Prion Test For Rare, Fatal Brain Disease Helps Families Cope

Feb 6, 2017
Originally published on February 6, 2017 11:24 am

By the time Kay Schwister got her diagnosis last summer, she couldn't talk anymore. But she could still scowl, and scowl she did.

After weeks of decline and no clue what was causing it, doctors had told Schwister — a 53-year-old vocational rehab counselor and mother of two from Chicago — that she had an incurable disease called Creutzfeldt-Jakob disease, or CJD.

The disease was shrinking Kay's brain, and riddling it with holes. She would likely live only a few more weeks, the doctors said.

It was a diagnosis that no one could ever want. But the fact that Schwister was able to get a firm diagnosis while still alive is a relatively new development that represents a step forward in understanding a group of devastating neurological disorders. And, some biochemists say, it could lead to better ways of diagnosing brain diseases that are much more common, including Parkinson's and Alzheimer's.

For Kay Schwister, it all started in the spring of 2016, when she started getting headaches and feeling dizzy all the time. Aging, she told herself, just didn't feel very good.

Over the next few weeks, she got steadily worse.

"She got to the point where she was so nauseous and so dizzy that she stopped driving and actually stopped working," says her husband, Tim Schwister.

By the time Kay entered the emergency room last June, her speech had changed. She was enunciating things in a strange way, and finishing each sentence on a really high note.

Doctors drew blood and spinal fluid and tested it for things like multiple sclerosis and mercury poisoning. Those tests came back negative.

Soon, Kay couldn't talk or walk.

"Not knowing what we were dealing with was probably one of the hardest things to ever go through in life," says Tim. "We really wanted to know what we were up against, and if there was anything that we could do."

Ultimately, Kay's doctors ordered a newly developed test for Creutzfeldt-Jakob disease — a very rare condition that's thought to kill about 1 in a million people worldwide every year, including about 300 deaths annually in the U.S.

That test came back positive. About a month after Kay entered the hospital, the Schwisters had their answer. It was ugly, but still an answer.

Normal proteins in Kay's brain had started misfolding, bending themselves into an unnatural shape and coaxing other proteins to do the same, like some kind of malicious origami. These misshapen proteins, known as prions, formed clumps in the brain, causing neurons to die.

"It's almost as if it starts to turn certain portions of your brain off," says Tim.

The vast majority of CJD cases worldwide are like Kay's, popping up for no apparent reason. Other cases seem to be inherited. A very small number of patients have contracted the illness through close contact with material from an infected person's brain or nervous system — during certain transplant procedures or via contaminated surgical equipment, for example. And another form, variant CJD, is the human version of mad cow disease, and has been linked to eating infected beef.

The last known time someone in the U.S. got CJD from contaminated surgical tools was in 1976; the last known U.S. death due to CJD acquired from infected human tissue was in 2014, says Safar, likely acquired years before from contaminated human growth hormone.

There is no cure or treatment for CJD. All Tim could do for his life partner of 35 years was to try to make her as comfortable as possible. Still, having a diagnosis spurred the many people who loved Kay into action, Tim says. Family and friends flew in from all over the country to visit. She was rarely alone.

"Every day, it was nonstop," Tim says. "People that were there to visit with her, just to try to keep her spirits up."

She never went home. Kay Schwister died within seven weeks of entering the hospital.

Until recently, families like the Schwisters wouldn't have known what their loved one was suffering from until it was all over, when an autopsy might have shown that the brain was smaller than expected. Under a microscope and using a special stain, a pathologist would have seen holes in the brain, along with tangles and clumps of misfolded proteins.

But diagnosis after death is too late — not just for the patient and families, but also for researchers trying to study potential therapies to slow down or stop the progression of the disease. These same diagnostic frustrations apply to some of the most common forms of dementia, including Parkinson's and Alzheimer's disease, which are also associated with protein misfolding.

"The trouble with many of these diseases, some of which are incredibly prevalent, is that it can take months or years [to diagnose]," says Byron Caughey, a biochemist at Rocky Mountain Laboratories in Hamilton, Mont., a part of the National Institute of Allergy and Infectious Disease.

A previous spinal fluid assay for CJD could identify brain cell injury, but not the cause of that injury. That's why Caughey recently teamed up with scientists in Italy, Japan and the U.K. to develop a different test. It's called RT-QuIC, which stands for "real-time quaking-induced conversion."

The test, developed a few years ago and still available via only a few laboratories, harnesses the bad protein's ability to induce normal, neighboring proteins to take on its twisted form. The test takes about 90 hours and involves getting a sample of spinal fluid, shaking it up with normal proteins and waiting to see if the normal proteins misfold.

Caughey and some Italian scientists have even figured out how to avoid the spinal tap; they can make the test work with a sample of cells taken from deep inside a patient's nostril, from a spot that is separated from the brain by just a bony partition.

"So, we now have the ability to collect a little bit of spinal fluid or nasal brushing from patients while they're still alive, and with quite a high degree of certainty, tell whether or not they have a prion disease," says Caughey. In several studies now, he says, the RT-QuIC test has sensitively and specifically identified CJD prions in symptomatic patients; the test has since been distributed to CJD surveillance centers in multiple countries.

"Technologically, it's a major new paradigm for testing protein misfolding," says Dr. Jiri Safar, director of the National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland and one of Caughey's collaborators. Since the center started using the assay in April 2015, it has tested more than 5,000 samples from patients referred by doctors scattered around the U.S., Canada and Mexico. And within that group, Safar says, about 500 people tested positive for CJD. The assay costs about $50 to run.

"It's a major game changer," says Safar, who hopes wider use of the test in suspected cases will help to completely eliminate the already scant possibility of transmitting CJD through infected blood or organs.

Caughey, Safar and colleagues reported in late November in the journal Annals of Neurology that a second-generation version of their test was just as effective in diagnosing the disease as an autopsy or biopsy of a living brain (which is another diagnostic option, but a risky, invasive one).

Alison Green, a biochemist at the University of Edinburgh in the U.K., is now working on a modified version of the test that has been shown capable of detecting Parkinson's disease and Lewy body dementia.

"It's very important, because there is no other diagnostic test for Parkinson's disease," Green says. "It's purely a clinical diagnosis at present."

Parkinson's is a chronic and progressive movement disorder that eventually includes symptoms of dementia in an estimated 50 to 80 percent of cases. Diagnosing it sometimes requires years of observation, at which point a patient has already lost a lot of neurons.

In a small study published last summer, Green used a version of RT-QuIC that looks for alpha-synuclein (a protein that's associated with Parkinson's) on 20 people who had a Parkinson's diagnosis, and 15 people in a control group.

"And you can get a nice, clear-cut positive result after 120 hours," she says. Nineteen out of 20 patients with Parkinson's were correctly identified, and there were no false positives. Green is now replicating the study with 110 subjects.

If the test proves to be as reliable as it was in her first study, Green says, it could become an important diagnostic tool for doctors to rapidly identify a patient's ailment and start therapies as soon as possible, when they might still make a difference.

"A lot of these drugs or therapies are being introduced way too late because patients aren't diagnosed early enough," Green explains. "And they may be effective treatments if you give them earlier."

She's also applied for funding to develop a test that would look for abnormal beta-amyloid peptides, possible indicators of Alzheimer's disease.

The ultimate goal, says Green, is to have a whole bank of RT-QuIC assays so that patients with any kind of undiagnosed dementia can get answers.

Knowing the prognosis earlier, she says, could give some patients and families more choices.

"If you have early onset dementia, do you really want to spend the last few years of your life working, or do you want to take early retirement?" says Green.

And even for diseases that have no option of being slowed or reversed, she says, a firm and accurate diagnosis can still offer something essential to families — a spur to move beyond tests and treatments.

"We really, truly wanted to know if there was something that we could do for her," says Tim Schwister of his wife, Kay. The diagnosis let him and his sons know that chasing further treatment at that point wouldn't help, and that the best they could do was to turn their attention to making Kay comfortable, and spending time with her.

The diagnosis also helped the Schwisters connect with other families who'd gone through the same experience.

In a time of such great loss, Tim says, "it's nice to know that you're not alone."

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Scientists have developed a better test for a very rare brain disease. And as NPR's Rae Ellen Bichell reports, this test could lead to new ways to diagnose more common diseases like Parkinson's and Alzheimer's.

RAE ELLEN BICHELL, BYLINE: Last spring, Kay Schwister started feeling strange. Her head hurt, and she felt dizzy all the time. She was 53 years old. And aging, she thought, just didn't feel very good. But her husband Tim says over the next few weeks, she just got worse.

TIM SCHWISTER: She was so nauseous and so dizzy that she stopped driving and actually stopped working.

BICHELL: Tim says by the time Kay was admitted to the hospital, she was talking in a strange way.

SCHWISTER: And she would end at a very high note as you were talking to her. And you knew right away that something certainly wasn't right.

BICHELL: Doctors drew blood and spinal fluid and tested it for all sorts of things, like multiple sclerosis and carbon monoxide poisoning. The tests all came back negative.

Tim and his two sons, one in college and one in high school, spent a lot of time at the hospital with Kay.

SCHWISTER: Not knowing what we were dealing with was probably one of the hardest things to ever go through in life. We really, truly wanted to know if there was something that we could do for her.

BICHELL: Weeks went by. Kay couldn't walk or talk anymore, but doctors still didn't know what was wrong. Then, Tim says, they ordered a brand new test for a rare condition, Creutzfeldt-Jakob disease, or CJD. It came back positive.

CJD is really rare, literally 1 in a million. It's fatal, and there's no treatment. The disease was shrinking Kay's brain and riddling it with holes.

SCHWISTER: It's almost as if it starts to turn certain portions of your brain off.

BICHELL: CJD is one of a number of diseases that happen when normal proteins in the brain get folded the wrong way, forming clumps that kill off neurons. Now that they had a diagnosis, the Schwisters knew Kay didn't have long. Tim says family and friends flew in from all over the country to visit her in the hospital.

SCHWISTER: No, she didn't come home.

BICHELL: Kay died a few weeks later.

The reason a test for CJD exists at all is because of people like Byron Caughey. He's a biochemist at Rocky Mountain Laboratories in Montana, who helped develop the method, which involves a spinal tap and takes about four days. But why bother coming up with a test if there's nothing anyone can do about CJD?

BYRON CAUGHEY: Well, there's a couple of reasons why that's important. One is to provide accurate information to the patient, their family and the doctors so that they know what's ahead of them.

BICHELL: Caughey says another is to help researchers study possible treatments. And then there's this.


UNIDENTIFED REPORTER: New this morning - a North Carolina hospital says surgical tools may have exposed 18 patients to a rare and deadly brain disease.

BICHELL: CJD can be passed between patients during certain surgeries, although the last report of that happening was in 1976. But the possibility can put hospitals on edge, says Caughey, because these misfolded proteins survive normal sterilization.

CAUGHEY: It's already a small risk, but it'd be nice to reduce it to zero since it's fatal and there's no treatment and it's really devastating to all concerned.

BICHELL: Alison Green, a biochemist at the University of Edinburgh in the U.K., sees another possibility for this test - as a template for many others. She says while CJD may be extremely rare, there are much more common diseases that also involve proteins misfolding.

ALISON GREEN: Such as Alzheimer's disease, Parkinson's disease, Lewy body dementia and some forms of motor neuron disease as well.

BICHELL: The test for CJD specifically detects proteins called prions. But Alison Green is modifying it to detect other proteins, like alpha-synuclein, which is associated with Parkinson's disease. In a small study, Green's modified test successfully detected Parkinson's in 19 people. She's now redoing the study on a larger scale. And she's applied for funding to work on a test that might someday spot Alzheimer's early on.

GREEN: So yes, the idea is to introduce it for Alzheimer's disease and other protein-misfolding disorders as we go along.

BICHELL: Ultimately, Green says she'd like to have a whole bank of tests so that patients with any kind of undiagnosed dementia can get answers.

GREEN: If you have early onset dementia, do you really want to, maybe, spend the last few years of your life working? Or do you want to take early retirement? They may be able to actually make decisions about their life.

BICHELL: Green and Caughey hope that in the future, their tests will give people the chance to make those decisions.

Rae Ellen Bichell, NPR News. Transcript provided by NPR, Copyright NPR.