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Seattle PI Special Parkinson’s Report

Tuesday April 03, 2001

Parkinson’s disease: The silent epidemic
By CAROL SMITH P-I REPORTER

April 1, 1999 - Although more people have Parkinson’s than multiple sclerosis, Lou Gehrig’s disease and muscular dystrophy combined, the disease has escaped much public notice and research funding.


It is a disease that renders its victims invisible, trapping them inside their houses, inside their bodies, inside their minds, until they simply vanish to the rest of us.


"Parkinson’s has been called the silent epidemic,’’ said Dr. Donald Calne, a neurologist at the University of British Columbia in Vancouver. And it’s a growing one.


But researchers are optimistic. Breakthroughs are on the horizon that they hope will not only help Parkinson’s patients, but also will advance the understanding of other degenerative brain diseases. New drugs and new kinds of surgery that could dramatically improve quality of life are becoming available.


Once thought of exclusively as an "old person’s disease," Parkinson’s is increasingly affecting younger people.


Scientists aren’t sure why. Possibly, greater awareness of symptoms has led to earlier diagnosis. But it may be something more sinister.


Parkinson’s is caused by a shortage of a chemical messenger in the brain. Dopamine, a key neurotransmitter involved in motor control, allows us to translate the will to move into action. What causes brain cells to die and stop producing dopamine, however, remains a mystery.


Scientists suspect that the disease is caused by a complex interaction between genes and the environment. Environmental toxins play a role in triggering the disease, although no one knows which toxins, or why they trigger the disease in some people and not others.


Many believe that until those answers are clear, the incidence of Parkinson’s is bound to increase.


Calne, who has tracked Parkinson’s patients for more than three decades, has already seen a fourfold increase in younger patients.


Although the average age of onset is about 57, 10 percent to 15 percent of patients show symptoms before 40.


An estimated 1 million people — 1 percent to 2 percent of people older than 60 — have Parkinson’s disease, a number that is expected to swell as baby boomers age.


And it could get much worse. Some experts call Parkinson’s the "iceberg disease.’’


Autopsy findings show that for every patient with overt symptoms of Parkinson’s, 10 or 20 more show traces of the brain damage associated with the disease.


Despite its prevalence, Parkinson’s hasn’t had the visibility of illnesses such as AIDS or cancer, partly because patients haven’t mobilized to raise money or awareness.


It’s hard to get Parkinson’s patients to take action, said Dennis Wright, 46, who was diagnosed four years ago. Parkinson’s patients can’t turn their own thoughts into actions, let alone act on the thoughts of others.


"Not responding is pretty natural in this group,’’ he said. Wright has lobbied in Washington, D.C., as well as Olympia to raise funds to fight the disease.


"We’re still way behind on per-patient spending compared to other diseases,’’ Wright said.


Parkinson’s affects about as many patients as HIV and AIDS, for example, but the National Institutes of Health last year spent $41 in research dollars per Parkinson’s patient, compared with $1,640 per patient with HIV or AIDS.


Now more and more Parkinson’s patients, especially younger ones, are speaking out about the need for more funding in the hopes of finding a cure. A Parkinson’s cure also could yield new approaches to treating other brain diseases, such as Alzheimer’s and Lou Gehrig’s disease.


"There are so many possible cures coming from so many different directions,’’ Wright said. "People always say a cure is 15 years away, but my goal is to get that to five years, or three years even.’’


OIL FOR THE TIN MAN:


A cure has already come tantalizingly close.


Dr. James Parkinson first described the mysterious "shaking palsy’’ in 1817. Although references to Parkinson’s symptoms date to Chinese and Indian medical texts more than 2,500 years ago, Parkinson was the first to recognize that many paradoxical symptoms were related to the same disease.


The symptoms included stiffness and tremors, rigid immobilization and a sudden unlocking of activity. Patients might sit for hours with an unblinking stare, or suddenly scoot off in a frenzy of tiny, accelerating steps, a stuttering gait that gave them a Chaplinesque quality. Apparently paralyzed, many patients were nonetheless capable of surprising reflexive action, such as running out of a house on fire, or jumping in a river to save a drowning victim.


It was as though some internal on-off toggle switch was malfunctioning.


It took 150 more years for scientists to figure out that the toggle switch was dopamine, which is vital for relaying motor signals in the brain.


"Dopamine is like oil for the tin man,’’ said Bill Bell of Seattle, whose mother, stepfather, godfather and another relative all live with the disease. Dopamine is what keeps people moving smoothly.


That discovery led to the first treatment for Parkinson’s: levodopa. L-dopa, made famous in Oliver Sacks’ book "Awakenings,’’ is converted to dopamine by nerve cells in the brain.


L-dopa miraculously roused Parkinson’s patients — even some who had been frozen for decades — but the "cure’’ was short-lived. As Parkinson’s progresses, there are fewer neurons to convert L-dopa to dopamine, and the drug’s efficacy wears off.


Parkinson’s symptoms occur when dopamine-producing neurons in the substantia nigra of the brain begin to die. In the exotic geography of the brain, the substantia nigra is a thumbnail-size structure at the top of the brain stem in one of the most primitive and evolutionarily ancient parts of the brain.


The neurons of the substantia nigra communicate with the basal ganglia — a constellation of neuron-dense structures buried deep in the cerebral hemispheres.


The basal ganglia provide a critical feedback loop that governs motor control, modulating information as it flows between the cerebral cortex, where complex movements originate as thoughts, and the spinal cord, where those thoughts are translated into action. Dopamine makes this loop work, giving people control over their voluntary movement.


By the time symptoms appear in most patients, the brain has already lost 80 percent of its ability to make dopamine.


Without dopamine, the nerve cells can’t tell which signals are important to relay, said Richard Palmiter, a professor of biochemistry at the University of Washington.


"Suppose you’re driving at night and you see hundreds of lights, but you can’t figure out that the red and green lights are the important ones to pay attention to,’’ he said. "Somehow, you’ve got to be able to focus on the right lights, or you’ll make the wrong decision when driving.’’


Dopamine helps direct the nerve cell traffic.


THE SEARCH FOR CLUES:


Although researchers don’t know what causes neurons in the substantia nigra to die, they suspect genetic susceptibility and environmental toxins both play a role.


A landmark study published recently in the Journal of the American Medical Association, for example, showed that the identical twins of Parkinson’s patients are no more likely overall to get the disease than non-identical siblings, indicating that genes play a limited role. (There was evidence that genetics play a stronger role in patients who show symptoms before age 50.)


"Parkinson’s is thought to be caused by the combination of aging, genetic predisposition and environmental factors,’’ said Dr. Ali Samii, a neurologist and movement disorder specialist at Harborview Medical Center in Seattle. Except in rare cases, it doesn’t run in families. But about 15 percent of patients have a close relative with Parkinson’s, which points to a complicated interplay between environment and genes.


"We think something quite transient might set (the disease) in motion,’’ Calne said. "That’s the simplest explanation. Some (environmental factor) kills some cells immediately and damages others.’’


An environmental trigger could alter the programming of the cells so they die over time, eventually depleting the dopamine supply.


"Rough epidemiological studies have linked higher incidence of Parkinson’s in areas of high industry, or where there is lots of chemical usage,’’ said Dr. Phil Ballard, director of the Movement Disorder Center at Swedish Medical Center. "Some studies have linked it to well water as well, but so far no one has been able to identify any one specific thing.’’


TREATMENT HORIZONS:


While scientists continue to search for the trigger, they also are devising new ways to treat Parkinson’s.


"What’s exciting about Parkinson’s is that the knowledge about the mechanism underlying nerve cell degeneration and regeneration is just exploding,’’ Ballard said.


Many scientists believe that Parkinson’s research will yield the big breakthrough that will allow them to someday reverse many kinds of degenerative brain diseases.


Work already is under way on new classes of drugs, including some that doctors hope will be neuroprotective — preventing the nerve cells from dying in the first place.


"This is a rather exciting time,’’ Calne said. "In the course of the last two years, five new drugs for Parkinson’s have come on the market, compared with about one every five years previously.’’


Three of the new drugs mimic the action of dopamine, and two block the breakdown of dopamine so that the brain’s supply doesn’t dwindle as quickly.


Some researchers are looking at ways to stimulate the brain to make new neurons, something thought impossible a few years ago, Ballard said.


In the meantime, new surgical techniques show promise for better symptom control, especially for tremors. Dr. Sean Grady, a neurosurgeon at Harborview, and Dr. Diana Kraemer at Swedish are doing "deep brain stimulation,’’ which involves threading a delicate electrode into the thalamus, one of the structures of the basal ganglia. The electrode is attached to a pacemaker-like device implanted in the patient’s chest. The patient activates the device by passing a magnet over his skin. The device then delivers a mild electrical current that essentially "turns off’’ the tremor by blocking nerve cells that are misfiring in the brain.


The device can be "tuned’’ up or down, depending on the tremors’ severity, and generally creates fewer side effects than traditional surgery for tremors. It also is reversible. Surgeons can remove the electrode, leaving the brain tissue intact. In the traditional approach, surgeons burn small lesions in the brain, permanently destroying tissue, Grady said.


As techniques improve, scientists also are experimenting with threading the electrodes into an even smaller part of the brain — the subthalamic region — which they think could control even more Parkinson’s symptoms.


There are even more futuristic therapies on the horizon. Scientists now believe that fetal cells implanted in the brain can replace the missing dopamine. For such implants to become widespread , however, researchers must develop a cell line that can be cultured in the lab and produced in large quantities.


Even more enticing is the lure of gene therapy.


The UW’s Palmiter recently demonstrated a technique for introducing new genes into the brain cells of mice, which could lead to gene therapy.


Palmiter used a modified virus to introduce a gene that caused mice with Parkinson’s-like symptoms to make more dopamine. Viruses, which are nature’s genetic engineers, can insert themselves into the DNA of host cells.


The trick is to find the right gene to put into human brain cells, Palmiter said. Researchers are looking for a gene that would protect the cells in the substantia nigra from being destroyed by Parkinson’s.


To find such a gene, however, scientists need to understand how the cellular machinery breaks down in the first place. This is the holy grail of brain research. Scientists now think there may be a common mechanism that causes cell death in patients with Alzheimer’s, Lou Gehrig’s disease, Progressive Supranuclear Palsy and other neurodegenerative brain disorders.


"Alzheimer’s and Parkinson’s — they have common threads running through them,’’ Calne said. "If patients live long enough with Alzheimer’s, they will develop some symptoms of Parkinson’s and vice versa.’’


Researchers hope unlocking the secret to Parkinson’s will help unlock the secret to all the degenerative brain diseases.


"We have pieces of information,’’ Ballard said. "It’s like a picture developing in a (darkroom) pan. The picture is just starting to get to where you can tell what it is.’’


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