Research

The Vanishing Mind

Promise Seen for Detection of Alzheimer’s

Dr. Daniel Skovronsky sat at a small round table in his corner office, laptop open, waiting for an e-mail message. His right leg jiggled nervously.

Daniel Skovronsky

Top, images from the brain of a cognitively normal volunteer; bottom, results from an Alzheimer’s patient. Plaque buildup is shown in red.

The Vanishing Mind

A Diagnostic Tool

Articles in this series are examining the worldwide struggle to find answers about Alzheimer’s disease.

Steve Legato for The New York Times

Dr. Daniel Skovronsky at Avid Radiopharmaceuticals in Philadelphia, telling his staff about the results of a study that showed that the company’s test for Alzheimer’s appeared to be effective.

A few minutes later, the message arrived — results that showed his tiny start-up company might have overcome one of the biggest obstacles in diagnosing Alzheimer’s disease. It had found a dye and a brain scan that, he said, can show the hallmark plaque building up in the brains of people with the disease.

The findings, which will be presented at an international meeting of the Alzheimer’s Association in Honolulu on July 11, must still be confirmed and approved by the Food and Drug Administration. But if they hold up, it will mean that for the first time doctors would have a reliable way to diagnose the presence of Alzheimer’s in patients with memory problems.

And researchers would have a way to figure out whether drugs are slowing or halting the disease, a step that “will change everyone’s thinking about Alzheimer’s in a dramatic way,” said Dr. Michael Weiner of the University of California, San Francisco, who is not part of the company’s study and directs a federal project to study ways of diagnosing Alzheimer’s.

Still, the long tale behind this finding shows just how difficult this disease is and why progress toward preventing or curing it has been so slow.

Ever since Alzheimer’s disease was described by a German doctor, Alois Alzheimer, in 1906, there was only one way to know for sure that a person had it. A pathologist, examining the brain after death, would see microscopic black freckles, plaque, sticking to brain slices like barnacles. Without plaque, a person with memory loss did not have the disease.

There is no treatment yet to stop or slow the progress of Alzheimer’s. But every major drug company has new experimental drugs it hopes will work, particularly if they are started early. The questions though, are who should be getting the drugs and who really has Alzheimer’s or is developing it?

Even at the best medical centers, doctors often are wrong. Twenty percent of people with dementia — a loss of memory and intellectual functions — who received a diagnosis of Alzheimer’s, did not have it. There was no plaque when their brains were biopsied. Half with milder memory loss, thought to be on their way to Alzheimer’s, do not get the disease. And with such a high rate of misdiagnosis, some who are mistakenly told that they have Alzheimer’s are not treated for conditions, like depression or low levels of thyroid hormone or drug side effects and interactions, that are causing their memory problems.

Brain scans that showed plaque could help with some fundamental questions — who has or is getting Alzheimer’s, whether the disease ever stops or slows down on its own and even whether plaque is the main culprit causing brain cell death.

Dr. Skovronsky thought he had a way to make scans work. He and his team had developed a dye that could get into the brain and stick to plaque. They labeled the dye with a commonly used radioactive tracer and used a PET scanner to directly see plaque in a living person’s brain. But the technology and the dye itself were so new they had to be rigorously tested.

And that is what brought Dr. Skovronsky, a thin and eager-looking 37-year-old, to his e-mail that recent day.

Five years ago, Dr. Skovronsky, who named his company Avid in part because that is what he is, had taken a big personal and professional gamble. He left academia and formed Avid Radiopharmaceuticals, based in Philadelphia, to develop his radioactive dye and designed a study with hospice patients to prove it worked.

Hospice patients were going to die soon and so, he reasoned, why not ask them to have scans and then brain autopsies afterward to see if the scans showed just what a pathologist would see. Some patients would be demented, others not.

Some predicted his study would be impossible, if not unethical. But the F.D.A. said it wanted proof that the plaque on PET scans was the same as plaque in a brain autopsy.

The Avid study was designed to provide that proof. And the full results, contained in the e-mail message sent that day, May 14, were the moment of truth. When he saw them, Dr. Skovronsky said they were everything he had hoped for.

“This is about as good as it gets,” he said that day.

He went into a rotunda that serves as Avid’s lunchroom to tell the company’s 50 employees. “This is a big day for us,” he continued. “I thought about what I would say, but I have totally forgotten it.”

His employees applauded. Then they had champagne in blue plastic cups.

A First Dye

The type of scans used in this study, PET scans, are expensive and patients have to go to a scanning center, get injected with a radioactive dye, wait for the dye to reach their brain and then have a scan.

Other tests are being studied — ones that look for amyloid in cerebrospinal fluid that bathes the brain; MRI scans that look for shrinkage of the brain in areas needed for memory and reasoning; PET scans that look for uptake of glucose, a cellular fuel, to show areas where the brain was active and where it was not. The tests, though, were not necessarily specific for Alzheimer’s and none had been studied to see if they accurately predicted plaque on autopsy.

Earlier this decade, two scientists at the University of Pittsburgh developed an amyloid dye that while not practical for widespread use, stunned scientists by showing it seemed possible to see amyloid in a living brain.

The researchers, Chester Mathis and William Klunk, began their work two decades ago, persevering even though they had no research money. In the first 10 years, they tested more than 400 compounds. When they finally found one that seemed promising, they tested more than 300 variations.

“On and on it went,” Dr. Mathis said.

Finally, in late 2001, they began working with collaborators in Sweden to test their dye in humans.

On Valentine’s Day 2002, the Swedish researchers injected the first Alzheimer’s patient with the dye, known as Pittsburgh Compound B, and scanned the patient’s brain.

It worked, the Swedish doctors told Dr. Mathis in an excited phone call.

A PET scan showed amyloid exactly where it would be expected. The Swedish doctors were convinced they were seeing actual plaque. They told Dr. Mathis it was time to celebrate.

But Dr. Mathis worried. What if the same pattern occurred in people without Alzheimer’s?

Two weeks later, he got another call from Sweden. His colleagues had scanned a person without Alzheimer’s. There was no sign of telltale plaques.

His sweet reward came in July 2002, when the scans were shown to an audience of 5,000 scientists at an international conference on Alzheimer’s.

“There was an audible gasp,” Dr. Mathis said. “The field was taken aback.”

“The rest is history,” he added.

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