Bi Sheng, Chen Zhigeng, Li Yixia, Cui Bixiao, Shan Yi, Yang Hongwei, Qi Zhigang, Wu Liyong, Yan Shaozhen, Lu Jie
Department of Radiology & Nuclear Medicine, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Xicheng District, Beijing, 100053, China.
Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing, China.
Eur J Nucl Med Mol Imaging. 2025 Aug 7. doi: 10.1007/s00259-025-07485-8.
OBJECTIVE: This study aimed to elucidate the spatial correlations among alterations in glucose metabolism, amyloid-beta (Aβ) deposition, and neurotransmitter systems across Alzheimer's disease (AD), mild cognitive impairment (MCI) and frontotemporal dementia (FTD), while assessing their associations with clinical cognitive decline. METHODS: In this retrospective cohort study, 507 participants (261 AD, 111 MCI, 62 FTD and 73 normal controls) underwent multimodal neuroimaging, including F-FDG PET, F-AV45 Aβ PET, and structural MRI. Spatial co-localization of imaging alterations with neurotransmitter receptor/transporter distributions was assessed using the JuSpace toolbox. Spearman correlations evaluated associations between imaging-neurotransmitter co-localization and cognitive scores. False discovery rate (FDR) correction was used to control for P < 0.05 for all analyses. RESULTS: AD showed glucose hypometabolism in temporoparietal and frontal regions, while FTD was observed in the frontotemporal areas. Spatial co-localization analyses revealed subtype-specific neurotransmitter vulnerabilities: AD glucose hypometabolism correlated with serotonergic, γ-aminobutyric acidergic (GABAergic), dopaminergic, and glutamatergic systems, while FTD correlated with serotonergic, dopaminergic, and opioid receptors. Aβ deposition co-localized with 5HT2a receptor, γ-aminobutyric acid type A (GABAa) receptors, and noradrenaline transporter (NAT) in AD, as well as D1 receptor in MCI. In AD, FDG or Aβ PET-neurotransmitter correlations significantly associated with MMSE/MoCA scores, while Aβ-serotonin transporter (SERT) or Fluorodopa (FDOPA) correlations linked to cognitive decline in Aβ-positive MCI (P < 0.05). CONCLUSION: This study demonstrates that AD and FTD exhibit unique spatial vulnerabilities in neurotransmitter systems, closely tied to glucose hypometabolism and Aβ pathology. The identification of disease specific neuroimaging-neurotransmitter signatures advances biomarker development and supports targeted therapeutic strategies tailored to molecular pathways. CLINICAL TRIAL NUMBER: not applicable.
目的：本研究旨在阐明阿尔茨海默病（AD）、轻度认知障碍（MCI）和额颞叶痴呆（FTD）患者葡萄糖代谢改变、β-淀粉样蛋白（Aβ）沉积和神经递质系统之间的空间相关性，同时评估它们与临床认知衰退的关联。 方法：在这项回顾性队列研究中，507名参与者（261名AD患者、111名MCI患者、62名FTD患者和73名正常对照）接受了多模态神经成像检查，包括F-FDG PET、F-AV45 Aβ PET和结构MRI。使用JuSpace工具箱评估成像改变与神经递质受体/转运体分布的空间共定位。Spearman相关性分析评估成像-神经递质共定位与认知评分之间的关联。所有分析均采用错误发现率（FDR）校正以控制P<0.05。 结果：AD患者在颞顶叶和额叶区域表现出葡萄糖代谢减低，而FTD患者则出现在额颞叶区域。空间共定位分析揭示了亚型特异性神经递质易损性：AD患者的葡萄糖代谢减低与血清素能、γ-氨基丁酸能（GABA能）、多巴胺能和谷氨酸能系统相关，而FTD患者与血清素能、多巴胺能和阿片受体相关。在AD患者中，Aβ沉积与5HT2a受体、A型γ-氨基丁酸（GABAa）受体和去甲肾上腺素转运体（NAT）共定位，在MCI患者中与D1受体共定位。在AD患者中，FDG或Aβ PET-神经递质相关性与MMSE/MoCA评分显著相关，而Aβ-血清素转运体（SERT）或氟多巴（FDOPA）相关性与Aβ阳性MCI患者的认知衰退相关（P<0.05）。 结论：本研究表明，AD和FTD在神经递质系统中表现出独特的空间易损性，与葡萄糖代谢减低和Aβ病理密切相关。疾病特异性神经成像-神经递质特征的识别推动了生物标志物的开发，并支持针对分子途径的靶向治疗策略。 临床试验编号：不适用。
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