Abstract
BackgroundMetabotropic glutamate subtype 5 receptors (mGluR5) modulate synaptic transmission and may constitute an important therapeutic target in Alzheimer’s disease (AD) by mediating the synaptotoxic action of amyloid-β oligomers. We utilized the positron emission tomography (PET) radioligand [18F]FPEB to investigate mGluR5 binding in early AD.MethodsSixteen individuals with amnestic mild cognitive impairment (MCI) due to AD or mild AD dementia who were positive for brain amyloid were compared to 15 cognitively normal (CN) participants who were negative for brain amyloid. Diagnostic groups were well balanced for age, sex, and education. Dynamic PET scans were acquired for 60 min, starting at 60 min after the initial administration of up to 185 MBq of [18F]FPEB using a bolus-plus-constant-infusion method (Kbol = 190 min). Equilibrium modeling with a cerebellum reference region was used to estimate [18F]FPEB binding (BPND) to mGluR5. Analyses were performed with and without corrections for gray matter atrophy and partial volume effects.ResultsLinear mixed model analysis demonstrated a significant effect of group (p = 0.011) and the group × region interaction (p = 0.0049) on BPND. Post hoc comparisons revealed a significant reduction (43%) in mGluR5 binding in the hippocampus of AD (BPND = 0.76 ± 0.41) compared to CN (BPND = 1.34 ± 0.58, p = 0.003, unpaired t test) participants, and a nonsignificant trend for a reduction in a composite association cortical region in AD (BPND = 1.57 ± 0.25) compared to CN (BPND = 1.86 ± 0.63, p = 0.093) participants. Exploratory analyses suggested additional mGluR5 reductions in the entorhinal cortex and parahippocampal gyrus in the AD group. In the overall sample, hippocampal mGluR5 binding was associated with episodic memory scores and global function.Conclusions[18F]FPEB-PET revealed reductions in hippocampal mGluR5 binding in early AD. Quantification of mGluR5 binding in AD may expand our understanding of AD pathogenesis and accelerate the development of novel biomarkers and treatments.
Highlights
Metabotropic glutamate subtype 5 receptors are seven-transmembrane G protein-coupled receptors located in excitatory synapses [1] and in glial cells [2]
Participant characteristics The study sample consisted of 31 participants—16 with amnestic mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or mild AD dementia and 15 who were cognitively normal (CN)
We observed no difference in whole cerebellar VT from 90 to 120 min postinjection between AD (9.3 ± 1.8) and CN (8.6 ± 2.2) groups, supporting the use of cerebellum as the reference region in Binding potential (BPND) calculations
Summary
Metabotropic glutamate subtype 5 receptors (mGluR5) are seven-transmembrane G protein-coupled receptors located in excitatory synapses [1] and in glial cells [2]. They are distributed throughout the cortex and hippocampus. Complexes of Aβo and PrPc create a hydrogel phase that recruits mGluR5 [13], leading to activation of the tyrosine kinase Fyn [10]. This activation of Fyn leads to downstream tau phosphorylation [14]. We utilized the positron emission tomography (PET) radioligand [18F]FPEB to investigate mGluR5 binding in early AD
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