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Notice of Special Interest (NOSI): In vivo Synaptic Function in Alzheimer's Disease and Related Dementias

National Institutes of Health

The synapse is fundamental to brain function. Phenomena such as long-term potentiation, neurotransmitter release, second messenger activation, and creation/pruning of dendrites during development involve the synapse, and many tools have been developed to study synaptic morphology and function in animals. Using intracranial confocal, 2-photon, and other in vivo microscopy methods, synaptic structure and function have been studied in animal models of neurodegeneration. However, nothing comparable has been possible in living humans, as our understanding of synapses in the human brain has been limited to post-mortem examinations. We have not been able to study synaptic structure or function in living humans.

Scientists have developed positron emission tomography (PET) radioligands based on levetiracetam (Keppra), an anticonvulsant that acts at synaptic vesicular protein 2A (SV2A). The PET radioligand, 11C-UCB-J, binds with high affinity to SV2A and provides proof of concept for studying the synapse in living humans. Since SV2A is found in presynaptic nerve terminals throughout the brain, it could serve as a marker of synaptic density or integrity. Similarly, the loss of synapses should be reflected in decreased SV2A binding.

This Notice of Special Interest (NOSI) has two aims:

To study in vivo synaptic structure and function in Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD), and
To advance the development of methods to study synapses, in vivo , in humans.

This notice applies to due dates on or after March 11, 2022 and subsequent receipt dates through November 13, 2024.

Application Due Date(s): March 11, 2022; July 8, 2022; Nov 14, 2022; March 10, 2023; July 10, 2023; Nov 13, 2023; March 11, 2024; July 9, 2024; Nov 12, 2024

NOT-AG-21-038