Parkinson’s Disease: a New Research Era

In the 1980s, a designer street drug* derived from the narcotic Demerol appeared in California and caused immediate and irreversible Parkinson’s disease in the young heroin addicts who used it.  At that time, scientific research into Parkinson’s disease had plateaued. The excitement surrounding the use of the drug L-Dopa to treat the disease in the 1960s had faded as the long term problems with its use became apparent.  But the Demerol derivative, called MPTP (short for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) gave researchers a new tool.  For the first time in history they had the ability to create an animal model of the disease. A new flurry of research began, providing hope for all patients with the progressive and debilitating disease.

The clinical picture

Most people know someone who has Parkinson’s disease because it is a relatively common ailment, affecting approximately one out of every 100 people over the age of 65 in all parts of the world.  To doctors, Parkinson’s disease is a “doorway diagnosis,” meaning that when all of its core components have developed, and there are no unusual features, the diagnosis can be made from the first sight of the patient.

The typical Parkinsonian patient sits quietly, with none of the spontaneous gestures or shifting of the trunk or extremities that most people exhibit when confined to a chair. His face is smooth and expressionless, and he looks slightly wide-eyed, blinking only 5-10 times a minute, about half the normal frequency. Both seated and standing, he has a forward flexed posture of head neck and trunk. His hands shake rhythmically unless he is using them, a problem known as a resting tremor.

When he gets up to walk he does not make preliminary movements to adjust his foot position.  Walking seems hard to start, but once started, his upper body may move ahead of his feet, and his steps “hurry up” to catch up to the body, a “festinating” gait.  His gait is simultaneously “shuffling,” since his feet barely clear the floor.  His elbows are bent with arms held slightly forward of his body.  They do not swing as he walks.  Should someone tap him on the chest, he does not make any quick postural adjustments such as stepping back with one foot, and he may topple over if someone does not catch him.

His voice is soft and monotonous, and his words are hurried. While he has normal muscular strength, he cannot generate any speed, so an action like clapping appears weak.  All of his motions are slow, a phenomenon called bradykinesia.

Parkinson disease begins most commonly in the sixth decade and is rare before age thirty. Many of the characteristics of the disease, in minor form, are also characteristics elderly people: forward flexed postures, shorter step lengths, softer voices, and slower, less forceful movements. But these signs in people who have Parkinson disease appear earlier and progress enough to impair normal activities within about 10 years.  Parkinsonian symptoms can also be side effects of drugs used in the treatment of some psychiatric disorders.

Where the symptoms originate

The symptoms of Parkinson’s disease come from nerve cell death a tiny area in the brain stem called the substantia nigra. These cells contain neuromelanin, a substance similar to the pigment in the skin, and they produce a chemical neurotransmitter called dopamine. When the cells die, the substantia nigra loses its black color and dopamine levels decline. The drugs that improve symptoms in Parkinson’s disease either raise dopamine levels or make it more effective at the junction between nerve cells where dopamine works to transmit information from cell to cell.

Replacing the lost dopamine

However, the pharmacologic treatment of Parkinson’s disease has limitations. Initially, the drugs that elevate dopamine levels work in most patients, but sooner or later they became less effective and dose increases produce unwanted movements called dyskinesias.  The drugs also have a peculiar tendency to produce an “on-off effect,” causing symptoms to reappear random times. Nevertheless, L-Dopa (in the form of Sinemet) and drugs that improve dopamine’s actions (like Eldepryl) remain the mainstays of treatment, supplemented by a few other drugs that alter the levels of another brain chemical called acetylcholine. Drug treatment of Parkinson disease requires patience and close attention to timing of doses, with frequent adjustments of schedules. Since dietary protein can interfere with the drugs, many doctors also suggest confining dietary protein to the evening meal.

The limitations of pharmaceutical treatment spurred a number of different surgical procedures aimed at restoring balance to the complicated interplay of brain signals that, under normal circumstances, control balance, speed and fluidity of movement. These procedures involve destruction of tiny localized areas in deep centers of motor control (pallidotomy), or stimulation with tiny electrodes of other nearby areas. Implants of dopamine-producing fetal stem cells have caused devastating side effects in some patients and enthusiasm for this approach has waned.

How the ‘frozen addicts” advanced Parkinson’s research

Because Parkinson’s disease does not run in families, researchers have long suspected that it is triggered by some type of environmental factor. They have examined the role of neurotoxins such as heavy metals and fertilizers because Parkinson disease is more common in industrialized countries and also in agrarian areas, but they have never been able to pin blame on any specific substance. Now, though, they know that the California street drug MPTP destroys the dopamine producing cells in the substantia nigra by damaging their mitochondria, the power houses of all cells. Mitochondria are susceptible to damage by other toxins. They also contain DNA, with all its variations from person to person, perhaps explaining why some people might be more susceptible to toxic damage than others.

New ideas for treating the disease pharmacologically will eventually emerge from animal models of Parkinson’s disease. For interested readers, the medical mystery posed by the young people who developed Parkinson disease after using MPTP is recorded in a fascinating book, The Case of the Frozen Addicts. ** The research born from their tragic losses will someday help all Parkinsonian patients.

 

*a drug produced by modification of the chemical structure just enough to make it no longer identical to drug regulated by the FDA

** The Case of the Frozen Addicts, by J. William Langston & Jon Palfreman, New York, Pantheon, 1995.

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