Tech & Innovation in Healthcare

Is synaptic density an indicator of early-stage AD? Find out.

With the number of patients affected by dementia and Alzheimer’s disease (AD) (thought to be the most common form of dementia) estimated to nearly double by 2050, researchers are working tirelessly to detect the disease at earlier stages and learn how to treat it effectively.

Learn how researchers at Yale University and Stony Brook University are using imaging tests to assess how AD affects the brains of living subjects.

Project the Effects of Alzheimer’s Disease on the Aging Population

According to a 2022 Alzheimer’s Association report, approximately 6.5 million Americans 65 years and older are living with AD, and that number is projected to reach 12.7 million people by 2050. AD slowly deteriorates the memory and thinking skills and is the most common cause of dementia among older adults.

In 2020, the National Institute of Health (NIH) announced the annual investment of funding for Alzheimer’s disease and dementia research was raised to $3.1 billion. While scientists have not discovered a common cause of AD for most people, researchers continue to try to understand the debilitating disease.

Use PET Scans to Assess Synaptic Density

Yale University researchers, led by Adam Mecca, MD, PhD, assistant professor of psychiatry, and Christopher van Dyck, MD, professor of psychiatry, neurology, and neuroscience, both from the Alzheimer’s Disease Research Unit at Yale University School of Medicine in New Haven, Connecticut, published a study in February 2022. During the study, researchers evaluated synaptic density in living brains to assess if a decrease in synaptic density causes AD to progress. Using a compound tracer that binds to the glycoprotein 2A (SV2A) synaptic vesicle, researchers could use positron emission tomography (PET) imaging to measure the synaptic density. Almost every synapse expresses the SV2A protein, which is located in synaptic vesicles at presynaptic terminals in the brain.

During the study, the researchers aimed to “examine the relationship between synaptic density and cognitive performance in early AD” using the PET imaging and “an extensive neuropsychological test battery,” Mecca and van Dyck wrote. The researchers hypothesized that synaptic density in brain areas typically affected by AD is associated with global neuropsychological function and in individual cognitive domains. Multiple studies have found that loss of synaptic function is a major factor in the cognitive impairment in AD.

Yale researchers studied 45 participants with early AD, ranging from 50 to 85 years old. During the study, researchers also examined the participants’ global cognition and performance on “five individual cognitive domains,” which included:

• Verbal memory
• Language
• Executive function
• Processing speed
• Visuospatial ability (orienting objects in space)

The results showed a correlation between the global cognition and the subjects’ performance on the cognitive domains listed above. Comparing the synaptic density as measured by the PET scans to the cognitive performance, researchers found that subjects with reduced synaptic density experienced lower test scores.

“These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the mild and prodromal stages of AD,” the authors wrote.

Even when comparing the synaptic density to gray matter volume, researchers found that the measure of synaptic loss measured by the PET scans provided a more accurate assessment. As AD progresses, patients can experience an overall loss of brain volume. Gray matter is the outer brain layer that normally houses a high density of neurons. During the study, the reduced gray matter volume accurately predicted lower test scores in only two of the five cognition performance tests.

While this study showed that PET scans can be useful in early detection of AD, longer studies are needed over time as the disease develops to assess if synaptic density can serve as a reliable predictor of cognitive health decline.

Image the Cholinergic System With Simultaneous PET/MRI

Researchers at Stony Brook University’s Renaissance School of Medicine, led by biomedical engineer, Christine DeLorenzo, PhD, are currently studying how damage occurs to the brain’s cholinergic neurons, which results in AD.

The cholinergic system of the brain handles the synthesis and secretion of acetylcholine. When the system experiences cholinergic neuron progressive degeneration, the acetylcholine depletes, which results in cognitive decline. This is a significant contributor to AD in patients.

Using PET scans, Stony Brook Medicine researchers can image the cholinergic system both mice and human beings’ living brains. With these scans, the researchers are able to compare the studies done with mice to the same gene expression in AD to further evaluate the human cholinergic system.

Stony Brook researchers are also using simultaneous PET and magnetic resonance imaging (MRI) scans to examine the cholinergic system and its effects on the brain structure and function. The concurrent scanning lets researchers to view human subjects’ brains in health and disease.

The Stony Brook University study is ongoing, but in September 2019, the NIH awarded the Stony Brook team a $4.3 million grant over five years to fund their study.