Pittsburgh at the Forefront of The Brain Revolution

Alzheimer’s disease is the most expensive ailment to treat and the sixth-leading cause of death in the United States. Pittsburgh has become a battleground in the fight against the devastating illness, thanks to the decade-long quest of two Pittsburgh researchers whose work is on track to change the face of medicine and affect millions worldwide.

Editor’s note: Niki Kapsambelis is the author of “The Inheritance: A Family on the Front Lines of the Battle Against Alzheimer’s Disease,” which chronicles the story of Alzheimer’s research through the lens of the DeMoe family of North Dakota. Stricken with an extremely rare genetic mutation that guarantees early onset Alzheimer’s, the DeMoes have worked with the University of Pittsburgh since the early 2000s to significantly advance scientific understanding of the disease and most recently to pilot test experimental prevention drugs. Their bond with Pitt researchers — particularly Dr. William Klunk of the Alzheimer’s Disease Research Center — is detailed in “The Inheritance” and has helped the field move toward a cure.
 


 

In 1994, a soft-spoken young doctor with a keen interest in brain disorders approached a colleague at the University of Pittsburgh with an idea: He wanted to develop a way to view Alzheimer’s disease in a living patient.
 

What Bill Klunk had in mind was nothing short of revolutionary and maybe a tad bit quixotic. Alois Alzheimer had discovered the disease 88 years earlier, and for much of that time, very little was known about it — including how widespread and deadly it was.

Part of the reason for that fatal misunderstanding was that doctors couldn’t definitively diagnose Alzheimer’s until the patient died, when they were able to look at the brain under a microscope. Another part of the reason was that Alzheimer’s, like many seemingly intractable illnesses, is such a biologically complex disease.
When I was researching my book, “The Inheritance,” one doctor remarked to me that we know more about the outer reaches of the universe than the inner workings of the brain.

​Klunk wanted to change that, and with good reason: despite flying under the radar for a good chunk of the 20th century, Alzheimer’s now is the sixth-leading cause of death in the United States, affecting 5.4 million Americans. Developing effective treatment — not to mention a cure — has proven to be maddeningly elusive.
Researchers in the Alzheimer’s field knew they could better identify the disease’s biological underpinnings if they could see its progression in real time. In so doing, they’d be better able to develop more precise treatments to halt or even prevent it.

It was a task easier said than done, as Chester Mathis knew well. Mathis, a Pitt radiochemist, had been trying since the 1980s — first in California and later in Pittsburgh — to develop a compound that would highlight the abnormalities in an Alzheimer’s brain, without success. Despite his other accomplishments, that incomplete task stuck with him.

And so began a decade-long quest that propelled Bill Klunk and Chet Mathis into the company of other Pittsburgh doctors whose work would change the face of medicine and impact millions of people worldwide.

Maybe it’s a side effect of working in a city that forged steel to build the world’s infrastructure. Perhaps it’s a ripple effect from living among people who refuse to give up in the face of failure. Whatever the X-factor may be, Pittsburgh boasts an impressive history of medical breakthroughs, often against long odds — whether it’s the polio vaccine or a multi-organ transplant.

There are parallels between the quest for a polio vaccine and the search for an Alzheimer’s cure. During the post-World War II epidemic, polls showed that the only thing Americans feared more than polio was nuclear war. Today, polls indicate the only disease Americans fear more than Alzheimer’s is cancer — although Alzheimer’s kills more people than breast and prostate cancer combined.

For Klunk and Mathis, the formula for success was a combination of persistence, hard work and the quiet but unwavering support of a mentor. And through a touch of serendipity, that eventual breakthrough would find a portal to the public in the unlikely form of a quirky family from the oil fields of North Dakota who came to think of Pittsburgh as a second home.
 

Pitt’s Dr. Chester Mathis (left) and Dr. William Klunk (right) discovered Pittsburgh Compound B, which made it possible for researchers to view Alzheimer’s disease in a living brain. | Photo courtesy University of Pittsburgh
 

An unlikely pair

A Pennsylvania native, Bill Klunk was a geriatric psychiatrist who had been recruited to Pitt nine years earlier. He proposed a window into the progression of a disease that has baffled science since its discovery in 1906. Long assumed to be part of the natural aging process, Alzheimer’s symptoms — forgetfulness, loss of organizational skills, difficulty finding words and names, delusions, paranoia and mood swings, among others — mimic those of many other diseases. That was why a clinical diagnosis was so difficult; doctors had to confirm their hunches postmortem by slicing open the brain and using a microscope to view the rogue proteins that are the Alzheimer’s signature.

Chet Mathis came to Pitt in 1992, lured by the medical school’s reputation for excellence and the presence of a dedicated cyclotron, a 100-ton, $2 million particle accelerator used in radiochemistry.

When Klunk proposed developing a new compound, what he had in mind was a riff on what Mathis already had tried unsuccessfully earlier in his career: adding radioactive atoms (a process called “radiolabeling”) to a dye that would stick to amyloid, one of the two abnormal proteins that are found in an Alzheimer’s brain. When doctors scanned the patient’s brain, the amyloid — coated in radiolabeled dye — in theory would show up on a scan.

Basic biology was working against them, however, due to the blood-brain barrier — the body’s natural filtering system that bars most substances from crossing into the brain past a series of tightly joined cells. Doctors needed a recipe for a compound that would successfully breach that barrier and stick to amyloid, which forms cotton ball-like clumps between neurons and disrupts their ability to signal each other.

What followed in the next 10 years was nothing short of systematic failure for Klunk and Mathis. Compound after compound flopped — hundreds in all.

“There were a lot of lean years here,” Klunk says in his characteristically understated way.

Those years were potential career killers. When an academic scientist is a candidate for tenure or promotion, universities typically ask colleagues in related fields to offer feedback on that scientist’s publications and grants.

But Klunk wasn’t focused on establishing that kind of track record. He and Mathis were on a Holy Grail kind of quest, one critically important to the future of Alzheimer’s research — but not one many other scientists were willing to tackle. Fortunately for them, they had David Kupfer in their corner. Kupfer, chairman of Pitt’s Department of Psychiatry from 1983 through 2009, had recruited Klunk.

“The promissory note from me in recruiting young, bright people who are ambitious is to try to let them run with their passion and see if I can play the role of a facilitator and an older brother,” says Kupfer, now a distinguished professor emeritus.

Klunk and Mathis established a friendship outside the laboratory. The two took fly-fishing trips together, where their unspoken rule dictated that they could talk about anything except work.

“When times were tough, when we were trying to keep things going, the mantra to live by was: You can always talk about fishing at work, but you can’t talk about work while fishing,” Klunk jokes.

In fishing, life imitated their art. The men who worked weekends and evenings, long hours in the lab in search of the elusive compound, would be wading into icy water at dawn on days when 30 degrees seemed warm. When dusk fell and it was too dark to see, they turned on their headlights and kept casting, casting.

Outside of Pittsburgh, despite their lack of success, other researchers were beginning to take notice. Many quietly pleaded with Kupfer to allow the quest to continue because of its importance to the rest of the field.

Finally in 2000 — after failing for nearly a decade — a long-awaited breakthrough occurred. The duo swapped out their original base molecule, known as “Congo Red,” for a simpler one that carried only a single positive charge. Within months, Mathis and Klunk had created roughly 100 derivatives of their compound, the most successful of which would come to be known as “Pittsburgh Compound B,” or PiB. On Valentine’s Day 2002, they collaborated with the Uppsala University PET Center in Sweden to test their creation in a human being. They would never know her name; all they would learn was that she was young and that memory problems had forced her to give up her career in health care.

When they learned that the experiment was a success, they wrote her a letter of thanks and celebrated with lunch at Fuel and Fuddle.

The first patient dosed with PiB would die from Alzheimer’s disease, proving that PiB could trace the disease in a living brain — an important milestone. Now, if the field could come up with a drug that attacked amyloid protein, they could watch its progress in real time, and compare it to any changes in a patient’s symptoms.
 

 


The late Gail DeMoe of Tioga, N.D.,  (top) and her six children (clockwise from top left), the late Brian DeMoe, the late Doug DeMoe, Karla DeMoe Hornstein, Dean DeMoe, the late Lori DeMoe McIntyre and Jamie DeMoe, in 2005. All of the children but Karla inherited the genetic mutation for early onset  Alzheimer’s. The family’s ongoing collaboration with Pitt researchers may hold the key to a cure for the disease.
 

Theory into practice

When thinking about significant medical breakthroughs, it’s important to remember that doctors form only half of the equation. The other half is made up of people who, whether by choice or by chance, often remain anonymous to history. They are the patients who are essentially the human testing ground for the science. On Valentine’s Day 1984, exactly 18 years before Klunk and Mathis’ PiB trial in Sweden, Thomas Starzl pioneered the world’s first heart and liver transplant thanks to a 6-year-old Texas girl named Stormie Jones, who inherited a rare disorder that caused her cholesterol levels to skyrocket. Thirty years earlier, on Feb. 23, 1954, Jonas Salk tested his polio vaccine on children at Pittsburgh’s Arsenal Elementary School.

With proof in hand that the discovery of PiB could track Alzheimer’s disease, Klunk now set his sights on putting it to practical use in other patients, where he could watch Alzheimer’s progression in real time, not just at autopsy. The field had been theorizing that the best time to target the disease was as early as possible — maybe even before people started showing symptoms. Now they were able to view how a buildup of amyloid proteins in the brain corresponded with a person’s cognitive abilities.

To examine the disease’s progression, Klunk sought a tiny sliver of the Alzheimer’s population: people born with a genetic mutation that guarantees early onset of the disease, typically when a carrier is in his or her 40s. Known as autosomal dominant Alzheimer’s, it affects only about 1 percent of the overall number of people who have the disease. Those who carry it have a 50 percent chance of passing it on to their children.

In 2004, just two years after the first patient was injected with PiB, a family of oil workers from North Dakota were undergoing a battery of tests designed to diagnose what was causing them to struggle with jobs they had done for virtually their entire adult lives.

Unlike the general population, people with genetic mutations for Alzheimer’s could get a definitive diagnosis through a blood test. Such was the case for the DeMoe family of Tioga, N.D., and the news went from bad to worse: five of the six siblings had the mutation. As did Stormie Jones, they had inherited a disastrous medical anomaly that could unlock solutions for the rest of the world. Determined to find some meaning in their fate, they sought research that might lead them to an experimental treatment.

In Bill Klunk, they found a champion. The DeMoes — and eventually many of their cousins and children — began making annual pilgrimages to Pittsburgh, where they would undergo days of testing designed to compare their cognitive levels with the amyloid load that PiB illuminated in their brains. Klunk learned about each of them in painstaking detail, quite literally inside and out. He celebrated their triumphs and walked with their ghosts. He helped them adjust to nursing homes. He advised their spouses on handling their combative outbursts.

In late 2012, when the scientific community finally was ready to begin clinical trials of drugs that fight amyloid buildup, he shepherded them into the Dominantly Inherited Alzheimer’s Network, which tests experimental Alzheimer’s drugs in people with mutations to determine whether they can stop the disease. One of the test sites is at Pitt.
Years earlier, in his book “The Puzzle People,” Starzl reflected on his interaction with transplant patients, many of whom introduced themselves after some time had passed by saying, “I know you won’t remember me, but …” He recalled how Stormie Jones’ shoelaces were always loose and how unforgettable her smile was.

“They were wrong about one thing. That I would not remember,” Starzl wrote.

In that same vein, Klunk will not forget the DeMoes; they have forever changed him, their lives giving purpose to his work just as his work gave purpose to their lives.

From the original six DeMoe siblings who came through the Pitt Alzheimer’s center, two since have died, and one is in a North Dakota nursing home, unable to participate any longer. But their children, cousins, nieces and nephews all have entered the research, carrying on their family’s legacy. Along the way, Klunk has helped them transition into nursing homes, comforted those left behind when someone dies, and counseled the younger generation as they contemplate whether they want to know their own genetic status.
“These people have kids the age your kids are, and you know all too well the impact of the disease in the elderly, and you try to extrapolate what it means for these people,” he says. “I feel like I’m a part of the family in a way because they make you feel that way.”
 

 


Dr. Oscar Lopez, a Pitt neurologist, heads a project in partnership with the University of Chile that is focused on developing a blood test that checks for abnormal levels of tau protein, which could help to diagnose and treat Alzheimer’s disease.
 

The road ahead

With clinical trials well underway through the DIAN study, Klunk and his colleagues are looking ahead to the next steps in the quest for a viable treatment.
Mathis continues to develop radiotracers at Pitt, this time focusing on tau, the other protein thought to cause Alzheimer’s. Various forms of tau are implicated in several brain diseases, including frontotemporal dementia and chronic traumatic encephalopathy. Compared to tau, finding a tracer that worked with amyloid “was relatively easy,” Mathis says. Tau is a more difficult target.

​Klunk is focusing on another population whose genetics dramatically impact their chances of developing Alzheimer’s: people with Down syndrome. If they reach the age of 60, anywhere from half to 80 percent of people affected by Down syndrome develop Alzheimer’s because the extra chromosome they carry — 21 — also is responsible for the body’s production of amyloid, so they make 50 percent more of the protein than the rest of the population.

“It’s the most well-defined genetic form of Alzheimer’s disease,” says Klunk.

Pitt has been testing a small group of about 40 subjects since June 2016, using the same protocol developed for the autosomal dominant patients, including the DeMoes. The eventual goal is to get those subjects to clinical treatment trials such as the ones the families with mutations are in.

“These are young folks who don’t have the other neurodegenerative pathologies,” says Klunk. “They’re a group that justifies themselves.”

Klunk and Mathis continue to go on fly-fishing expeditions, and they’ve relaxed the no-shop-talk rule somewhat. Now, though, they’re talking about where they’ll fish in their retirement.

Another important project, headed by Pitt neurologist Dr. Oscar Lopez in partnership with the University of Chile, focuses on developing a blood test that checks for abnormal tau levels, helping to diagnose members of the general population.

“All these are pieces of a big puzzle,” Lopez says. “In the future … if we have a preventive treatment, we’ll be able to determine the timing of the treatment.”

In 2013, G8 nations participating in an international summit on dementia set an ambitious goal: Find a viable treatment for Alzheimer’s disease by 2025. It was the first G8 summit on a disease since HIV and AIDS, and it represented a call to action, including funding for research.

Klunk says the effect of increased funding “has certainly been palpable,” and he, like many other researchers, remains hopeful — though they always worry about funding cuts. After all, he knows something about maintaining optimism after years of failure: he’s been there and done that.

Contemplating the work that led him and Mathis to discover PiB, Klunk said once: “You’ve got to fail to understand and proceed.”

Mathis puts it more bluntly: “Bill always says we got really lucky,” he muses. “I say, ‘No, Bill, we didn’t get lucky. We were due success. A blind squirrel does find a nut once in awhile.’”

On Valentine’s Day in February, Mathis turned to his wife and said: “Do you know what happened today, 15 years ago?”

She didn’t, so he reminded her: The first human being was dosed with PiB. Time hasn’t dimmed the satisfaction in his voice:

“That was a very sweet day.”  

Niki Kapsambelis is a freelance journalist who lives in Mt. Lebanon and a previous contributor to Pittsburgh Magazine. Her work also has appeared in publications around the world, including the Washington Post, Los Angeles Times, People and the Associated Press. “The Inheritance” is her first book.
 

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