Imaging of Synaptic Density in Neurodegenerative Disorders
Open accessAbstract
PET technology has produced many radiopharmaceuticals that target specific brain proteins and other measures of brain function. Recently, a new approach has emerged to image synaptic density by targeting the synaptic vesicle protein 2A (SV2A), an integral glycoprotein in the membrane of synaptic vesicles and widely distributed throughout the brain. Multiple SV2A ligands have been developed and translated to human use. The most successful of these to date is 11C-UCB-J, because of its high uptake, moderate metabolism, and effective quantification with a 1-tissue-compartment model. Further, since SV2A is the target of the antiepileptic drug levetiracetam, human blocking studies have characterized specific binding and potential reference regions. Regional brain SV2A levels were shown to correlate with those of synaptophysin, another commonly used marker of synaptic density, providing the basis for SV2A PET imaging to have broad utility across neuropathologic diseases. In this review, we highlight the development of SV2A tracers and the evaluation of quantification methods, including compartment modeling and simple tissue ratios. Mouse and rat models of neurodegenerative diseases have been studied with small-animal PET, providing validation by comparison to direct tissue measures. Next, we review human PET imaging results in multiple neurodegenerative disorders. Studies on Parkinson disease and Alzheimer disease have progressed most rapidly at multiple centers, with generally consistent results of patterns of SV2A or synaptic loss. In Alzheimer disease, the synaptic loss patterns differ from those of amyloid, tau, and 18F-FDG, although intertracer and interregional correlations have been found. Smaller studies have been reported in other disorders, including Lewy body dementia, frontotemporal dementia, Huntington disease, progressive supranuclear palsy, and corticobasal degeneration. In conclusion, PET imaging of SV2A has rapidly developed, and qualified radioligands are available. PET studies on humans indicate that SV2A loss might be specific to disease-associated brain regions and consistent with synaptic density loss. The recent availability of new 18F tracers, 18F-SynVesT-1 and 18F-SynVesT-2, will substantially broaden the application of SV2A PET. Future studies are needed in larger patient cohorts to establish the clinical value of SV2A PET and its potential for diagnosis and progression monitoring of neurodegenerative diseases, as well as efficacy assessment of disease-modifying therapies.
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In Alzheimer's disease, widespread SV2A reductions, particularly in hippocampus and association cortex, correlate with cognitive impairment and track A/T/N pathology.
“In Alzheimer’s disease, widespread reductions, particularly in hippocampus and association cortex, correlate with cognitive impairment and track amyloid/tau/neurodegeneration (A/T/N) pathology; similar decreases emerge in Parkinsonian and other neurodegenerative conditions, underscoring presynaptic vulnerability across networks [206,211,213,214,215].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [206]
The AD section (page unavailable) reports widespread cortical and subcortical SV2A reductions, hippocampal associations with cognitive-test performance, and associations with amyloid, tau, and FDG measures. But “track A/T/N pathology” overstates the relationship: the Abstract says synaptic-loss patterns differ from amyloid, tau, and FDG patterns, and the AD section reports that the amyloid association depended on disease stage. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLongitudinal SV2A PET is poised to answer these gaps, but validation demands harmonized kinetic modeling, test-retest data across centers, and standardized reference strategies from mouse to human cohorts.
“Longitudinal SV2A PET is poised to answer these gaps, but validation demands harmonized kinetic modeling, test–retest data across centers, and standardized reference strategies from mouse to human cohorts [206,214,235,236].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [206]
The Abstract (page not provided) says future studies are needed to establish SV2A PET’s value for progression monitoring. The Quantification section (page not provided) discusses kinetic models, test–retest reproducibility, reference regions, and validation in each population. It does not call for harmonized modeling, test–retest data across centers, or standardized reference strategies spanning mouse and human cohorts. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPET targeting SV2A has matured into a practical readout of synaptic density in vivo, with 11C and 18F ligands enabling cross-species translation.
“PET targeting SV2A has matured into a practical readout of synaptic density in vivo, with carbon-11 (11C) and fluorine-18 (18F) ligands enabling cross-species translation [206,207,208].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [206]
Similar SV2A decreases emerge in Parkinsonian and other neurodegenerative conditions, underscoring presynaptic vulnerability across networks.
“In Alzheimer’s disease, widespread reductions, particularly in hippocampus and association cortex, correlate with cognitive impairment and track amyloid/tau/neurodegeneration (A/T/N) pathology; similar decreases emerge in Parkinsonian and other neurodegenerative conditions, underscoring presynaptic vulnerability across networks [206,211,213,214,215].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [206]
Mild depressive symptoms in later life might be a prodrome of neurodegenerative diseases, where synaptic density decrease is increasingly described.
“Mild depressive symptoms in later life might be a prodrome of neurodegenerative diseases [52], where synaptic density decrease is increasingly described [53].”
From Preliminary evidence for preserved synaptic density in late-life depression (2024) · cites this paper as [53]
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Research works printed but not linked: 1
- Cai H, Mangner TJ, Muzik O, Wang M-W, Chugani DC, Chugani HT. Radiosyn- thesis of 11 C-levetiracetam: a potential marker for PET imaging of SV2A expres- sion. ACS Med Chem Lett. 2014;5:1152-1155.
Cited by
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Synaptic changes in psychiatric and neurological disorders: State-of-the art of in vivo imaging
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Visser, M., O’Brien, J. T., & Mak, E. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102197 · Cited by 28 · see citing works
Preliminary evidence for preserved synaptic density in late-life depression
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Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery
Tanaka, M. (2026) · Biomedicines · doi:10.3390/biomedicines14061265
- Authors
- Carson, R. E., Naganawa, M., Toyonaga, T., Koohsari, S., Yang, Y., Chen, M.-K., Matuskey, D., & Finnema, S. J.
- Affiliations
- Yale University (US)
- AbbVie (United States) (US)
- ORCID
- Venue
- Journal of Nuclear Medicine
- Publisher
- Society of Nuclear Medicine
- Published
- 2022-06
- Volume
- 63
- Issue
- Supplement 1
- Pages
- 60S-67S
- ISSN
- 0161-5505 (ISSN-L)
- 2159-662X
- PMC
- PMC12530506
- OpenAlex
- W4281683565
- Cited by
- 104
- References
- 93
- Citations by year
- 2026: 24 · 2025: 20 · 2024: 42 · 2023: 16 · 2022: 2
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Nuclear Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG066508)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- synaptic density, SV2A, [11C]UCB-J, levetiracetam, synaptophysin, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, [18F]SynVesT-1, compartmental model, synaptic loss
- MeSH terms
- Alzheimer Disease, Animals, Humans, Membrane Glycoproteins, Nerve Tissue Proteins, Radiopharmaceuticals, Positron-Emission Tomography, Mice, Rats
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