Toward molecular phenotyping of temporal lobe epilepsy by spatial omics

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY Epilepsia Pub Date : 2025-03-20 DOI:10.1111/epi.18366

Isabeau Vermeulen, Ronny Mohren, Micca Neusinger, Tobias A. Dancker, Michiel Vandenbosch, Jan Beckervordersandforth, Benjamin Balluff, Rianna P. Van der Hel, Olaf E. M. G. Schijns, Govert Hoogland, Kim Rijkers, Berta Cillero-Pastor, ACE epilepsy surgery group

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Abstract

Objective

In temporal lobe epilepsy (TLE), detection of the epileptogenic zone predicts a good surgical outcome. When submitted to ¹⁸F-fluorodeoxyglucose positron emission tomography (PET), some patients display lateralized, focal hypometabolism in the temporal lobe (PET+), whereas others appear normometabolic (PET−). However, the mechanism behind this metabolic difference remains unclear. This study aimed to identify differential molecular mechanisms in these patient subtypes.

Methods

Neocortical and hippocampal biopsies of TLE patients (n = 3 PET+, n = 3 PET−) and nonepileptic postmortem controls (n = 3) were analyzed for lipid distribution using mass spectrometry imaging (MSI). Laser capture microdissection of the neocortical gray matter and hippocampal cornu ammonis and dentate gyrus was guided by MSI-derived lipid profiles and histological annotations. Dissected areas were then subjected to liquid chromatography– tandem mass spectrometry-based label-free quantitative proteomic analysis.

Results

MSI showed distinct lipid profiles, namely, phosphatidylserines were more abundant in PET+ samples in both the neocortex and hippocampus. Proteomic analysis showed significant differences between TLE and nonepileptic postmortem controls involving pathways in neuron excitability and neurotransmitter transporters, which were upregulated in TLE. Compared to PET−, all PET+ specimens displayed significantly dysregulated calcium signaling. Additionally, the neocortex of PET+ patients showed a shift from mitochondrial to cytosolic (cytoplasm of the cell) processes, whereas the hippocampus was characterized by a disruption of glycosylation and polyamine metabolism.

Significance

The applied spatial omics approach demonstrated localized molecular differences between metabolic subtypes of TLE patients. These findings may further specify these TLE subtypes and provide leads for targeted treatment.

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空间组学研究颞叶癫痫的分子表型。

目的：在颞叶癫痫（TLE）中，检测致痫区预示着良好的手术效果。当进行18f -氟脱氧葡萄糖正电子发射断层扫描（PET）时，一些患者表现为颞叶侧化，局灶性低代谢（PET+），而另一些患者表现为正常代谢（PET-）。然而，这种代谢差异背后的机制尚不清楚。本研究旨在确定这些患者亚型的差异分子机制。方法：采用质谱成像（MSI）分析TLE患者（n = 3例PET+， n = 3例PET-）和非癫痫死后对照（n = 3例）的新皮质和海马活检组织的脂质分布。在msi衍生的脂质谱和组织学注释的指导下，激光捕获显微解剖了新皮质灰质、海马角状体和齿状回。然后对解剖区域进行基于液相色谱-串联质谱的无标记定量蛋白质组学分析。结果：MSI显示明显的脂质谱，即在新皮层和海马的PET+样品中，磷脂酰丝氨酸更丰富。蛋白质组学分析显示，TLE与非癫痫性死后对照组之间存在显著差异，涉及神经元兴奋性和神经递质转运的通路，这些通路在TLE中上调。与PET-相比，所有PET+标本均表现出明显的钙信号失调。此外，PET+患者的新皮质显示出从线粒体到细胞质（细胞的细胞质）过程的转变，而海马的特征是糖基化和多胺代谢的破坏。意义：应用空间组学方法揭示了TLE患者代谢亚型之间的局部分子差异。这些发现可能进一步明确这些TLE亚型，并为靶向治疗提供线索。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Epilepsia 医学-临床神经学

CiteScore

10.90

自引率

10.70%

发文量

319

审稿时长

2-4 weeks

期刊介绍： Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.