Lesser-Known Dementias and the Difficulty of Diagnosing Them

The recent death of beloved University of North Carolina sports radio broadcaster Woody Durham has brought attention to a lesser-known type of dementia called primary progressive aphasia (PPA). The neurocognitive disorder took away Durham’s ability to speak before complications with it led to his death in March.

PPA is just one of several neurocognitive diseases that too often get confused with Alzheimer’s disease, said Dan Kaufer, MD, cognitive neurologist and director of the UNC Memory Disorders Program. (Editor’s note: Dr. Kaufer died in 2020.)

“Many people aren’t aware of other disorders because Alzheimer’s disease, which is equated with memory disorders, has gotten most of the attention,” Dr. Kaufer said.

We sat down with Dr. Kaufer to better understand lesser-known dementias and the problems with diagnosing them.

First, what is dementia?

“Dementia” is a general term that describes acquired cognitive impairment that’s clinically significant in multiple domains. It is actually an old term that has been around for over a century, and it has a lot of negative connotations. It literally means being crazy.

More recently, we’ve adopted a new term, “neurocognitive disorder,” for two reasons; one is to get beyond the negative connotations of “dementia,” and the other is to emphasize that when people have problems with memory or language or other cognitive domains, that it is a brain-based disorder that affects different areas of cognition.

How many kinds of dementia—or neurocognitive disorders—are there? How are they diagnosed?

There are many different types of neurocognitive disorders. The most common one, which most people are familiar with, is Alzheimer’s disease. What distinguishes Alzheimer’s disease from others is that the primary manifestation is typically short-term memory problems.

The second most common disorder next to Alzheimer’s disease is Lewy body dementia. Lewy body dementia has overlapping features of Alzheimer’s disease and Parkinson’s disease, as well as some unique ones. Patients with Lewy body dementia can present either with cognitive problems that look like Alzheimer’s or motor problems that look like Parkinson’s disease, or both. They often have marked sleep problems, particularly acting out dreams, and other features such as prominent visual hallucinations.

One of the big challenges with Lewy body dementia is that there’s not one single way to screen for it like there is for Alzheimer’s disease. If you’re trying to screen for Alzheimer’s disease, you do a memory test, and if the person has trouble with the memory test, then it’s appropriate to work them up for Alzheimer’s disease.

But that single assessment doesn’t apply very well to Lewy body dementia because the initial symptoms can be quite varied.

The same is true for another neurocognitive disorder called frontotemporal degeneration, or FTD. This disorder also has different presentations—either changes in behavior and personality or changes in language functioning.

The latter refers to primary progressive aphasia, which was first described only a few decades ago. PPA symptoms revolve around speech and language; the person may have trouble expressing thoughts or difficulty understanding words. PPA is difficult to diagnose because the early signs are very subtle and progress slowly over time. As with memory problems in Alzheimer’s disease, the progressive language difficulties are often attributed to old age. There hasn’t been a large treatment study for PPA, in part because it is not easy to diagnose, but this is something that we desperately need.

If you do notice some of these symptoms and behaviors in a loved one, what should you do?

I think the first step is understanding what’s attributable to normal aging and what’s not.

There are many people who view short-term memory difficulties as something that’s expected with aging, and something that is in some ways unavoidable, which is not true.

Most people do have more difficulty remembering names as they get older. On the other hand, if you forget events, if you repeat yourself, if you misplace things repeatedly—those are early signs of a potential memory problem.

I think people are pretty well aware of what those early signs of memory problems are, but I don’t think there is awareness of what changes are potentially significant when it comes to personality.

People with a neurocognitive disorder may not be interested in things as much as they used to be. It can be difficult to distinguish this from just an effect of age or just a life phase, but losing interest in things is one of the common early signs of frontotemporal degeneration, as is difficulty expressing oneself.

As a starting point, if there is concern about symptoms, families should always talk to their primary care doctors. And remember that neurocognitive disorders do not just show up as memory problems. They can also present as language problems, hallucinations, motor changes or acting out dreams at night.

How do these disorders manifest differently in the brain?

The common framework for all of these disorders is that they’re caused by one or more abnormally folded proteins that accumulate in different parts of the brain. Whatever parts of the brain are affected determine what the clinical manifestations are. This provides a common framework for understanding Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), chronic traumatic encephalopathy (CTE, associated with brain damage from repeated head trauma), frontotemporal degeneration and other rare disorders called progressive supranuclear palsy and corticobasal degeneration.

For example, in Alzheimer’s disease, neurofibrillary tangles composed of tau protein accumulate in the memory center. That’s why you get memory problems.

In Parkinson’s disease, Lewy bodies, which are formed by a different protein, accumulate in parts of the brain that control motor function. In some cases, Lewy bodies can also accumulate in other areas of the brain that affect thinking and behavior, which results in Lewy body dementia.

And in ALS, a different protein accumulates in different parts of the nervous system that control motor function.

How are these conditions related?

As an example, we tend to view Alzheimer’s and Parkinson’s as completely distinct and separate entities. Another way to think about them is that they lie on opposite poles on a spectrum, with Alzheimer’s being a primary cognitive disorder and Parkinson’s being primarily a motor disorder.

But over time, many patients with Alzheimer’s develop motor symptoms and many patients with Parkinson’s develop cognitive symptoms, and then there are patients with dementia with Lewy bodies who initially develop both motor and cognitive symptoms.

What is next for diagnosing and treating these lesser-known dementias?

Most of the major neurocognitive disorders can be understood as involving the accumulation of one or more abnormal proteins from four different “families”: amyloid, tau, synuclein and TDP-43. Each protein affects a different part of the brain, and whatever part of the brain is affected determines what the clinical symptoms are.

Current thinking is that blocking the accumulation of these abnormal proteins will be critically important for effectively treating the major neurocognitive disorders. To date, there have been a number of amyloid-targeted studies in patients with Alzheimer’s that have, unfortunately, not been very successful. This has obviously been disappointing, and suggests that these treatments may only work if we can start them before the clinical symptoms become debilitating.

We’re now working on brain imaging tools that can detect amyloid and other proteins, and these likely will eventually play a very important role for diagnostic imaging in clinical practice and as a way to identify targets for treatment.

I think a general understanding by the public of neurodegenerative brain disorders has been lacking, and this probably has contributed to the lack of progress in the field. To appreciate that these disorders involve brain changes that begin long before the first clinical signs appear is critically important. This suggests that there is a window of opportunity to diagnose and treat these disorders before they become disabling that we need to more fully embrace.

Although clinical symptoms are very important for early screening and detection and referral for appropriate assessment, we need to get a better handle on developing diagnostic tests and effective treatments, both of which will likely involve pinning down these abnormal proteins. Success will ultimately depend on bringing committed researchers and courageous patients together.

Concerned that you or a loved one is at risk for a neurocognitive disorder? Talk to a doctor near you.

Editor’s note: Dan Kaufer, MD, died July 2, 2020. He was the founding director of the UNC Memory Disorders Program. Renowned for his research and treatment of memory disorders, Dr. Kaufer was deeply devoted to his patients and their families.