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Neurology Today:
doi: 10.1097/01.NT.0000396250.31229.3f
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A Million Dollar Idea — A Potential Biomarker for ALS

Talan, Jamie

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Neurologist Seward Rutkove, MD, has won $1 million for research that uses an impedance method to monitor the electrical properties of muscle fibers in patients with amyotrophic lateral sclerosis (ALS).

DR. SEWARD RUTKOVE s...
DR. SEWARD RUTKOVE s...
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As part of his award-winning proposal, Seward Rutkove, MD, posited that electrical impedance myography (EIM) could identify small changes in muscle fibers and be used to detect ALS disease progression. The award was given to him last month by Prize4Life, a nonprofit organization founded by a Harvard University business school graduate who was diagnosed with ALS at the age of 29. [See “More About Prize4Life.”]

The idea seemed intuitive — pass an electrical current through muscle fibers to see how the current changes over time — but it had not been used among neurologists working with ALS patients.

The technique involves placing four surface electrodes along the muscle of interest. A minute alternating current is applied across the outer two electrodes, and the inner electrodes record voltage signals. From these recordings, the electrical impedance of the muscle at a given input frequency can be calculated. The current travels differently through healthy and diseased tissue, Dr. Rutkove explained, and clinicians can compare the size and speed of the electrical current over time to track the progression of the disease.

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THE INCEPTION OF AN IDEA

Dr. Rutkove, chief of the Division of Neuromuscular Diseases in the department of neurology at Beth Israel Deaconess Medical Center, began working on this idea in 1999.

Dr. Rutkove was sick of watching his patients squirm under the long probing needle of an EMG test used to measure the electrical impulses of muscle. There had to be a better way, he thought.

Dr. Rutkove, a neuromuscular expert, scoured the literature for anything that had ever been used to evaluate nerves and muscles. He found it in a reference to a small 1997 study by two physicists, Carl Shiffman and Ronald Aaron, at Northeastern University, who had been studying the characteristics of electrical current flow through localized areas of muscle By testing impedance methods in muscle. The publication was in an obscure journal, Physics in Medicine and Biology, but the Harvard neurologist could not let go of the idea.

Dr. Rutkove began collaborating with Joel Dawson, PhD, a professor in the Department of Electrical Engineering and Computer Science at MIT, to develop a portable, handheld device designed to measure the health of muscles.

Dr. Rutkove obtained a bioimpedance analyzer and 60 ALS patients volunteered to be tested with the technique, which was noninvasive, painless, and fast.

The patients in his ongoing studies underwent repeated EIM measurements of one or more muscles for a period of up to 18 months. So far, the measurements have been restricted to five muscles: biceps, forearm flexors, quadriceps, tibialis anterior and medial gastrocnemius. Mean values and standard deviations were also taken from data from over 100 healthy volunteers from 18-90 years old.

He analyzed the information from the first 60 patients, all of whom have had at least one repeat EIM measurement, and found that he could identify changes in the EIM data in ALS patients showing that the disease was progressing even over relatively short periods of time.

Dr. Rutkove and his colleagues calculated the potential power of the EIM measure assuming the treatment effect was 30 percent, 20 percent, and 10 percent. They compared the readouts over several points in time to assess changes in electrical impedance moving through the muscle.

They extrapolated, for example, that EIM would have about an 84 percent power to detect a treatment effect of 30 percent with just 50 patients in each arm in six months of a placebo–controlled trial.

Like any measure, Dr. Rutkove said, EIM has its limitations. He found that certain factors can affect the reliability of the results. For example, edema and artificial joints may alter the measurements. He also found that the voltage electrodes need to be placed in the same positions on repeat testing to insure an accurate measure.

It is still too early in the research to know exactly what muscles will need to be used in ALS. Dr. Rutkove said that it will probably be the muscles in the limbs that are deteriorating “but only future research will answer that.”

Neurologists have no easy way to monitor the relentless progress of ALS, Dr. Rutkove noted. The standard approach is the ALS Functional Rating Scale that measures 12 different functions — from breathing to activities of daily living. It is powerful over time but is not incredibly sensitive in the short term, given that individuals are so variable in the course of their disease.

The scientific committee who reviewed the material he submitted for the award agreed that it was a better biomarker than the strength functional testing because it can detect changes before such functional/strength changes have taken place; it can detect changes in very weak muscles and gives faster and more reliable information on the muscle than the classic muscle/strength training, which provides variable results because clinicians are evaluating groups of muscles.

Dr. Rutkove said that the test can also assess muscles on the tongue that have not been amenable to strength testing.

The neurologist started a company, Convergence Medical Devices, which is designing and building EIM machines for use in ALS and other muscle disorders. Beth Israel Deaconess has filed patents covering the device and the underlying technique.

“I want to use the [prize] money to free up my time for this and other research pursuits,” he said.

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EXPERTS COMMENT

“We are hoping that EIM can cut the cost of ALS clinical trials in half from an average of $10 million to less than $5 million,” said Melanie Leitner, PhD, a neuroscientist and chief scientific officer for Prize4Life. She said that she was enormously encouraged that two major biotechnology companies, Genzyme and Biogen Idec, are considering incorporating the technology into upcoming clinical trials to accelerate the development of potential treatments for ALS. An additional small start-up company, NeuralStem, is already using the biomarker in an ALS clinical trial.

“We hope that it can be a valuable biomarker-like device,” said Jeffrey D. Rothstein, co-director of the Brain Science Institute at Johns Hopkins School of Medicine and director of the Robert Packard Center for ALS Research, who was not a member of the awards committee but has been following Dr. Rutkove's work in published studies. “But while we are excited about this as a potential tool we have to wait and see. The good news is that it will be used experimentally in clinical trials so we can learn whether or not it will be useful.”

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More About The ALS ‘Prize4 Life'

The ALS ‘Prize4Life' set its goals and rewards high when it announced its ALS Biomarker Challenge award. A million dollars would be paid to anyone who came up with a good biomarker for ALS that was testable, reproducible, and sensitive enough to see differences within months. It had to be powerful enough to cut a phase 2 clinical trial down to half its cost and, of course, it had to be safe, tolerable, and preferably noninvasive to virtually all patients.

This was not a merit award like the Lasker or Nobel Prize. This was an incentive prize, the brainchild of 35-year-old Avi Kremer, a young Harvard University business student who himself was diagnosed with ALS at the age of 29.

Kremer and his friends co-founded Prize4Life in 2006 and they put forth the million-dollar charge of finding a biomarker for ALS, raising money from private donors for the prize.

Behind the scenes, Prize4Life was hitting a nerve. The young organization watched as 50 teams from 18 countries began competing for the million-dollar prize. But no one reached the high benchmark that the Prize4Life scientific committee had set. (See “Prize4Life Science Advisors.”)

A few months ago, eight members of the organization's scientific committee sat around a table in Boston and studied the four submissions received up to that point. When they got to Dr. Rutkove's, one by one, the scientists nodded their heads. It seemed intuitive, the kind of technique the field needed but never had.

Lucie Bruijn, PhD, a member of the Prize4Life science advisory board who is the science director and vice president of the ALS Association, said: “While the team of scientific advisors were excited about this research, a biomarker is not proven until it goes into a clinical trial with a promising drug and the biomarker can consistently measure a change in the muscle over the course of the study. The machine records the response of a muscle and the wave pattern is sensitive to change over a short period of time. Clinicians may be able to measure groups of muscles that may already be affected in the disease process but have not been picked up clinically. I am enthusiastic about the technology. But we are still not at the point where we have a biomarker for ALS.”

The young man whose disease inspired this transformative business model is now back home with his family in Israel and even though he can no longer speak or move his hands or legs, he remains active in the non-profit organization as its CEO.

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PRIZE4LIFE SCIENCE ADVISORS

* Robert H. Brown, MD, DPhil, head of neurology at University of Massachusetts Medical School and University of Massachusetts Memorial Medical Center

* Lucie Bruijn, PhD, science director and vice president, ALS Association

* Valerie Estess, co-founder Project ALS

* Adrian Ivinson, PhD, founding director of the Harvard NeuroDiscovery Center (originally the Harvard Center for Neurodegeneration and Repair)

* Edward M. Kaye, MD, group vice president and therapeutic area head in clinical research, Genzyme Corporation

* Tom Maniatis, PhD, the Thomas H. Lee Professor of Molecular and Cellular Biology, Harvard University

* Michal Preminger, PhD, MBA, executive director of the Harvard Medical School Office, Harvard University's Office of Technology Development

* Al Sandrock, MD, MD, senior vice president of neurology research and development, Biogen Idec

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References:

Rutkove S. Electrical impedance myography as a biomarker for ALS. Lancet Neurol 2009; 8(3):226.

Rutkove SB, et al. Electrical impedance myography to assess outcome in amyotrophic lateral sclerosis clinical trials. Clin Neurophysiol 2007; 118(11):2413-2418.

Rutkove SB. Electrical impedance myography: Background, current state, and future directions. Muscle Nerve 2009;40(6):936-946.

Aaron R, Huang M, Shiffman CA. Anisotropy of human muscle via non-invasive impedance measurements. Phys Med Biol 1997; 42(7): 1245-1262.

©2011 American Academy of Neurology

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