Cortical Motor Hierarchy Disruption Is Associated With Functional Status in Early Amyotrophic Lateral Sclerosis
4 affiliations
- 1Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases Qilu Hospital of Shandong University Jinan Shandong China
- 2Department of Radiology Qilu Hospital of Shandong University Jinan Shandong China
- 3Department of Radiology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan Shandong China
- 4School of Nursing and Rehabilitation, Cheeloo College of Medicine Shandong University Jinan Shandong China
Abstract
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.
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BibTeX
@article{luan2026cortical,
title = {{Cortical Motor Hierarchy Disruption Is Associated With Functional Status in Early Amyotrophic Lateral Sclerosis}},
author = {Jixin Luan and Yan Yun and Yichang Jiao and Yao Wang and Mingjie Ma and Didi Shan and Hongxu Wang and Xinbo Ji and Yao Tang and Jianing Li and Zexin Zhan and Xiaohan Sun and Ninglu Gao and Pengfei Lin and Chuanzhu Yan and Xiulian Sun and Dexin Yu and Shuangwu Liu and Fuchen Liu},
journal = {Journal of Cachexia, Sarcopenia and Muscle},
year = {2026},
month = oct,
doi = {10.1002/jcsm.70411},
url = {https://doi.org/10.1002/jcsm.70411},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cortical Motor Hierarchy Disruption Is Associated With Functional Status in Early Amyotrophic Lateral Sclerosis
AU - Jixin Luan
AU - Yan Yun
AU - Yichang Jiao
AU - Yao Wang
AU - Mingjie Ma
AU - Didi Shan
AU - Hongxu Wang
AU - Xinbo Ji
AU - Yao Tang
AU - Jianing Li
AU - Zexin Zhan
AU - Xiaohan Sun
AU - Ninglu Gao
AU - Pengfei Lin
AU - Chuanzhu Yan
AU - Xiulian Sun
AU - Dexin Yu
AU - Shuangwu Liu
AU - Fuchen Liu
PY - 2026
DA - 2026/10/01
JO - Journal of Cachexia, Sarcopenia and Muscle
DO - 10.1002/jcsm.70411
UR - https://doi.org/10.1002/jcsm.70411
AB - 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.
SN - 2190-5991
SN - 2190-6009
ER -