Frontotemporal Dementia Diagnosis, Head Impacts, and Emerging Treatment Approaches

Former NASCAR driver Darrell Waltrip recently announced a diagnosis of frontotemporal dementia (FTD). Waltrip, a 3-time NASCAR Cup Series champion and NASCAR Hall of Famer, and his family has decided he will step away from the public eye for the first time in more than 6 decades, raising questions about the disease, its varied clinical presentations, and the potential role of repetitive head impacts in neurodegeneration.

FTD encompasses a group of neurodegenerative syndromes characterized primarily by changes in behavior, personality, language, and, in some cases, motor function. Although clinical presentation and neuroimaging can help clinicians identify an FTD syndrome, determining the underlying pathology remains challenging, particularly in the absence of definitive biomarkers for many forms of the disease.

To discuss the clinical presentation and diagnosis of FTD, NeurologyLive spoke with Carmela Tartaglia, MD, FRCPC, professor of medicine at the University of Toronto and cognitive/behavioral neurologist at the University Health Network Memory Clinic. In the discussion, Tartaglia highlighted the potential relationship between repetitive head impacts and neurodegeneration, as well as advances in biomarkers and disease-modifying research.

NeurologyLive: Can you provide a general overview of frontotemporal dementia, including the main clinical presentations and symptoms clinicians should recognize?

Dr. Tartaglia, MD, FRCPC: Frontotemporal dementia is really an overarching term that has been used alongside frontotemporal degeneration. It's related to a family of syndromes that cause changes in behavior and language, but can also cause motor changes. The term frontotemporal tells you where the bulk of the pathology is—in the frontal and temporal lobes—and that's really why you get the symptoms that we see in this family of diseases.

From a frontal lobe perspective, you end up with symptoms related to changes in personality and comportment. People can become apathetic, lose empathy, or change their eating habits. You really see changes in personality, while cognitive function can actually be relatively well preserved. Their memory many times is still quite good, although sometimes it is also affected.

Patients can also present with language problems. Sometimes it's a problem with speaking—they can't get the words out even though they know what they want to say. Other times, it's really understanding words. Frontotemporal dementia is really this umbrella term that includes a number of syndromes.

Why can diagnosing FTD be challenging, and how can clinicians distinguish it from Alzheimer disease or other neurologic disorders?

That's a great question because when your brain changes, you change, right? And that doesn't necessarily tell you about the cause of something else. The good thing with respect to Alzheimer disease (AD) is that we actually have really good biomarkers. We have tests that we can do while you're alive that can tell us whether somebody has AD or not as the cause of the syndrome, because the syndrome can also be caused by AD. It's just less likely in frontotemporal degeneration.

However, we don't really have great tests right now for FTD. It's a work in progress that’s getting better. There are some people who have a genetic cause of their FTD, and for those people, we know for sure what the pathology will be. But for the rest of them, it's what we call a syndromic diagnosis. We take the patient's story and put it together with the imaging—what the brain looks like—and say, "OK, the most likely explanation of what you've told us is frontotemporal dementia."

The most common one is actually behavioral variant frontotemporal dementia. That's the one where there's really a significant change in personality and comportment and loss of social norms. We can see that the frontal lobes are atrophied or the anterior temporal lobe is affected. These are parts of the brain that, when you look on imaging, don't look right; they're too shrunken for the person's age.

The issue is that early on in the disease, they can still look relatively normal. As the disease advances, there's more shrinkage of the brain because the cells are dying, and it becomes easier to make a diagnosis.

Following the diagnosis of former NASCAR driver Darrell Waltrip, there has been discussion about repetitive head impacts and neurodegenerative disease. What does the current evidence tell us about a potential relationship between head impacts and FTD specifically?

Repetitive head impacts are a risk factor for neurodegeneration. The disease that they're most affiliated with is chronic traumatic encephalopathy, or CTE. Repetitive head impacts don't even require a concussion. That repetitiveness, and even concussion, have been associated with all the neurodegenerative diseases. It doesn't mean that they caused the disease necessarily, but there is that association. Whether it accelerates it or decreases your threshold for it, we don't know.

All brain injuries, even the mild ones, have been associated with neurodegenerative disease. In ALS, which is a disease that has pathology that overlaps with frontotemporal dementia, there has also been an association with repetitive head impacts. But to say that it causes ALS or FTD is very difficult. We don't have the same kind of evidence that we have, for example, with smoking and certain diseases. It's that association that makes us concerned.

How does the possibility of multiple neuropathologies further complicate the relationship between FTD and CTE?

One disease of the brain does not protect you against other diseases. Many times, people will have more than one disease in the brain, and even people with FTD will have more than one disease in the brain. I've seen a patient who had FTD, specifically semantic-variant primary progressive aphasia.

They were a boxer and had a classical presentation of semantic-variant primary progressive aphasia. They even had a genetic mutation. The person died, we got their brain, and sure enough, there was lots of TDP-43, the FTD pathology, but there was some CTE there as well.

So when somebody has FTD, a concussion or other brain injury can interact with that FTD. The same is true for other factors. If somebody has high blood pressure, diabetes, and high cholesterol, they can develop cerebrovascular disease, and that can make their FTD worse. It can accelerate it or perhaps make it show up earlier. In a case like Darrell Waltrip's, we don't know which variant of FTD he has. Without knowing those specifics, it's hard to know how quickly it's changing.

What has stood out to you from recent FTD research, particularly in areas such as biomarkers, pathology, and diagnosis?

FTD is a really exciting area because it hasn't been that long since we actually made discoveries into what the underlying pathologies are. We have discovered that this family of syndromes, which used to include only 3 diseases, now includes 6 of them. We now have a biomarker for 1 of those 6 syndromes, progressive supranuclear palsy, which also belongs to the frontotemporal lobe degeneration family. We have a diagnostic test.

We've also been lucky to have many interventions that have been tried. So far, we have not been lucky enough to get one that works, but it's nice to see that there's an increasing interest. If nobody takes a shot on goal, nobody is going to score.

In AD, there were many clinical trials—almost 200 failed trials—and eventually 2 worked. So we're happy to see that there has been interest in FTD trials and that this work is ongoing, with the hope that we can eventually bring something useful to patients.

In the absence of disease-modifying therapies, how are clinicians currently approaching symptom management and supporting patients and caregivers?

Even without disease-modifying therapies, we have many symptom-based treatments that we can offer. A lot of the symptoms we see in FTD can be quite troublesome. Behavior changes, for example, can be associated with agitation, depression, or anxiety, and we have medications that we can give for those symptoms.

If somebody has a speech problem, we prescribe speech therapy, which can be quite useful. There's a lot of evidence that speech therapy can slow down the loss of speech.

FTD has also been really instrumental in providing resources for families. One of the problems with FTD is that it's much rarer than AD, and it's a different type of population because patients are quite young. A lot of times, people feel very isolated. Nobody knows about their disease.

Having organizations like the Association for Frontotemporal Degeneration to provide information and resources and make programs available for people has been very valuable, even if we don't have disease-modifying therapy.

There's also a lot of advocacy being done for these patients with organizations and pharmaceutical companies to continue investing in FTD research. Even meetings with the FDA and European Medicines Agency are important to make sure they understand the challenges faced by the community. When you think about clinical trials for AD, there are thousands of patients available. FTD, especially genetic FTD, is much rarer, so trials have to be much smaller.

Looking ahead, which developments in FTD research or patient care give you the most optimism?

Some of the interventions that have been tried recently and the novel interventions are encouraging. We have some gene therapy trials that have started. So far, the ones that we've done haven't succeeded, but these types of trials have started.

We have trials targeting tau, one of the abnormal proteins, as well as trials using different approaches, such as antisense oligonucleotides. People are thinking outside the box in terms of how to approach disease modification.

People are also looking at other avenues, such as inflammation and mitochondria. There's a lot of technology that has allowed us to do large-scale assessments worldwide. Instead of looking at 1 or 2 or 10 proteins, we can look at thousands of proteins and see how they change.

So we are learning a lot. You can't treat something if you don't actually know that much about it. All the little discoveries that we make are moving us toward the disease-modifying therapy that will come.

Transcript edited for clarity.