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Neurology Today:
doi: 10.1097/01.NT.0000415048.54525.a9
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In the Field: Takeshi Iwatsubo, MD, PhD: ‘No Regrets’ — From Neuropathology and Back to the Clinic

Collins, Thomas R.

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Takeshi Iwatsubo, MD, PhD, had thought of himself as a clinical guy. Early in his career, he worked as a clinical neurologist at the University of Tokyo Hospital. Then he branched out into basic research in neuropathology — but that was just temporary, he thought.

“I was going to come back to clinical neurology,” Dr. Iwatsubo recalled from his office in Tokyo recently. It was then, though, that renowned Alzheimer disease (AD) researcher Yasuo Ihara, MD, was appointed as the chairman of the neuropathology department. He suggested to Dr. Iwatsubo that he do immunohistochemical work on the tau protein found in neurofibrillary tangles.

Making his overture even more persuasive was something they had in common: Dr. Ihara also had started as a clinician. Dr. Iwatsubo couldn't exactly say no.

“I was very clinical and diagnostics-oriented,” he said. “But he came here as chairman and there was no way other than to follow him.”

His venture into the lab started him toward a series of critical discoveries in AD research that — along with his work on the ongoing Japanese Alzheimer's Disease Neuroimaging Initiative — have won him the 2012 Potamkin Prize for Research in Pick's, Alzheimer's, and Related Diseases, which comes with $100,000.

Dr. Iwatsubo has called the honor “the highlight of my career as a researcher.” Dr. Ihara, as it happens, won the Potamkin Prize in 1995.

The fateful encounter with Dr. Ihara has had reverberations throughout the field of AD research. In the early 1990s, Dr. Iwatsubo was one of the first to show that amyloid beta (Abeta) peptide 42 is implicated in the early deposition of amyloid in the brains of AD patients.

Then, beginning in the mid-90s, his lab meticulously described the components and processes at work in the gamma-secretase complex that generates Abeta.

He also has shown that alpha synuclein is the major component of the Lewy bodies present in dementia and in Parkinson disease.

The day of the alpha synuclein breakthrough still resonates. The graduate student he was working with, Minami Baba, was doing the immunostaining to test for matches with alpha synuclein.

“I clearly remember she ran into my room and said, ‘It's positive, positive!’” Dr. Iwatsubo said. “I asked, ‘What is positive?’” Then he looked at the slide himself.

“I had never seen that strong (of an) immunostain with other previously known components — it was very striking,” he said.

But there were other inroads to make. After the US began to get its Alzheimer's Disease Neuroimaging Initiative (ADNI) off the ground, Dr. Iwatsubo began to get somewhat concerned — he didn t want Japan to be left behind.

“We realized that this ADNI project will set the basis and the standard for the future clinical studies or clinical trials for Alzheimer disease.”

With that, he decided to, after all these years, come back to the clinic, at least partially.

He called Michael Weiner, MD, of the Center for Imaging of Neurodegenerative Diseases at the VA Medical Center in San Francisco. Dr. Weiner was leading the US ADNI project. Dr. Iwatsubo said he wanted to do the same thing in Japan and that he would lead the effort.

“They said, ‘This is a clinical study project,’” Dr. Iwatsubo recalled. “So they were not sure if a clinician shouldn't become the principal investigator.”

In the United States, the ADNI team was largely already assembled since many of the core investigators had participated together in the Alzheimer's Disease Cooperative Studies. Dr. Iwatsubo's task was much taller.

He had to conduct everything,h he said — raising funds, explaining the significance and the practices to potential clinicians, recruiting specialty core principal investigators.

Eventually, Dr. Iwatsubo set up a coordinating site and a network of 38 clinical sites throughout Japan. Making it more impressive, the Japanese ADNI has a protocol that is almost exactly the same as that of the US, allowing the data of the two countries to be compared more reliably and to make the data more powerful for use in guiding clinical trials of treatments.

So far, no data from the Japanese ADNI have been published, but researchers have found that the results have generally mirrored those in the US — people with amyloid tend to progress to dementia more rapidly than those with non-Alzheimer's pathologies, Dr. Iwatsubo said.

DR. TAKESHI IWATSUBO...
DR. TAKESHI IWATSUBO...
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Dr. Iwatsubo acknowledges the leap from his role in the lab. “I'm very happy,” he said. “I have a feeling that we are really bridging the basic findings into the clinical scene. I'm excited.”

©2012 American Academy of Neurology

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