Finding Simple Tests For Brain Disorders Turns Out To Be Complex
If you're having chest pain, your doctor can test you for a heart attack. If you're having hip pain, your doctor could test for osteoarthritis.
But what if you're depressed? Or anxious? Currently there are no physical tests for most disorders that affect the mind. Lab tests like these could transform the field of mental illness. So far efforts to come up with biomarkers for common mental health disorders have proved largely fruitless.
That doesn't stop people from trying. Doctors are looking to create them, and patients are taking them, too, even though they know that existing biomarkers — for Alzheimer's disease, for instance — have serious limitations.
Six years ago, Robin Jones of Menlo Park, Calif., found himself in a parking lot. He had no idea where his car was. That was unlike him. A 67-year-old scientist who worked on nuclear energy plants, he was good with details. "It was, you know, I can't believe this," Jones says now. "I can always remember where the car is."
At work, he had a hard time finding the right words. He'd come home and tell his wife, Anne, "Something's different."
Robin Jones made an appointment at the Stanford Center for Memory Disorders, where he went through the standard cognitive evaluation for Alzheimer's disease — memorizing lists of words and so on.
Jones did pretty well on the tests. Better, says Stanford neurologist Michael Greicius, than you'd expect from someone in the early stages of the disease.
"He didn't fit neatly into this classic presentation of Alzheimer's disease," Greicus says, "and that's one of the reasons we talked fairly early on about looking at biomarkers."
When Greicius says "biomarkers," he's referring to a very new thing in Alzheimer's disease and a very old thing in many other diseases: objective lab tests. Those are physical measures that can help doctors understand what is going on in a patient's body.
One Alzheimer's test checks spinal fluid for proteins that are signatures of the disease. Another uses a PET scan to look for physical evidence of brain changes.
Jones chose the spinal fluid test. "It seemed to me it would sharpen up my understanding of what was happening," he says.
These tests don't offer the certainty of, say, a pregnancy test. Some people who test positive for the Alzheimer's-linked proteins show no outward signs of the disease.
But a positive result, in combination with symptoms like Jones experienced, is a pretty definitive diagnosis of Alzheimer's, Greicius says.
Researchers say the Alzheimer's tests, limited as they are, give a hint as to what may be ahead with other mental disorders, like bipolar disorder or post-traumatic stress disorder (PTSD).
As evidence, they point to the transformation that's happened with biological tests for disorders like heart disease and cancer.
"When I was a medical student 40 years ago, patients would come in with chest pains and we would spend a lot of time talking to them," says Dr. Michael Weiner, a professor in radiology and biomechanical engineering at the University of California, San Francisco.
"Nowadays you draw blood enzymes," Weiner says. "And if a person has a rise in certain enzymes that come out of the heart, we say they had a heart attack. And if there's no rise in the enzymes, we say you didn't have a heart attack."
These days, Weiner is looking for patterns in brain imaging to see if the scans can reveal PTSD or traumatic brain injury.
But the brain is vastly more complicated than the heart. And it is taking Weiner and others much longer than many might have hoped to find biomarkers for mental disorders.
Weiner shows three MRIs of three different people. One is a healthy 23-year-old man. Another is a 32-year-old man who has quite severe PTSD. The third is of an older woman with Alzheimer's disease.
He points in each scan to a part of the brain called the hippocampus that's involved in memory. He says this part of the brain tends to be smaller in people with Alzheimer's and PTSD than in healthy people.
That's true when groups of people are averaged together. But when it comes down to individuals, it's impossible to tell who's in trouble, and who's not, he says.
"Here's the hippocampus in a healthy person and here's a hippocampus in the person with PTSD," Weiner says, "and they both look pretty much the same."
Despite the difficulties, scientists are still hunting mental health biomarkers that would be clearcut and simple — similar to the kind of blood and urine tests we're all familiar with.
One multimillion-dollar effort, funded by private foundations and the U.S. military, is looking for biomarkers for PTSD and traumatic brain injury. the idea is to explore whether changes in certain brain chemicals like cortisol and norepinephrine, which have been associated with anxiety and fear, could be signals of PTSD, according to Dr. Charles Marmar, head of psychiatry at New York University Langone Medical Center, who is leading the project. "There is a biological footprint of learned fear," Marmar says. The question is, he adds, "are there downstream effects?"
If there were, it would be easier to identify soldiers with PTSD and get them treatment.
In the case of Robin Jones, he and his wife were just looking for a clearer diagnosis.
Anne Jones was the first to find out the results of her husband's Alzheimer's test. The spinal tap test came back positive for tau and amyloid proteins, both suggestive of Alzheimer's disease.
"Sad, yes, there was sadness," she says. "But there is a certain amount of relief. There's relief knowing why your arm hurts or why you have a bad cough. Knowing how to sort of chart out the rest of our time together."
The test helped the couple realize that soon he was going to need her in ways he hadn't before. They decided she should take a trip by herself, to Florence, Italy, to see the great works of art she had studied in college.
And when she came back she felt refreshed, she says, and ready for the challenges ahead.
DAVID GREENE, HOST:
This is MORNING EDITION, from NPR News. I'm David Greene.
It's Monday, and today in Your Health, tracking brain disorders, which are different from other disorders in an important way. If you're feeling run down, a blood test can show whether you have anemia. If your joints hurt, medical tests can help determine whether you have arthritis. But what if you're depressed or anxious? What if you're having memory problems? Currently, there are no definitive lab tests for most brain disorders.
Amy Standen from KQED in San Francisco reports on the latest efforts to develop medical tests for problems that affect the brain.
AMY STANDEN, BYLINE: Six years ago, Robin Jones found himself in a parking lot. He had no idea where his car was.
ROBIN JONES: It was, you know, I cannot believe this. I can always remember where the car is.
STANDEN: This was unlike him. He was a scientist who worked on nuclear energy plants, good with details.
JONES: And I parked it there. Why can't I remember?
STANDEN: At work, he had a hard time finding the right words. He'd come home and tell his wife Anne something's different.
ANNE JONES: He would start to say that his brain didn't feel like it was working the same way it used to be. We said, well, why not talk to your primary care physician about it? And that started a cascade of events.
STANDEN: Robin made an appointment at the Stanford Center for Memory Disorders, where he went through the standard run-up for Alzheimer's disease, memorizing lists of words and so on. But at 67 years old, he did pretty well on them, better, says Stanford neurologist Mike Greicius, than you'd expect from someone in the early stages of the disease.
MIKE GREICIUS: He didn't fit neatly into this classic presentation of Alzheimer's disease, and it was one of the reasons why we talked fairly early on about looking at biomarkers.
STANDEN: When Greicius says biomarkers, he's referring to a very new thing in Alzheimer's disease and a very old thing in many other diseases: objective measures, or lab tests that can help doctors understand what's going on in a patient's body. One Alzheimer's test looks at spinal fluid for proteins that are signatures of the disease. Another uses a PET scan. Robin chose the spinal fluid test.
JONES: It would sharpen up my understanding of what was happening.
STANDEN: These tests don't offer the certainty of, say, a pregnancy test - at least not yet. Some people who test positive show no outward signs of the disease.
But a positive result, in combination with symptoms like Robin Jones', is a pretty definitive diagnosis of Alzheimer's. And in that sense, these tests may be a preview of what's ahead with other mental disorders, like bipolar disorder, or PTSD.
Michael Wiener, a brain scientist at UC San Francisco, says consider the transformation happened with heart disease a generation ago.
MICHAEL WIENER: When I was a medical student 40 years ago, patients would come in with chest pain, and we would spend a lot of time talking to them.
STANDEN: Asking them questions, like...
WIENER: Where is the pain in the chest? What brought it on? How does it radiate into your arm? This and that.
STANDEN: Then scientists discovered biomarkers of heart disease, for example, certain enzymes that leak into the blood stream when the heart is damaged. And voila: A blood test was born.
WIENER: Nowadays, you draw blood enzymes. And if a person has a rise in certain enzymes that come out of the heart, we say they had a heart attack. And if there's no rise in the enzymes, we say you didn't have a heart attack.
STANDEN: But the brain is vastly more complicated than the heart, which is why it's taken researchers much longer than many might have hoped to find biomarkers for mental disorders. Take Weiner's own area of expertise: brain scans, like Magnetic Resonance Imaging, or MRI. If scientists could see an anatomical signature of, say, bipolar disease in a brain scan, maybe they'd have a diagnostic tool, much the same way an X-ray is used to diagnose a broken bone. But Weiner says that hasn't happened.
WIENER: A perfect example - I have to get my computer to wake up here.
STANDEN: He pulls up an image on his computer.
WIENER: Here, we're looking at the MRIs of three different people. One is a healthy, 23-year-old man. Another is a 32-year-old man who unfortunately has quite severe post-traumatic stress disorder.
STANDEN: And the third is of an older woman with Alzheimer's disease. Weiner points to a part of the brain called the hippocampus that's involved in memory. He says this part of the brain tends, on average, to be smaller in people with Alzheimer's and PTSD than in healthy people. But when it comes down to individuals, it's impossible to tell.
And can we see that here? Can...
WIENER: No, we can't see it. That's the point. That's the point of this. Here's the hippocampus in a healthy person, and here's a hippocampus in the person with PTSD. And they both look pretty much the same.
STANDEN: You just can't measure the size of someone's hippocampus to see whether they have PTSD. But there may be other kinds of tests in the pipeline, tests involving blood or urine.
Charles Marmar, head of psychiatry at New York University's Langone Medical Center, is bullish about those.
CHARLES MARMAR: Blood, urine, cerebral spinal fluid will, over time, have something very important to say about risks for psychiatric illness, the presence or absence of illness, the prognosis of a given depressive illness.
STANDEN: Marmar leads a multi-million dollar effort funded by private foundations and the U.S. military to look for biomarkers of PTSD and traumatic brain injury. He believes PTSD may involve changes in the levels of certain brain chemicals, like cortisol and norephinephrine. These changes could indicate a brain that is overwhelmed by fearful memories.
MARMAR: There is a biological footprint of learned fear. And the question is, are there downstream effects?
STANDEN: In other words, biomarkers that would turn up elsewhere in the body, like in your blood.
Not all biomarkers involve lab tests. There may be other ways to objectively measure whether someone is suffering from a specific mental disorder.
BRUCE KNOTH: (Reading) When the sunlight strikes raindrops in the air, they act as a prism and form a rainbow.
STANDEN: Bruce Knoth reads a piece of writing called the rainbow passage. It's a standard tool that speech pathologists use to judge a patient's pronunciation and cadence. And Knoth thinks it could one day be used to pick up signs of mental disorders.
KNOTH: (Reading) A boiling pot of gold at one end; people look but no one ever finds it.
STANDEN: With funding from the NYU effort, Knoth and other scientists at SRI International, a private research in Menlo Park, California, are developing computer algorithms to pick up subtle differences in the way people with PTSD read the passage. That involves analyzing each and every word, looking for differences like this...
MALE COMPUTER VOICE: No.
FEMALE COMPUTER VOICE #1: No.
FEMALE COMPUTER VOICE #2: No.
STANDEN: Those differences are pretty obvious, says SRI's Dimitra Vergyri. Clues to a mental disorder could be much subtler, she says - the kinds of things a computer would do a better job picking up than a human.
DIMITRA VERGYRI: All we want to show is that there are features that we can extract automatically, measure them, and they can be an indicator of a very specific emotional state.
STANDEN: It could be a way to quickly screen lots of returning soldiers, for instance, to see who's at risk for PTSD. But biomarkers aren't just about screening, or diagnosis, says David Kupfer. He's heads the psychiatry department at the University of Pittsburgh. Kupfer believes biomarkers could end up changing way our society thinks about mental disorders, and also changing the experiences of people who have them.
DAVID KUPFER: It clearly increases hope.
STANDEN: Hope that if a mental disorder can be measured and quantified, that knowledge could one day lead to better treatments. Understanding the biological basis for mental disorders might also chip away at some of the social stigma around them.
KUPFER: It makes it more apparent, if you will, which is the reality, that these disorders are no different from other kinds of disorders.
STANDEN: Like heart disease or arthritis or Alzheimer's.
Anne Jones, Robin's wife, who we met in the beginning of the story, she was the first to find out the results of Robin's Alzheimer's test. The test came back positive for amyloid proteins, which form plaques in the brain, and tau proteins, another telltale signal of Alzheimer's disease.
JONES: Sad, yeah, most of its sadness. But there is a certain amount of relief. There's relief knowing, you know, why your arm hurts or, you know, why you have a bad cough, and knowing how to sort of chart out the rest of our time together.
STANDEN: The test helped her and Robin realize that soon, he was going to need her in ways he hadn't before. They decided she should take a trip, by herself, to Florence, to see the great works of art she had studied in college. And when she came back, she felt refreshed, she says, and ready for the challenges ahead.
For NPR News, I'm Amy Standen, in San Francisco.
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GREENE: And you're listening to MORNING EDITION from NPR News. Transcript provided by NPR, Copyright NPR.