Probing a Mind for a Cure

Bob Moore's brain lay on a white plastic cutting board.

There was something beautiful about its convoluted hills and valleys, the way rivers of dusky purple and red meandered through the beige flesh.

And mysterious. Here was the essence of a man who had gone to Yale, loved a woman, fathered six children, relished ice cream and Mozart and Kierkegaard and e.e. cummings, favored questions over answers and change over complacency, hated camping, loathed golf, and, over the last 20 years, had slowly lost the capacity to understand any of it.

He had died that morning in a Wilmington nursing home, years past being able to feed himself or walk or recognize the woman he had married 56 years before.

What had gone wrong with his brain?

Before neuropathologist Mark Forman lifted his knife last December in a basement autopsy suite at the Hospital of the University of Pennsylvania, he could see that Bob Moore's brain wasn't normal. But it would be weeks before he could tell Moore's family what had made the man they loved disappear long before his heart stopped beating.

Robert B. Moore, a Presbyterian minister, was a spiritual man, but he was also a believer in science and medicine.

After being diagnosed with Alzheimer's disease in 1993, at age 67, he entered a clinical trial of an experimental drug. He let doctors, intent on finding ways to detect dementia earlier, tap his spinal fluid and compare it with healthy people's.

And he decided that his brain would be autopsied at Penn's Center for Neurodegenerative Disease Research, founded and run by two nationally prominent dementia researchers.

Doctors can tell with about 90 percent accuracy whether a patient has Alzheimer's, the most common dementia. But looking through a microscope at brain tissue after death is still the only way to diagnose it with absolute certainty.

Perfecting diagnosis is critical in the emerging era of drugs designed for specific types of dementia.

But diagnosis is just the beginning. By studying brains from patients such as Bob Moore, scientists hope to figure out how and why the damage occurred - and learn to prevent it. More than one in five women and one in six men who reach age 65 will develop dementia before they die, a study this month reported. By 2050, more than 13 million Americans will have Alzheimer's, another study estimated.

"We want to cure this damn disease," said John Trojanowski, a neuropathologist who launched the center in 1982 with his wife, Virginia Lee, a biochemist and cell biologist. The center performed 86 autopsies last year - its record. Researchers there publish 40 to 50 scientific papers a year.

For Trojanowski, this is an epic battle.

"I talk about this as a threat to our economy and way of life that equals any natural disaster, and I think it will be worse... . The baby boomers start turning 60 this year," said Trojanowski, who is 59 himself. "We really are in a race with time."

For Moore's family, it's personal.

What exactly, they wonder, turned this gentle man into an unruly stranger who shouted obscenities and hit his wife? Why did the disease strike him a decade earlier than the average? Could the car accident that gave him amnesia briefly in 1950 have triggered this calamity years later?

Because of their family history, Moore's children also feel some urgency about the science that their father's brain cells may fuel. Three of their grandparents also died with dementia. Even their 78-year-old mother, who jokes that she is a "normal control" in Penn's studies, has a gene that raises risk for Alzheimer's.

With most now well into middle age, the children - a pediatric physical therapist, an architect, a computer consultant, a classical musician, a foreign-service officer, and a daughter whose own ministerial career was sidetracked by an autoimmune disease - all worry about their futures.

At 51, Alison Moore, the would-be minister, already has taken medicine for mild cognitive impairment, a condition that often precedes dementia.

Betsy Shieh, 45, the foreign-service officer, said her memory doesn't seem any worse than her peers' now. Still, she says, "when you forget something when your father's just died of Alzheimer's, you say: 'Oh s-, here I go.' "

Long after it was obvious that he was losing his fight with dementia, Bob Moore believed that doctors might save him. His children hope the cure he was so optimistic about will come in time for them.

Bob Moore came into the world with a superior brain. He used it hard and well.

As a young man, his fascination with life's big questions led him to Yale University's Divinity School and, later, a master's in philosophy. It drew him to the civil rights movement and a lifelong quest to broaden his church and improve the lot of the poor.

In 1970, he rose to executive of the Delaware-based New Castle Presbytery, the denomination's regional ruling body.

A 1978 sermon, in which he mused about the meaning of faith, revealed a complex man and graceful writer, a minister who saw religion not as an easy comfort, but as a struggle for self- and world-betterment. He quoted the Bible, of course, but also the New York Times, Dostoyevsky, and Thomas Hobbes.

"I believe that faith is like the free, innocent, life-entrusting leap of a child into the arms of a parent," he said. That trust erodes as adults learn that "faith does not always, does not often, win."

Ultimately, he said, "our leap of faith is a lifetime thing, and what is unknown remains unknown for us and what is hidden remains hidden. Faith is the posture of our lives, the bent of our spirit, the foundation and definition of who we are."

An only child, the robust, red-haired man who liked quiet and order had three sons and three daughters with Joanna, a warm, practical preacher's daughter he met in college. He was the animated, emotional one - a belly-laugher and great hugger. She was stoic, gentle, forgiving. They fit.

Although he would sometimes call for silence as he listened to his classical music, he mostly delighted in the chaos of their Wilmington home. He was a joyful, supportive father.

"When my dad was proud of you, you knew it," said Alison Moore, who followed him to Yale Divinity School. "His whole body would light up... .

"You felt like you were illuminated."

"This is a really small brain," Forman said on Dec. 1 as he took his first look at case number 05-274.

A normal man's brain weighs 1,200 to 1,400 grams. Bob Moore's weighed 1,005 grams - a little more than 2 pounds. The folds at its surface were half the usual thickness, a sign that many cells had died.

Several diseases with similar symptoms can cause this kind of atrophy. A surprising number of patients have more than one. Knowing whether they had Alzheimer's, frontotemporal dementia, or dementia with Lewy bodies is important for families because each carries genetic risk. It helps doctors sharpen diagnoses in preparation for the day when they'll have different treatments for different dementias. Twenty-seven dementia drugs are now in human clinical trials or awaiting approval.

Forman looked at and felt the surface of the brain. It was symmetrical, as it should be. No areas were squishier than normal. There were yellow flecks in the carotid arteries, evidence of blood-vessel clogging. The olfactory bulbs were exceptionally small. Poor sense of smell is an early sign of dementia, and Moore did, in fact, do poorly on a scent test soon after his diagnosis.

His brain stem was also unusually small - not typical of Alzheimer's patients, Forman pointed out, but not unheard of.

He cut the brain stem from the rest of the brain and looked at the substantia nigra, dark lines that run through the midbrain. In Parkinson's disease, these lines lighten. The lines in Moore's brain had lost some pigment, but less than usual for Parkinson's.

Using a long knife, Forman sliced the gelatin-like brain in half. The center would use one hemisphere for the autopsy. The other would be frozen and used only for research.

Again, Forman, a wiry, graying man whose grandmother had Alzheimer's, noticed atrophy. The ventricles - pools of cerebrospinal fluid - were much larger than normal, a sign that surrounding tissue had died.

Forman cut the hemispheres into half-inch slices. Each had brown scalloped edges - the gray matter or nerve cells - and creamy, white centers - the electrical wiring. He saw no signs of tumors or stroke.

The big-picture work over, Forman took samples from about 20 parts of the brain, including the hippocampus, the seat of memory and the place where Alzheimer's is thought to start; the amygdala, an emotional center that's also involved in smell; the brain stem, responsible for involuntary activities such as heartbeat and breathing. Especially shrunken was the visual cortex, a part of the brain usually unaffected by Alzheimer's.

What Forman saw was "consistent" with Alzheimer's, but, he said, "none of this tells me definitively what the diagnosis is going to be. Every patient doesn't read the book." He still had to study Moore's brain cells.

Forman's caution would prove justified.

Bob Moore began complaining about his memory to his doctor in 1985. He wasn't even 60 yet, and the doctor discounted his fears. Most people don't have noticeable problems until their early- to mid-70s.

By 1988, Bob Criswell, pastor of the church that Moore attended, was also concerned. He pulled Moore aside to tell him he was repeating himself.

"Does it show that much?" Moore asked.

A few months later, his assistant at the presbytery, Bob Bolt, gently told Moore that he was returning phone calls more than once.

Within days, Moore, who'd had some health problems and was feeling the stress of his job, announced his retirement. He was 62.

Still curious and energetic, he began teaching philosophy at the University of Delaware's Academy of Lifelong Learning. But late in 1992, after he struggled with an ambitious class on philosophy and religion, he questioned his students. They said he'd been making mistakes.

Moore demanded an appointment with a specialist. A psychiatrist told him that he probably had Alzheimer's.

"How long do I have?" Moore asked.

"About 10 years," the psychiatrist said.

With characteristic forthrightness, Moore told each of his children. In a letter to his son Tom, now a computer consultant in New York, he wrote: "I'm in good shape psychologically. I'm not depressed... . However, I will not teach anymore. I know I could, but I also know that I have sometimes been embarrassed in classes I have taught when I have made minor slips, not just once but several times... . I am sensitive about this... .

"All people die... . I have a good chance of living many years yet, with very gradually decreased acuity."

Bob Moore did, indeed, live well for several years. He took classes and enjoyed them. He and Joanna traveled.

In a 1996 letter to their children, Joanna Moore, a retired teacher who thought it important to record their family history, described the disease's progress. Her husband could still drive well, with her help as navigator, but could not do simple arithmetic. He still enjoyed reading and going to movies. He had trouble with time and was unable to follow through on plans. In conversation, he failed at finding even ordinary words. He could no longer compare two thoughts or visualize something.

"He wants to open his own mail, answer the phone, continue the routines he has followed for many years," Joanna wrote. "Bob does the dishes and usually does the laundry. I'm grateful. He washes the kitchen floor and vacuums the rugs. He locks the house at night and turns out the lights and pulls the blinds... .

"Normal life consists of a hundred small responsibilities, and I hope we can continue our normal life for a long, long time."

From autopsies of people who died in different stages of Alzheimer's, scientists know that its first physical signs usually appear in the medial temporal lobes. These reception areas for sensory input near the temples help produce memories.

Particularly hard hit is the hippocampus, a three-inch-long portion shaped like a sea horse that records new memories. Trojanowski calls it "the epicenter of disaster."

From there, the protein hallmarks of Alzheimer's - plaques, or clumps of protein fragments that form outside nerve cells, and tangles, twisted strands of a different protein that form inside cells - move up, forward and back through the brain. Scientists do not know how or why.

The amygdala, which is beside the hippocampus, is an early casualty. Damage there may cause emotional changes. As the disease moves along the sides of the brain, it affects language skills. In the frontal lobe near the top of the brain, executive function - the ability to make rational decisions - is disrupted. As this section erodes, people find it harder to plan and understand time. At roughly the same time, the parietal lobe, which helps people orient themselves in space, is damaged, making it harder for people to find their way around.

The path and its connection to behavior grow hazier after that because the disease destroys not only brain cells but also the connections between them, isolating regions that may still look fine. "It just sits there and rips the brain apart," Trojanowski said.

There's no clear physical explanation for the incessant walking, agitation and violent behavior that some patients exhibit.

Some agitation likely stems from the fear that constant surprises breed. As memories fade, people do not know how to react.

"Their frame of reference is disappearing," said Christopher Clark, director of Penn's Memory Disorders Clinic and Bob Moore's doctor after his diagnosis. "You know who you are based on your past. You use that to project what's going to happen in the future. As your past disappears, your ability to project into the future essentially disappears, too."

Ultimately, Alzheimer's destroys enough of the brain that patients can't walk. By the time they can't swallow, the brain may be so far gone that it's hard to pinpoint why.

"At one point," Trojanowski said, "this is a train wreck, and there's so much damage it's hard to say what killed the passengers."

As the '90s waned, Bob Moore became increasingly dependent on Joanna and increasingly angry.

For one who had taken such pride in his verbal abilities, being incapable of finding the right words was humiliating, Alison Moore said. Unable to marshal an argument, he'd exclaim: "Damn it! I am... I am..." Finally, he'd remember. "I'm a man," he'd say emphatically.

As the dementia worsened, his frustration grew. "I am...," he'd stammer. "I am..."

The sentence would hang unfinished, a reminder of what he'd lost.

By 2000, an exhausted Joanna Moore was keeping a journal. Pages and pages are devoted to the vagaries of her husband's behavior. Like the mother of a difficult toddler, she focused on his bowels and his tantrums, and was grateful for the good days when he was pliable and she could get a full night's sleep.

She had to watch him now so he wouldn't step in front of cars. He was a dangerous passenger who grabbed the steering wheel or tried to open his door while the car was moving. He shouted swear words and walked constantly, sweeping belongings off tables as he strode. He had hit his oldest son, Andy, a Wilmington architect, and he had hit Joanna.

"Yesterday was the day I reached my own personal limit," she wrote that November, "fighting him to get clothes off, keep him in the shower while I washed him, getting him dressed. I think we've gone back to another good day/bad day cycle, but the good days (today) aren't very good, and the bad days are horrible."

The next month, she decided she could no longer handle him. Rejected as too violent by nursing homes, Moore was admitted to a psychiatric hospital. To Joanna's horror, he rode there in handcuffs.

By spring 2001, she was no longer sure her husband remembered her or other family members. She had decided to decline hospital care if he got sick, choosing hospice, instead. "I know that this was Bob's choice, as well," she wrote. "He is now in the process of dying. I expect the disease will steadily deprive him of his humanity until there is nothing left but the shadow of life. First it took his memory; then it took his dignity; now it is taking his life."

A century ago, when German scientist Alois Alzheimer first identified the disease that bears his name, doctors thought dementia was rare. In reality, few lived long enough to get it.

By the time Trojanowski and Lee decided to take on Alzheimer's, the dark side of a lengthening life span was emerging. The longer people's bodies lived, the more often their minds failed.

In 1982, scientists knew little about the diseases that make brains die. They did not even know what made up the plaques and tangles that Alzheimer had seen under his microscope.

Lee and Trojanowski would prove that tangles are made of an abnormal form of the protein tau. Later, they showed how it weakens and kills cells. Other scientists found that plaque contained a different protein, beta-amyloid. In 1998, the protein in Lewy bodies - round clumps found in one part of the brain in Parkinson's patients and in other parts in those with Lewy body dementia - was identified.

Trojanowski and Lee then proposed a unified theory of dementia. All of the dementias, they said, have in common misfolded proteins, that accumulate in the brain. How to derail that process is the billion-dollar question.

Much remains a mystery.

How and why do cells die? What role do the errant clumps of protein play? What makes the diseases appear in more and more of the brain? How can some people have Alzheimer's pathology without symptoms? What triggers violence?

Then there's the key question for Moore's children: What's my risk? For late-onset Alzheimer's, which starts after age 60, there's no easy answer. Genes certainly are a factor, though only one for this type has been found.

One study estimated that 39 percent of people with a parent or sibling who'd had Alzheimer's will eventually develop the disease.

Another of male twins released this month found that genes mattered most, but lifestyle seemed to make a difference. Twins who did not have Alzheimer's when their brothers did tended to have more education. This supports the theory that "cognitive reserve" can help prevent or delay the disease, said the study's author, Margaret Gatz, a University of Southern California psychologist.

Experts say there's no way to predict an individual's late-onset Alzheimer's risk. It's even murkier for other dementias.

"I don't think it means anything to the kids that they can deal with one way or the other," Clark said of the Moore family history.

He could only suggest activities that seem to lower risk: Eat healthy food, exercise, and keep your mind active. Moore's children do all that.

It was January 2004, and Joanna arrived at Bob's nursing home to feed him lunch, just as she had almost every day for two years.

Bob was in a padded chair with a sloped back so he could slump without falling out. The legs of his gray sweatpants rode up almost to his knee, revealing his thin, pale shins. He made singsongy sounds that an administrator explained as singing and preaching. It helped other patients and families accept his outbursts. He wore thick glasses. Joanna didn't know whether he could see or whether he even knew she was there.

He had trouble swallowing, so he was fed ground or mashed food. Joanna gave him milk, rubbing his shoulder as she held a baby's sippy cup to his lips. Unable to cough properly, he cleared his throat with a loud, staccato laugh - "Ah hah hah hah" - that fell like a roller-coaster.

While waiting for his bean soup to arrive, Joanna looked at him intently. "Hi, sweetie," she said, tenderly brushing his wavy hair back from his forehead. On some days, she thought he responded to her touch. She'd whisper "I love you" in his ear, and he'd babble a response. Maybe some part of him still knew her. On this day, he sometimes looked right at her, but there was no hint of understanding.

He still loved to eat, and it was keeping him alive. Once a big man - 5-foot-10 and 200 pounds - he had dropped to 130 at one point. Now, he was back up to 156. His health had improved so much that hospice was no longer appropriate.

"When I start blithering, I want you to shoot me," he had told Joanna after he got sick.

He was blithering now, but she couldn't follow his orders. Well-aware of the irony, she spooned the soup, a big helping of pureed chicken and noodles, mashed carrots, a roll, sugar cookies softened in milk, and ice cream into his gaping mouth.

When the food was gone, she wheeled him back to his room. She lowered the back of the chair until it was almost flat and gently removed his glasses. Not knowing whether it mattered, she turned on a classical music tape. In no time, he was asleep.

Last fall, Bob Moore's trouble with swallowing worsened. He got pneumonia, probably because improperly swallowed food lodged in his lungs. Told that he would die within days, Joanna called their children home.

On the morning of Nov. 30, the sons - Tom, Andy and John, a double-bass player who'd left a tour with the Pittsburgh Symphony Orchestra - sat uncomfortably around their father's bedside, reminiscing and staring at the pale, open-mouthed man whose chest rose and fell beside them.

"Feel free to touch him," Joanna told her sons. "I got a lot of comfort last night out of sitting here and just touching him." His warmth had soothed her.

"You just realize there's such a big break between life and death," she said.

That night, the daughters arrived - Kathy Thomas, the physical therapist from Pittsburgh; Betsy from Hyde Park, N.Y.; and Alison, of Wilmington. They cried, surprised that their father's imminent death freed them to remember the man they had loved.

He breathed quietly in bed as his children's voices swirled around him.

The six of them and a grandson held hands with Joanna as they circled the bed to pray. "I am thankful for this unbroken chain of family," Joanna said.

Bob Moore died before the sun rose. His wife and children were relieved.

On the afternoon of Feb. 8, Forman opened the first of five folders containing 60 slides of Bob Moore's brain.

Each of the slides held a fragile slice of brain tissue treated with antibodies and chemicals to bring out, with color or light, the protein landmarks of dementia.

As always, Forman started with the fuchsia slides, the standard stain for seeing cell structure.

What struck him right away was what was not there. Slides from a normal brain would be solid pink. Many of these were dappled with white spots that made them look like slices of baby Swiss or leaves eaten down to the veins. The white holes were the abandoned homes of dead cells.

The hippocampus was sparsely populated, with far fewer pyramid-shape neurons than normal. Even with this stain, not designed to show clumps of proteins, Forman saw his first tangles - dark, flame-shape interlopers flowing from some cell nuclei.

This was typical for Alzheimer's.

But in the brain stem, he saw something intriguing: planet-like circles with pale rims and dark pink centers.

These were Lewy bodies. Forman would expect to find them in the brain stems of patients with Parkinson's, but with more damage. This might mean that Moore's disease was more complicated than his doctors had thought.

Forman moved on to the next slides. These had been stained to reveal abnormal tau, the key component in tangles, by turning it brown. Slides from a normal brain would be all white, with a bluish cast. Moore's had a dark ribbon of brown on the edges.

"I call that my Alzheimer's disease diagnosis," Forman said. "I don't even have to look at the slide to know what the disease will be." He looked anyway and saw what he had expected: "wall-to-wall" pathology.

Curious about what he'd found in the brain stem, Forman now picked up the set of slides that stained alpha-synuclein, the protein in Lewy bodies, dark brown.

Developed in 1998, the stain has turned up Lewy bodies in many Alzheimer's patients, raising questions about this protein conglomeration's relationship with plaques and tangles.

In half of Alzheimer's patients, Lewy bodies are in the amygdala - the part of the brain key to processing emotions. In a quarter, the Lewy bodies are widespread enough to warrant a different diagnosis.

Doctors often miss this dual problem while patients are alive, probably because symptoms of the two dementias are so similar. But Lewy body dementia is more likely to involve hallucinations, sleep disruptions, fluctuations in thinking ability - plus the tremors and rigidity of Parkinson's.

Moore had not had movement problems, but he may have had some of the others.

Forman peered through his microscope and saw that Moore's amygdala was packed with Lewy bodies. The surprise, though, was how many Forman saw throughout the brain, particularly in the upper regions.

"This," he said, "is an extraordinary case of Lewy body pathology."

Finally, it was time for fluorescent slides that light up both the plaques and tangles of Alzheimer's in glow-stick green. The plaques - puffs of protein stuck together like popcorn balls - are seen best in these slides.

In a normal brain, Forman would see only black. The slide of Moore's hippocampus lit up like the Milky Way, chock full of oddly shaped fluorescent stars and twisting streaks.

"We know what the diagnosis is," he said.

Bob Moore had gotten a dementia double whammy. Separately, he had enough plaques and tangles - and enough Lewy bodies - to ruin his brain.

Brain 05-274 would have a new job now. It would join 900 others stacked on shelves in the lab, waiting to help scientists vanquish their killers.

Clark, Bob Moore's doctor, heard the news first and was surprised by how many Lewy bodies his patient had.

One of his research goals is to create simple tests of spinal fluid or urine that detect and sort out dementias early. He has already added Moore's information to his database. And, he said, the next time he sees an Alzheimer's patient with behavior problems like Moore's, he'll be more likely to think of Lewy bodies.

Joanna Moore slit open the envelope containing Forman's report on Tuesday.

She read it, re-read it, and read it again. She lingered on Forman's diagnosis: "Lewy body variant of Alzheimer's disease."

It was gratifying to see proof that Bob had, indeed, had Alzheimer's disease. But what was a Lewy body?

She still had questions, but having something concrete to explain what her family had been through felt good. Her children would want the news. "They're the inheritors," she said.

Alzheimer's disease

Alzheimer's usually begins after age 60 with mild memory problems and progresses to serious disruption of language and thinking. In the brain, scientists see plaques (clumps of the protein beta-amyloid) and tangles (twisted fibers of the protein tau).

Multi-infarct or vascular dementia

Small strokes cause this dementia. Symptoms tend to come on suddenly and remain stable.

Dementia with Lewy bodies

This dementia is characterized by small, round deposits of protein within cells. Clustered in the brain stem, Lewy bodies are the hallmark of Parkinson's disease, but they may occur elsewhere in the brain, with symptoms more like Alzheimer's.

Frontotemporal dementia

This is a rarer group of diseases that damage the frontal and temporal lobes, areas that control executive functions such as the abilities to reason and organize. These patients have tangles, but not plaques.

SOURCE: Alzheimer's Disease Education and Referral Center