In-Your-Face Studies of Alzheimer's

This is one of a series of articles about how basic research discoveries at Harvard are leading to new tests and treatments for cancer, Alzheimer's, heart disease, and other illnesses.

By William J. Cromie

Gazette Staff

Looking someone in the eye, or in the mouth, could turn out to be the best way to determine if he or she has Alzheimer's disease.

Researchers at the Medical School and Brigham and Women's Hospital have identified the disease in elders simply by measuring an increase in pupil size in response to eye drops. Tests conducted since at Harvard and elsewhere verify that Alzheimer's patients do, indeed, respond differently from those who are free of the disease.

"We have retested subjects in our original study two or more times, and confirmed our original finding with a reliability greater than 95 percent," said Leonard Scinto, a neuroscientist at Brigham and Women's Hospital. "Patients who show a decline in cognitive abilities, such as memory, tend to exhibit exaggerated pupil dilation."

"Promising new drugs to slow the deterioration of Alzheimer's are now undergoing tests and could be available in four or five years," notes Huntington Potter, associate professor of neurobiology at the Medical School. "Once such drugs are available, it is imperative to detect the disease early when treatment would be most effective."

Potter, who first came up with the idea for the eye test, thinks it also may be possible to diagnose Alzheimer's by examining cells scraped from the inside of a person's cheek.

All those with Down's syndrome, a mental handicap once known as "mongolism," get Alzheimer's by age 40. Down's sufferers possess three copies of chromosome 21, rather than the normal two. Therefore, the presence of the same abnormality in mouth cells may provide advance notice of the mental deterioration of Alzheimer's. Down's sufferers also show an increase in pupil diameter when a drop of a drug called atropine is placed in their eyes.

The mouth connection is now being investigated by Lisa Geller, a Medical School researcher.

Diagnoses By Default

Detecting Alzheimer's has dogged doctors for decades. The only sure way is an autopsy, which reveals sticky Brillo-like plaques and threadlike tangles in the brain. These deposits are associated with memory loss, impaired judgment, and other mental and physical problems that make independent living impossible. An estimated 4 million to 6 million people suffer from the disease, and new cases are found at the rate of 500,000 a year.

Dementias caused by other diseases such as encephalitis or Parkinson's produce some of the same symptoms, so identification is tricky. Usually it involves a battery of cognitive and genetic tests. When all other causes are eliminated, Alzheimer's is diagnosed by default. It's a lengthy and expensive process, but it still misses as many as 50 percent of the cases, according to Potter.

The eye test, then, could save a tremendous amount of time, money, and misery.

Researchers at Temple University in Philadelphia combined pupil dilation and memory-loss tests and confirmed a correlation with Alzheimer's. However, they examined only five people, not enough to provide the conclusive proof sought by Scinto and Potter.

Experimenters at Baylor University in Texas found the eye test harder to do in a doctor's office than under the tightly controlled conditions of a research lab. Patients can become startled when devices are brought close to their eyes, and some of the measurements are made in the dark. The combination may produce confusing pupil adjustments.

"Such 'noise,' or interference, resulted in a reduction in accuracy of the test that we did not expect," Potter admitted.

Scinto is looking at ways to eliminate this problem. "We're trying to determine what factors influence pupil dilation, such as how quiet patients need to be kept between measurements," he explained.

But retesting done under laboratory conditions during the past year convinces Scinto that "Alzheimer's probably can be determined by pupil dilation measurements alone, without other expensive, time-consuming tests." If he is right, inconclusive tests that cost thousands of dollars could be replaced by an easy procedure costing only a few hundred dollars.

To determine why the eye reveals dementia, Scinto examined the brains of Alzheimer's victims who underwent autopsies. He noted extensive cell damage in a part of the middle brain called the Edinger-Westphal nucleus. "It appears as if this damage triggers events in a nearby region that control pupil dilation," Scinto explains.

Bringing It to Market

The Medical School and Brigham and Women's have obtained patents on both the eye and mouth tests and have licensed those patents to commercial companies.

Meanwhile, a decisive test of this window on the brain has begun at Massachusetts General Hospital. Under the direction of Neurology Professor John Growdon, 100 people will be examined, 50 with, and 50 without, signs of Alzheimer's. The mouth cells of some of these people will also be checked for clues to the disease. Neither those who do the measurements nor those who evaluate them know who has the disease and who doesn't.

"Because of the double-blind nature of this research, no results are available yet," Growdon notes. The tests should be completed before the end of this year.

A successful test, however, will leave doctors with a dilemma. They will be able to diagnose a disease for which no cure exists.

The only drug now on the market, called tacrine, slows the progression of Alzheimer's in only 30 percent of those who take it. Side-effects include life-threatening liver damage.

"New and better drugs are undergoing tests," Potter assures us. "In the past five years, we have come to understand a great deal about the changes that lead to Alzheimer's. This gives us insights into diagnostic and treatment methods unimaginable two to three years ago. Drugs now being developed are based on this knowledge. We should see new medications in the next five years, and better ones within ten years."