Background: In Alzheimer’s disease (AD) the progressive accumulation of misfolded proteins, notably amyloid-β and hyperphosphorylated tau, initiates a cascade of metabolic and synaptic dysfunction, and ultimately neurodegeneration. These early molecular alterations interact with diffuse neurotrasmitter projection systems, contributing to cognitive and behavioural manifestations. Methods: This study assessed baseline [18F]FDG-PET metabolism and its relationship with neurotransmitter receptor/transporter maps and cerebrospinal fluid (CSF) markers of AD neuropathology (Aβ42/Aβ40, pTau181, t-Tau), neuroaxonal (NFL), and synaptic damage (NPTX2, neurogranin) in 49 Mild Cognitive Impairment (MCI)-AD patients. Relative hypometabolism was derived by comparing [¹⁸F]FDG-PET scans of patients and 40 healthy controls. Spatial correlation coefficients between hypometabolism maps and normative cortical maps of neurotransmitter receptor/transporter density were computed and included in linear models with CSF biomarkers, adjusting for demographic and cognitive variables. Results: Patients exhibited significant hypometabolism in bilateral temporo-parietal regions. Negative correlations emerged between hypometabolism and receptor distributions for 5-HT1A (r = − 0.36, p < 0.001), D1 (r = − 0.15, p = 0.03), and mGluR5 (r = − 0.14, p = 0.02), which indicates that reduced glucose uptake in MCI-AD was mostly found in areas with normally high receptor densities. Noteworthy, CSF NPTX2 levels correlated with the co-localization of hypometabolism and 5-HT1A receptor distribution (β = 0.003, p = 0.038) with no significant associations for other CSF markers. Conclusions: According to our findings, correlations between reduced glucose metabolism and specific neurotransmitter receptor densities suggest early involvement and vulnerability of these systems in MCI-AD. Moreover, the association between CSF NPTX2 and 5-HT1A receptor vulnerability indicates that synaptic dysfunction in AD may parallel serotonergic involvement, and supports CSF NPTX2 as a potential biomarker for disease staging.
Cerebrospinal fluid NPTX2 and [18F]FDG PET track serotonergic vulnerability to neurodegeneration in prodromal Alzheimer’s disease
Massa, Federico;Orso, Beatrice;Pelagotti, Virginia;Garbarino, Sara;Raffa, Stefano;Mattioli, Pietro;Argenti, Lucia;Lombardo, Lorenzo;Losa, Mattia;Bozzo, Giulia;Kreshpa, Wendy;Cirone, Alessio;Lorenzini, Luigi;Bozzano, Federica;Visigalli, Davide;Brugnolo, Andrea;Girtler, Nicola;Piana, Michele;Arnaldi, Dario;Morbelli, Silvia;Sambuceti, Gianmario;Uccelli, Antonio;Pardini, Matteo
2025-01-01
Abstract
Background: In Alzheimer’s disease (AD) the progressive accumulation of misfolded proteins, notably amyloid-β and hyperphosphorylated tau, initiates a cascade of metabolic and synaptic dysfunction, and ultimately neurodegeneration. These early molecular alterations interact with diffuse neurotrasmitter projection systems, contributing to cognitive and behavioural manifestations. Methods: This study assessed baseline [18F]FDG-PET metabolism and its relationship with neurotransmitter receptor/transporter maps and cerebrospinal fluid (CSF) markers of AD neuropathology (Aβ42/Aβ40, pTau181, t-Tau), neuroaxonal (NFL), and synaptic damage (NPTX2, neurogranin) in 49 Mild Cognitive Impairment (MCI)-AD patients. Relative hypometabolism was derived by comparing [¹⁸F]FDG-PET scans of patients and 40 healthy controls. Spatial correlation coefficients between hypometabolism maps and normative cortical maps of neurotransmitter receptor/transporter density were computed and included in linear models with CSF biomarkers, adjusting for demographic and cognitive variables. Results: Patients exhibited significant hypometabolism in bilateral temporo-parietal regions. Negative correlations emerged between hypometabolism and receptor distributions for 5-HT1A (r = − 0.36, p < 0.001), D1 (r = − 0.15, p = 0.03), and mGluR5 (r = − 0.14, p = 0.02), which indicates that reduced glucose uptake in MCI-AD was mostly found in areas with normally high receptor densities. Noteworthy, CSF NPTX2 levels correlated with the co-localization of hypometabolism and 5-HT1A receptor distribution (β = 0.003, p = 0.038) with no significant associations for other CSF markers. Conclusions: According to our findings, correlations between reduced glucose metabolism and specific neurotransmitter receptor densities suggest early involvement and vulnerability of these systems in MCI-AD. Moreover, the association between CSF NPTX2 and 5-HT1A receptor vulnerability indicates that synaptic dysfunction in AD may parallel serotonergic involvement, and supports CSF NPTX2 as a potential biomarker for disease staging.
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