Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype-specific, and severity-linked alterations

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-09-08 DOI:10.1002/alz.70631

Yohannes A. Ambaw, Peter A. Ljubenkov, Shubham Singh, Abdi Hamed, Sebastian Boland, Adam L. Boxer, Tobias C. Walther, Robert V. Farese Jr.

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引用次数: 0

Abstract

INTRODUCTION

Biomarkers are essential for monitoring the progression of frontotemporal dementia (FTD). Although dysregulated brain lipid metabolism, particularly sphingolipids enriched in the nervous system, is a key feature of neurodegeneration, plasma lipids remain underexplored as biomarkers compared to imaging and serum proteins.

METHODS

We examined plasma lipidomes using liquid chromatography–tandem mass spectrometry (LC-MS/MS) from individuals carrying pathogenic variants linked to autosomal dominant FTD (GRN, C9orf72, MAPT) and non-carriers.

RESULTS

FTD subjects exhibited increased plasma levels of gangliosides (GM3(d18:1_16:0), GM3(d18:1_24:1)), ceramide Cer(d18:1_23:0), and select polyunsaturated triacylglycerols. In contrast, phosphatidylethanolamine (PE(18:0_24:0) and sphingomyelin (SM(38:0) were reduced. Subtype-specific changes included elevated glucosylsphingosine (GlcSph(d18:1) in GRN carriers, reduced SM(34:1) in C9orf72, and decreased TG(16:0_18:1_20:3) in MAPT carriers. GM3(d18:1_16:0) was consistently elevated across all subtypes. Furthermore, the levels of these lipids correlated with disease severity.

DISCUSSION

Our findings suggest that specific plasma lipid changes, notably several sphingolipids, may be useful biomarkers for FTD disease or progression.

Highlights

Plasma lipidomics reveals both shared and mutation-specific lipid alterations in frontotemporal dementia (FTD).
Glucosylsphingosine is specifically elevated in FTD caused by GRN mutations and correlates with disease severity.
The ganglioside GM3(d18:1_16:0) is consistently elevated across GRN, MAPT, and C9orf72 variants and correlates with disease severity.
Plasma sphingolipids emerge as promising biomarkers for FTD diagnosis, subtype differentiation, and disease monitoring.

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额颞叶痴呆的血浆脂质组失调揭示了共同的、基因型特异性的和严重相关的改变

生物标志物对于监测额颞叶痴呆（FTD）的进展至关重要。尽管脑脂质代谢失调，特别是神经系统中丰富的鞘脂，是神经变性的一个关键特征，但与成像和血清蛋白相比，血浆脂质作为生物标志物的研究仍然不足。方法：采用液相色谱-串联质谱法（LC-MS/MS）检测携带常染色体显性FTD致病变异（GRN、C9orf72、MAPT）和非携带者的血浆脂质组。结果FTD患者血浆中神经节苷(GM3（d18:1_16:0）、GM3（d18:1_24:1）、神经酰胺Cer（d18:1_23:0）和选择性多不饱和三酰基甘油水平升高。磷脂酰乙醇胺（PE）（18:0 ~ 24:0）和鞘磷脂（SM）（38:0）降低。亚型特异性变化包括GRN携带者中葡萄糖-鞘氨酸(GlcSph（d18:1）升高，C9orf72中SM（34:1）降低，MAPT携带者中TG（16:0_18:1_20:3）降低。GM3（d18:1_16:0）在所有亚型中均持续升高。此外，这些脂质水平与疾病严重程度相关。我们的研究结果表明，特定的血浆脂质变化，特别是几种鞘脂，可能是FTD疾病或进展的有用生物标志物。血浆脂质组学揭示了额颞叶痴呆（FTD）中共享的和突变特异性的脂质改变。葡萄糖鞘苷在由GRN突变引起的FTD中特异性升高，并与疾病严重程度相关。神经节苷脂GM3（d18:1_16:0）在GRN、MAPT和C9orf72变异体中持续升高，并与疾病严重程度相关。血浆鞘脂成为FTD诊断、亚型分化和疾病监测的有前途的生物标志物。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.