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Seattle PI Special Parkinson’s Report

Tuesday April 03, 2001

Scientist fights disease at work—and in life

April 1, 1999 - Paul Gladstone understands at a more intimate level than most the anatomy of the damaged brain.

As a scientist, he is on working terms with the intricate molecular pathways in the brain. He can describe what happens when neurons die and neurotransmitters disappear. He details which circuits get disrupted, which loops of neural programming get erased.

As a patient, he lives with the consequences.

On this particular day, Gladstone, 51, is hunched over his kitchen table contemplating the links between the immune system and the central nervous system, two areas of particular scientific interest to him.

He speaks rapidly in a soft, breathy voice, barely audible at times. His words tumble over each other, the sentences speeding away from him like eager dogs let out on a trail. He pauses frequently, as if to call back his thoughts, before his words take off again. It’s a curious, involuntary acceleration of speech. It’s also a symptom of Parkinson’s disease.

There are other signs as well. His body has a strangely restless quality, as though he were responding to a cacophony of nervous impulses. His foot rocks with a constant tremor. His hands shake. When he crosses the room, his gait is unsteady, his balance tenuous. He still has a yellowing bruise on one cheekbone from a recent spill.

It’s a particularly cruel turn for Gladstone, whose second love is the stage. A former actor with an improv group, it’s as though his body now improvises without him.

Diagnosed at 38, Gladstone is one of the growing number of younger people with Parkinson’s, a disease that attacks the brain’s main motor signal pathways. Relentless and progressive, it eventually disconnects the mind and body so patients lose the ability to initiate or control movement.

Effortless movement is, by definition, something most of us don’t think much about. When we walk, we don’t have to will our arms to swing in opposition to our steps. When we’re amused, we laugh without considering how to arrange our facial muscles to convey our emotion.

For Parkinson’s patients, however, that autopilot function is turned off. Controlling movement requires intense concentration and exertion.

Although no two people with Parkinson’s exhibit symptoms exactly the same way, the most recognizable signs are a tremor in the hands and feet, rigidity and a stooped posture.

The disease leads to a profound poverty of movement that robs patients of gesture and expression. Their faces take on an unblinking, masklike look; they take short, shuffling steps; their arms don’t swing. They may slow to the point of freezing. With no balance reflexes, they frequently fall. About 30 percent of patients eventually suffer some cognitive impairment, ranging from memory lapse to dementia.

Scientists know the disorder stems from a shortage of dopamine, a chemical messenger necessary for the smooth transmission of motor signals. And they know the shortage is caused by the death of the main dopamine-producing neurons in the brain. They can even pinpoint where in the brain the cells begin to die.

But they don’t know what causes the neurons to die.

Treatment, vastly improved in recent years, means many patients can live for years with relative control of their symptoms.

But in the end, there is no stopping it - at least not yet.

"It is the second most common degenerative disorder after Alzheimer’s," said Dr. Sean Grady, a neurosurgeon at Harborview Medical Center and professor at the University of Washington. "Everyone knows someone with Parkinson’s."

Gladstone first suspected something was wrong when one arm didn’t swing correctly when he went jogging. He had other subtle symptoms as well - a puzzling slowing of his movements, a breathiness that stole into his voice.

A research immunologist, Gladstone’s scientific intuition told him something wasn’t working right.

It would be two years before his diagnosis, however, because few doctors thought to consider Parkinson’s in someone so young.

"The doctors couldn’t see my symptoms, but they believed me," he said. "They just couldn’t tell me what was wrong."

There is no blood test or laboratory test for Parkinson’s. Only an autopsy can lead to a definitive diagnosis.

Like detectives, pathologists dust for fingerprints of the disease on the brain. In Parkinson’s patients, slides of brain tissue show distinctive granules of dark matter called Lewy bodies strewn throughout the area damaged by the disease.

These dark clumps appear to be related to the breakdown of the neurons, said Dr. Donald Calne, a neurologist at the University of British Columbia in Vancouver and a Parkinson’s expert. They may be made of cellular refuse, the miscellaneous building blocks in the structure of the cell.

"They’re like little bags of bones," he said.

For the living, there is no such telltale evidence. In the absence of lab tests, doctors must deduce Parkinson’s from its symptoms.

Frustrated by a lack of answers, Gladstone finally went to the Mayo Clinic in Rochester, Minn., where a doctor recognized the Parkinsonian quality of his voice and speech patterns.

It was almost worse knowing. "I have a very high tolerance for ambiguity," he said. "It’s easier to deny something that doesn’t have a name."

For about six years after the diagnosis, Gladstone hid the disease from colleagues, not wanting to lose his place in the fast-paced, ultra-competitive world of medical research.

Then a senior scientist with Bristol-Meyers Squibb Co., he was studying the regulation of the immune system at the cellular level.

"I was afraid they would take me less seriously," said Gladstone, who earned his doctorate in genetics from Harvard University and worked for a time as a researcher at the University of Washington.

As the disease progressed, however, it became more difficult to hide - and not just from colleagues.

Separated from his wife, he has an 8-year-old daughter, Danielle, who spends two nights a week with him. Danielle learned at an early age the nuances of the disease.

"Since I’ve been alive, my Dad has had it," she said. It means she must help him around the house and explain to friends why her Dad seems different sometimes.

When his medication starts wearing off, for example, Gladstone’s face begins to freeze. She tells friends: "Poppy doesn’t smile when he gets stiff."

She is nonchalant about occasionally having to help her Dad up when he falls.

"Most kids don’t have to worry about doing stuff like that at such a young age," she said. "It makes you so that you recognize things when people need your help."

As his motor control became more erratic, Gladstone eventually had to let go of his bench work in the lab. He stopped working full-time about a year ago.

"I couldn’t do the fine-motor work anymore," he said. But his mind is still a working laboratory. He reads constantly and communicates with researchers all over the country, looking for new ideas about the disease.

He’s also in demand as a consultant, brainstorming with colleagues and ferreting out new directions for research.

"Paul was always an extraordinarily creative thinker," said Jerry Nepom, director of Virginia Mason Research Center, during one such session recently.

Others try to think outside the box, he said. "There is no box for Paul."

In some ways, however, having Parkinson’s has changed how Gladstone approaches scientific questions.

He knows the forces that drive "big science.’’ He knows how easy it is to forget about the patients behind the disease.

"Before I got sick, I didn’t think: This is about sick people, people who need help," he said of his days in the lab. "I have very different criteria for judging research now. So much federally funded research has so much to do with its own internal logic, and so little to do with patients. I wish there were a patient on every institute panel - a group of people, patients, asking: ’What will this (study) do for the patient?’ "

Gladstone hopes that will happen someday. In the meantime, he focuses on not letting Parkinson’s take over his life.

"Having Parkinson’s has meant losing so much of what characterized me as a person - my work, my energy, my acting, my relationship with my daughter," he said. "No area of my life is unspared."

But he refuses to give in to the disease, and he continues to search for answers.

He acknowledges that having a scientist for a patient has been a challenge for his doctor.

"She tells me to just back off and take my pills and be a patient, but I can’t," he said. "That’s not me. I’m always trying to figure out another way."

P-I reporter Carol Smith can be reached at 206-448-8070 or via e-mail: <a href="mailto:carolsmith@seattle-pi.com">carolsmith@seattle-pi.com</a><P> <i>See the <a href="http://www.seattle-pi.com/local/park01.shtml">original special report</a> in the Seattle Post-Intelligencer </i>