Two decades ago, neuroscientists began to look more closely at frontotemporal dementia (FTD), a unique set of clinical symptoms caused by the degeneration of the frontal and temporal lobes of the brain—areas that are generally associated with personality, behavior, and language. Bruce Miller, M.D., a neurologist at the University of California, San Francisco, and a Fellow of the American Academy of Neurology (AAN), began describing people who seemed to lose the ability to navigate social interactions.
In FTD, portions of these lobes atrophy or shrink. Signs and symptoms vary depending upon the portion of the brain affected. People with behavioral variant FTD (bvFTD) undergo dramatic changes in their personality and become socially inappropriate, impulsive, or emotionally indifferent. People with other types of FTD may lose the ability to use and understand language.
Behavioral variant FTD seems to alter the core of the feeling self. For example, people who have spent a lifetime in meaningful relationships may lose their ability to empathize with the emotions of their loved ones. As a result of bvFTD, many patients also lose the capacity to read facial cues, which is an important part of relating to other people.
Often misdiagnosed as Alzheimer's disease (AD), FTD tends to occur earlier than AD. FTD symptoms typically begin in the 50s to early 60s (or earlier), whereas AD usually strikes after the age of 65. People with FTD don't often experience memory loss, either, which is the key feature of AD.
Although no treatments designed specifically for FTD are available, neurologists and neuroscientists are working to understand precisely what occurs in the brain of someone with the disease in order to develop experimental drugs.
FROM BRAINSTORM TO THE BRAIN STUDY
Elizabeth Finger, M.D., an assistant professor in the department of clinical neurological sciences at the University of Western Ontario in Canada, has been particularly interested in the inability of people with bvFTD to understand and respond properly to social cues.
Dr. Finger began thinking about the power of oxytocin: In study after study, this so-called “love hormone” had been shown to play a pivotal role in the human capacity to recognize and attend to the feelings of other people. The first evidence of this role was captured in the delivery room two decades ago when Thomas Insel, M.D., now director of the National Institute of Mental Health, reported higher than normal levels of oxytocin were measured in new mothers.
Over time, scientists linked oxytocin to other emotions, including understanding the expression of fear and anger in another person. These discoveries quickly moved into studies of conditions that cause problems with social functioning, such as autism. Oxytocin has been shown in studies to increase the ability of people with autism to read facial expressions and understand emotional cues.
While oxytocin is not involved in the disease process of frontotemporal lobe degeneration, Dr. Finger still thought the hormone might help people in the early stages of bvFTD improve their ability to recognize different emotions. The hormone is produced in the hypothalamus and sent out through the amygdala, which is another part of the brain damaged in FTD. Best known for its role in recognizing and dealing with fear and anger, the amygdala is an important circuit for many emotions.
In a small study published online in Brain in August 2011, Dr. Finger reported that a single dose of oxytocin tested in patients with FTD improved social cognition and behavior as measured by neuropsychological tests and caregiver rating scales.
The Brain study investigators enrolled 20 patients in mild to moderate stages of FTD. The initial screening visit included extensive neuropsychological tests of memory, language, and executive function (the ability to plan, organize, and carry out tasks). This provided a baseline measurement against which the effects of oxytocin could be judged.
Patients were randomly selected to receive either oxytocin or saline (the inactive “placebo”) on their first testing day. In a clinical trial, people receiving the drug are called the “treatment group”; those receiving the placebo are called the “control group.”
None of the patients knew which substance they were receiving (they were “blinded” as to the substance). None of the researchers or caregivers did either. This is often done in clinical trials so that expectations don't unduly influence the outcome (the placebo effect). Two weeks later, all of the patients were given a second dose, which was the opposite of what they received on the first testing day.
On both testing days, patients were asked to complete a number of tasks to assess their ability to process emotional stimuli after administration of either substance. They were asked to look at faces and listen to voices and then rate the type and intensity of the emotions expressed. Caregivers were also asked to rate the behavior of their loved ones on the testing days. The scientists then compared the responses of the two sessions to see if oxytocin made a difference.
When patients were taking oxytocin, they were less likely to misinterpret facial expressions as angry compared with their placebo dose.
The hormone was associated with a statistically significant improvement: an average 13 percent improvement from baseline testing on the neuropsychological tests compared to 3 percent when the patients were given saline on the first treatment day, Dr. Finger says. (As used in statistics, the word “significant” does not mean “meaningful.” A study result is considered statistically significant if it was unlikely to have occurred by chance.)
Investigators also compared caregiver ratings of their loved one's behavior after delivery of oxytocin or saline. They found a 9 percent improvement in behavior as rated by the caregivers following oxytocin compared to a one percent improvement following the saline on day one, although this was not statistically significant.
However, a single dose of oxytocin did not improve patients' ability to interpret the emotional tone of voices correctly. Patients also performed worse on questions designed to test “theory of mind,” which is a person's ability to attribute mental states—such as desires, beliefs, and intentions—to oneself and others (and to differentiate between the mental states of oneself and others).
Frontotemporal Dementia: The Basics
According to the Association for Frontotemporal Degeneration, FTD affects approximately 50,000-60,000 Americans. However, no one really knows how many people have FTD; many are misdiagnosed as having either AD or psychiatric problems such as bipolar depression or schizophrenia.
When Does FTD Occur? FTD symptoms typically begin in the 50s or early 60s (or earlier), whereas AD usually strikes after the age of 65.
What Are the Symptoms of FTD? People with behavioral variant FTD (bvFTD), which is the most common type, often become withdrawn, emotionally blunted, and inappropriate in social situations.
What Causes FTD? FTD is caused by frontotemporal lobe degeneration, a disease that attacks important brain regions for social functioning. The disease involves abnormalities in several proteins in the brain: tau; TDP-43, which has also been linked to amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease); and progranulin, a growth factor involved in inflammation and wound healing.
What Treatments Are Available for FTD? Some studies have shown that the group of antidepressants known as selective serotonin-reuptake inhibitors (SSRIs) may be helpful in calming the aggression, agitation, and impulsiveness of bvFTD.
What Research Is Being Done Into FTD? Research into the genetics of frontotemporal lobe degeneration has led to a greater understanding of how the brain is damaged by specific genetic mutations. Several experimental compounds are in development based on this research. Some target the protein tau, which accumulates in the brains of many patients with the disease. Others target the growth hormone progranulin, which plays an important role in inflammation. Progranulin seems to accumulate in the brain of FTD patients due to a mutation in the gene that makes the hormone.
WHAT DOES IT MEAN FOR PATIENTS AND CAREGIVERS?
“It's too early to say whether oxytocin will be a treatment for FTD symptoms,” Dr. Finger says. “We may continue to find that it enhances positive cues in the environment and reduces negative ones. But this was a small group of patients,” she says.
Dr. Finger is now expanding her study to test the effects of the hormone delivered two times a day for a week in patients with FTD. “We need to assess the safety of repeated doses of oxytocin and determine whether any benefits are observed when more patients are enrolled,” she says.
“It is too early to know what to make of the oxytocin results,” says neurologist Adam Boxer, M.D., Ph.D., member of the AAN and director of the Alzheimer's Disease and Frontotemporal Dementia Clinical Trials Program at the Memory and Aging Center of the University of California, San Francisco. “It may enhance social bonding, which is seriously disrupted by FTD. If oxytocin can restore some social interactions with family members, it would be a huge step forward. But a lot more work needs to be done,” Dr. Boxer says.
“Remember, this is a single dose study, and there is no way to know how oxytocin would work over a longer time course. Would there be a lasting benefit?” asks Bradford Dickerson, M.D., associate professor of neurology at Harvard Medical School in Boston, MA, and director of the FTD Unit at Massachusetts General Hospital, also in Boston. “We just don't know. Further experiments are necessary to answer that question,” he says.
C. Sue Carter, Ph.D., professor of psychiatry and co-director of the Brain-Body Center at the University of Illinois in Chicago, has been studying oxytocin and other hormones in people. “There are good reasons that oxytocin would have these effects in patients with FTD. Oxytocin is a general manager of all sorts of social challenges,” she says.
However, most of the findings on oxytocin in humans have been based on single-dose studies, Dr. Carter explains, such as Dr. Finger's study in Brain.
More recently, Dr. Carter says, scientists are gaining new insight by giving more than a single dose of oxytocin to patients—including the fact that not everyone responds positively to the love hormone. “We are starting to see more variation in people depending on emotional and neurologic states,” Dr. Carter says.
“We have to be careful not to portray oxytocin as a cure-all,” she adds. “The concern when thinking about long-term use of oxytocin is figuring out how to use it. It will really be important to do these studies carefully. We need to know who may be vulnerable to negative experiences with oxytocin. Furthermore, the consequences of long-term exposure must be studied, since it is possible that giving oxytocin treatments will interfere with naturally produced oxytocin in the body.”