Presynaptic density determined by SV2A PET is closely associated with postsynaptic metabotropic glutamate receptor 5 availability and independent of amyloid pathology in early cognitive impairment

Jie Wang; Qi Huang; Kun He; Junpeng Li; Tengfei Guo; Yang Yang; Zengping Lin; Songye Li; Greet Vanderlinden; Yiyun Huang; Koen Van Laere; Yihui Guan; Qihao Guo; Ruiqing Ni; Binying Li; Fang Xie

doi:10.1002/alz.13817

Presynaptic density determined by SV2A PET is closely associated with postsynaptic metabotropic glutamate receptor 5 availability and independent of amyloid pathology in early cognitive impairment

Alzheimers Dement. 2024 Apr 18. doi: 10.1002/alz.13817. Online ahead of print.

Authors

Jie Wang¹, Qi Huang¹, Kun He¹, Junpeng Li¹, Tengfei Guo², Yang Yang³, Zengping Lin⁴, Songye Li⁵, Greet Vanderlinden⁶, Yiyun Huang⁵, Koen Van Laere⁶, Yihui Guan¹, Qihao Guo⁷, Ruiqing Ni^{8

9}, Binying Li¹⁰, Fang Xie^{1

11}

Affiliations

¹ Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China.
² Institute of Biomedical Engineering, Shenzhen Bay Laboratory, Shenzhen, China.
³ Beijing United Imaging Research Institute of Intelligent Imaging, Beijing, China.
⁴ Central Research Institute, United Imaging Healthcare Group Co., Ltd, Shanghai, China.
⁵ Department of Radiology and Biomedical Imaging, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
⁶ Department of Imaging and Pathology, Nuclear Medicine and Molecular Imaging, KU Leuven, Leuven, Belgium.
⁷ Department of Gerontology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
⁸ Institute for Biomedical Engineering, University of Zurich & ETH Zurich, Zurich, Switzerland.
⁹ Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland.
¹⁰ Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹¹ State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.

PMID: 38634334
DOI: 10.1002/alz.13817

Abstract

Introduction: Metabotropic glutamate receptor 5 (mGluR5) is involved in regulating integrative brain function and synaptic transmission. Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the pathophysiological mechanism of Alzheimer's disease (AD).

Methods: Ten cognitively impaired (CI) individuals and 10 healthy controls (HCs) underwent [¹⁸F]SynVesT-1 and [¹⁸F]PSS232 positron emission tomography (PET)/magnetic resonance to assess synaptic density and mGluR5 availability. The associations between mGluR5 availability and synaptic density were examined. A mediation analysis was performed to investigate the possible mediating effects of mGluR5 availability and synaptic loss on the relationship between amyloid deposition and cognition.

Results: CI patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and cognition.

Conclusions: Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD and are closely linked.

Highlights: Cognitively impaired patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and global cognition. With further research, modulating mGluR5 availability might be a potential therapeutic strategy for improving synaptic function in AD.

Keywords: Alzheimer's disease; PET/MR; amyloid deposition; cognition; mGluR5 availability; synaptic density.

Abstract

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