肌萎缩性侧索硬化症（ALS）患者和无症状C9orf72突变携带者体内脑代谢改变模式：横断面1H和31P磁共振波谱7T成像研究

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-10-15 DOI:10.1016/j.ebiom.2025.105963

Henk-Jan Westeneng, Abram D Nitert, Kevin van Veenhuijzen, Carrie Wismans, Graziella Donatelli, Harold H G Tan, Wytse van Hoek, Michael A van Es, Dennis W J Klomp, Alex A Bhogal, Jan H Veldink, Jannie P Wijnen, Leonard H van den Berg

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引用次数: 0

摘要

背景：导致肌萎缩性侧索硬化症（ALS）神经退行性变发病的过程在很大程度上是未知的。为了深入了解疾病机制，我们测量了无症状C9orf72突变携带者和ALS患者体内的脑代谢。方法：我们招募了15名无症状的家庭成员（AFM C9+）和18名没有C9orf72突变（AFM C9-）， 4名患有（ALS C9+）和35名没有这种突变（ALS C9-）的ALS患者，以及25名基于人群的对照组（CO）。二维质子（1H）和全脑磷（31P）磁共振波谱成像（MRSI）数据采用7T磁共振扫描仪。采用加权贝叶斯线性多水平模型比较各组间11种脑代谢物。结果：与AFM C9-相比，AFM C9+表现出神经元功能障碍的证据（总n -乙酰天冬氨酸/总肌酸（tNAA/tCr））降低，膜分解产物（甘油磷酸乙醇胺/磷酸肌酸（GPE/PCr））广泛增加，谷氨酸兴奋毒性（谷氨酸+谷氨酰胺/tNAA (Glx/tNAA)）增加，并且在额顶区，糖原前体尿苷二磷酸葡萄糖/PCr （UDPG/PCr）增加。与AFM C9+相比，ALS C9+的神经元功能障碍和膜破裂相似，但谷氨酸兴奋性毒性和糖原前体增加更为严重和广泛，也累及初级运动区。此外，ALS C9+出现了较低的总三磷酸腺苷/PCr (tATP/PCr)，以及膜合成、细胞内第二信使系统和神经胶质病理（肌醇+甘氨酸/tCr (mI + Gly/tCr)）紊乱的迹象。ALS C9-的特点是谷氨酸兴奋毒性、ttp /PCr升高和磷脂水平降低。解释：1H和31p7t mri可以检测无症状突变携带者和ALS患者脑代谢改变的演变模式。ALS C9+患者的异常与ALS C9-患者的异常似乎有所不同。在体内测量的代谢标记物可以作为包含或分层的生物标记物，也可以作为临床试验中药物靶标参与的生物标记物。这种方法可以促进识别新的和个性化的药物靶点，以预防或治疗这种毁灭性的疾病。资助：ALS基金会荷兰。

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Patterns of altered in vivo brain metabolism in patients with amyotrophic lateral sclerosis (ALS) and asymptomatic C9orf72 mutation carriers: a cross-sectional ¹H and ³¹P magnetic resonance spectroscopic 7T imaging study.

Background: Processes leading to the onset of neurodegeneration in amyotrophic lateral sclerosis (ALS) are largely unknown. To gain insight into disease mechanisms, we measured brain metabolism in vivo in asymptomatic C9orf72 mutation carriers and patients with ALS.

Methods: We enroled 15 asymptomatic family members with (AFM C9+) and 18 without a C9orf72 mutation (AFM C9-), 4 patients with ALS with (ALS C9+) and 35 without this mutation (ALS C9-), and 25 population-based controls (CO). Two-dimensional proton (¹H) and whole-brain phosphorus (³¹P) magnetic resonance spectroscopic imaging (MRSI) data were obtained using a 7T MR scanner. 11 brain metabolites were compared between groups using weighted Bayesian linear multilevel models.

Findings: Compared to AFM C9-, AFM C9+ showed evidence of neuronal dysfunction (decreased total N-acetyl aspartate/total creatine (tNAA/tCr)), widespread increased membrane breakdown product (glycerol phosphorylethanolamine/phosphocreatine (GPE/PCr)), glutamate excitotoxicity (increased glutamate + glutamine/tNAA (Glx/tNAA)) and, in frontoparietal regions, an increase in the glycogen precursor uridine diphosphoglucose/PCr (UDPG/PCr). Compared to AFM C9+, neuronal dysfunction and membrane breakdown are similar in ALS C9+, but glutamate excitotoxicity and increased glycogen precursor are more severe and widespread, also involving the primary motor region. Moreover, lower total adenosine triphosphate/PCr (tATP/PCr) emerged in ALS C9+, and signs of disturbed membrane synthesis, intracellular second messenger system and glial pathology (myo-inositol + glycine/tCr (mI + Gly/tCr)). ALS C9- is characterised by glutamate excitotoxicity, increased tATP/PCr, and lower phospholipid levels.

Interpretation: ¹H and ³¹P 7T MRSI can detect evolving patterns of altered brain metabolism in asymptomatic mutation carriers and patients with ALS. Abnormalities in patients with ALS C9+ appeared to be different from those in patients with ALS C9-. Metabolic markers, measured in vivo, can serve as biomarkers for inclusion or stratification as well as for drug-target engagement in clinical trials. This method can facilitate identification of new and personalised drug targets to prevent or treat this devastating disease.

Funding: ALS Foundation Netherlands.

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.