Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging
Open accessAbstract
Importance: Synaptic loss is well established as the major structural correlate of cognitive impairment in Alzheimer disease (AD). The ability to measure synaptic density in vivo could accelerate the development of disease-modifying treatments for AD. Synaptic vesicle glycoprotein 2A is an essential vesicle membrane protein expressed in virtually all synapses and could serve as a suitable target for synaptic density. Objective: To compare hippocampal synaptic vesicle glycoprotein 2A (SV2A) binding in participants with AD and cognitively normal participants using positron emission tomographic (PET) imaging. Design, Setting, and Participants: This cross-sectional study recruited 10 participants with AD and 11 participants who were cognitively normal between November 2015 and June 2017. We hypothesized a reduction in hippocampal SV2A binding in AD, based on the early degeneration of entorhinal cortical cell projections to the hippocampus (via the perforant path) and hippocampal SV2A reductions that had been observed in postmortem studies. Participants underwent high-resolution PET scanning with ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), a compound more commonly known as 11C-UCB-J, for SV2A. They also underwent high-resolution PET scanning with carbon 11-labeled Pittsburgh Compound B (11C-PiB) for β-amyloid, magnetic resonance imaging, and cognitive and neurologic evaluation. Main Outcomes and Measures: Outcomes were 11C-UCB-J-specific binding (binding potential [BPND]) via PET imaging in brain regions of interest in participants with AD and participants who were cognitively normal. Results: Ten participants with AD (5 male and 5 female; mean [SD] age, 72.7 [6.3] years; 10 [100%] β-amyloid positive) were compared with 11 participants who were cognitively normal (5 male and 6 female; mean [SD] age, 72.9 [8.7] years; 11 [100%] β-amyloid negative). Participants with AD spanned the disease stages from amnestic mild cognitive impairment (n = 5) to mild dementia (n = 5). Participants with AD had significant reduction in hippocampal SV2A specific binding (41%) compared with cognitively normal participants, as assessed by 11C-UCB-J-PET BPND (cognitively normal participants: mean [SD] BPND, 1.47 [0.37]; participants with AD: 0.87 [0.50]; P = .005). These reductions remained significant after correction for atrophy (ie, partial volume correction; participants who were cognitively normal: mean [SD], 2.71 [0.46]; participants with AD: 2.15 [0.55]; P = .02). Hippocampal SV2A-specific binding BPND was correlated with a composite episodic memory score in the overall sample (R = 0.56; P = .01). Conclusions and Relevance: To our knowledge, this is the first study to investigate synaptic density in vivo in AD using 11C-UCB-J-PET imaging. This approach may provide a direct measure of synaptic density, and it therefore holds promise as an in vivo biomarker for AD and as an outcome measure for trials of disease-modifying therapies, particularly those targeted at the preservation and restoration of synapses.
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In a study comparing 11 controls with 10 AD, 11C-UCBJ PET showed reduction in hippocampal binding in keeping with neuropathological findings in AD.
“One of the first studies in 11C -UCBJ PET comparing 11 controls with 10 AD showed reduction in hippocampal binding in keeping with neuropathological findings in AD [203].”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [203]
Quantification of radiotracer binding to SV2A does correlate with measures of synaptic vesicle number and expression of other pre-synaptic proteins classically used in postmortem and in vitro work.
“quantification of radiotracer binding to SV2A does correlate with measures of synaptic vesicle number [8,9,69,70] and expression of other pre-synaptic proteins classically used in postmortem and in vitro work (e.g., synaptophysin, synapsin).”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [70]
PET studies have found lower cerebral SV2A density in patients with several neuropsychiatric disorders linked to synaptic dysfunction, including depression, compared to healthy individuals.
“PET studies on several neuropsychiatric disorders linked to synaptic dysfunction, including depression, have found lower cerebral SV2A density in patients compared to healthy individuals [17–22].”
From Effects of escitalopram on synaptic density in the healthy human brain: a randomized controlled trial (2023) · cites this paper as [17]
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- Authors
- Chen, M.-K., Mecca, A. P., Naganawa, M., Finnema, S. J., Toyonaga, T., Lin, S.-F., Najafzadeh, S., Ropchan, J., Lu, Y., McDonald, J. W., Michalak, H. R., Nabulsi, N. B., Arnsten, A. F. T., Huang, Y., Carson, R. E., & van Dyck, C. H.
- Affiliations
- Yale University (US)
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Corresponding author
- Chen, Ming-Kai
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2018-10-01
- Volume
- 75
- Issue
- 10
- Pages
- 1215
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC6233853
- OpenAlex
- W2883737562
- Cited by
- 431
- References
- 47
- Citations by year
- 2026: 30 · 2025: 50 · 2024: 58 · 2023: 47 · 2022: 61 · 2021: 70 · 2020: 66 · 2019: 40 · 2018: 8
- FWCI
- 36.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG052560, K23AG057794, P50AG047270)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- Alzheimer's disease, synaptic density, SV2A, [11C]UCB-J, hippocampus, positron emission tomography, binding potential, amyloid-beta, Pittsburgh compound B, perforant path, entorhinal cortex, synaptic loss, cognitive impairment, amnestic mild cognitive impairment, mild dementia, disease-modifying therapy
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Amnesia, Cross-Sectional Studies, Female, Hippocampus, Humans, Male, Membrane Glycoproteins, Nerve Tissue Proteins, Pyridines, Pyrrolidinones, Synapses, Biomarkers, Positron-Emission Tomography, Cognitive Dysfunction, Memory, Episodic
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