Guo Kai, Savelieff Masha G, Jang Dae-Gyu, Teener Samuel J, Zhao Lili, Hur Junguk, Goutman Stephen A, Feldman Eva L
Department of Neurology, University of Michigan, Ann Arbor, MI.
NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI.
Ann Neurol. 2025 Jul;98(1):19-34. doi: 10.1002/ana.27208. Epub 2025 Feb 20.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by altered metabolome and energy homeostasis, manifesting with body mass index changes and hypermetabolism-both prognostic of disease progression and survival. The cross-sectional ALS metabolome has been characterized, but longitudinal correlations to functional decline are lacking.
We longitudinally evaluated metabolomes from ALS plasma and terminal postmortem spinal cord and brain motor cortex tissue. We constructed 3 plasma models. A linear mixed effects model correlated all metabolite levels across all timepoints to their corresponding functional scores. An interaction model predicted a longitudinal change in function from baseline metabolites, whereas a progression model identified metabolites linked to a 20% or 50% drop in function. In postmortem samples, differential metabolites in onset versus second spinal cord segments served as a surrogate of disease progression. Mendelian randomization assessed potential causality from metabolites.
In plasma, all models primarily selected lipid metabolites and sub-pathways, in addition to amino acids, xenobiotics, and various less frequently selected pathways. Among lipids, fatty acids and sphingomyelins were predominant, along with plasmalogens, phosphatidylcholines, and lysophospholipids. Sex interaction findings were nominal. In the spinal cord, sphingomyelin and long-chain saturated and monounsaturated fatty acids were more abundant in the onset segment tissue, whereas phosphatidylcholines and phosphatidylethanolamines were less abundant. Mendelian randomization suggested that impaired carnitine and short chain acylcarnitine metabolism may be genetically determined in ALS, along with various antioxidant derivatives.
Our findings suggest metabolomic changes primarily involving different lipid classes and carnitine metabolism may underscore ALS severity and progression. ANN NEUROL 2025;98:19-34.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征为代谢组和能量稳态改变，表现为体重指数变化和高代谢，二者均为疾病进展和生存的预后指标。ALS的横断面代谢组已得到表征，但缺乏与功能衰退的纵向相关性。
我们纵向评估了ALS患者血浆以及终末期尸检脊髓和脑运动皮质组织的代谢组。我们构建了3种血浆模型。线性混合效应模型将所有时间点的所有代谢物水平与其相应的功能评分相关联。交互模型根据基线代谢物预测功能的纵向变化，而进展模型则识别与功能下降20%或50%相关的代谢物。在尸检样本中，起始段与第二脊髓段的差异代谢物作为疾病进展的替代指标。孟德尔随机化评估了代谢物的潜在因果关系。
在血浆中，除氨基酸、外源性物质和各种较少被选择的途径外，所有模型主要选择脂质代谢物和子途径。在脂质中，脂肪酸和鞘磷脂占主导，还有缩醛磷脂、磷脂酰胆碱和溶血磷脂。性别交互作用的结果不显著。在脊髓中，鞘磷脂以及长链饱和脂肪酸和单不饱和脂肪酸在起始段组织中更为丰富，而磷脂酰胆碱和磷脂酰乙醇胺则较少。孟德尔随机化表明，ALS中肉碱和短链酰基肉碱代谢受损可能由基因决定，还有各种抗氧化剂衍生物。
我们的研究结果表明，主要涉及不同脂质类别和肉碱代谢的代谢组变化可能突出了ALS的严重程度和进展。《神经病学纪事》2025年；98:19 - 34。
