Tangled memories: Alzheimer's disease: the story so far.

It's a disease of the brain, but it breaks the heart.

Alzheimer's starts with symptoms you can ignore. We all forget where we put our keys. But ever so gradually, over months or years, Alzheimer's patients forget how to use a key. Eventually, they forget how to walk, talk, and eat. Gone is the person who--like all of us--would have done anything to avoid such a slow, pitiful end.

In fact, the odds of avoiding Alzheimer's aren't good. An estimated third to half of people older than 85 have Alzheimer's or some other form of dementia. The good news: Researchers are hunting down leads to vitamins, herbs, drugs, and lifestyle changes that may keep our memories intact.

"There's been an explosion of potentially good, exciting ways to prevent or slow Alzheimer's," says Steven Ferris of New York University. "What's on the horizon is unbelievable compared to what we had 10 or 20 years ago."

Nearly 1,000 people are diagnosed with Alzheimer's disease every day in the U.S. And their ranks are growing.

"The demographics are pushing people into older age groups, so by 2050, there could be up to 14 million Americans with Alzheimer's," says Neil Buckholtz, chief of the Dementias of Aging Branch at the National Institute on Aging (NIA).

Alzheimer's disease accounts for 70 percent of all cases of dementia. Vascular dementia, which is caused by clogged brain arteries and strokes, makes up most of the rest.

Scientists don't know what triggers the disease. But they know that it's not a normal part of aging.

"We see some of the same pathological changes in the brains of normal people, but it's the difference between getting a cold and getting pneumonia," says Trey Sunderland, chief of the Geriatric Psychiatry Branch at the National Institute of Mental Health (NIMH). "Normal aging doesn't interfere with daily life, while Alzheimer's eventually takes you out of the loop entirely."

In most people, Alzheimer's first attacks the parts of the brain that we use for memory and visual-spatial thinking--that is, picturing where things fit in space.

"The first symptoms are often difficulty reading a map, or people can't negotiate getting off a highway because they can't interpret the signs," explains Sunderland.

Or their memory falters more than usual. "It's common to forget names or where you put your keys," says Sunderland. "But people with early Alzheimer's might forget the birth date of a child or how to turn on their computer or the name of a person who's dear to them."

Their memory loss is also more profound, and it spreads more quickly over time, says Sunderland. "You'd see a change after six months in a person with early Alzheimer's,' he explains. "In a normal person, you would see no change in that short a time."

People with greater-than-average memory loss may have what researchers now call "mild cognitive impairment." They perform worse on memory and other tests than normal people their age, but they have little difficulty functioning in daily life (see "Mild in Name Only," p. 5).

"About 10 to 15 percent of people with mild cognitive impairment are diagnosed with Alzheimer's each year, so within five to seven years, more than half have the disease," says Buckholtz.

In about one in ten people, Alzheimer's begins with behavioral changes. "If the disease starts in the frontal lobe of the brain, you might see depression or psychosis," says Sunderland. "But eventually, the impairment spreads to all parts of the brain. We know that 70 percent of patients become depressed at some time during the illness, and all eventually get memory and visual-spatial impairment."

What's going on in the brain during that time? When researchers examine Alzheimer's patients who have died, they find two hallmarks of the disease: plaques and tangles.

* PLAQUES. "Plaques are little dead zones between the nerve cells," explains Lee Eiden of the National Institute of Mental Health's Laboratory of Cellular and Molecular Regulation.

"They're like atherosclerotic plaques in arteries, but instead of being filled with fats and cholesterol, they're filled with protein fragments called beta-amyloid." (See "Plaque Attack," p. 4.)

Along with the beta-amyloid proteins are immune system cells that are supposed to engulf and digest damaged cells or foreign invaders.

"An emerging notion is that a small amount of beta-amyloid plaque forms and then the immune system sends in cells to gobble up the debris," explains Eiden.

But instead of clearing out the plaque, the immune cells get trapped in the plaque and make it worse.

"The immune cells may irritate neighboring cells in the brain," he says. "It's as though you were trying to demolish one building in a row of houses, but you cause collateral damage."

* TANGLES. Neurofibrillary tangles are the second hallmark of Alzheimer's. "They come from deposits of tau, a structural protein that gives neurons their shape," explains Eiden. In healthy brains, "the tau proteins help form the cables that hold the nerve cells together."

But in Alzheimer's, the tau forms filaments that get twisted, so the threads wind around each other into tangles. "Instead of a smooth, strong structural element, the cables become large and frayed," he explains. That interferes with the signals between nerve cells and may eventually kill the cells.

In fact, scientists now think that misshapen proteins could be the key to a host of illnesses, from Creutzfeldt-Jakob disease to cataracts and diabetes.

"The idea that abnormalities of protein folding lead to protein accumulation in the cell and cell death in many diseases is a very important concept," says Jeffrey Cummings, director of the Alzheimer's Center at the University of California at Los Angeles (UCLA).

"It suggests that there may be new and previously unthought of ways of intervening in these processes. So that suddenly things we are learning in Alzheimer's become applicable to Parkinson's, Huntington's disease, and even ALS." (ALS, or amyotrophic lateral sclerosis, is also known as Lou Gehrig's Disease.)

It's still not clear that plaques and tangles actually cause Alzheimer's. "We don't know if they're the injury that causes disease or only the scars from the real injury," says Eiden.

Nevertheless, researchers are searching for new drugs that might halt or even erase plaques and tangles. "Drugs that block enzymes that make the beta-amyloid are generating the most excitement right now," says Sunderland.

But the research is still in its infancy. Treatments that work in animals sometimes fail in people. "Animal studies on anti-Alzheimer's vaccines were promising, but the one human study had to be stopped because of meningitis and other side effects," Sunderland explains.

Meanwhile, scientists are pursuing clues that suggest that vitamins, supplements, or drugs that are already on the market may slow the disease that millions of Americans dread.

ANTIOXIDANT VITAMINS

"It's clear that oxidative damage is involved in Alzheimer's disease," says the National Institute on Aging's Neil Buckholtz.

The body produces free radicals as part of its day-to-day operations, and it tries to get rid of them before they attack fats, proteins, and DNA. The brain is especially sensitive because it uses so much oxygen, it contains cholesterol and other fats that are easily oxidized, and it's not rich in antioxidants. And researchers can see evidence of oxidative damage in the brain tissue of Alzheimer's patients.

"No one's suggesting that free radicals cause degeneration," explains Steven Ferris, who directs the Aging and Dementia Research Center at New York University (NYU). "It's that the accumulation of free radicals plays a part by exacerbating the degeneration."

In theory, antioxidants like vitamin E may keep free radicals from accumulating and causing damage. "The notion is that by taking larger amounts of antioxidants than we get from our diet, you might tilt the balance more favorably away from damage and slow the disease," says Ferris.

But so far, scientists have only a smattering of evidence from research on humans.

Last June, two studies made headlines when they reported that people who consumed more vitamin C or E from foods had a lower risk of Alzheimer's. (1) But in one of them, which tracked more than 5,000 residents of Rotterdam in the Netherlands, the vitamins were only protective in smokers. And in the other, people were asked about their diets an average of only two years before they were diagnosed with Alzheimer's. That raised the possibility that they ate--or remembered having eaten--fewer vitamin-C-rich foods because their memories were already impaired.

So the evidence that antioxidants can prevent or slow Alzheimer's is still more promise than reality. "The closest we have is a clinical trial showing that high doses of vitamin E may slow the disease," says Ferris.

That study randomly assigned patients with advanced Alzheimer's to either a high dose of vitamin E (2,000 IU a day) or a placebo for two years. (2) On average, the vitamin-E-takers took seven months longer to reach some landmark--dying, entering a nursing home, or losing daily living skills like dressing or bathing on one's own.

"The problem was that vitamin E had no effect on tests of mental function," says Ferris. "So we couldn't interpret it as clear evidence that vitamin E slows Alzheimer's down."

Maybe the vitamin E came too late to help those patients. "Some argue that the more entrenched the disease, the less likely antioxidants are to have an effect," says Ferris.

So researchers are now testing vitamin E on people with mild cognitive impairment, which often precedes Alzheimer's. "These people are beginning to have symptoms, but the impairment has no obvious impact on how they function in daily life," Ferris explains.

Each participant will get vitamin E (2,000 IU a day), Aricept (a drug that seems to help patients with mild Alzheimer's), or a placebo for three years. "The question is: Can you delay the time they take to get to a diagnosis of Alzheimer's?" says Ferris.

He and others also want a trial on people with no symptoms. "Ideally, we'd do a trial in people over 75 with no signs of cognitive impairment who are at risk only because of their age," he explains. "And we'd give them a cocktail of antioxidants, including vitamins E and C."

That's an expensive undertaking, because it means following 2,000 to 3,000 people for four or five years. But, he adds, "it needs to be done."

Should healthy people take vitamin E in the meantime? "It's not expensive and it's not going to do you any harm," says Ferris. But if you do take it to hedge your bets, don't assume that you need 2,000 IU a day.

"They used 2,000 IU to give a whopping amount to people with advanced Alzheimer's," says Ferris. "But we only tested one dose. It's possible that 400 IU may be all you need."

ESTROGEN

"There was a pretty good rationale that estrogen might slow Alzheimer's," says Ferris.

The part of the brain that the disease first attacks, called the hippocampus, has many estrogen receptors. At least some studies have found a lower risk of Alzheimer's in women who take estrogen. (3) And estrogen seems to reduce the mild memory problems that sometimes come with menopause. (4)

"But the definitive test is a clinical trial, and the only decent trial so far was negative," says Ferris. "When 120 women with Alzheimer's were treated with estrogen or a placebo for 12 months, there wasn't the slightest hint of a benefit. (5)

"Some would say that the dice were loaded because the women already had Alzheimer's when the study began," he adds. "We won't know if estrogen can help prevent Alzheimer's until we go back and do a trial on healthy people." In fact, a new study is under way in healthy women aged 65 or older (see "Alzheimer's on Trial," p. 8).

FOLATE 

Folate (or folic acid) is one hot ticket. The B-vitamin can prevent neural tube birth defects like spina bifida. And numerous studies suggest that--along with vitamins B-6 and B-12--it may prevent heart disease and stroke by lowering levels of a damaging amino acid called homocysteine.

Now scientists think that by keeping homocysteine low, folate may also curb the risk of Alzheimer's.

In February, researchers reported on a study that measured blood levels of homocysteine in more than 1,000 residents of Framingham, Massachusetts, and then waited for eight years to see who got dementia. (6)

"This was the first study to find that people with higher homocysteine levels are more likely to develop Alzheimer's or other dementias," says senior investigator Philip Wolf of the Boston University School of Medicine.

How too much homocysteine--or too little folate--may cause Alzheimer's is unclear, but possibilities abound.

"Our findings suggest that homocysteine acts directly on nerve cells in the brain to increase damage to their DNA," says Mark Mattson, chief of the National Institute on Aging's Laboratory of Neurosciences.

Another possibility: "Homocysteine may over-activate receptors on nerve cells," says Mattson. Over-activating nerve cells can kill them.

Homocysteine may also damage the tiny blood vessels in the brain. "That could impair the brain's blood supply, which would enhance the vulnerability of nerve cells to insults," says Aaron Troen of the U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University in Boston. Or "homocysteine may damage the blood-brain barrier, which would also decrease the blood supply to the brain."

Nevertheless, Troen and others caution, those leads don't prove that too much homocysteine can cause Alzheimer's or that getting enough folate (or B-12 or B-6) can prevent it.

"Whether homocysteine causes Alzheimer's or is an innocent bystander isn't clear," says Paul Jacques of the Tufts Human Nutrition Research Center on Aging.

Trials using high doses of folate, B-6, and B-12 to slow or reverse the damage in Alzheimer's patients are due to start in 2003. In the meantime, healthy people shouldn't go overboard.

"Taking a multivitamin with folate, B-12, and B-6 is within reason," says Troen. "But we don't want people to think that the more you take, the better off you are."

Seniors should take a multi anyway. Many older people don't have enough stomach acid to extract the B-12 that occurs naturally in food, so experts recommend that anyone older than 50 get at least 2.4 micrograms a day of B-12 from a supplement or fortified food. (Most multis have at least 6 micrograms.)

And a B-12 deficiency can cause dementia that masquerades as Alzheimer's. In fact, anyone with symptoms of Alzheimer's should get a blood test for B-12 and methylmalonic acid, which is high in people with a B-12 deficiency.

GINKGO BILOBA

Ginkgo is an herb that's touted as a memory tonic. Some people take it to treat Alzheimer's disease, and some take it to prevent the disease. Are they kidding themselves?

When researchers pooled the results of the four best studies on Alzheimer's patients, they saw that 120 to 240 mg a day of ginkgo for three to six months produced small improvements in the patients' ability to perform the activities of daily living and in test scores measuring their mental function. (7)

"But the effects were minimal, and those who received ginkgo did slightly worse than those who were given the prescription drug donepezil [Aricept]," says Barry Oken of the Oregon Health & Science University in Portland.

Still, says Oken, "some people opt to take ginkgo because it may be helping, it's relatively safe and inexpensive, and there's really not much else out there that's very good."

Can taking ginkgo reduce your risk of getting the disease? No good research has ever looked. At least until now.

The National Institutes of Health is funding two studies of ginkgo in healthy older people. One is looking to see if the herb can prevent Alzheimer's in men and women at least 75 years old.

The other is testing whether ginkgo can prevent mild cognitive impairment in people 85 and older. The studies will take four to five years to complete.

"We're just going to have to wait for the results of these trials to be able to make any recommendations about using ginkgo to prevent memory decline or dementia in healthy older people," cautions Oken.

NSAIDs

The first clues showed up in people who were taking daily doses of NSAIDs (non-steroidal anti-inflammatory drugs) like ibuprofen (Advil or Motrin) for arthritis pain. When researchers looked at those who had taken the NSAIDs (pronounced EN-seds) for at least two years, they found a lower risk of Alzheimer's. And that seemed to fit with studies that examined brain tissue from Alzheimer's patients.

"We know that inflammation plays a role in Alzheimer's," explains Robert Green, associate director of the Boston University Alzheimer's Disease Center. "It's a lower-grade inflammation than an infection or rheumatoid arthritis, but it may contribute to cell death."

Among the most compelling evidence: Last November, researchers in Rotterdam reported that healthy people who were taking NSAIDs daily for at least two years were only 20 percent as likely to develop Alzheimer's as those who took few or no NSAIDs. (8) More than 80 percent were taking diclofenac, ibuprofen, or naproxen (Naprosyn or Aleve). Aspirin didn't lower the risk. (Acetaminophen, or Tylenol, isn't an NSAID.)

"The Rotterdam study suggests that there's a window of opportunity that may close a couple of years before Alzheimer's develops," says Green. "If you wait until the early stages of the disease, it may be too late."

It's not clear what dose of NSAIDs might preserve brain function. For example, in the Rotterdam study the risk of Alzheimer's was lower in NSAID-takers, no matter how much they were taking. (The people in the study who were on ibuprofen were taking it under doctors' supervision, so their average daily dose, 1,200 mg, was high.)

But some studies that track healthy people for years have seen no protection from NSAIDs. Researchers won't know if NSAIDs can prevent Alzheimer's until they complete clinical trials, which randomly assign people to NSAIDs or a placebo.

"As we learned from estrogen, things that look useful may not be helpful when we do a clinical trial," says the National Institute on Aging's Neil Buckholtz.

At least three studies using NSAIDs like celecoxib (Celebrex) or naproxen to treat people who already have Alzheimer's have flopped, says NYU's Steven Ferris. And in a recent animal study, ibuprofen was more effective than the prescription NSAIDs used in the human trials. "Ibuprofen seemed to modify amyloid, while celecoxib and naproxen didn't," says Buckholtz.

But that's not definitive, he adds. It's really too early to say if any NSAIDs can prevent dementia, since the first trial is just getting under way (see "Alzheimer's on Trial").

"We're giving celecoxib or a placebo to healthy people who are 70 or older and have a parent or sibling who has Alzheimer's or another form of serious memory loss," says Green. "We want to answer the fundamental question of whether anti-inflammatory drugs can prevent the disease."

What should people do until the studies end?

"It's tempting to take ibuprofen because it's sold over-the-counter and it seems benign," says Green. "But if a million people take ibuprofen every day, a small number will have severe gastrointestinal bleeding, and if they have vulnerable kidneys, there's a potential for kidney damage."

Most important, he warns people against jumping to conclusions. "Until the trials end, we don't have the answers, and they often surprise us."

STATINS 

Statin drugs--like Pravachol, Zocor, and Lipitor--dramatically lower cholesterol and cut the risk of heart disease and stroke. Could they also keep Alzheimer's at bay?

"We have compelling retrospective evidence that statin use has a strong protective effect against Alzheimer's disease," says Boston University's Robert Green.

In several studies, researchers found that people with Alzheimer's were 60 to 70 percent less likely to have taken statins than similar healthy people. (9) In Green's study--not yet published--statin-takers had a 39 percent lower risk.

But Green and others are cautious. "Almost all the early studies suggested that estrogen could prevent heart disease," he explains, "but the trials found that it wasn't true."

Exactly how statins might work is still up for grabs. One possibility: They might act directly on beta-amyloid. "There are five or six different lines of evidence, but the most compelling is that animals given statins have fewer amyloid deposits in their brains," says Green.

Statins might also work by curbing inflammation and lowering cholesterol. "Having high cholesterol accelerates the production of beta-amyloid," explains NYU's Steven Ferris. Scientists used to think that Alzheimer's had no connection to clogged arteries, "but now we think that high cholesterol raises the risk of the disease."

In fact, a gene called apolipoprotein E e4 (ApoE e4), which helps determine cholesterol levels, raises the risk of Alzheimer's dramatically. "If you don't have an ApoE e4, your chances of getting Alzheimer's are roughly 10 percent by age 85," says UCLA's Jeffrey Cummings. "If you do have an ApoE e4, your chances are roughly 30 percent by age 85. So the gene increases the risk three-fold."

But Cummings and others don't advise people to get their ApoE e4 tested. "Ten percent of people without the gene still get the disease, and 70 percent of people with the gene still don't get the disease. So the test doesn't provide enough information to do anything except to worry people." And, since there's no way to prevent Alzheimer's anyway, worrying won't help anybody.

So far, the National Institute on Aging has only funded a trial that will look at whether statins can slow Alzheimer's in people who already have the disease. "The evidence is strong enough to spend money on clinical trials to see if statins can prevent Alzheimer's," argues Green.

PLAQUE ATTACK

Researchers still don't know whether beta-amyloid plaques cause Alzheimer's or whether they are a by-product of the disease. The plaques contain a protein fragment called beta-amyloid, as well as immune cells and other proteins. Once the plaque matures (right), parts of the nerve cell (neuron), like the axon and dendrites, begin to degenerate. (Axons transmit messages to other neurons; dendrites receive messages from other neurons' axons.)

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TANGLED TAU

Neurofibrillary tangles form in the transport system of nerve cells (neurons). In healthy cells, microtubules are like train rails that have long parallel tracks with crosspieces. The rails carry nutrients from the body of the cell to the ends of the axons. In Alzheimer's disease, a protein called tau, which normally helps form the crosspieces, gets twisted, like two threads wound around each other. When the crosspieces can no longer hold the microtubules together, the tracks fall apart. The transport system's collapse interferes with the cell's ability to send signals and may lead to the cell's death.

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MILD IN NAME ONLY

"People with mild cognitive impairment have a memory deficit compared to other people their age, but otherwise they function well," says Neil Buckholtz of the National Institute on Aging.

"These people are at such a high risk for Alzheimer's that some researchers think it is the earliest form of the disease," he adds. In fact, the brains of people with mild cognitive impairment may already bear the neurofibrillary tangles characteristic of Alzheimer's. (1)

How can you tell if you or someone you know has mild cognitive impairment? One simple clue is whether you can remember three words after being distracted. For example, a tester might:

* Give you three unrelated nouns that name concrete objects--like "apple," "penny," and "string"--and make sure that you can repeat them.

* Ask you to start with 100 and keep subtracting seven from the answer until told to stop.

* Ask you to spell the word "world" backwards.

* Ask you to repeat the three words you were given when the test began.

People with mild cognitive impairment often can't recall the three words, because the words were never deposited into their memory in the first place. And prompting doesn't help.

"In an ordinary `senior moment,' the information is there, so if a person has a clue, or if they have enough time, they can retrieve it," says Jeffrey Cummings, director of the UCLA Alzheimer's Center. "So you can't remember Bob's name, but as soon as someone says `Bob,' you immediately recognize it.

"In the earliest stages of Alzheimer's, recognition as well as recall is impaired. The typical example is the person who asks the same question again and again, because they don't recall the answer that they were given."

The three-word test is far from definitive, though. A tougher test, which requires patients to recall details from a paragraph they had previously read, is better for detecting the earliest stages. And physicians would have to rule out other problems. "We would screen patients for thyroid and B-12 deficiency and other causes of memory impairment," says Cummings.

Ten to 15 percent of people with mild cognitive impairment are diagnosed with Alzheimer's each year. Within five years, more than half have the disease. But researchers still don't know whether everyone with the condition eventually gets Alzheimer's.

"It appears that up to 20 percent of those with mild cognitive impairment may have a benign form that doesn't convert to Alzheimer's," says Cummings.

"But the science is not there to sort out whether it is truly benign or whether they're just unusually slow in accruing the plaques and tangles that drive the disease."

(1) Annals of Neurology 51: 567, 2002.

BRAIN DRAIN

These PET (positron emission tomography) scans show differences in brain activity between a normal brain (left) and a brain affected by Alzheimer's disease (right). The blue and black areas are regions of inactivity.

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ALUMINUM

"Aluminum is the cause of Alzheimer's," salespeople for Royal Prestige, an expensive line of stainless steel pots and pans, were caught telling customers earlier this year by hidden ABC News television cameras.

"Aluminum has been linked to Alzheimer's and dementia" (not to mention cancer and mad cow disease), claim the makers of (aluminum-free) Get Real Natural Deodorant.

The truth isn't that simple.

"Unfortunately, there is no clear-cut answer either to implicate or absolve the role of aluminum in causing Alzheimer's disease," says Zaven S. Khachaturian, former director of the National Institute on Aging's Office of Alzheimer's Research.

While high levels of aluminum are found in the brains of Alzheimer's victims, "it's not clear whether the aluminum starts the process or got there because there is disease already in progress," explains Khachaturian.

Injecting aluminum directly into the brains of rabbits, cats, and dogs produces memory problems similar to those found in Alzheimer's patients, but the injury to the animals' brain cells is different.

Until we know more, it's not worth avoiding aluminum pots and pans, tin foil, and anti-perspirants and antacids that contain aluminum, says Khachaturian. "We don't know whether aluminum, in the environment is a risk factor, but even if it were, the potential exposure from pots and pans and those other sources is minor compared to our exposure to aluminum from water, food, dust, glass, cosmetics, and some medications. Avoiding those minor sources would be penny wise and pound foolish."

ALZHEIMER'S ON TRIAL

"When people ask me what they can do about Alzheimer's, I suggest that they participate in a study," says Trey Sunderland of the National Institute of Mental Health.

Some, like the Baltimore Longitudinal Study on Aging, simply give you memory tests and brain scans every few years. Others, like the trials below, test drugs or supplements on your risk of Alzheimer's. Check www.alzheimers.org or www.clinicaltrials.gov for the latest list of trials.

* NSAIDs. ADAPT (Alzheimer's Disease Anti-Inflammatory Prevention Trial) is giving a placebo or an anti-inflammatory drug (Celebrex or Naprosyn) to healthy people aged 70 or older who have a sibling or parent with Alzheimer's or other dementia. Participants must make up to three visits a year to a medical center in one of four cities (Baltimore; Boston; Rochester, New York; and Sun City, Arizona). For information, call 1-866-2stopAD or go to www.2stopAD.org.

* Estrogen. The Alzheimer's Disease Prevention Trial is giving estrogen or a placebo to healthy women in 13 states aged 65 or older with a family history of Alzheimer's. For more information and locations contact Evelyn Dominguez-Rivera at [phone] or [e-mail].

THE BOTTOM LINE

* Take a multivitamin that has at least 100 percent of a day's folate and vitamins B-6 and B-12.

* Until clinical trials are completed, it's too early to say whether estrogen, ginkgo, NSAIDs, statins, or vitamin E can prevent Alzheimer's.

* So far, estrogen and NSAIDs don't seem to slow the progression of Alzheimer's, but large doses of vitamin E may.

(1) J. Amer. Med. Assoc. 287: 3223, 3230, 3261, 2002.

(2) New Eng. J. Med. 336: 1216, 1997.

(3) Neurology 48: 1517, 1997.

(4) J. Amer. Med. Assoc. 285: 1489, 2001.

(5) J. Amer. Med. Assoc. 283: 1007, 2000.

(6) New Eng. J. Med. 346: 466, 476, 2002.

(7) Arch. Neurol. 55: 1409, 1998.

(8) New Eng. J. Med. 345: 1515, 1567, 2001.

(9) Arch. Neurol. 57: 1439, 2000.