At 59, the old Ted, the sensitive husband who cried during sad movies, is gone. A scan of Ted’s brain helps explain it: Discrete regions of the right temporal lobe that regulate emotion are getting smaller; the tissue is shrinking.
Ted can still do some of the things he has done for decades. Until a few years ago, he was the president at a construction company. Lately, he’ll see someone he is supposed to know but forgets who they are. He sleeps a lot. And he can’t be left alone for too long or his wife may find him trying to eat a battery or a hammer. He’s agitated. He’s always putting things in his mouth.
Ted Prewitt, who has behavioral variant frontotemporal dementia (bvFTD), is one of a growing number of people in midlife diagnosed with an atypical form of dementia. Unlike Alzheimer’s, which generally occurs in older people, these are rarer dementias — including bvFTD; another frontotemporal variant that leads to language disturbances called primary progressive aphasia; a visual and spatial dementia called posterior cortical atrophy; Lewy body dementia; and early-onset Alzheimer’s in people with no family history.
These conditions show up in people in their 50s and 60s, sometimes even earlier and sometimes a bit later. No one knows whether these conditions are becoming more common or doctors are better at diagnosing them.
What is clear is that some of the same underlying pathology seen in people with typical Alzheimer’s — amyloid plaque and tau tangles in the brain — is also present in people who have Alzheimer’s with a young age of onset or atypical dementias that affect vision or language or behavior. Some of these atypical dementias are caused by a toxic buildup of other abnormal proteins. These proteins become abnormally shaped or clustered together in ways that distort how the brain processes information. This is true for Alzheimer’s, too.
No treatments are available to slow or stop the progression of these diseases. The few drugs that treat symptoms associated with Alzheimer’s are often prescribed for people with these rarer forms of dementia. The drugs may help with some of the symptoms.
The National Institute on Aging suspects that these early-onset dementia cases represent about 5 percent of the total number of Alzheimer’s patients. There is growing interest in studying these atypical forms of dementia to understand why they affect people much earlier in life than the more common Alzheimer’s, and whether there is a way to target the pathology and slow the disease’s progression.
“There is still limited awareness about early-onset dementias. When people come in with cognitive complaints in their 40s or 50s, nobody believes them. We are trying to improve our understanding of the risk factors and various disease presentations, and raise awareness about it,” said Liana G. Apostolova, a professor of neurology, radiology, and medical and molecular genetics at Indiana University School of Medicine and the Indiana Alzheimer’s Disease Research Center.
Apostolova is a co-principal investigator of the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS), a multicenter observational trial enrolling 500 cognitively-impaired people between ages 40 and 64 with early-onset dementia due to Alzheimer’s. The investigators are conducting annual clinical and cognitive assessments, imaging, biomarker, and genetic studies. They hope to define patients and characterize their symptoms and rate of disease progression, and then enroll them into clinical trials.
Apostolova and colleagues published a study in August that looked at dementia in people under 65 and found that they have more brain pathology than those diagnosed later in life. Since the availability of biomarkers to identify the pathological changes — brain scans, blood and cerebrospinal fluid tests — it has become clear that the earlier onset of the disease, the more severe the cognitive decline.
“No one knows why these diseases start in specific regions of the brain but we think it is influenced by the normal organization of brain networks,” said Bradford Dickerson, a behavioral neurologist at Massachusetts General Hospital and co-principal investigator in the LEADS trial. “These circuits talk to one another. There is a shared vulnerability to these disease pathologies. These early onset dementias may be rare and are very frequently misdiagnosed or unrecognized.”
His FTD clinic started 12 years ago with just a trickle of patients and now sees about 400 patients a year. He believes the increased numbers are due to increasing awareness, and not likely to increasing rates of the diseases.
No matter what the presentation, virtually everyone in midlife with visual or spatial problems, language or behavioral symptoms has been through the wringer in trying to get the right diagnosis. It took Ted Prewitt, for instance, two years to get the right diagnosis.
When patients show up at clinics specializing in atypical dementias, there is a lengthy battery of tests to figure out just what is wrong.
On one visit at the Memory and Aging Center at the University of California at San Francisco, a young woman stared, owl-eyed and empty as time ticked on. A sound broke her gaze and her eyes locked on to a new target. The young mother who had showed such immense joy and love was nowhere to be found, said her husband, who added that he often moves her around the streets of their city like he’s pulling a 100-pound weight on wheels. She no longer speaks. She is led to the bathroom, to the shower, to the table where they put a fork or spoon in her hand for her to eat.
“She goes with the flow,” said her husband. She is only 38.
The culprit that destroyed so much of her brain is a gene called microtubule associated protein tau, or MAPT. The normal gene makes tau protein that forms a transport system carrying proteins from the body of the nerve cell down the axon. A mutation in the gene causes a buildup of toxic tau proteins that form into tangles and eventually kill the neurons. Her frontal and temporal lobes are abnormally small and significant chunks of brain tissue are missing.
She is a member of one of about 300 families enrolled in two National Institutes of Health-funded studies called ARTFL and LEFFTDS (now merged into ALLFTD) that are underway at more than a dozen medical centers. The studies are designed to gather data on families with rich genetic histories of FTD.
For Elizabeth Wheat, her problems began when she was 50. She also was having visual perception problems. She thought there was a hole in her field of vision. Several ophthalmologists threw out a variety of opinions about what was happening — the most common explanation was macular degeneration. Her doctor advised her to see a neuropsychologist.
The neuropsychologist put seven plastic shapes in front of her and asked her to use the shapes to reproduce a series of geometric drawings. She couldn’t mimic any of them. And she was a landscape architect and spent her career drawing from her mind’s eye. She failed all of the visual tests that day.
Her husband, Eric Scharf, said that the grueling, six-hour assessment of spatial and verbal capabilities produced unsettling results, prompting the doctor to refer her to a neurologist, who concluded at the end of the visit: “You’ve got some kind of dementia and I am surprised you are still working. Would you like samples of medications used to treat Alzheimer’s?”
The family continued their search for the right diagnosis and the right doctor. Four years later, Wheat was diagnosed with an atypical dementia, posterior cortical atrophy.
By 2012, at 58, Wheat’s brain could no longer process visual information correctly — patients become cortically blind — and her cognitive abilities were fading fast. Her husband and sisters had to place her in a memory care facility. When family came to visit, they often caught a glimpse of Wheat standing alone in the courtyard, discussing design ideas with clients visible only to her. In 2015, 10 years after her first symptoms, she entered hospice; she died in February 2017.
As for Ted Prewitt, whose atypical dementia causes abnormal proteins to accumulate in areas of the brain that are important for emotional regulation, decision-making and remembering social information, life had grown much more confined — for him and his family.
He has moved through different stages since his diagnosis in 2014. For a while, he was apathetic and spent a lot of time in his room. Now he asks to help but he often doesn’t know what to do or how to do it. If you ask him to get a cup he will not know what a cup is. Laura handed him a toothbrush to clean his teeth and she saw that he was brushing it through his hair. Ask him to go lie down, his wife said, and he will walk upstairs and come right down again. She recently found him eating a bar of soap. After he broke a tooth, Laura found a hammer while making his bed. Another day, his mouth was black and she found that he had poured gray paint in a cereal bowl and started drinking it like soup. Now, she watches his every move.
“There are times that this disease makes me feel like a terrible person,” she said, “that I just don’t have enough . . . patience.”
Recently, Ted asked her, “Do you have kids?” Yes, and she named them. “Hey, I have two kids with the same names.” Laura had to laugh.
Organizations and studies
●The Longitudinal Early-Onset Alzheimer’s Disease Study is still recruiting. For information, go to leads-study.medicine.iu.edu.
●For information on the Longitudinal Frontotemporal Lobar Degeneration, a multisite research consortium, go to allftd.org.
●For information on the MGH FTD Unit, go to ftd-boston.org.
●For information on language dementias, visit the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University at brain.northwestern.edu/dementia/ppa/research.html.
●Duet Partners in Health and Aging (DuetAZ.org) in Arizona has a new virtual program called Finding Meaning and Hope for family and caregivers of people with neurodegenerative diseases. The program features Pauline Boss, author of the book “Loving Someone Who Has Dementia: How to Find Hope while Coping with Stress and Grief” and her work on ambiguous loss, a concept that Boss developed to help people who are dealing with experiences where there is “no verification of death or no certainty that the person will come back or return to the way they used to be.”
●For information on the Association for Frontotemporal Degeneration, go to theaftd.org.
40 years of research in illness
Many atypical dementias have been identified and characterized only in the past 40 years.
In the late 1970s, Marek-Marsel Mesulam had just finished a neurology residency at Boston City Hospital and was asked by his mentor, Norman Geschwind, to follow him to Beth Israel Hospital to start a behavioral neurology unit. They had a shared interest in aphasia patients who are no longer talking or are limited in what they say.
One of the patients was a woman who explained that she was having “syntax errors and no articles.” They began collecting other patients with unusual language problems, or aphasia, with no evidence of stroke. Their first six patients were described in a paper published in 1982. That puzzle was the beginning for Mesulam, now at Northwestern University in Chicago and the director of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease.
He is considered the father of language dementias. There are many forms and they fall under an umbrella term called primary progressive aphasia.
“I came up with this name because the language problems were the primary cause of the changes in patients’ daily activities,” said Mesulam, who in 1991 described the neural network for these language differences.
There are so many possible things that can go bump in the brain and cause deficits in how we process and use language, he said. People can have word-finding trouble, word usage problems, issues with putting words in a sentence in the correct order, spelling, or word comprehension problems.
Mesulam identified patients who also had reduced word output, and these patients had the same abnormal buildup of the Alzheimer’s proteins or FTD proteins in the language areas of the brain. He has described 10 language diseases under primary progressive aphasia. Each of these symptoms suggests a different underlying pathology.
Also during the 1980s, the late D. Frank Benson, a neurologist at UCLA, identified unusual visual and spatial symptoms in a handful of his patients.
He coined the term “posterior cortical atrophy” to describe people who have problems seeing things that are right in front of them. Numbers fly off the page. They have difficulty locating objects in space and judging spatial relationships. They have trouble writing and reading words on a page.
Like all of these neurodegenerative conditions, it is progressive.