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Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the pathophysiological mechanism of Alzheimer's disease (AD).<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Ten cognitively impaired (CI) individuals and 10 healthy controls (HCs) underwent [<jats:sup>18<\/jats:sup>F]SynVesT\u20101 and [<jats:sup>18<\/jats:sup>F]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.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD and are closely linked.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Cognitively impaired patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Regional synaptic density was closely associated with regional mGluR5 availability.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and global cognition.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>With further research, modulating mGluR5 availability might be a potential therapeutic strategy for improving synaptic function in AD.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13817","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T05:26:36Z","timestamp":1713417996000},"page":"3876-3888","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["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"],"prefix":"10.1002","volume":"20","author":[{"given":"Jie","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine &amp; PET Center Huashan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine &amp; PET Center Huashan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"He","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine &amp; PET Center Huashan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junpeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine &amp; PET Center Huashan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengfei","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, Shenzhen Bay Laboratory  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Beijing United Imaging Research Institute of Intelligent Imaging  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengping","family":"Lin","sequence":"additional","affiliation":[{"name":"Central Research Institute, United Imaging Healthcare Group Co., Ltd  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songye","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging PET Center Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greet","family":"Vanderlinden","sequence":"additional","affiliation":[{"name":"Department of Imaging and Pathology Nuclear Medicine and Molecular Imaging, KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging PET Center Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Van Laere","sequence":"additional","affiliation":[{"name":"Department of Imaging and Pathology Nuclear Medicine and Molecular Imaging, KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihui","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine &amp; 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