Harvard Health Letter

Adding antifreeze – Parkinson’s Disease, part 1

Adding antifreeze – Parkinson’s Disease, part 1 – includes related article

Harriet Washington

In Awakenings neurologist Oliver Sacks plays Pygmalion to a ward full of human statues, shepherding them from the rigid purgatory of their frozen bodies into the world of life and laughter, only to watch them slip back. On Guam a real-life “invasion of the body snatchers” is unfolding as previously healthy people are transformed first into brawlers, then into slow-moving zombies, before they reach middle age. These are two of the many faces of parkinsonism, and neither is the type officially termed Parkinson’s disease (PD).

Each year in the United States, 50,000 people are diagnosed with PD. Their first symptoms may be as innocuous as listlessness or as ominous as frequent, unexplained falls. Although this diagnosis is frightening, some of the worst imaginings of people with PD — and of those who love them — may prove unfounded, thanks to a burgeoning store of scientific knowledge.

Slip-sliding away

PD progresses over a number of years and may eventually produce three obvious signs: bradykinesia (slowness and “poverty” of movement), tremor, and rigidity. Bradykinesia not only impedes the acceleration and slows the pace of mundane activities like walking and eating but also ultimately erases the ruffles and flourishes that make us who we are — such as talking with our hands, swinging our arms jauntily, or even raising a skeptical eyebrow. About 85% of people with PD also have tremor that affects limbs more when they are at rest than when they are in motion. The third major sign, rigidity (sometimes called “cogwheel” rigidity), is peculiar to Parkinson’s disease. When a limb is bent, it seems to catch at regular points throughout its range of motion, much as a second hand jerks from interval to interval instead of smoothly traversing the face of a clock. Weakness often compounds this rigidity. Another common sign is micrographia, handwriting that becomes progressively smaller.

Among PD’s many manifestations are a festinating gait (a small-stepped shuffle, with the person hunched forward, “chasing his center of gravity”), blunted affect, soft, slow, monotone speech, and an expressionless “Parkinson’s mask” caused by facial rigidity and bradykinesia. Researchers disagree about whether dementia is an integral part of PD. Although only 15-20% of all PD patients suffer from dementia, Alzheimer’s disease strikes more than 33% of PD sufferers over 65 years old (compared with 10% of the general population that age).

No two cases are alike: although PD generally worsens over time, some people never develop serious symptoms and a few get worse quite quickly. And although the disease subtracts from quality of life, the average life expectancy for people with PD is roughly the same as for their peers.

Parkinson’s is largely a disease of older people living in the Western world, including an estimated 500,000 to one million patients in the U.S. The average age at diagnosis is 57. Rarely identified in people under 30, the disease becomes more common after 55. It strikes men and women in equal proportions, and some studies hint that whites may be at greater risk than people of African or Asian descent.

Kill the messenger

The physiological hallmark of PD is the progressive death of nerve cells in a small area of the brain called the substantia nigra. On postmortem examination, pathologists see both this dramatic cell loss and another baffling signature of the disease — tiny, dense structures called Lewy bodies. No one knows why substantia nigra (SN) cells die or what the role of Lewy bodies might be.

The loss of SN cells is devastating because they lie at the heart of the brain’s movement control center and are uniquely equipped to produce dopamine, a chemical messenger essential for normal, fluid movement. By the time PD symptoms are evident, at least 80% of these dopamine-producing cells have died. Although alterations in other neurotransmitters also play some role in the disease, the loss of dopamine is what matters most.

The central mystery

The most common form of PD is called idiopathic, meaning that its cause is unknown despite an abundance of theories. Looking for culprits in the environment and in the genetic code of patients, scientists have assembled a rogues, gallery of malefactors responsible for some cases of parkinsonism. (See box.) Among them are viral infections, brain trauma, and exposure to heavy metals. Because these factors clearly explain certain types of parkinsonism, some investigators have been driven to keep searching for a single explanation for the specific entity that doctors label Parkinson’s disease.

Despite a few reports of familial PD, many researchers agree with epidemiologist Caroline Tanner’s assessment that “genetic factors alone are unlikely to be the cause of PD.” Most experts subscribe to a two-hit theory, in which the combination of a genetic “powder keg” and an environmental “match” are needed to produce full-blown Parkinson’s, according to Dr. Tanner, clinical research director of the California Parkinson’s Foundation in San Jose.

Compensating for what is lost

Because the loss of dopamine renders people unable to move normally, attempts to treat or cure PD have focused on replacing this key neurotransmitter or on helping the brain get by with the amount it still has. Treatment would be relatively easy if a patient could just swallow a few dopamine pills and be done with it. Unfortunately, dopamine taken by mouth is shut out by the blood-brain barrier, a biological “filter” that shields the brain from a large variety of substances. As a result, PD patients are treated with one or more of a handful of agents that can reach the brain.

The most widely used and effective of these drugs is sold under the name Sinemet. It combines L-dopa, an amino acid that the brain makes into dopamine, with carbidopa, a related substance that keeps the L-dopa intact until it reaches the brain. Sinemet is beneficial in about 90% of PD patients for at least a few years. Scientists can,t yet explain why, but the drug’s effectiveness wanes as the disease progresses, and patients may fall into an “on-off” pattern in which frozen periods alternate with dyskinesia (excessive and uncontrollable movements). For a few people L-dopa may disturb sleep or cause auditory or visual hallucinations.

Physicians may put patients on Sinemet early and keep the dose low in the hope of extending its benefits. But most doctors simply delay giving it for as long as possible, which usually means prescribing other drugs in newly diagnosed patients or in those with mild symptoms.

Slowing the clock

Several treatment strategies are used to postpone a patient’s reliance on Sinemet. One is the influenza drug amantadine, which relieves or at least reduces symptoms in about half of patients with early-stage PD. Its effectiveness as a single-agent therapy sometimes diminishes after about one year, so a person may then need to take Sinemet as well. Other people find that low doses of amantadine control their symptoms for years.

Other drugs used to postpone the need for Sinemet (and, later, given in addition to it) include bromocriptine and similar dopamine agonists, which trick the brain into thinking there’s more dopamine on hand than there really is. Patients with pronounced tremor but relatively little bradykinesia and stiffness often benefit from taking anticholinergic drugs, although caution is needed because such agents can cause urinary retention in older men and can interfere with both vision and memory in elderly people. Antidepressants are sometimes given to newly diagnosed patients who are depressed.

The newest PD therapy is selegiline, originally known as deprenyl and now sold under the trade name Eldepryl. “Selegiline should be considered as soon as a diagnosis of Parkinson’s disease is made,” advised neurologist J. Stephen Fink, an associate professor at Harvard Medical School. When used promptly, this agent appears to extend the time before a patient must add Sinemet to the regimen by an estimated eight or nine months. Unfortunately, many patients-especially elderly ones — cannot tolerate selegiline and must stop taking it.

Scientists are working to develop new medications that will work better for longer. Clinical trials are just beginning for GM1 ganglioside, which may prop up or even rejuvenate damaged nerve cells. Also in the works is a new type of dopamine agonist that may be suitable for delivery via skin patches.

A role for vitamins?

Because unstable oxygen free radicals may account for some of the nerve cell degeneration in PD, researchers have asked whether taking antioxidant vitamins, such as C and E, could alter the course of the disease. But the largest and best-designed trial of vitamin E given for this purpose has come up empty-handed so far. “We do not see a therapeutic role for vitamin E in Parkinson’s disease,” said neurologist Ira Shoulson, a professor of neurology at the University of Rochester Medical Center and lead investigator in the study. For the time being, patients who wonder about taking antioxidants should consult their physician.

Although vitamin E is a relatively harmless substance, PD patients who dose themselves with dietary supplements — without first checking with their doctor — can imperil their health. In 1984 an encouraging account in a popular magazine led some PD patients to treat themselves with phenylalanine. They did not realize that the article concerned research with one form of this amino acid, and that health food stores stocked its chemically different evil twin — which had already been shown to make PD symptoms worse, not better.

A recent study led by Harvard researcher David Eisenberg found that over 70% of patients do not tell their doctors when they experiment with alternative medicine — a practice that may endanger people with PD. A strong working partnership between patient and physician is crucial for this disease, which must often be managed by using many different drugs on a precise schedule.

Hope in the operating room?

Some of the most encouraging news about future therapies for Parkinson’s comes from neurosurgeons, who have been experimenting since 1986 with ways of replenishing the brain’s supply of dopamine. Oddly enough, this enterprise owes much to the 1982 misadventure of a group of young drug addicts in California. An underground chemist who took a shortcut while trying to synthesize a cheap heroin substitute called MPPP inadvertently created MPTP, a similar compound. Soon after the addicts injected the tainted mix, they became indistinguishable from people with very advanced cases of PD.

Researchers discovered that MPTP kills exactly the same dopamine-producing cells in the substantia nigra that are lost to PD. This knowledge enabled scientists to reproduce Parkinson’s disease in animals and to test potential remedies — including the transplantation of dopamine-producing fetal neurons into adult brains. Good results in these experiments paved the way for fetal tissue transplants for Parkinson’s patients. (See the Harvard Health Letter, October 1992.) In most cases the effect has been encouraging but far from curative, improving symptoms somewhat and allowing patients to use less L-dopa than before.

In an ironic twist, the most spectacular experimental results have been obtained in some of the original “frozen addicts.” These findings, reported in November 1992, led to such a ground swell of support for the idea that on his first day as president, Bill Clinton rescinded a five-year-old federal moratorium on fetal tissue research.

Even cautiously optimistic scientists emphasize that the “frozen” addicts aren’t like other Parkinson’s patients: their disease isn’t still progressing; they’ve been immobilized for only a decade, not for 20-30 years; and they are considerably younger than the typical Parkinson’s sufferer.

A number of research teams are working to perfect sources of dopamine-making cells that are more plentiful and carry less cultural baggage than fetal tissue does. A group at the University of California in San Diego is using genetically engineered skin cells, which it hopes to have ready for clinical trials in a few years. Dr. Eugene Redmond, head of a Yale University team that has done well with fetal tissue transplants, sees promise in a variety of human or animal cells that can be “taught” to produce dopamine.

Although the details are far from certain at this point, many researchers hope that transplantation will eventually enable physicians to replace the brain cells whose death deprives Parkinson’s patients of the cherished ability to move freely in the world.

Parkinson’s Disease Is Not Parkinson

“Parkinsonism” is a broad term that can be applied to anyone whose movements are impaired by rigidity, tremor, and bradykinesia. Parkinson’s disease is a special kind of parkinsonism, distinguished from all others by the selective death of cells in the substantia nigra. Parkinsonism can also result from other types of brain damage, caused by a variety of agents.

Drugs. Various medications (including phenothiazines, used to treat mental illness, and methyldopa, taken for hypertension) can cause one or more signs of Parkinson’s disease — sometimes long after patients stop taking them. This form of parkinsonism may be even more common than regular PD but is usually reversible once the offending drug is discontinued or the dose is lowered.

Encephalitis. An unusual epidemic occurred in pockets around the globe between the years 1916 and 1926. Nearly everyone who survived acute infection with encephalitis lethargica eventually developed post encephalitic parkinsonism. Although this particular phenomenon has never recurred, each year a handful of cases of parkinsonism are attributed to an influenza virus.

Heavy metals. Many manganese miners develop bizarre behavioral symptoms-such as compulsive fighting — followed by parkinsonism. And postmortem studies have detected iron in the brains of other PD patients, but scientists do not know whether this plays a causal role.

Miscellaneous. In 1947 researchers discovered that an extraordinary number of islanders in the Western Pacific — especially residents of Guam — were afflicted by PD plus either dementia or amyotropic lateral sclerosis. At first scientists suspected that cycad tea, a traditional drink of the islands, was the culprit. But subsequent investigations have indicated that the island’s volcanic soil, rich in manganese and aluminum ores, is probably to blame.

Other causes of parkinsonian symptoms include a brain disorder called progressive supranuclear palsy and exposure to toxins including carbon monoxide and carbon disulfide.

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