Diagnosing Dementia: Neuroimaging Technique Could Speed Detection

Yale School of Medicine (YSM) researchers have tested a new and potentially more sensitive neuroimaging tool for diagnosing behavioral variant frontotemporal dementia (bvFTD). They reported their findings on April 9 in Alzheimer's & Dementia.

BvFTD is the second most common form of dementia for individuals younger than 60 years of age. However, in nearly half of all cases, bvFTD is initially misdiagnosed, mistaken for conditions such as bipolar disorder or atypical depression. The neuroimaging technique fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) can help diagnose bvFTD. However, this method only indirectly measures the neurodegeneration underlying the condition.

A newer technique, developed at Yale, uses PET imaging to detect a protein known as synaptic vesicle glycoprotein 2A (SV2A), which is found throughout the brain near synapses, where brain cells meet and communicate. Loss of synapses can indicate neurodegeneration or dementia. By detecting SV2A, researchers can measure synaptic density in the brain regions most affected by bvFTD.

The approach represents a new method for diagnosis that could help detect bvFTD earlier and potentially improve patients’ prognoses.

“It would be incredibly valuable to have better ways to diagnose bvFTD,” says David Matuskey, MD, associate professor of radiology and biomedical imaging, of psychiatry, and of neurology at YSM and the study’s co-principal investigator. “Our study gives us new hope that this new method is clinically viable and something we could potentially start using fairly fast.”

As neuropsychiatrists, Matuskey and Arman Fesharaki-Zadeh, MD, PhD, say the most challenging patients they see are those with bvFTD, which is associated with significant personality changes including loss of empathy, impulse control, and social decorum.

“One of the characteristics that makes us human is empathy,” says Fesharaki-Zadeh, an assistant professor of psychiatry and of neurology at YSM and co-principal investigator of the study. “Seeing your loved one morphing into a different individual who’s disconnected is devastating.”

Unlike other dementias such as Alzheimer’s disease, in which researchers have a greater understanding of the underlying pathology, bvFTD is understudied in part due to the lack of a unified target for diagnosis and treatment, the researchers say.

“We have all these tools that are relatively nonspecific, but they can correlate to the disease process,” says Fesharaki-Zadeh. “That is why this study is exciting—that we can have this synaptic density window as a potentially viable diagnostic option for the future.”

In their study, the researchers explored the potential of SV2A PET imaging as a diagnostic tool for bvFTD.

“Synaptic density is especially important in the context of diseases like frontotemporal dementia because we see very early onset neurodegeneration—more than in any other type of dementia,” says Salih Cayir, MD, postdoctoral fellow in the Yale NeuroPET imaging program and the study’s co-first author.

The team recruited 10 patients with bvFTD and 10 people without the condition. Each cohort underwent SV2A PET and ¹⁸F-FDG PET imaging. SV2A PET, the researchers found, detected reduced synaptic density, including in the frontal and temporal cortices of the brain, the regions most affected by bvFTD.

The study also found a strong correlation between lower synaptic density and cognitive outcomes as measured by the Frontal Assessment Battery, a screening tool for frontotemporal dementia. Additionally, the researchers observed that SV2A PET showed a stronger correlation with cognitive outcomes than 18F-FDG PET.

“SV2A can potentially provide a much more focused look at the disease process,” says Fesharaki-Zadeh.

In 2023, the family of actor Bruce Willis announced his diagnosis with FTD. Since then, his wife, Emma Heming Willis, has published a book about her experience as her husband’s caregiver.

“This is someone who has access to every single medical facility imaginable, yet she still faces immense struggles,” says Fesharaki-Zadeh. “Imagine the typical FTD patient—the stigma they face, the lack of providers who have knowledge about this condition, and the limited infrastructure for treating them.”

He adds that earlier detection of the disease can improve patients’ prognoses. “A diagnosis can provide clarity, guide future treatment, and decrease caregiver burden.”

The researchers hope this new tool can help clinicians detect earlier stages of the disease that are commonly missed with current neuroimaging methods and reduce misdiagnoses. In future studies, they plan to test the approach in larger groups and see if it can help detect other forms of FTD.

“Every single one of the bvFTD patients I have seen in the clinic have left a mark on me because their presentation is so devastating and unique,” Fesharaki-Zadeh says. “Hopefully, this study is a step forward towards a new diagnostic tool that can help with earlier detection of the disease in a way other modalities are not able to do so.”