Yale Daily News

Yale researchers at the School of Medicine developed a new imaging technique that measures synaptic activity in patients with Alzheimer’s disease to hopefully link the loss of activity with cognitive decline.  

In a paper published in late February, Christopher van Dyck, a professor of psychiatry and neuroscience at the medical school, and Adam Mecca, the lead author of the paper and an assistant professor of psychiatry at the medical school, detail their use of SV2A in imaging synapses. According to van Dyck, synaptic vesicle glycoprotein 2A, or SV2A, is a protein located in the presynaptic vesicle. These are located at the ends of neurons and are involved in communication between them, Mecca explained. The new imaging technique uses SV2A to track the quantity and frequency of synapses within patients’ brains. 

“The general idea is that synaptic density has long been thought to be the prime correlate of cognitive impairment in Alzheimer’s disease, better than amyloid plaques,” van Dyck told the News. “It stands to reason that the connections between brain cells might be a good correlate for cognitive function.”

Previously, scientists could only study this correlation by documenting cognitive performance in patients with Alzheimer’s disease, van Dyck explained. After a patient’s death, an analysis of their brain would reveal their synaptic density. Scientists could then correlate the level of synaptic density with the last documented level of cognitive function for that patient.

However, the researchers believe that the degree of deficit in cognition is related to the stage of Alzheimer’s disease. Mecca said that they would expect to see changes in nerve cells as cognition levels declined. Previously, it was not possible to track this evolution since analysis could not be done until after the patient had died. 

To confront this problem, Mecca and van Dyck developed an imaging technique using PET that tracks the SV2A in the brains of patients in order to track synaptic activity. 

“The way PET works is that the scanner is a passive detector of radioactivity,” van Dyck said. “A radiopharmaceutical is injected intravenously, circulates in the bloodstream, is taken up in the tissue and binds to a target of interest. Depending on the type of radiopharmaceutical, it can be used to label and image different things. In this case, it binds to the SV2A protein. Radioactivity is emitted from the patient’s brain, and the 3D images are reconstructed.”

Since SV2A is located in the presynaptic vesicles that are involved with synaptic activity, tracking SV2A movement through the neurons allows doctors to image the synaptic activity of their patients.

Previously, doctors were limited in their ability to correlate clinical symptoms with physiological markers, according to Mecca. This new imaging technique seeks to provide a solution to this problem by allowing doctors to continuously monitor their patients’ cognitive abilities as well as their synaptic density. 

“Ideally, what we would do is follow the same person over time and track the quantity of protein in their brain,” Mecca said. “What we have evidence for right now is that people with Alzheimer’s disease have less of this SV2A, a surrogate marker for synapses. Ideally, we want to see how that quantity changes over time in a longitudinal study. Right now, we only compare across people who have the disease.” 

Mecca and van Dyck both mentioned the importance of future applications for this imaging technique. This type of imaging can be used when testing the efficacy of Alzheimer’s therapeutics in clinical trials. The effects of therapeutics that claim to increase synaptic density can be tracked through this imaging process. 

Most important, according to both Mecca and van Dyck, is using the imaging technique to track the synaptic activity of patients who may not have developed symptoms for Alzheimer’s disease. Their hope is that identifying patients at risk of developing Alzheimer’s disease, imaging their brains and starting to measure synaptic loss can allow for earlier — and therefore more effective — intervention. 

An important future direction will be to image participants pre-symptomatically to see if they have synaptic loss in relation to Alzheimer’s pathogenesis before symptoms begin — and then to follow their progress by measuring synaptic density every two to three years, van Dyck explained. 

“This paper is an exciting advancement for the role of synaptic [vesicle] glycoprotein SA (SV2A) PET imaging in the study of Alzheimer’s disease (AD),” Emily Sharp, an assistant professor of clinical neurology at the medical school and the neuropsychologist on the study, wrote to the News. “We found a clear relationship between in-vivo measures of synaptic density and cognitive performance in Alzheimer’s disease. High stakes clinical trials rely on neuropsychological measures to assess cognition longitudinally as a marker of treatment efficacy […] These novel findings lend further support for the use of SV2A PET imaging in future clinical trials of Alzheimer’s disease and potentially other neurodegenerative and neuropsychiatric syndromes.”

Mecca concluded that the “gold standard” is to follow the same patients over time and track their progression in order to establish a correlation between synaptic activity loss and onset of Alzheimer’s disease. 

Alzheimer’s disease most commonly affects people over the age of 65.