Understanding frontotemporal dementia, the leading cause of dementia in people under 60

Bruce Willis’ family recently announced that the 67-year-old actor has been diagnosed with a progressive neurodegenerative disorder called frontotemporal dementia (FTD). The grim news helped explain how his condition has changed since he retired a year ago because of aphasia – a disorder involving speech and listening comprehension problems that can occur when disease or injury damages certain areas of the brain.

“Unfortunately, communication challenges are only one symptom of the illness Bruce is dealing with,” his family said in a public statement released in February. “Although this is painful, it is a relief to finally have a clear diagnosis.”

Last week, Willis’ wife, Emma Heming Willis, described how the family is learning to navigate dementia care. Because there is no cure for FTD, a clear diagnosis—and learning how to deal with the disorder’s inevitable progression—is basically the main lifeline that loved ones and caregivers of people with FTD have to work with. Scientists are studying people who currently have FTD and those who are at risk of developing the disease to better understand what is happening in the brain. Currently, several drugs are undergoing clinical trials.

Although less common overall than some other neurodegenerative diseases such as Alzheimer’s and Parkinson’s, FTD is the most common form of dementia for people under 60. but FTD usually appears between the ages of 40 and 60. It affects about 60,000 people in the US alone.

FTD refers to a group of disorders that affect the frontal and temporal lobes of the brain—areas involved in personality, behavior, language, and other high-level brain functions. The disease can be devastating for people with FTD and their spouses, children or grandchildren, says Elizabeth Finger, a neurologist and professor at Western University in Ontario. One of the most insidious aspects of FTD is the way it can suddenly seem to change one’s personality.

“Physically they can be fine for quite some time, so it’s like families almost have a stranger living with them,” says Finger. “Once families get the diagnosis, it helps, because they often live with this alienation for a while, and now at least they can understand that it’s a brain disease and it’s out of the patient’s control.”

What are the symptoms of FTD?

FTD has many variations. Each is characterized by a set of symptoms linked to the location in the brain where the disease begins. The behavioral variant, which is associated with changes in the frontal and temporal lobes, is the most common. It includes symptoms such as apathy, emotional blunting, impulsivity, and problems with decision-making and judgment.

Variants associated with changes in language abilities are known as primary progressive aphasia and usually involve the dominant frontal and temporal lobes (for most people, these are on the left side of the brain). These variants come in three main subtypes: semantic, non-fluid and logopenic. The semantic subtype mainly leads to a loss of word understanding. An affected person’s vocabulary decreases over time, making it increasingly difficult for them to read, write and understand conversations. People with the non-fluent subtype have trouble speaking but retain the meaning of words. In the early stages of this subtype, people may have difficulty pronouncing words and slur their speech. In advanced stages, they may stop speaking altogether. Those with the dyslexic variant struggle to find the right words during conversation. As the disease progresses, these individuals may have difficulty understanding complex sentences.

Impaired movement is the most obvious symptom of the other variants. This sometimes happens when FTD occurs alongside amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder that leads to the progressive loss of neurons involved in movement.

All these variants overlap to some extent, says Yolande Pijnenburg, a neurologist and professor at the University of Amsterdam Medical Centers. “Syndromes are more distinct when they are in their original state,” he says. “But when they’re more advanced, they start to look more like each other.”

Identifying causes

FTD is generally associated with the loss of neurons in the frontal and temporal lobes of the brain. But what causes this loss? Post-mortem examinations of the brains of people with FTD have revealed that the condition is mainly linked to the abnormal accumulation of two proteins: tau and TDP-43, which are also thought to be involved in Alzheimer’s disease. Scientists have found other proteins that could be responsible for FTD, but changes in tau and TDP-43 account for more than 90 percent of cases overall, says Chiadi Onyike, a neuropsychiatrist at Johns Hopkins University.

Studies show that a genetic mutation is the cause of FTD in about one-third of affected individuals. More than a dozen mutations are linked to the condition, and the most common appear to be in specific genes that lead to abnormal accumulations of tau and TDP-43.

But scientists know little about what causes disease in the other two-thirds of affected people without an inherited condition, those who have so-called sporadic FTD. The only risk factor that has yet been identified is a history of concussion or traumatic brain injury, Finger says. But that explains only a small percentage of the risk, he adds, because the majority of people with FTD haven’t had such brain injuries—and most people who have had them don’t get FTD.

Knowing the Signs

There are many challenges in diagnosing FTD, according to Pijnenburg. It currently takes an average of 3.6 years for people to receive an accurate diagnosis of the condition. Most people with FTD, especially the behavioral variant, don’t realize a change is happening and rarely seek medical help on their own. Another problem is that such behavioral changes may have alternative explanations such as depression or another mental health condition. Importantly, says Pijnenburg, there is a relative lack of public awareness about the disease.

A definitive diagnosis of FTD is possible only if researchers perform a postmortem brain examination, Finger notes, or if a person carries a so-called autosomal dominant mutation, in which a single copy of a mutated gene can lead to the disease.

But there are other tools for evaluating FTD, including neurological and psychiatric evaluations, neuroimaging, genetic testing, and analysis of a person’s medical history. Neuroimaging techniques such as MRI or positron emission tomography can reveal signs of damage or functional abnormalities in the brain that indicate FTD. Genetic testing can identify FTD-related mutations in the subset of people with FTD who have them. According to Pijnenburg, these techniques can accurately identify somewhere between 74 percent and 93 percent of FTD cases.

Researchers around the world are now studying people who carry genetic mutations linked to FTD but have no symptoms. This is an attempt to understand how the disease occurs and potentially help develop treatments, including treatments that could slow, stop or even prevent the disease.

In Canada and several European countries, a research consortium called the Genetic Frontotemporal Dementia Initiative (GENFI) is conducting a study following more than 1,000 people with genetic mutations associated with FTD. The team is trying to determine how early changes can be detected in asymptomatic people who have been judged to be at risk, says GENFI coordinator Jonathan Rohrer, a neurologist at University College London. Now, 10 years after the study, Rohrer says the observations of behavior and brain pathology so far show that subtle changes in cognitive function and brain structure can occur years before the onset of symptoms.

GENFI joined forces in 2019 with researchers based in the US, Australia, and several countries in Asia, South America, and Africa to form the Frontotemporal Dementia Prevention Initiative (FPI), Rohrer says. The teams involved are pooling their data to create an international registry of FTD research participants who can enroll in clinical trials. Ultimately, the global research effort plans to prepare for clinical trials of treatments that could prevent people from ever developing FTD symptoms.

Trials of new treatments

Studying people with genetic forms of FTD has already led to a variety of potential disease-modifying treatments, and some are being tested in clinical trials. These include a phase 3 trial of a treatment targeting progranulin, a multifunctional protein whose reduced levels in FTD lead to an accumulation of TDP-43. Trials are also underway for therapies aimed at either restoring or eliminating the activity of known mutated genes associated with FTD.

Scientists hope that if these treatments work, some may also be used to help people with sporadic FTD. “Because of the similarity in the underlying molecular pathology, there is a growing idea in the field that treatments for genetic forms may translate to sporadic forms,” ​​says Finger.

But Rohrer notes that before that happens, scientists must overcome another major hurdle to treating sporadic FTD: identifying biomarkers — such as those that can reveal tau or TDP-43 proteins in blood and spinal fluid or through imaging – in order to determine which pathological processes are at play.

Currently there are ways to manage and treat specific FTD symptoms. A key aspect of ongoing care is family and caregiver education. Other approaches include psychotherapeutic and pharmaceutical interventions that target specific behavioral or cognitive symptoms and speech difficulties. Physical or occupational therapy can address language and movement problems, while lifestyle or environmental changes (such as limiting driving or credit card use, maintaining a calm environment, and providing structured routines) can help with behavioral symptoms . Onyike says researchers are also starting to look at ways to help boost brain function—for example, combining speech therapy with brain stimulation in people with aphasia.

Although there are no disease-modifying treatments available yet, researchers are finding some promise in therapeutic advances in recent years. “We are optimistic and making progress,” says Onyike. “Ten years ago clinical trials were about drugs to reduce symptoms or boost cognition. Today they are about stopping neurodegeneration and restoring the brain.”

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