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

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.