Related Experiment Video
Updated: Dec 30, 2025
Hybrid PET/MRI Imaging of Alzheimer's Disease Based on 18F-AV-1451
Published on: April 18, 2025
PET imaging of mGluR5 in Alzheimer's disease
Adam P Mecca1,2, Julia W McDonald1,2, Hannah R Michalak1,2
1Alzheimer's Disease Research Unit, Yale University School of Medicine, One Church Street, 8th Floor, New Haven, CT, 06510, USA.
Background:
Metabotropic 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.
Methods:
Sixteen 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.
Results:
Linear 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.
Insights
Positron emission tomography (PET) imaging revealed reduced metabotropic glutamate subtype 5 receptors (mGluR5) in the hippocampus of early Alzheimer's disease (AD) patients. This finding may aid in developing new AD biomarkers and treatments.
Area of Science:
- Neuroscience
- Radiochemistry
- Medical Imaging
Background:
- Metabotropic glutamate subtype 5 receptors (mGluR5) play a role in synaptic transmission and are implicated in Alzheimer's disease (AD) pathogenesis.
- mGluR5 receptors are a potential therapeutic target for AD due to their involvement in the synaptotoxic effects of amyloid-β oligomers.
Purpose of the Study:
- To investigate mGluR5 binding in the brains of individuals with early Alzheimer's disease (AD) using positron emission tomography (PET).
- To assess the potential of [18F]FPEB as a PET radioligand for quantifying mGluR5 binding in AD.
Main Methods:
- 16 individuals with mild cognitive impairment (MCI) or mild AD dementia (amyloid-positive) and 15 cognitively normal (CN) participants (amyloid-negative) underwent dynamic PET scans.
- The radioligand [18F]FPEB was administered, and binding potential (BPND) to mGluR5 was estimated using equilibrium modeling with a cerebellum reference region.
- Analyses considered corrections for gray matter atrophy and partial volume effects.
Main Results:
- A significant reduction in mGluR5 binding was observed in the hippocampus of AD participants compared to CN participants (43% decrease).
- A trend towards reduced mGluR5 binding was noted in a composite association cortical region in AD patients.
- Exploratory analyses indicated further reductions in the entorhinal cortex and parahippocampal gyrus in the AD group.
- Hippocampal mGluR5 binding correlated with episodic memory scores and global cognitive function.
Conclusions:
- [18F]FPEB-PET imaging demonstrates reduced hippocampal mGluR5 binding in early AD.
- Quantifying mGluR5 binding in AD could enhance understanding of disease mechanisms.
- This approach may accelerate the development of novel AD biomarkers and therapeutic strategies.
