Ted Huey, director of the Memory and Aging Program, is excited about Brown’s potential to change the research landscape.
The early stages of dementia play out in a variety of subtle and insidious ways. It can be far more than just misplaced keys and forgotten names: people’s entire personalities may gradually change; their social skills deteriorate; their ability to command spoken language slowly disappears (a symptom that has famously—and tragically—plagued movie star Bruce Willis).
All these different symptoms reflect physical changes in the human brain, or the gradual scrambling of the neural circuits that make us who we are. While the exact causes of dementia can vary, the damage that occurs in the brain can be strikingly similar in all cases.
Professor of Psychiatry and Human Behavior Edward “Ted” Huey, MD, has spent his career working to understand and treat those neurological changes. As the new director of the Memory and Aging Program at Butler Hospital and an affilated faculty member of the Center for Alzheimer’s Disease Research in the Division of Biology and Medicine and the Carney Institute for Brain Science, he’s particularly interested in a rare form of the disorder called frontotemporal dementia, or FTD. It’s a strange beast marked not by memory loss, but by precipitous declines in a patient’s ability to control social and behavioral skills. In this interview, Huey talks about his fascination with FTD, how he studies its causes, his vision for the future of dementia research at Brown, and more.
Dementia can take a lot of different forms—how do you define it as a whole?
A lot of people think of dementia as being synonymous with Alzheimer’s disease. But dementia’s really a clinical or observational diagnosis. What that means is that a patient has observable problems in at least two areas of thinking, like memory, visuospatial abilities, language, executive function, and so on. If it’s affecting those to the point where it’s causing problems, or the patient can’t do everything they need to do in their life, that’s dementia. The root cause for the disorder could be damage to the brain from Alzheimer’s disease, Parkinson’s disease, a stroke—and the symptoms aren’t always related to memory. They can be related to language, to social cognition, to behavior and emotion—or they can be all of those things.
How is frontotemporal dementia different from other forms of dementia?
FTD specifically affects patients’ frontal lobes, which are areas of the brain that are right behind the forehead and the anterior temporal lobes. The frontal lobes split into two areas: a dorsal or upper section, and a ventral or lower section. The upper one controls a lot of non-social executive function, like balancing a checkbook, doing math, and so on; the lower one is really important for judgment, decision-making, understanding social norms, and self-control.
In Alzheimer’s disease, there’s a lot of pathology in the upper area. Those patients may have trouble balancing a checkbook, doing math, and so on, but their social cognition may be preserved. Patients with FTD, however, get the whole thing. They’ll have deficits in executive function, and also in areas that help them function socially. They start to act strangely. They experience emotional changes or emotional blunting where they just don’t feel anything deeply. They might do things that are socially inappropriate. The most common thing we hear about patients with FTD—or patients that have other kinds of damage to the frontal lobes—is that their spouse says, “This is just not the person I married. They’re acting totally out of character.”
How did you first choose to study this particular disorder?
After my residency, I did a fellowship at the National Institutes of Health in Bethesda, MD. It was actually to study biomarkers for Alzheimer’s disease—but for reasons that had nothing to do with me, the lab closed after I’d been there only a little while, and there wasn’t really anyone else doing clinical Alzheimer’s disease research there. So I asked around and found a neuropsychologist at the National Institute of Neurological Disorders and Stroke who was studying frontotemporal dementia. It wasn’t my focus, but I needed a job, so I went to go work with him. That’s when I started really digging into the disease, and pretty quickly found it fascinating. I spent the next 13 years after studying FTD and other types of dementia as an associate professor of psychiatry and neurology at Columbia University’s College of Physicians and Surgeons.
One of the things that is so fascinating about the disease is that it reveals how the brain processes complex behavior and emotion. Take social cognition, for example: A lot of thought has to go into interacting with people, and most of the time, we’re not really conscious about it because it’s so natural. In this conversation we’re having right now, we both intuitively know things like, “When do I speak? When do you speak? What topics should we be speaking on?” But in people with frontotemporal dementia, that all starts to break down, and we can link those deficits to changes in a specific part of the brain. In studying the disease and looking for treatments, we also use it as a sort of Rosetta stone for understanding how things like emotion, complex behavior, empathy, these higher human functions, actually function. That’s kind of a new frontier for science. We don’t understand those processes nearly as well as we do memory.
What are some of the specific elements of the disease that you’re interested in studying?
I find changes in people’s motivation to be especially interesting. In frontotemporal dementia, you’ll often see patients developing a sort of general apathy. They suddenly don’t feel like doing a lot of the things they used to enjoy, but they aren’t sad, they aren’t clinically depressed. If you convince them to participate in an activity like a family barbecue, they may say they had fun, but they’re less motivated to go in the first place. This happens because the systems that are involved with motivation are being damaged.
Tell me about how you actually study those changes.
We do lots of things here at the Memory and Aging Program. We’re very interested in testing therapeutic agents; we even have an infusion suite where we’re giving drugs designed to inhibit or remove some of these disease pathologies. Most of them are focused on amyloid plaques, which are collections of proteins in the brain that play a role in Alzheimer’s disease.
We’re also very interested in bringing people in and following them over time. We do a lot of things like imaging their brains—taking MRIs and other data that can tell us what areas of the brain are associated with specific forms of dementia as they develop and change over time. One group of people that we’ve been very fortunate to work with are people with genetic illness, where mutations in a specific gene have predisposed them to dementia. We can identify people with those genes even before they get sick, and then follow them through the progression of the disease while treating them. From our imaging, we can see the specific changes that occur in their brains along the way, and then compare those changes to scans of their siblings and relatives who don’t have the mutation.
Do you often see a single mutation that causes dementia? Or do changes in different genes cause different symptoms?
Different mutations give you different neurodegenerative diseases. There definitely are some that can cause Alzheimer’s disease. Just having a single mutation be the cause of Alzheimer’s is quite rare. It only happens in about 1 percent of all cases of Alzheimer’s. For frontotemporal dementia, a higher proportion of people, about 25 percent of cases, come from mutations in a specific set of genes. At the extreme end of things, there’s dementia related to Huntington’s disease—100 percent of those cases are caused by single gene mutation. There’s a big range. This leads to many kinds of fascinating and puzzling questions about how genetics are involved in the disorder.
How could that information potentially help treat these diseases? Do we even know exactly what all those gene mutations do?
That gets complex pretty quickly. We’ve been interested in doing work in identifying gene mutations, or basically just finding areas that are breaking down in the genome to cause dementia. Ultimately, we want to be able to know the specific changes that are happening, and be able to show that those changes are sufficient to give you the disease. Once we know that, basic scientists can work out how the genetic changes actually trigger dementia, and we can figure out if it’s possible to target any of the steps along the way to try to prevent it.
The problem, however, is that the vast majority of Alzheimer’s disease and the majority of frontotemporal dementia isn’t caused by just one mutation. Instead, the genetic components are really complicated. People may have some sort of genetic predisposition for it, but they won’t actually develop the disease unless changes occur in many, many genes with small additive effects.
The other thing that kind of makes it even more complicated is that you can technically have diseases like Alzheimer’s without having dementia. So if an older person comes in, and I do a scan of their brain, I might see that they have large amounts of amyloid plaque in there—sometimes the same amount that we’d see in a person suffering from the symptoms of Alzheimer’s—yet they’re cognitively fine. They may actually be asymptomatic and not know that they have it. One very key question is, does this reflect a kind of resilience to dementia? Why do some people get amyloid plaques or tau tangles and do OK, whereas other people with the same amount of amyloid and tau have memory problems and trouble doing basic tasks? We just don’t know. That’s why we spend a lot of time trying to understand the biology underlying a specific type of dementia, and how it’s linked to the clinical presentation of a patient.
You were at Columbia’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain for more than a decade. What made you want to come to Providence?
What attracted me here was a real opportunity to grow. The Warren Alpert Medical School, the Brown Center for Alzheimer’s Disease Research, the Carney Institute [for Brain Science at Brown], and the Memory and Aging Program here at Butler are all developing in very exciting ways. The experience so far has been better than I could have ever anticipated. Brown and Carney have really focused on helping to grow the program on research into Alzheimer’s disease and related dementias as a whole. They’re building bridges to help people facilitate new programs. And it’s so valuable—I mean, to my mind, it’s been such a rare and great resource. We also have access to amazing data that you just can’t get anywhere else. The New England Family Study, for instance, which has followed a cohort for more than 50 years, starting before birth and lasting until today—it’s going to be able to answer some questions about the genetic variants of dementia, the effects of race and ethnicity, and so on. And now that cohort is getting to the age where they may start to have cognitive issues. We have this lifetime of data to correlate, and I think there’s going to be some really important work that’s going to come out of it.
What areas of dementia research are you hoping to expand?
I think, and I suspect others here would agree with me, that there are some gaps we’ll need to fill in to make a really comprehensive dementia program. We need to grow our brain bank, which is a repository of samples from people who have suffered from dementia and later donated their organs to science. That is definitely a priority. At the same time, I think we’ll need to find new ways of leveraging the unique strengths of Brown—namely, the huge number of world-class researchers who are all right here. We need to combine research in pathology, genetics, bioinformatics, and other areas, and find ways for them to work together and collaborate in order to have a really effective center.
As a final word, what is one of the most important things you’d want readers to understand about dementia?
I think there can be a little bit of an ageist assumption that dementia just happens to people and there is nothing anyone can do about it. There are a growing number of treatments that are being developed. They’re getting better and better each year. This is a disorder that we hope will ultimately be treatable or even preventable, not something people should consider a natural part of aging.
There’s still a lot of work to be done—but just because someone’s old doesn’t mean they should have memory problems or neurological problems in general.