Human brain MRI

Early in Alzheimer’s, connections between neurons begin to wither and die. One of the defining features of AD, this synapse loss underlies cognitive impairment, but has proven hard to track in the living brain. A paper in the July 20 Science Translational Medicine may change that. Scientists led by Richard Carson and Sjoerd Finnema at Yale University in New Haven, Connecticut, report on a positron emission tomography (PET) tracer that binds to a protein on presynaptic vesicles, revealing the density of synapses throughout the brain. In healthy people, the compound entered the brain quickly and bound predominantly gray matter. In epilepsy patients, it picked up areas of synaptic loss near the focal point of seizures.

“This paper shows what appears to be the first radioligand to bind to sites at synapses in the brain, ” wrote Richard Mohs, Global Alzheimer’s Platform Foundation, to Alzforum. If confirmed, this could provide a way to measure synaptic density in living people and track changes in density regionally and with disease, he added. “These scans would complement other newly developed radioligands that allow imaging of amyloid plaques, neurofibrillary tangles, and other types of brain pathology.”

Synaptic signal. [11C]UCB-J binds synapses and lights up in a PET scan of a healthy subject. [Science Translational Medicine/AAAS.]

Until now, researchers could only measure synaptic density in postmortem tissue by using antibodies to detect proteins such as synaptophysin (Buckley and Kelly, 1985). A molecule that binds synaptophysin might prove useful as a PET ligand but scientists have yet to find one. However, levetiracetam—an anti-epileptic drug—targets a similarly widespread protein called synaptic vesicle glycoprotein 2A (SV2A). Previous studies have reported that every synaptic vesicle in the brain carries two to five copies of this protein, said Finnema. UCB, the Brussels-based company that developed levetiracetam and provided some of the funding for this study, derived several PET tracer candidates based on this drug. A couple have been tested in animals and humans, but no reports on human brain imaging had been published (Estrada et al., 2016; Bretin et al., 2015). Carson, who directs the Yale PET Center, which specializes in developing and using new PET ligands, chose one of the derivatives, [11C]UCB-J, to test in people.