Cortical Motor Hierarchy Disruption Is Associated With Functional Status in Early Amyotrophic Lateral Sclerosis
Jixin Luan, Yan Yun, Yichang Jiao, Yao Wang, Mingjie Ma, Didi Shan, Hongxu Wang, Xinbo Ji, Yao Tang, Jianing Li, Zexin Zhan, Xiaohan Sun, Ninglu Gao, Pengfei Lin, Chuanzhu Yan, Xiulian Sun, Dexin Yu, Shuangwu Liu, Fuchen LiuABSTRACT
Background
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.
Methods
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.
Results
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).
Conclusions
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.