Losing It

r. William Frey reaches down with both hands into a big white bucket and brings up the brain of a woman in her late 80s who died the day before. He slides it gently into a silver pan. There is only one way to make a definitive diagnosis of Alzheimer's, and that is by examining the brain tissue under a microscope. Because there is currently no cure or effective treatment, this type of examination almost always occurs post-mortem.

Frey is the research director of the HealthPartners Alzheimer's Treatment & Research Center at St. Paul Ramsey Hospital, where he presides over one of the world's largest brain banks. Approximately twice a week, a bucket arrives at Ramsey containing the brain of someone thought to have suffered from Alzheimer's or some other degenerative neurological condition. Frey or one of his assistants then sends about two-thirds of the brain on to the neuropathologist for an official diagnosis, and cuts the rest into 10 cross-sectioned slices that are frozen in liquid nitrogen and stored for further analysis. Something over 1,700 brains have come through the Ramsey clinic. Nearly 1,000 are still in their freezers.

"You need a microscope for an exact diagnosis," says Frey, "but it's clear that this woman had a degenerative brain disease." A normal brain weighs about 1300 grams; this one is barely 900. "A third of the brain is missing from atrophy, from nerve cell loss and degeneration. That caused these invaginations to widen," he says, pointing to the crevices, "and the ventricles to enlarge," he adds, lifting and spreading the lobes to expose a large, cave-like hollow in the lower middle of the mass.

After a little cutting he locates the hippocampus, an apparatus about the length and width of a large worm. Tucked inside the temporal lobes, it runs from the front to the back of the brain and functions as sort of a central memory switching terminus. The hippocampus is critical to short-term memory, and it is almost always damaged in Alzheimer's patients.

Frey's cross-sections reveal that the brain's grayish surface does not extend throughout the tissue; visually at least, it's more like a thick rind surrounding predominantly white brain matter. Generally speaking, this outer gray matter functions as storage space, while the white matter is more involved with the transmission and movement of information. Damage to the white matter is common in diseases such as multiple sclerosis; Alzheimer's mostly attacks the gray matter.

But this is all very general, Frey warns me near the end of our talk. "It's important to remember that the brain is very complex, and different functions are using parts from all over, so it is a little hard to get too specific. Frankly, we don't know much about what some areas do. We're in the dark a lot of the time," he says.

"We know a lot about what happens to the brain [in Alzheimer's cases]," concurs Dr. David Knopman, director of the University of Minnesota's Alzheimer's clinic. "But we don't know why it starts to happen."

What happens is that the brain cells in Alzheimer's patients begin to degenerate and die, particularly in the areas involved with memory and cognition. More specifically, nerve cells in the brain fail to produce enough of a substance called acetylcholine, which is the chemical messenger primarily responsible for transmitting memory information from one cell to the next. This deterioration is accompanied by an accumulation of abnormal proteins that further disrupt brain functions. One of these abnormal proteins, amyloid, causes degenerative nerve cells to harden and form plaque; another protein, tau, is found in dying cells that are twisted into fibrous tangles. These plaques and tangles are what the German psychiatrist Alois Alzheimer saw under a microscope in 1906, providing a medical explanation for the progressive dementia from which a certain segment of the population--mostly elderly--had always suffered. Today microscopic plaques and tangles are still the definitive physical basis for an Alzheimer's diagnosis.

After Alzheimer's discovery, there were no major research breakthroughs until 1976, when the acetylcholine deficiency in the brain cells of Alzheimer's patients was confirmed. Initially, this was thought to be a momentous breakthrough, akin to the discovery that patients with Parkinson's disease had a dopamine shortage in their brain cells. But whereas Parkinson's patients improved markedly when given dopamine-replenishing drugs, acetylcholine treatments proved far less effective for Alzheimer's patients. The reason, apparently, is that the degeneration of brain cells in Alzheimer's patients is a more complex and systemic process: While the brain cells that produce acetylcholine appear to be affected first and most severely, other types of cells and other chemical transmitters are breaking down as well.

The most significant aspect of Alzheimer's research in recent years involves the likelihood of a genetic element at the roots of the disease. Experts in the field now generally concede that there are people whose genetic makeup puts them at a much higher risk of developing the disease, and tests to determine the presence of "Alzheimer's genes" have recently been made commercially available. Many experts question the value of the tests, however, because they are not definitive and because the disease, in any case, remains incurable.

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