR = 0.001) and decreased in the default mode network (DMN; t = -4.124, p_FDR < 0.001). Within the ALS-ES group, higher SMN gradient values were associated with lower ALSFRS-R scores, whereas higher DMN gradient values were associated with higher ALSFRS-R scores. These macroscale alterations showed spatial correspondence with normative 5-HT4 receptor and norepinephrine transporter maps. PLS analysis identified a primary gene set (PLS1+) enriched in oligodendrocytes and mitochondrial functions (p_FDR < 0.05), whereas the negative set (PLS1-) was associated with astrocytes, GABAergic neurons and RNA splicing pathways. Chromosome-level analysis revealed significant enrichment of PLS1- genes on chromosomes 5 and 16 (p < 0.05).

Early-stage ALS is characterised by a collapsed cortical functional hierarchy centred on the motor-somatosensory axis. These alterations were spatially associated with normative neurochemical maps and distinct transcriptomic annotations related to energy metabolism and RNA processing. These findings identify cross-sectional cortical functional-hierarchy alterations associated with functional status in early-stage ALS and provide a multi-scale framework for investigating their neurochemical and transcriptomic correlates.