Easing social symptoms of a cruel disease

London researchers explore first-of-its-kind treatment for frontotemporal dementia

Seven years ago, Ray Jacobs was diagnosed with frontotemporal dementia (FTD) when he was just 63 years old. One of the less common forms of dementia, FTD causes the frontal and temporal lobes of the brain to shrink and lose function.

Looking back, his wife Linda realizes there were personality changes long before they had a diagnosis – as far back as 14 years. “The three years before the diagnosis were the hardest because I knew something was changing, but it seemed more psychological than dementia-related.”

There are many subtypes of the illness with behavioural variant FTD being the most common. Symptoms include disinhibition, apathy, loss of sympathy and empathy, compulsive or ritualistic acts such as examining objects by the mouth, and dietary changes. Each person’s experience differs depending on which areas of their brain are affected.

“The MRI scans in patients with FTD are striking,” says Dr. Elizabeth Finger, Scientist at Lawson and Neurologist at St. Joseph’s Health Care London specializing in FTD. “Specific parts of the frontal or temporal lobes stop functioning and can shrink dramatically. Right beside those affected brain regions, we have other parts that are functioning normally.”

Many people with FTD also have thinning of the cingulate cortex, a part of the brain that’s important in initiating behaviours. When the cingulate isn’t functioning, the person becomes very apathetic. “Even though the individual could have a conversation, wash the dishes or read a book, they don’t,” adds Dr. Finger, also an Associate Professor at Western University.

People with this type of dementia are usually unaware of the changes or chalk them up to memory trouble. “In the clinic we have people who’ve had a complete change in personality and yet they can’t see it. The affected frontal and temporal regions are critical for regulating behaviour and emotion,” explains Dr. Finger.

As a result, some become resistant to care and support. The disease is not well recognized and often misdiagnosed. It can take an average of five years before a clear diagnosis is made. Ray didn’t have any awareness of the changes, and didn’t understand the concern. “He just didn’t get it,” remembers Linda.

FTD can also hinder the ability to consider other people’s wellbeing, needs and emotions. Relationships can be severely impacted and loved ones alienated.

Over time, Linda and Ray started to have some confrontational discussions. Ray, who loved working, lost his job. He soon experienced depression and started to drink more. Convinced something wasn’t right, Linda encouraged him to see a doctor.

“He’s had language trouble from the start. He would forget the words for things and fit in other words instead,” says Linda. “The doctor showed him a picture of an elephant and he didn’t have a word for it.”

When they received the diagnosis, the loss of brain function was visible in the MRI.

Linda remembers how the doctor explained to Ray that he had a disease in his brain, and that he’ll have trouble making decisions and it will affect many things. “He never quite understood.”

Ray was happy but had difficulty relating to people. “We would be out and he would say something completely inappropriate, like his social filter was gone. People showed a lot of grace when they understood why, but there was embarrassment and shame.”

There are no treatments for dementia symptoms related to empathy and apathy. This has been the focus of Dr. Finger and her team’s research.

In the early 1990s, researchers identified differences in social behaviour in mammals related to levels of the hormone oxytocin. Oxytocin is thought to have an important role in social behaviour, acting as a neurotransmitter in our brains.

There was an explosion of studies showing that acute doses of oxytocin increased behaviours such as social recognition, pair bonding, nest building and grooming while decreasing anxiety. For people with autism, oxytocin improved reaction to social cues, processing of facial expressions and cooperative decision-making.

Dr. Finger’s team conducted the first oxytocin clinical trial for treating symptoms of FTD, with patients at St. Joseph’s. It was a crossover study where each participant was given the drug and
a placebo.

Oxytocin was administered as an intra-nasal spray. After getting the dose, participants looked at facial expressions and were asked to describe the emotions they saw. Caregivers rated their loved one’s behaviour that evening.

The results showed that oxytocin lessened recognition and processing of fear and anger expressions. This could be linked to reduced threat detection that allows for more positive social interactions. Caregivers also reported more social behaviour afterwards.

“We moved on to a second study focusing on safe and effective dosing,” says Dr. Finger. “Again, we saw improvement in behaviours and the changes were directly related to apathy and indifference. About half of the patients who had oxytocin saw improvements in these areas, compared to no changes at all after placebo.”

Encouraged by these initial findings, the team sought more objective results. At Robarts Research Institute, they measured brain activity, using fMRI, in participants who were given a single dose of oxytocin and then asked to watch and imitate expressions. “We could clearly see in the scans that oxytocin increased brain activation in the frontal and temporal regions.”

Dr. Finger’s team is now leading the FOXY Trial, a Phase II multi-centre clinical trial of oxytocin for empathy deficits and apathy in FTD, with participating sites across North America. The study will take several years to complete.

FOXY is a crossover study designed to also look at dosing schedules. With chronic dosing over time, oxytocin can lose its effectiveness in some participants.

“We are testing a variety of ways to measure apathy and empathy, and we have several secondary measures to put those results into context to decide whether to proceed to a Phase III trial,” explains Dr. Finger.

One of those important measures is caregiver experience and burden. Maybe the patient is improving, but does that translate to better outcomes from the caregiver’s perspective?

“It’s a rotten and cruel disease. It affects so many parts of someone’s life and their loved ones,” adds Dr. Finger. “We finally feel we can improve quality of life and are gathering proof that it’s not hopeless.”

Ray has been in long-term care for the past year. He was no longer safe at home due to wandering and obsessive eating of inedible objects.

“Ray’s communication and recognition of family is rarely evident. Most of our seven grandchildren have few memories of Ray without dementia, but they enjoy visiting him with their parents,” shares Linda.

“Our retirement has not been what we might have hoped for, but I am grateful for the support of family, friends and community resources throughout our journey. You learn quickly with FTD that you must develop patience, a thick skin and a good sense of humour if you’re going to survive. And most importantly, you must ask for help. I’m still learning.”

Ray and Linda were involved in a number of clinical trials including those testing the oxytocin spray. These are small but important pieces of the larger puzzle. “It made me feel like at least what we’re going through may have some value down the road. This is painful and not what either of us would have chosen. But, if there’s a glimmer of hope that our contributions will make a difference, it helps me accept this difficult journey.”