Illuminating Frontotemporal Dementia

Landmark study identifies imaging biomarkers that can detect earliest signs of brain decay in those most at risk for this devastating disease

At first, Jane (not her real name) didn’t think much of her sister’s odd behaviour. The mismatched clothes and erratic driving were benign, even comical, offenses that could easily pass for middle-aged eccentricity. At the time, Jane’s sister was in her mid-50s, highly educated and fiercely independent. But then quite rapidly her judgment seemed to deteriorate. She made uncharacteristically rash and dramatic decisions. She would botch simple tasks. Her writing became like a child’s, riddled with spelling errors and jumbled words. To Jane’s dread, her sister’s increasingly peculiar behaviour reminded her of what had happened to their father and some of his siblings, back when all dementia was considered Alzheimer’s disease, or just a cruel symptom of old age.

Today there is a name for the brand of dementia that runs in Jane’s family: frontotemporal dementia (FTD), the dementia you’ve probably never heard of, but which is one of the most common types to strike people in their 50s and early 60s, unlike Alzheimer’s, which usually comes on after age 65 years. Whereas Alzheimer’s most often damages the mesiotemporal and parietal lobes, gradually affecting memory and thinking, FTD swiftly attacks the anterior temporal and frontal areas, which control judgment, behaviour and language, eventually obliterating one’s personality or ability to communicate. Frontotemporal dementia is highly heritable (most often caused by mutations in three genes) and has been less-studied than Alzheimer’s and other more common neurodegenerative disorders. In the last several years, however, the research gap has been closing.

I wanted to know so I could draw up a plan for my children; there was no way I wanted them to have to take care of me.

A new study by the Genetic Frontotemporal dementia Initiative (GENFI)—an international team that includes Sunnybrook Research Institute (SRI) scientists—has illuminated very early structural changes of the disease. By peering into the brains and behaviour of at-risk participants several years before they show symptoms, researchers have been able to locate some of the earliest sparks of FTD, so that they may one day be stamped out before igniting an uncontrollable fire. “Once the brain cells die, we can’t do much,” says Dr. Mario Masellis, an SRI researcher-neurologist and the study’s lead Canadian investigator. “So if we can prevent the cells from dying, treat people before they show symptoms—that is the ultimate goal of this research.”

Published in The Lancet Neurology this past March, it is the largest and most statistically powerful presymptomatic genetic FTD study to date, involving 220 participants from five countries. This sort of collaboration is crucial, says Masellis, since FTD is reasonably uncommon and it would take one jurisdiction years to amass such a cohort.

As her sister’s condition worsened, Jane became a full-time caregiver. “She couldn’t be left alone,” Jane says. “She had to be watched at all times otherwise she would wander off and get lost.” The daily care, the constant curbing of minor catastrophes, the up-close horror of the brain disease that eventually killed her sister left Jane terrified that she would be next. “I wanted to know so I could draw up a plan for my children; there was no way I wanted them to have to take care of me.” As she pursued genetic testing, Jane got word about Masellis and the FTD study. Even though she tested negative for the known familial mutation, she qualified for the study because she had a first-degree relative who’d had FTD, which meant she was at risk of developing the disease. She didn’t think too long before volunteering, and even recruited nieces and nephews to participate—anything she could do to help shed light on the disease that had felled so many of their family members.

Along with blinded genetic testing and a standard clinical assessment, participants underwent behaviour and cognitive tests, for example, connecting letters on a page, naming objects, or listing animals or words that start with a certain letter—all to determine the existence or degree of FTD symptoms. But it was the 70-plus minutes participants spent lying inside the MRI machine that showed a compelling picture of the earliest traces of brain decay, in some cases more than 10 years before symptoms would be expected.

Dr. Brad MacIntosh used magnetic resonance imaging to identify changes in the insula region of the brain, a discovery that might be useful as a biomarker for frontotemporal dementia and to measure treatment response.

Across all three genetic subgroups, FTD seemed to take its first blow at the insula, a region that SRI’s Dr. Brad MacIntosh describes as, “the brain’s brain.” The insula is a prune-sized tissue embedded deep behind where the frontal, temporal and parietal lobes meet. “It’s integral to the brain-body connection,” says MacIntosh, a neuroimaging scientist who was part of the SRI science team, rounded out by Dr. Sandra Black, head of the Hurvitz Brain Sciences Research Program. “It’s a critical hub involved in everything you don’t think about: the rate of your heart beat, maintaining homeostasis, but also raw emotions and perception.” The early effect of FTD on the insula was a huge discovery. “We’ve introduced roughly a 10-year window where we can say there’s early evidence that a patient is at risk for FTD,” says MacIntosh. (Participants will be scanned again next year to track the progression of insula damage.) As a sort of ground zero for FTD, the insula can now serve as a biomarker of the disease and could be used to test human responses to new treatments that might, for instance, slow the pace of the brain erosion, which, for Jane, could have bought at least a few more years with the sister she once knew.

Along with imaging biomarkers like the insula, Masellis hopes to find fluid biomarkers in the spinal fluid and blood samples that were also collected. (Those results haven’t yet been analyzed.) Masellis suspects that spinal fluid biomarkers might be more sensitive in detecting the earliest signs of the disease.

He is also conducting a study using DNA samples from participants that will analyze genetic markers located across the genome. The hope is to identify risk factors that contribute to why one person may develop early language symptoms and why another may develop early behavioural issues. Some genetic factors may also protect against the development of disease or at least cause a later onset. These so-called modifying genes could be other potential targets for therapies under development.

Brain scans of a patient with genetic frontotemporal dementia (FTD; top) and a patient with early onset familial Alzheimer’s disease (AD; bottom). The patterns of brain decay are strikingly different in the two diseases: atrophy is asymmetric between the left and right sides in the FTD brain, whereas in the AD brain, it is symmetric. The scans were acquired using magnetic resonance imaging.

Image: Courtesy of Dr. Mario Masellis

Though FTD was found to erode the insula across all gene mutation groups, outwardly the disease looks different among carriers. In their study, the team found hints that mutations in the three different genes strike the brain in specific patterns, and so FTD symptoms may vary depending on from which genetic subgroup you come. Mutations in the progranulin (GRN) gene tends to impair one side of the brain faster than the other. A patient with left-side damage may first lose the ability to speak, while a right-side deterioration would manifest as behavioural changes, as Jane’s sister’s had done. Mutations in the other two genes—microtubule-associated protein (MAPT) and C9orf72—have been found to affect both sides of the brain fairly equally, sometimes causing a broad range of symptoms all at once. (However, in asymmetric cases, as the disease progresses, it’s likely that both sides would suffer eventually, says Masellis.)

These glimpses into the brain structure of presymptomatic FTD comprise just one phase of the study; subsequent papers will focus on brain function: blood flow and connectivity between regions, data gleaned from what’s called a functional MRI. Masellis and MacIntosh are parsing the data, but Masellis has a hunch the findings will be encouraging. “It’s my belief that we’ll see functional changes even earlier than we see structural changes,” he says, possibly paving the way for an even earlier FTD imaging biomarker.

There are no treatments for FTD beyond antidepressants and antipsychotics, which tamp behavioural and mood symptoms. And it’s not like they offer long-term relief, anyway, says Masellis. Such drugs work by modulating neurotransmitters that get depleted as brain diseases progress, so the effects are fleeting. This is why dementia researchers are pinning hopes on preventive therapies, for instance, medication that targets the aggregated proteins that kill brain cells (a feature of all dementias).

In his quest to unlock the mysteries of FTD, Masellis has published several papers describing variability in clinical presentation of FTD due to mutations in progranulin, a type of protein important in brain development. Masellis found that all the mutations in this gene cause progranulin levels to drop. “So, if we can find a treatment that elevates progranulin levels,” he says, “then we might be able to prevent FTD.” Small clinical trials of such a drug are underway in the U.S., though they mark the early phases of drug testing. If the treatment should prove safe and well-tolerated, then the international FTD study participants could serve as a ready platform to launch further clinical trials, says Masellis.

During his many years as a neurologist and researcher, Masellis has seen the effects of FTD up close: the rapid robbing of lives at a time when they are still working or raising families. “They stop being who they are,” he says. “You can imagine someone who’s 50 years old and still has a 12-year-old child at home. They can’t work, and often the spouse has to stop working to care for their partner full time. It’s a huge effect on family and income.” For Jane, who lost her father and, she suspects, three siblings (this was before FTD was a well-defined diagnosis), it’s an unfathomably cruel disease that leaves the caretakers and surviving family members in ruins. The best thing she can do now in service of her family is to be part of studies that continue to shine a light in the shadows and make important advances. “The progress on FTD has been spectacular,” says Jane. “I think back to my sister [some 20 years ago], and she got a different diagnosis every time she saw the doctor. And now they know what it is, they’ve got it down to the genetic level; they’re finding biomarkers so the disease is more predictive, and when it’s predictive they can do something about it.”

The work of Masellis for this study is funded by the Canadian Institutes of Health Research and the Ontario Ministry of Research and Innovation.