Edit ModuleEdit ModuleShow Tags
Edit ModuleShow Tags

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.



(page 1 of 3)


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.
 

Edit ModuleShow Tags
Edit Module

Edit Module Edit ModuleShow TagsEdit ModuleShow Tags
Edit Module Edit ModuleShow Tags

The Latest

Watch: Sid and Geno Break out the Big Guns

Think Sid is good in the shootout? Watch him with a T-Shirt cannon.

Local Filmmakers and Global Issues in Row House Outdoors Week

Documentary films highlighting environmental struggles get the spotlight at the Lawrenceville theater.

The 400-Word Review: The Dirt

Netflix's Mötley Crüe biopic offers plenty of rock-star mayhem, but no insight or substance.

An Impressive Duck Lands at Spork in Bloomfield

Executive chef Chris Frangiadis introduces a tableside classic to the restaurant's menu.

Summer Camp Helps Children Deal with Loss

Now accepting applications, Experience Camp welcomes children who have lost immediate family members.

PM on KD: Spirit Is in Our After Dark Hall of Fame

PM nightlife and culture editor Sean Collier appeared on KDKA's Pittsburgh Today Live to discuss the latest inductee into Pittsburgh Magazine's After Dark Hall of Fame: Spirit.

Duke’s Williamson Transcends the Madness

Freshman Zion Williamson makes this year’s NCAA Tournament, always fascinating on its own merits, even more of a can’t-miss event.

A New Steel Curtain Is Rising

Will the new Steelers zone at Kennywood Park be ready in time for opening day?

Refucilo Winery Brings a Taste of Argentina to the North Side

Dr. Juan Antonio Lora's passion project is linked to youthful memories.

After Dark Hall of Fame: Spirit

The lauded Lawrenceville hotspot is the latest inductee in the After Dark Hall of Fame.

The 400-Word Review: Us

Jordan Peele's new film is terrifying, essential viewing.

Why These Pittsburgh Brides Said Yes to the … Jumpsuit?

Comfort, mobility and style were all considerations for these brides’ perfect wedding wardrobe.

Pittsburgh Tops the List For First-Time Homebuyers

The report from Bankrate.com touts Pittsburgh’s affordability, job market and culture.

On Trend: Add a Touch of Velvet to Your Decor

Local designers say the fabric can give a room a luxurious feel. Here’s how to incorporate it into your home.

Spring Clean Your Attic at This Reuse Festival

Just in time for Earth Day, local organizations are giving you the opportunity to recycle, learn about sustainability and get rid of unwanted stuff at home.
Edit Module
Edit ModuleShow Tags


Watch: Sid and Geno Break out the Big Guns

Watch: Sid and Geno Break out the Big Guns

Think Sid is good in the shootout? Watch him with a T-Shirt cannon.

Comments

Local Filmmakers and Global Issues in Row House Outdoors Week

Local Filmmakers and Global Issues in Row House Outdoors Week

Documentary films highlighting environmental struggles get the spotlight at the Lawrenceville theater.

Comments


All the foodie news that's fit to blog
An Impressive Duck Lands at Spork in Bloomfield

An Impressive Duck Lands at Spork in Bloomfield

Executive chef Chris Frangiadis introduces a tableside classic to the restaurant's menu.

Comments

Refucilo Winery Brings a Taste of Argentina to the North Side

Refucilo Winery Brings a Taste of Argentina to the North Side

Dr. Juan Antonio Lora's passion project is linked to youthful memories.

Comments


Not just good stuff. Great stuff.
The 5 Best Seats at PPG Paints Arena

The 5 Best Seats at PPG Paints Arena

From ultra-premium experiences to bargains with great views, here are five perfect places to watch the Pens.

Comments

Fitness: Five Great Trails to Run in the Fall in Pittsburgh

Fitness: Five Great Trails to Run in the Fall in Pittsburgh

Don’t resign yourself to the gym treadmills just yet – fall is one of the best times of the year to get outside and pound the pavement, surrounded by falling leaves and the possibility of grabbing a hot latte on the way home.

Comments


After Dark Hall of Fame: Spirit

After Dark Hall of Fame: Spirit

The lauded Lawrenceville hotspot is the latest inductee in the After Dark Hall of Fame.

Comments

It's 2019. We Need a Modern, Dine-In Cinema

It's 2019. We Need a Modern, Dine-In Cinema

Pittsburgh is long overdue for a new movie palace where you can get an actual meal brought to your seat.

Comments


Mike Prisuta's Sports Section

A weekly look at the games people are playing and the people who are playing them.
Duke’s Williamson Transcends the Madness

Duke’s Williamson Transcends the Madness

Freshman Zion Williamson makes this year’s NCAA Tournament, always fascinating on its own merits, even more of a can’t-miss event.

Comments

Brown and Bell are Gone – What the Steelers Need to do Next

Brown and Bell are Gone – What the Steelers Need to do Next

Whether the Steelers are better or worse off, whether they’re culpable or deserve to be applauded for finally resolving two of their biggest problems remains to be seen.

Comments


The movies that are playing in Pittsburgh –– and, more importantly, whether or not they're worth your time.
The 400-Word Review: The Dirt

The 400-Word Review: The Dirt

Netflix's Mötley Crüe biopic offers plenty of rock-star mayhem, but no insight or substance.

Comments

The 400-Word Review: Us

The 400-Word Review: Us

Jordan Peele's new film is terrifying, essential viewing.

Comments


Everything you need to know about getting married in Pittsburgh today.
Why These Pittsburgh Brides Said Yes to the … Jumpsuit?

Why These Pittsburgh Brides Said Yes to the … Jumpsuit?

Comfort, mobility and style were all considerations for these brides’ perfect wedding wardrobe.

Comments

The Big Fake Wedding Offers Everything But the “I Dos”

The Big Fake Wedding Offers Everything But the “I Dos”

This nontraditional wedding showcase gives couples real-world insight into planning their big day.

Comments


Weekly inspiration for your home from the editors of Pittsburgh Magazine
On Trend: Add a Touch of Velvet to Your Decor

On Trend: Add a Touch of Velvet to Your Decor

Local designers say the fabric can give a room a luxurious feel. Here’s how to incorporate it into your home.

Comments

Leanne & Steve Dish on Season 2 of "Restored by the Fords"

Leanne & Steve Dish on Season 2 of "Restored by the Fords"

Siblings Leanne and Steve Ford talk renovating Steve’s new warehouse, Leanne’s new baby — and their two new HGTV shows.

Comments