A study published in the journal Alzheimer’s & Dementia evaluates the potential utility of a novel PET tracer for progressive supranuclear palsy (PSP) while also exploring how the disorder damages synapses.  

The Mechanisms of Synaptic Loss in PSP are Unknown 

Synapses are the junctions that connect neurons, transmitting electrical or chemical signals to assist with brain functions. Synaptic loss is a prominent feature of all neurodegenerative disorders, often occurring early in disease progression.  

As the authors note, considerable work remains to further our understanding of synaptic loss in PSP, a condition commonly associated with tau protein dysfunction. Synaptic loss in PSP has been reported to have extended beyond areas of the brain generally associated with tau pathology, though how this occurs is unknown. Additionally, there are no verified biomarkers for PSP that can be used to track synaptic damage. 

Because synaptic damage commonly occurs early in PSP, a biomarker that reflects damage in synapses could aid in earlier diagnosis of the disorder. Other biomarkers that are more specific to PSP would still be necessary to make a complete diagnosis, as synaptic loss is a common feature of neurodegeneration.  

The study authors cited recent studies that evaluated the novel synaptic PET tracer UCB-J in people with PSP. The tracer binds to a common synaptic protein called SV2A; the signal from the radioactive tracer can then be measured using a PET scanner. While the tracer shows potential as a tool for understanding PSP’s synaptic pathology, the studies have only provided limited information about the mechanics behind UCB-J’s interactions with cells.  

To better understand the synaptic characteristics of PSP and the binding mechanisms of UCB-J, the authors conducted a series of validation studies using brain tissue samples contributed by people with PSP. Brain tissue from individuals with PSP and control samples from those without PSP were provided by the Netherlands Brain Bank. The tissues included samples from different regions of donors’ brains so researchers could gain a clearer picture of the synaptic damage caused by PSP. 

UCB-J Tracer Reveals Patterns of Synaptic Loss in PSP 

The tissue samples were analyzed multiple times in different ways. In the first round of experiments, samples were cryogenically frozen for radiographic analysis, then processed into a uniform mixture called “brain homogenate,” which is easier to analyze in a laboratory setting. The study used two forms of UCB-J: a mixture of UCB-J without a radioactive tracer for binding reference, and 33H-UCB-J, which was used to take lab measurements.  

Analyzing the results of the frozen samples, the authors saw a reduction in 3H-UCB-J binding in tissues from people with PSP in two brain regions. They noted a 40% reduction in the caudate nucleus, which assists in numerous functions from motor control to emotional regulation, and a 20% reduction in the globus pallidus, which helps with coordination and regulating movement. The loss of binding indicates a decline in synaptic density, as SVA2 is produced (or “expressed”) less by synapses as they degrade.  

Analysis of the brain homogenate confirmed the decline in synaptic density in the globus pallidus of people with PSP compared to controls. An in-depth study of synaptic proteins further confirmed that SVA2 and other key proteins were expressed less than in control samples; synaptophysin (SYP) and synaptotagmin (SYT), which play different roles in facilitating transmissions between neurons, were down in the globus pallidus by 28.3% and 59.3%, respectively.  

The authors discovered a potential link between synaptic loss and the presence of tau protein aggregates, which contribute to the progression of tauopathies like PSP. In samples from people with PSP, the researchers discovered tau aggregates and reduced expression of synaptic proteins.  

Overall, the researchers found that UCB-J and 3H-UCB-J performed well, aiding in discovering that synaptic loss from PSP was most prominent in the globus pallidus. The study authors note that the level of reduction in specific synaptic proteins could indicate how damaged a synapse may be. However, no single marker could represent the complete state of synaptic loss. In addition to having different expression levels across the brain, the authors note that synaptic proteins could also be unequally affected by PSP.  

Brain donation through an institution like a brain bank is just one way you can participate in research. Learn about additional opportunities to join in FTD research on our Ways to Participate page.