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Study suggests that Alzheimer’s can be detected before the onset of symptoms.
August 28, 2017

One of the greatest difficulties plaguing efforts to find effective treatments for Alzheimer’s is the enormous lag between the disease’s inception and the appearance of clinical symptoms, according to Paul Coleman, an Alzheimer’s researcher at the ASU-Banner Neurodegenerative Disease Research Center.

In a new study, Coleman and his colleagues demonstrate the promise of an early blood test for Alzheimer’s disease. The results suggest that Alzheimer’s can be detected even before the onset of symptoms in persons at genetic risk for Alzheimer’s disease.

Paul Coleman

In addition to the ASU-Banner Neurodegenerative Disease Research Center, study collaborators include ASU, the Mayo Clinic, University of Rochester, Banner Alzheimer Institute and Barrow Neurological Institute.

The new method successfully distinguished between Alzheimer’s, Parkinson’s and healthy controls, indicating that the test does not simply identify general phenomena of neurodegeneration but is able to pick out Alzheimer’s disease from other degenerative brain conditions.

“What we’ve done in our paper is to replicate our own work multiple times with different populations and even using different technologies,” Coleman said. “We also presented data showing the ability to detect people at risk of a future diagnosis for Alzheimer’s disease.”

The method accomplishes this feat by examining white blood cells, or leukocytes. Here, segments of RNA known as transcripts — derived from specific DNA genes — hold vital clues regarding health.

The study was recently published in the journal Neurobiology of Aging.

Hidden menace

Alzheimer’s disease continues its pitiless ascent. The illness afflicts 11 percent of those 65 or older, with the figure soaring to 45 percent for people older than 85. Current trends predict some 14 million Americans will be afflicted with the disease by midcentury at a cost of a trillion dollars.   

Alzheimer’s tears out its victim’s memory, reasoning capacity and personal identity, necessitating around-the-clock care before death eventually ensues. The crippling toll of the disease on patients, family and society at large makes it a global health crisis of frightening proportions.

Researchers now know that by the time the first outward manifestations of Alzheimer’s appear, in the form of confusion, memory loss and other classic hallmarks, Alzheimer’s has been ravaging the brain for decades. If the disease could be identified much earlier — close to its origin — there is hope that perhaps it could be slowed or even halted in its tracks.

Given the vital need for a safe and reliable early diagnostic for Alzheimer’s, many previous efforts have taken aim at the problem. Ideally, such a method should be appropriate for primary-care settings, allowing a broad swath of the public to be accurately and regularly tested.

Until now, however, efforts to develop a reliable early diagnostic for Alzheimer’s have run aground. Further, the accuracy of diagnosis even after the disease has entered its clinical phase remains poor.

Signposts of disorder

It has long been known that Alzheimer’s produces changes in the brain, which can stimulate genes relating to such conditions as stress and inflammation. Expression of these genes appears in the blood in the form of specific RNA transcripts.

The research results clearly demonstrate that these RNA transcripts can be combined into a potent early diagnostic or biomarker, able to distinguish normal patients from those with Alzheimer’s or Parkinson’s disease and — most importantly — make accurate predictions about patients at risk for future development of Alzheimer’s disease.

The diagnostic precision of the new test is significant. Existing diagnostic screening results for known Alzheimer’s disease cases (identified through clinical and neuropathological factors) showed diagnostic sensitivityIn medical diagnosis, sensitivity is the ability of a test to correctly identify those with the disease, known as the true positive rate, whereas specificity refers to the ability of the test to correctly identify those without the disease or the true negative rate. was between 71 percent and 87 percent while specificity ranged from 44 percent to 70 percent.

Such diagnoses are typically conducted in specialized facilities devoted to the study of Alzheimer’s. As the authors note, the accuracy of standard diagnosis falls significantly in primary-care settings. The result is that Alzheimer’s is generally detected very late in the disease process, if it is correctly identified at all — a blueprint for treatment failure, because the illness has already irreparably damaged the brain. The high rate of misdiagnosis leads to frequently unnecessary and ineffective treatment.

Disease in the crosshairs

In a fresh approach, the authors identify RNA transcripts in blood using two different RNA-analysis techniques, known as cDNA array and reverse transcriptase polymerase chain reaction (RT-PCR). Results of the two methods were in close agreement and were further shown to be replicable across multiple sample populations. This allowed the researchers to design a consistent suite of transcripts that could be used to diagnose the disease. This multivariate analysis demonstrated impressive accuracy in a number of critical experiments described in the new paper.

The study divides 177 blood and 27 postmortem brain samples into several groups, establishing that careful analysis of RNA transcripts in blood samples has the ability to distinguish early clinical Alzheimer’s disease, Parkinson’s disease and cognitively healthy patients. It can accurately identify those carrying two copies of the APOE4 gene — known to be a severe risk factor for developing Alzheimer’s. Transcript screening was also used to identify those at risk for future cognitive impairment due to having at least one direct relative with Alzheimer’s disease.

The study reveals that both cDNA and RT-PCR methods managed to distinguish probable Alzheimer’s disease from normal controls with an accuracy of 93.8 percent, using just five RNA transcripts for the test. As the authors note, the blood test’s accuracy may be even higher as some of the “false positives” — healthy cases mischaracterized as Alzheimer’s — may be from subjects who are actually positive for pre-symptomatic manifestations of Alzheimer’s.  

Assessing future risk

The results demonstrate that multivariate analysis of transcripts in blood samples provide an accurate and minimally invasive strategy for diagnosis of Alzheimer’s and early detection of its risk. Further, the results were consistent with examination of the same transcripts identified in the post-mortem brains of subjectsThe brain samples, obtained through the Banner Sun Health Research Institute, were taken from a region known to be vulnerable to the most devastating effects of Alzheimer’s. with Alzheimer’s compared with those diagnosed with Parkinson’s disease and with normal controls.

In addition to RNA transcripts linked with inflammation and stress, the study examines a series of epigenetic transcripts — RNA sequences that have undergone post-transcriptional modification. Results again found a strong correlation between the presence of these epigenetic markers and AD, implying they may also provide a compelling diagnostic tool.

Future refinements should sharpen the method’s ability to accurately identify Alzheimer’s disease at an early stage — prior to the onset of clinical symptoms — in a primary-care setting, with just a simple blood extraction. Efforts to conduct long-term longitudinal studies and hunt for additional diagnostic transcripts should eventually be combined with testing of new therapeutics aimed at early intervention.

Intriguingly, one or more of the many existing drugs for Alzheimer’s that have failed in clinical trials may actually succeed in slowing or arresting Alzheimer’s if they can be delivered early enough in the disease process. Further, trials for new drugs targeting at-risk patients can be ramped up significantly if a simple, non-invasive blood test can replace costly imaging like PET scan.

The new early diagnostic therefore represents a promising milestone in the war on Alzheimer’s disease.  

 

Top image: In a new study, ASU-Banner Neurodegenerative Disease Research Center researcher Paul Coleman and his colleagues at ASU, Mayo Clinic, University of Rochester, Banner Alzheimer Institute and Barrow Neurological Institute describe a blood test to detect Alzheimer's disease at a pre-symptomatic state. 

Richard Harth

Science writer , Biodesign Institute at ASU

480-727-0378

 
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Your career may not match your degree and that's ok, say these ASU professors.
August 28, 2017

3 ASU faculty aren't doing what they originally set out to — and their lives are better, and more interesting, for it

Education is what’s left after you’ve forgotten what you learned in school, Albert Einstein said.

Curiosity and learning how to learn — what some call being a master learner — are far more powerful indicators of success than a choice of major. A specific field of study might just be a stepping stone to something else.

Only 51 percent of college graduates working said their job is related to their major, and 32 percent said they never worked in a field related to their majors, according to a pair of surveys by CareerBuilder.

As crushing as that might sound right now to students immersed in differential equations or thesis wrangling, it’s not the end of the world.

In fact, it might be the beginning of a whole new one. Three of Arizona State University’s most accomplished faculty members aren’t doing what they set out to do, and they couldn’t be happier or more successful.

Rolf Halden is an engineer who practices chemistry. Phil Christensen is a planetary geologist who engineers instruments. Randy Nesse is a psychiatrist who studies biology.

Curiosity carried all three of them away. They more or less fell into what they do now.

Halden has a bachelor’s degree, two master’s degrees and a doctorate. He is the spokesman for the American Chemical Society, but of those four degrees, not one is in chemistry.

“I’ve found a place I really appreciate and love to work in,” Halden said. “I got the job based on being an engineer, but I keep the job by combining chemistry and biology and using the quantitative tools from engineering. It’s a convoluted professional path. It’s also a long one if you look at how many degrees I’ve picked up.”

Christensen has four instruments in space and three more slated for flight.

“For me, it’s really been fun,” he said. “I’ve gotten to the point now where I find coming up with the idea, designing it, making it happen and seeing the end product of this instrument that was a cartoon on the back of an envelope five years ago and now it’s a piece of hardware sitting on a desk — that is really satisfying. … That creative process is almost more fun than the science you do with that instrument once you’ve built it.”

Nesse became curious about evolutionary processes when he was a professor of psychiatry at the University of Michigan. He asked some biologists a few questions about evolution. They laughed at him.

“It was really made possible by these really receptive biologists at the University of Michigan,” said Nesse, founding director of ASU’s Center for Evolution and Medicine. “It really started with curiosity, not just about evolution again, but how things in the body seem out of design. ... A lot of it is we just can’t help ourselves. We get interesting ideas and that’s how we are.”

A chemist who isn’t

ASU Professor Rolf Halden
ASU Professor Rolf Halden (during a Feb. 8 lecture about his research on non-degradable toxins that reside for generations in humans' fat layers) is the spokesman for the American Chemical Society — but none of his four degrees is in chemistry. Photo by Charlie Leight/ASU Now

HaldenRolf Halden is director of the Center for Environmental Security at the Biodesign Institute, professor in the Ira A. Fulton School for Sustainable Engineering and the Built Environment, and senior sustainability scientist in the Global Institute of Sustainability at ASU. began his career studying zoology and botany in Germany.

“Then I looked at the job market and found there are not a lot of jobs in that area,” he said.

He specialized in microbiology, biotechnology, and sanitary engineering as a second elective, and earned his diploma.

“Even with those changes, there wasn’t a lot of opportunity,” Halden said.

He then started working on a doctorate in genetics: “I also thought this is probably not going anywhere good.”

He rebooted as an engineer by leaving Germany and studying civil engineering in the U.S.

“What I took from the biology was an understanding of microorganisms,” Halden said. “When I went into engineering, I used engineering quantitative tools to design remediation strategies for cleaning groundwater and soil.”

However, “neither engineering nor biology work well if you don’t have a good understanding of chemistry,” he said.

Halden always liked chemistry. When he started working in engineering, he worked on dioxins, cancer-causing agents that pollute groundwater and soil. He was in soil remediation, looking at how to move these carcinogens, using microorganisms that are supposed to gobble them up. In order to see what worked, he had to extract chemicals from soil and analyze them with tools like high-resolution mass spectrometers.

“In order to complete my studies I needed to learn analytic chemistry,” he said. “I always had an appreciation for chemistry. A lot of people don’t like chemistry. It’s just painful. I see chemistry as a unifying scientific discipline that brings all aspects together.”

Halden is a board-certified professional civil engineer, but he runs a mass spectrometry facility and is one of the experts for the American Chemical Society.

“They have selected me as a spokesperson to best represent their science, although I don’t carry a degree in chemistry, which is a bit bizarre,” he said.

A bug for space

Scientists work in a clean lab
Phil Christensen (with doctoral student John Hill, left, and project engineer Greg Mehall last summer in the thermal vacuum test chamber on the Tempe campus) went from working on other's space instruments to proposing his own, to eventuallying helping design and build his own. The geologist has four instruments in space and three more slated for flight. Photo by Charlie Leight/ASU Now

Christensen was always interested in geology. When he was in high school, he watched the moon landing and became intrigued with space.

“But it never occurred to me growing up that I could work for NASA,” said the Regents' Professor in ASU's School of Earth and Space Exploration. “That was smart people.”

He got a degree in geology. During his senior year at UCLA, he worked for a guy who was building an instrument to go on a NASA mission to Mars.

“Wow, this was incredible,” Christensen said. “Mars. Geology. Planetary science. Space.”

Christensen went on to earn a doctorate in planetary geology.

“But that involvement with a mission ... that was an addictive process. It was so much fun,” he said. “You wake up every morning, and you go in and you see new pictures coming back from Mars today that no one has ever seen. Early on I really got this bug of wanting to be involved with missions: the exploration part, the new data, the new discoveries.”

Christensen knew he could be a part of someone else’s mission. A faculty member at Arizona State — Mike Malin, now CEO of a San Diego company that designs, develops and operates instruments to fly on unmanned spacecraft — said to Christensen, “Why don’t you propose your own instrument?”

Christensen called up an engineer he knew through his adviser and said he wanted to propose an instrument.

“I was 30 at the time. I knew nothing,” he said. “This man — Stillman Chase, who is still one of my best friends — was amazingly supportive. Here’s this young kid, calls him out of the blue, says, ‘Sure, come out to Santa Barbara. We’ll talk. We’ll see how this goes.’”

Christensen went out to the Santa Barbara Research Center, became a lead scientist and proposed an instrument.

“To everyone’s amazement, including my own, NASA selected that instrument to go on a mission,” he said.

That was in the late 1980s. For years, Christensen worked with the center, as a scientist working with engineers who did the hardware. Then he got a new bug. Instead of telling engineers what kind of measurements he wanted to make and what kind of data he wanted to collect, he wanted to be involved with the building and design.

Jump forward 20 years. The Santa Barbara company closed down. ASU wanted to build more capability on campus. About five years ago Christensen suggested hiring some of the engineers to come work for him at ASU.

“Now suddenly I find myself the CEO of a little aerospace company,” he said. “I’m now an engineer, working with 20 engineers. They look at me as sort of a pseudo-engineer: ‘OK, Phil — we’ll take it from here.’”

Jobs that don’t even exist yet

ASU Professor Randy Nesse
Randy Nesse was laughed at when, as a professor of psychiatry, he began asking biologists about evolution. He's now one of the world's preeminent researchers in the field of evolutionary medicine and is the founding director of ASU's Center for Evolution and Medicine. Photo by Deanna Dent/ASU Now

There are some pitfalls to avoid when transitioning from one field to another. Halden has a long and distinguished track record — his resume is 67 pages — of chasing chemistry through food and water and soil into people, but he is humble.

“I know I lack a lot of knowledge, which is a risk when you move into an area where you have not been formally trained,” he said. “There are things you are not aware of. You can make mistakes that others would not make, but you also bring more creativity and awareness of other fields with you.”

Christensen’s progression went from being interested in the science to wanting to use science data to wanting to get his own science data to wanting to build the instruments that get that science data.

“A lot of science is that way — it’s an experimental process,” he said. “A lot of scientists end up designing and building their own experiments. It’s not that unusual.”

Now he builds instruments to go to strange places like asteroids and Jovian moons and study strange objects.

“It’s been this wonderful transition and it’s been a lot of fun,” he said. “I really enjoy what I do now.”

A lot of people in school right now will ultimately perform in a job that doesn’t even exist or for which there are no training programs, Halden said.

“That might sound odd, but if you look at the environment and the marketplace and how quickly it’s changing — self-driving cars and solar power and decentralization of a lot of services — people have to be willing and able to work in areas where they have not been trained,” he said. “It really pays off if you have engineering training because there are certain things you can always use that are always applicable.”

Nesse, a professor in ASU's School of Life Sciences, said he doesn’t consider his path as switching fields.

“I’ve always been an evolutionary biologist at heart,” he said. “It’s just there aren’t any evolutionary biologists in medicine.”

 

Top photo by Charlie Leight/ASU Now

Scott Seckel

Reporter , ASU Now

480-727-4502