January 7, 2022
PAR-22-093, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)
PAR-22-094, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Not Allowed)
National Institute on Aging (NIA)
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:
As demonstrated in the 1990s and reconfirmed in the 2000s, the earliest change in AD detectable at autopsy is the loss of presynaptic terminals. Important, unanswered questions include: When does synapse loss occur in relation to the appearance of ß-amyloid plaques, tau tangles, and other biomarkers? What are the regional relationships? What happens in normal aging or in other neurodegenerative diseases?
11C-UCB-J PET imaging of synapses, in vivo, may help answer these questions. Studies of SV2A PET in AD have been encouraging but not definitive. Longitudinal data are lacking, and the limitations of SV2A PET remain undefined. This NOSI encourages the rapid testing and development of SV2A PET imaging in AD/ADRD.
A second goal of this NOSI is to encourage the development of other methods to study in vivo synaptic structure or function in humans, using, for example, novel neuroimaging, PET, and magnetic resonance imaging (MRI) methods, neurophysiological (e.g., electroencephalography (EEG), magnetoencephalography) (MEG), event-related potentials (ERPs)) measures, or some other novel approach.
Preclinical or animal studies could be appropriate for either of this topic's aims. This topic is appropriate for R21 applications that already have preliminary data.
Studies of neurotransmitter receptor density (e.g., raclopride D2 PET, or DASB SERT PET) would not be considered high priority, unless the research aim is to understand synaptic structure or function. The development of novel fluid biomarkers measuring overall synaptic damage (e.g., CSF NfL) would also not be considered high priority. In addition, applications proposing clinical trials would not be considered a high priority.
Application and Submission Information
This notice applies to due dates on or after March 11, 2022 and subsequent receipt dates through November 13, 2024.
Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
John Hsiao, M.D.
National Institute on Aging (NIA)