Notice Number: NOT-AG-18-050
Release Date: November 28, 2018
NOT-AG-22-006 - Notice to Expire NOSIs to PAR-19-070, "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)"PAR-19-070
National Institute on Aging (NIA)
This Notice of Information specifies a high-priority topic of interest for PAR-19-070 "Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)".
?In vivo Synaptic Function in Alzheimer's Disease and Related Dementias
This high-priority topic of interest has two aims: 1) to study in vivo synaptic structure and function in Alzheimer's and related dementias, and 2) to advance the development of methods to study synapses in living humans.
Recent development of PET radioligands for a synaptic protein, SV2A, has established proof of concept for studying the synapse in living humans. This high-priority topic encourages the rapid testing and development of this potentially game-changing biomarker in AD and AD-related dementias (ADRD). This high-priority topic also seeks to advance the development of other methods to study synaptic structure and function in living humans.
The synapse is fundamental to brain function. Phenomena like long-term potentiation, neurotransmitter release, second messenger activation, and formation and pruning of dendrites during development all involve the synapse. Many tools have been developed to study synaptic morphology and function in living 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 humans. 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 PET radioligands based on levetiracetam (Keppra), an anticonvulsant that acts at synaptic vesicular protein 2A (SV2A). Since SV2A is found in presynaptic nerve terminals throughout the brain, it could serve as a marker of synaptic density or integrity. Loss of synapses should be reflected in decreased SV2A binding.
11C-UCB-J binds with high affinity to SV2A. Recent data, including preliminary studies in AD, using 11C-UCB-J PET have been tantalizing but require replication, validation, and exploration, particularly longitudinal studies in larger cohorts. As demonstrated in the 1990s and reconfirmed in the 2000s, the earliest change in AD (detectable post mortem) appears to be loss of presynaptic terminals. Important, unanswered question 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? What are the limitations of 11C-UCB-J PET: does it provide unique information, not available from existing methods, like FDG PET or volumetric MRI?
11C-UCB-J PET provides proof of concept for in vivo study of synapses in human. A second goal of this high-priority topic 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 MRI methods, neurophysiological (EEG, MEG, ERPs) measures, or some other new technique. Studies of neurotransmitter receptors (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.
Preclinical or animal studies could be appropriate for either of this topic's aims. This topic is appropriate for applications that already have preliminary data.
Applications proposing clinical trials would not be considered a high priority.
Submissions should indicate that they are in response to NOT-AG-18-050 in Field 4.b on the SF 424 form.
Please direct all inquiries to:
John Hsiao, M.D.
National Institute on Aging (NIA)