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. 2026 Jan;53(2):1169-1182.
doi: 10.1007/s00259-025-07485-8. Epub 2025 Aug 7.

Glucose metabolism alterations and Aβ deposition in AD and FTD are related to the distribution of neurotransmitter systems

Sheng Bi #  1   2   3 , Zhigeng Chen #  1   2   3 , Yixia Li #  1   2   3 , Bixiao Cui  1   2   3 , Yi Shan  1   2   3 , Hongwei Yang  1   2   3 , Zhigang Qi  1   2   3 , Liyong Wu  4 , Shaozhen Yan  5   6   7 , Jie Lu  1   2   3
Affiliations

Glucose metabolism alterations and Aβ deposition in AD and FTD are related to the distribution of neurotransmitter systems

Sheng Bi et al. Eur J Nucl Med Mol Imaging. 2026 Jan.

Abstract
in English, French

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 18F-FDG PET, 18F-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.

1. Decreased glucose metabolism in AD and FTD has spatial localization relationship with different neurotransmitter systems.2. Aβ deposition has a co-localization relationship with 5HT2a, GABAa, NAT, and D1 distribution in AD or MCI.3. In AD, FDG or Aβ PET-neurotransmitter correlations significantly associated with MMSE/MoCA scores, while Aβ PET-SERT or FDOPA correlations linked to cognitive decline in Aβ-positive MCI.

Keywords: 18F-FDG PET; Alzheimer’s disease; Amyloid-beta PET; Frontotemporal dementia; Neurotransmission.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Capital Medical University (No. [2023]044]). Consent for publication: Written informed consent was obtained from the parents. Competing interests: The authors have no relevant financial or non-financial interests to disclose.

Figures

Fig. 1
Fig. 1
Spatial maps of the voxel-wise based analysis with the patterns of reduced 18F-FDG PET SUVR after (a) and before PVC (b) in patients with AD, MCI, and FTD compared with NC participants (PFDR < 0.05). Colors indicate t scores
Fig. 2
Fig. 2
Results of spatial correlation analyses of 18F-FDG PET SUVR after (a) and before PVC (b) with spatial distribution of neurotransmitter systems in patients with AD, MCI, and FTD (FDR corrected, *: PFDR<0.05, **: PFDR<0.01, ***: PFDR<0.001)
Fig. 3
Fig. 3
Results of spatial correlation analyses of Aβ PET SUVR with spatial distribution of neurotransmitter systems in patients with AD (a), MCI (b), Aβ positive MCI (c), and Aβ negative MCI (d) (FDR corrected, *: PFDR<0.05, **: PFDR<0.01)
Fig. 4
Fig. 4
Correlations of MMSE (a) and MoCA (b) with 18F-FDG PET SUVR–neurotransmitter strength of association after PVC with 5-HT1a, 5HT2a, GABAa, and mGluR5 in AD patients (P < 0.001). Symbols represent individual Fisher’s z-transformed spearman correlation coefficients between 18F-FDG PET SUVR–neurotransmitter correlations after PVC and each neuropsychological scale
Fig. 5
Fig. 5
Correlations of MMSE (a) and MoCA (b) with 18F-FDG PET SUVR–neurotransmitter strength of association before PVC with 5-HT1a, 5HT2a, D2, DAT, FDOPA, GABAa, SERT, and mGluR5 in AD patients (P < 0.05). Symbols represent individual Fisher’s z-transformed spearman correlation coefficients between 18F-FDG PET SUVR–neurotransmitter correlations and each neuropsychological scale
Fig. 6
Fig. 6
Correlations of MMSE and MoCA with Aβ PET SUVR–neurotransmitter strength of association with 5HT2a, GABAa, and NAT in AD patients (a, b, P < 0.05), and SERT, FDOPA in Aβ positive MCI patients (c, P < 0.05). Symbols represent individual Fisher’s z-transformed spearman correlation coefficients between Aβ PET SUVR–neurotransmitter correlations and each neuropsychological scale
See this image and copyright information in PMC

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