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In the Clinic


A Renowned ALS Researcher Dies from the Disease. Now His Son Is Looking for Its Biomarkers.

Hurley, Dan

doi: 10.1097/01.NT.0000522269.36434.2d
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Nicholas T. Olney, PhD, the recipient of a research award in amyotrophic lateral sclerosis (ALS), is researching neurofilament-light and a cervical spine imaging method called phase sensitive inversion recovery as ALS biomarkers. He was inspired by his father, Richard K. Olney, MD, a renowned ALS researcher who developed the disease and died in 2012.

BOSTON—Neurologists may recall the story of Richard K. Olney, MD, who studied amyotrophic lateral sclerosis (ALS) for over 30 years before developing the disease himself and dying in 2012. Fewer may know how that tragic turn of events changed the life of his son.

When his father was diagnosed in 2004, Nicholas Olney was two years out of college at the University of California, San Diego, where he had double-majored in biochemistry and theatre. Working at a biotechnology firm, he figured he would eventually get a PhD.

And then, within two months of his father receiving the diagnosis of ALS, Nicholas Olney dropped everything and became his father's full-time caregiver, eventually applying to and attending medical school at the University of California, San Francisco (UCSF). Upon completing his residency after the death of his father, his research interest turned, perhaps inevitably, to ALS.

In April, at the AAN Annual Meeting here, Dr. Olney received the Clinical Research Training Fellowship in ALS Research, cosponsored by the AAN and the ALS Association. His research project seeks to identify biomarkers of the disease, using both neurofilament-light (NF-L) and a novel method of cervical spine imaging called phase sensitive inversion recovery, or PSIR.

Although NF-L is not specific to ALS, he said, “Higher levels have been associated with ALS and disease severity. At a certain level, it could mean that someone is a faster progressor.”

Even more exciting to Dr. Olney is PSIR, a new technique for MRI imaging. “I'm the first to look at this in ALS spinal cords as a potential biomarker,” he said. “I've scanned eight patients so far. The PSIR sequence gives good differentiation between gray and white matter, and this is the first time we can see this in vivo. We're getting a good signal, and I think there may be a clinical correlation.”

The most far-reaching implication of the work, he said, is that it could one day serve as a marker for ALS diagnosis or disease progression. “Much more research needs to be done before PSIR could be used for a single subject but potentially this could help in areas where expert EMG-ers are not available to make a diagnosis by imaging. Also, nobody wants to go in for an EMG test twice,” he said, because the test can be painful for patients. “If this technique continues to show good signal with longitudinal data, PSIR could be used to look at cord stability in clinical trials as well.”

One of Dr. Olney's first published studies grew directly out of a symptom he saw in his father: pseudobulbar affect, marked by pathological laughing or crying.

“A large portion, perhaps one-third of our ALS patients, have pseudobulbar affect,” he said. “In my dad, the symptom was really surprising, because at work, he was very strait-laced. But as his disease progressed, if a Visa commercial came on with certain music, he would start crying. No one else seemed to be researching pseudobulbar affect, so I got a grant to work on studying the mechanism of pseudobulbar affect in Dr. Levenson's emotions lab at UC Berkeley. My dad was a participant and helped me look at the data after it was collected.”

The younger Dr. Olney took a year off from medical school as a Doris Duke fellow to study the condition, collaborating with the UCSF ALS Center, which his father founded; the UCSF Memory and Aging Center, and the UC Berkeley emotions laboratory. Bruce L. Miller, MD, FAAN, professor of neurology at UCSF and a longtime collaborator of the elder Dr. Olney, supervised the research.

Contrary to many clinical descriptions, the episodes of pathological laughing and crying his group observed were usually induced by contextually- appropriate stimuli and associated with strong experiences of emotion. But rather than being associated with general emotional hyperactivity, the study found that the disorder may be due to dysfunction in frontal neural systems that support voluntary regulation of emotion. The results were published in 2011 in the journal Brain.

Three other mentors of Dr. Olney's also served as coauthors of the study: Howard J. Rosen, MD, professor of neurology at UCSF; Catherine Lomen-Hoerth, MD, PhD, FAAN, professor of neurology at UCSF; and Robert W. Levenson, PhD, professor of psychology at UC Berkeley. The experience of collaborating with them, he said, “sold me on doing research and neurology.”

That hadn't always been the plan. In October of 2004, he was happily ensconced at a biotech start-up when he learned that the symptoms of a “bone spur” that had been compressing his father's spine was actually ALS.

“When his arms got weak, they pretty much knew,” Dr. Olney recalled. “I was deeply involved in a project at work, but I said I wanted to move home, to spend as much time as I could with my father. I bowed out in two months.”

Although his father had worked six days a week, and Nicholas and his sister rarely saw him on weekdays, “We did see him most Saturday nights and Sundays,” he said. “We would hike in Marin County, or go out to a movie and then for a nice dinner as a family. In middle school — I don't know how he did it — he became my troop's scoutmaster for three years. He was very involved planning big backpacking trips. He wanted to make sure I became an Eagle Scout, which I eventually did.”

His father declined quickly during the first two years after the diagnosis. “They kept saying he had six months to live,” Dr. Olney recalled. “But then his breathing numbers stabilized below 50 percent. He remained stable for four years or so. It was definitely an atypical case.”

A lift system was installed to help the elder Dr. Olney get out of bed and move from one room to the next. He used a laser pointer on his glasses to communicate, which even allowed him to help his son as he studied, first for the MCATs and then in medical school at UCSF.

The two sometimes discussed whether it was purely due to chance that a world-class ALS expert came down with the very rare disease himself.

“He had some theories, but nothing certain,” the younger Dr. Olney said. “As many patients do, he questioned if something previously contributed to his acquiring ALS. He was involved in a car accident at a young age. He did not think his contact with ALS patients had anything to do with it. I think eventually he just accepted that it was random chance.”

One thing he knew for sure was that the family had no genetic risk for the disease. “My grandma Fran did genealogy research back to the 1600s,” he said. “She found no trace of any neurological diseases.”

As for the future, Dr. Olney hopes to continue his ALS research in developing biomarkers for early and correct disease detection, which should lead to cures and treatments.

Dr. Olney continues to be interested in the overlap of cognitive symptoms and ALS as well. For now, working with ALS patients remains deeply meaningful for him. “They remind me of things about my dad,” he said. “Sometimes that can be painful,” he admitted, “but sometimes it's a good thing too.”

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•. Olney NT, Goodkind MD, Lomen-Hoerth C, et al Behavior, physiology and experience of pathological laughing and crying in amyotrophic lateral sclerosis Brain 2011; 134 (Pt 12): 3458–3469.
    © 2017 American Academy of Neurology