Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
EMBO Mol Med. 2021 Jan 11;13(1):e12595. doi: 10.15252/emmm.202012595. Epub 2020 Dec 3.
Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.
肌萎缩侧索硬化症（ALS）是一种多系统疾病，主要表现为进行性肌肉无力。认知功能障碍在患者中很常见；然而，影响认知功能障碍风险的因素仍难以捉摸。使用稀疏典型相关分析（sCCA），一种无监督机器学习技术，我们观察到在来自多中心肌萎缩侧索硬化症和相关疾病治疗开发临床研究（CReATe）联盟的大型 ALS 患者队列（N=327）中，单核苷酸多态性共同与基线认知表现相关。我们证明，使用 sCCA 得出的多基因风险评分与同一队列的纵向认知衰退以及眶额皮质、前扣带皮质、外侧颞皮质、运动前皮质和海马体（N=90）的皮质变薄以及宾夕法尼亚大学综合神经退行性疾病生物库中独立 ALS 队列的死后运动皮质神经元丧失（N=87）相关。我们的研究结果表明，常见的遗传多态性可能对 ALS 中皮质疾病易感性和认知功能障碍的风险产生多基因贡献。
