The Rochester Review, University of Rochester, Rochester, New York, USA

The Mystery of 'The Shaking Palsy'

For 150 years after James Parkinson described it as the shaking palsy, nobody knew what to do for the illness to which he gave his name. Then, in the 1960s, came L-Dopa, an as-yet imperfect answer. The disease still has its mysteries--but neurological scientists are beginning to unravel the puzzle.

By Tom Rickey

"Touch your nose and then my finger."

"Hold your hands in front of you and then relax."

"Point your toes toward the ceiling."

"OK, now tap your index finger and your thumb together as fast as you can."

The scene is the University Medical Center's mind unit (that's short for Movement and Inherited Neurological Disorders). Taking time out of her busy schedule, Doris Hammer has stopped in to engage in a kind of diagnostic Simon Says game with nurse Nancy Pearson.

The Unfortunate Addict Scientists can thank a desperate drug addict for opening one of the most promising avenues of research into Parkinson's disease so far. Twenty years ago, an amateur chemist sat down to create an "improved" mood- altering drug, and got more than he bargained for: The home brew immediately gave him an irreversible, advanced case of what looked just like Parkinson's disease. When the man died the next year, the autopsy showed a depletion of dopamine neurons, exactly as is found in Parkinson's patients. Tragic as it was, the case gave scientists a new forum for their questions about Parkinson's. "Why do these cells die? For as long as we have known about Parkinson's disease clinically, the answer has been, 'We just don't know,'" says Howard Federoff, chief of the Division of Molecular Medicine and Gene Therapy. To answer such questions, Federoff and Suzanne Haber, professor of neurobiology and anatomy, are studying MPTP, one of the chemicals found in the unfortunate addict's brain cells when he died. MPTP destroys a cell's mitochondria, or energy source, and a similar process may play a role in the cell death seen in Parkinson's patients, in whom physicians have discovered poorly functioning mitochondria. MPTP and Parkinson's are very specific as to the neurons they both attack, and Haber has long been interested in the molecules that either protect these neurons or, alternatively, seem to invite attack. "Why are some cells vulnerable while others are selectively spared?" asks Haber. "If you can know why they are vulnerable, you may be able to protect them. By the time a patient shows clinical symptoms, he or she has lost a lot of cells. And by that time, it's too late--you can't protect cells that are already dead." The cell death leaves a key part of the brain with a dearth of dopamine, a crucial brain chemical messenger; without it, a cascade of inefficient and imprecise signaling ripples through the brain's circuitry. In a Parkinson's patient, the shortfall is in the basal ganglia, a region of the brain that under normal conditions swiftly filters through huge quantities of information and plays a central role in motor behavior, cognition, and motivation--explaining the array of symptoms seen in these patients. Haber and others have shown that, in the neurons targeted by Parkinson's, there is a higher level of a molecule known as the dopamine transporter, whose job it is to vacuum up dopamine left between nerve cells and return it the cell's nucleus. Clearing out chemical messengers like dopamine is crucial to maintaining the brain's crisp signaling; when the molecule lingers, signals become muddied. The transporter, however, sops up not only beneficial dopamine but also the toxic MPTP, sometimes delivering a lethal dose to neurons. Federoff is studying the role the transporter may play in Parkinson's susceptibility, using a system his laboratory has developed to implant and then turn on or off genes in an animal's nervous system. And Haber continues to look for other clues as to why some neurons are especially vulnerable to attack. In one study she and neuropsychologist Peter Como are studying the effects of attack, using motor and cognitive tests to compare Parkinson's patients with animals that are affected by MPTP but have not yet exhibited any outward symptoms. Tom Rickey

"All right, now walk back and forth in front of me," Pearson tells Hammer. Then she grabs her from behind to see if she can put her off balance. Hammer holds steady. "Solid as a rock," Pearson pronounces.

Then the encounter begins to get rough: Numbers--lots of them, one after another. Nancy peppers Hammer with seven-digit numbers, asking her not only to repeat the digits but to put them in order from lowest to highest. Hammer aces most of them, prompting an observer who finds the task difficult to ask her how she does it. "Oh, you just rearrange them in your head as they come up," Hammer explains, looking like, "Well, can't everybody do that?"

Hammer was diagnosed three years ago with Parkinson's disease. How she responds to each of the nurse's requests helps doctors precisely assess the progress of the disorder.

Today Hammer has just one complaint to report: a recent bout of light-headedness, which she attributes to 18 holes of golf in the hot midsummer sun. In fact, the only sign that something is amiss in the brain of this sharp, cheerful 70-year-old is a slight, but constant tremor in her right hand, often the first sign of the disease.

"I tell myself it's not going to interfere with my golf game," says Hammer, who sports a deep tan from regular rounds on the links. The toll of the disorder on her life thus far? "I don't run down stairs as fast as I once did."

Hammer's good report today is not unusual for patients with Parkinson's, says Dr. Roger Kurlan '74, chief of the mind unit. Although the illness is chronic and progressive with no cure yet in hand--and the effectiveness of currently available treatment wanes as time passes--the life span of someone with Parkinson's is nearly average. Further, patients usually are able to live normal lives for years after diagnosis, just as Hammer is doing.

That's despite the fact that deep in her brain, in the substantia nigra--a tiny black region smaller than a pea--lies a tangle of several hundred thousand dopamine-producing neurons, many of which, in her case, have died.

No one knows why neurons die here in the brain's motor-control center, nor does anyone know how to keep it from happening. But scientists do know that this cell death is what causes the symptoms collectively known as Parkinson's disease, a disorder first described in an essay on "The Shaking Palsy," written in 1817 by the English physician James Parkinson. Some years later, a baffled French neurologist wrote that the disease "remains so utterly inexplicable that we are constantly drawn to it by the lure of the mysterious." It was not until the 1960s, with the advent of l-dopa, that researchers even began to get a handle on effective treatment.

Parkinson's affects about 1 million people in North America, and every day more than 100 others are diagnosed with it. By the time a patient first feels symptoms--movement problems like slowness, rigidity, and tremors--about 80 percent of the neurons in the substantia nigra are already gone. And by the time of death, in many patients, virtually all have been destroyed. The average age of onset is 57, although a few people get it earlier. Janet Reno suffers from the disease. So does Billy Graham. The Pope reportedly does also. And some have even speculated that the Good Samaritan in Rembrandt's famous etching embodies a classic Parkinson's patient.

Without the crucial brain messenger dopamine produced by the neurons in the substantia nigra, critical brain signals go awry, resulting in a litany of symptoms that vary widely from individual to individual. Besides the symptoms mentioned above, about one in three patients also experiences depression, and nearly three of every four ultimately see some decline in their cognitive skills. Stooped posture, shuffling gait, loss of balance, fatigue, and difficulty speaking and swallowing are common. Tasks like brushing one's teeth, handwriting, shaving, fastening small buttons, and stirring coffee gradually become more and more difficult, and patients may end up in a wheelchair, or bedridden.

The outlook was woefully dimmer until the 1960s, when scientists first discovered the dopamine shortage in Parkinson's brains. Later researchers developed the amino acid l-dopa as a way to replenish this critical chemical messenger. Now part of the drug Sinemet (which helps to buffer unwanted side effects), l-dopa is still the best treatment for the disease. Its effectiveness, however, drops off over time, usually waning faster than the 15 years the average patient lives after diagnosis.

"Before l-dopa, there really was no good treatment," says Kurlan. "People progressed to death on a fairly short time frame, and they had nothing to control their symptoms. The l-dopa era changed that dramatically. Even so, it's like putting your finger in the hole of a dike. Eventually the pathology of the disease overcomes the benefit of the medication."

The testing of new medications that might supplement or replace l-dopa is one of the primary concerns of researchers at the Medical Center's mind unit, which treats nearly 1,000 Parkinson's patients from throughout New York State and northern Pennsylvania.

One person who is especially thankful for this work is Dr. Milton Luria, professor emeritus of medicine, who retired in 1993 after spending 40 years caring for patients at the Medical Center.

As it happened, many of those patients had Parkinson's disease, yet Luria (like many others with the illness) let creep up on him, unheeded, his own similar symptoms. In his case, it was slower and smaller handwriting and the typical Parkinson's shuffle. He finally acknowledged his problem three years ago when a colleague told him, "You know, the spring has gone out of your step." Luria realized that his usual five-minute walk from parking lot to office was now taking more like 15, "and that it was more than pain that kept me from walking briskly." Shortly after that he was diagnosed with Parkinson's.

A year ago Luria's symptoms suddenly worsened: It took him more than an hour to sign a sheaf of 50 letters he was writing for a committee, and jotting comments on student papers became a chore. "I thought, 'If I have to go through the rest of my life at this speed, I'll never make it,'" he says, smiling a little now at the recollection. Then one day his sister sent pictures of him she'd taken on a trip. "I looked at those pictures and I said right away, 'That's the picture of somebody who has classic Parkinson's.'"

He decided he needed more help. So he visited his physician, Dr. Ira Shoulson '71M (MD). Shoulson offered him a spot in a two-year trial comparing two drugs, Sinemet (containing the old standby, l-dopa) and a newer drug, Mirapex. (As with all such studies, nobody will know which patients got which until the study code is broken.) Within a few days, Luria started feeling better, and soon he was back to his five-minute stride and enjoying mile-long hikes in Mendon Ponds Park. Teaching again, he is serving as a mentor to incoming medical students and is helping teach internal medicine.

"Whatever I'm on is certainly working," he says. " I'm one hundred percent better than I was before I started the medication, no question about it."

The current Mirapex study is being coordinated through the University's Division of Experimental Therapeutics. The results of its previous study of the drug contributed to its FDA approval. More than a dozen studies on Parkinson's are under way or in the pipeline at the division, says Dr. Karl Kieburtz '85M (MPH, MD), who coordinates the effort. Especially exciting to the researchers are tests of remacemide--a completely new type of drug that targets a different chemical system in the brain--that is being conducted in studies code-named ramp and real. (The division gives out gifts like bottles of champagne to the people who come up with the snazziest acronyms.) The division is also testing an agent that acts much like nicotine. (People who smoke, it seems, are less likely to develop the disease, although no one is recommending taking up the habit as a preventive measure.) The Rochester team has so far participated in more than 30 studies of new Parkinson's drugs, some of them still in progress.

Parkinson's research at the Medical Center rose to prominence in the 1980s when Shoulson, the Louis Lasagna Professor in Clinical Pharmacology, founded both the mind unit at the Medical Center and the Parkinson's Study Group, a collection of dozens of medical centers nationwide brought together for multi-center clinical trials of experimental medications. The multi-center group is best known for Shoulson's landmark datatop study, which tested two experimental treatments in 800 patients with early untreated Parkinson's disease. The drug study, the largest ever in Parkinson's patients, inaugurated an era of institutional cooperation in the quest for new therapies.

People who participate in such clinical research fare better than those who don't, says Kurlan. Earlier access to new medicines is of course one of the reasons why, but there are also other, equally important, factors involved. Participants meet more regularly with doctors and nurses than those who don't take part in the studies, and they're given a thorough battery of tests at each visit. Perhaps the greatest boost, though, comes from the psychological benefits.

"One of the biggest problems many patients have when they're diagnosed with a chronic, progressive neurologic disease," says Kurlan, "is that their sense of self-worth deteriorates. Eventually they may lose their jobs, and their role in the family also changes. Being in a research study restores some of that self-worth. They feel good about themselves. If the medicine we're testing doesn't help this particular patient, maybe someday it will help a friend or neighbor or a son or daughter. People feel good about that. It raises their spirits. And that's a very long-lasting benefit.

"People who were patients in some of our research studies of 10 years ago are still beaming today because they contributed to the understanding of a new medication that is now being prescribed."

While new drugs are the focus of much of the research at Rochester, there is a variety of other procedures being developed elsewhere. One is deep-brain stimulation, in which a pacemaker type of device is implanted in the brain to help control its errant signals. Another is pallidotomy, a surgical procedure in which a small part of the brain is destroyed in an effort to damp down unwanted brain signaling. While some patients at other medical centers have shown dramatic results--walking normally for the first time in years--others have experienced major problems, including paralysis and blindness, leading Rochester physicians to adopt a cautious approach toward the procedure.

For a long-term cure, Kurlan says, two other approaches look more promising: grafting of fetal dopamine neurons into the brains of adult patients (a technique pioneered at the Medical Center) and gene therapy to protect the dying neurons. Earlier this year University researchers took a significant step toward achieving the latter, when they were able to shuttle into rat brains a gene that codes for a substance that shields dopamine neurons.

Such a permanent solution would be welcome news to patients like David Carter (as he would prefer to be called), an engineer who was diagnosed with the disease 11 years ago, at age 46. For the first 10 years his symptoms were almost completely controlled, but last year an outbreak of problems caused him to take medical disability from his job.

During a recent interview in which he talked about his disease, Carter's arms and legs jerked constantly and randomly. Such movements are due to a condition known as dyskinesia, a side effect of the l-dopa in Sinemet that is common in patients who have been on the drug for a few years. Carter says the movements are tiring, painful, and distracting, and that he has had to begin eating more to compensate for the energy these uncontrollable movements demand.

"Your muscles fight back," says Carter, sitting with one leg tucked under the other to keep it from straying. "You're trying to make the muscle do one thing, and it's trying to do something else at the same time."

When the medicine is not working, Carter is free from the side effects but, he says, then he's even worse off than before: He slips from "on" to "off," a condition in which he is nearly frozen in place and may have to resort to crawling to move even a short distance. The change is completely unpredictable and happens several times a day. "It can switch just like that," he says, eyes lighting up as he suddenly snaps his fingers smoothly and quickly. Carter takes about 30 different pills a day, mainly Sinemet, and carries a small buzzer that reminds him every two hours to take his next dose.

(His father, like Luria's, also had Parkinson's and was one of the first to benefit from l-dopa treatment. Parkinson's, however, is not believed to be an inherited disease in the sense of hemophilia, for instance, although it is possible that there is some slight genetic predisposition to it.)

When Sinemet fades in effectiveness, Dr. Kurlan says, there are other steps that physicians can take--like trying countless combinations of other drugs. They can also enlist the help of social workers and physical therapists to help keep other problems at bay, encourage a healthy lifestyle, and support the spouse or caregiver. Emotional support, Kurlan says, is highly important.

"Being able to help the patient or the family at any given point is very rewarding," he says. "And there's always something we can do to help these people.

"It sounds pretty bad when you hear that you've been diagnosed with a chronic, progressive neurodegenerative disorder. And, yes, there will be difficulties, but, on the other hand, patients will have many, many, many years of time to experience the good things in life. We encourage people to stay active, to play their golf, to do their traveling, and to keep up with all the other activities they enjoy."

So it is that, as Kurlan and his colleagues here and elsewhere are gradually closing in on a still-elusive cure, Hammer is out whacking golf balls, Luria is passing on his art of doctoring to young physicians, and Carter, open as ever to new experiences, is learning to express himself in a new way: He is taking up the study of Japanese. Hey, you never know when you might need a new skill like that.

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