近日，美国神经退行性疾病基因组学中心教授Hemali Phatnani及其小组的研究开发出了肌萎缩性侧索硬化症中语言和执行能力下降的不同细胞表型。2026年8月4日出版的《细胞》杂志发表了这项成果。
在认知分层的患者队列中，研究小组通过整合空间和单核转录组学来绘制ALS患者的前额皮质区域。该研究团队发现，ALS患者的认知障碍与不同区域和认知亚型的神经元功能障碍和神经胶质血管失调的不同模式有关。执行功能障碍与深层背外侧前额叶皮层神经元的线粒体和突触活动减少有关，而语言相关的缺陷则与涉及神经胶质和血管异常的弥漫性泛区域反应有关。他们的分析经过多路成像验证，进一步确定了前额皮质中跨越运动和认知表型的特征，包括多细胞胶质瘤反应。研究结果表明，ALS的临床异质性是由大脑运动和非运动区域的表型特异性细胞相互作用驱动的。
据了解，认知表现，包括语言和执行功能的损害，在肌萎缩侧索硬化症（ALS）中可见，但潜在的机制尚不清楚。
附：英文原文
Title: Distinct cellular phenotypes of language and executive decline in amyotrophic lateral sclerosis
Author: Joana Petrescu, Cláudio Gouveia Roque, Christopher A. Jackson, Aidan C. Daly, Zoé Butti, Kristy Kang, Obadele Casel, Matthew Leung, Luke Reilly, Jacqueline Eschbach, Brhan Gebremedhin, Karina McDade, Jenna M. Gregory, Richard Bonneau, Colin Smith, Hemali Phatnani
Issue&Volume: 2026-08-04
Abstract: Cognitive manifestations, including impairments in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain unclear. We mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in deep-layer dorsolateral prefrontal cortex neurons, whereas language-related deficits track with a diffuse pan-regional response involving glial and vascular abnormalities. Our analyses, validated by multiplexed imaging, further identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that clinical heterogeneity in ALS is driven by phenotype-specific cellular interactions in motor and non-motor regions of the brain.
DOI: 10.1016/j.cell.2026.07.008
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00806-8