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What Your Doctor May Not Tell You About Parkinson's Disease

Warner Books

Chapter One

Parkinson's disease cannot take away your hope ... or your relationships ... or your dreams ... or your faith. Parkinson's disease cannot take away your spirit. -Jill Marjama-Lyons

Parkinson's disease was first described in 1817 by James Parkinson, and the disease is named after him. In his classic essay The Shaking Palsy, he described the three most prominent features of Parkinson's disease:

Tremor, a rhythmic shaking of a part of the body such as the arm, leg, or chin;

Rigidity, an increase in muscle tone or muscle stiffness; and

Bradykinesia, slowness of movement-for example, walking, writing, or getting out of a chair.

While the actual mechanism behind the disease wasn't understood by Parkinson, experts today understand that Parkinson's disease occurs when a group of cells deep in the middle of the brain-in an area called the substantia nigra compacta (SNc)- begin to malfunction and eventually die. These brain cells, known as neurons, contain a chemical called dopamine, and can be easily seen through a microscope on postmortem examination of the brain. The tremor, rigidity, and bradykinesia associated with Parkinson's disease usually become evident after 60 to 70 percent of these dopamine-producing neurons have died.

A normal healthy brain and the brain of a person with Alzheimer's disease. The pigmented, dopamine-containing cells of the substantia nigra compacta (SNc) die off, and an Alzheimer's sufferer may lose 50 percent or more of these cells.

THE CAUSES OF PARKINSON'S DISEASE

What causes Parkinson's disease and triggers the neurons to malfunction and die? Scientists have no definitive answers, but many researchers and Parkinson specialists believe that the disease is caused by a number of factors and that it's likely that an environmental factor such as a virus, a toxin, or stress to the body triggers the expression of a genetic, inherited risk in the form of Parkinson's disease. This is called the "double hit" hypothesis, meaning that more than one thing has to occur for a person to get Parkinson's disease.

Oxidative Stress and Free Radicals

Oxidative stress refers to stress on a cell that makes the cell less able to function in its assigned way. Oxidative stress occurs when a cell has become fragmented due to the presence of free radicals. Free radicals are molecules in the body that have become split as a result of various stressors, and that then can attach themselves to other cells or membranes, or even break up other molecules. When free radicals are built up in excessive amounts, they can lead to injury of the cells' proteins and molecules, including DNA, and cause cell death. Oxidative stress is one of the leading theories as to what might cause dopamine cell death in Parkinson's disease.

The body's immune cells can scavenge free radicals, but if the immune system isn't functioning optimally, free radicals can proliferate. The effects of free radicals can be reversed by nutrients known as antioxidants-vitamins C and E are two very common antioxidants, for example. These nutrients are able to give up parts of their cells, which then partner with the free radical and neutralize its destructive capacity. In the case of Parkinson's disease, researchers are trying to identify those factors that cause oxidative stress on dopamine brain cells. When dopamine is broken down, it is metabolized into several different molecules, including peroxides, which react with iron and form toxic free radicals.

In a healthy brain these peroxides are detoxified by the presence of glutathione. But in a brain where excessive dopamine has caused overproduction of peroxides, or where there is a deficiency of glutathione, overproduction of toxic free radicals can occur and cause oxidative stress and subsequent cell injury and death. Ultimately, when enough cells die, Parkinson's disease symptoms appear. The theory of oxidative stress as a cause of Parkinson's disease is the basis for studies of agents that prevent or lessen oxidative stress, such as glutathione.

Mitochondria, Complex I, NADH, and Coenzyme Q10

The mitochondria are the energy producers of each living cell and are vital for normal cell function. After reports in 1983 that a street drug, MPTP, could cause an acute parkinsonian syndrome in young people who injected the drug intravenously, mitochondria were given center stage as a possible link to the cause of Parkinson's disease. When it enters the body, MPTP is metabolized into MPP+, which is toxic to and causes death of dopamine brain cells. MPP+ does this by entering the mitochondria and interfering with complex I, which is part of the necessary energy-producing machinery of the mitochondria. Specifically, MPP+ inhibits NADH (nicotinamide adenine dinucleotide hydrogen), which blocks the formation of ATP (adenosine triphosphate), the key energy molecule of all cells. When there is no energy for cell function, the result is rapid cell death.

Another important molecule that is part of complex I is Coenzyme Q10 (CoQ10 for short), also called ubiquinone. CoQ10 acts as an antioxidant by binding toxic free radicals, preventing them from killing healthy cells. In fact, this observation led scientists Dr. Richard Haas and Cliff Shults from the University of California, San Diego, to study and show a deficiency or lower activity of CoQ10 in persons with Parkinson's disease. Their research led to a multi-center, National Institutes of Health study of CoQ10 for the treatment of Parkinson's disease, the results of which are expected to shed light on the role of this supplement.

Experts believe that the mitochondria and impaired complex I function appear to have a likely role in the cause of Parkinson's disease and are also looking at other agents that can, like MPP+, interfere with complex I activity. These agents include the pesticide rotenone, diphenylether herbicides, carbon monoxide, hydrogen sulfide, cyanide, and nitric oxide, among others.

Other Theories

Other theories about the causes of Parkinson's disease are covered in chapter 11's discussion of future directions. Some of these cutting-edge ideas-including excitotoxicity, inflammation, apoptosis, and clumping of cellular proteins-may hold keys to the answer of the cause of Parkinson's disease.

UNDERSTANDING PARKINSON'S DISEASE

It is important to have a basic overview of the part of the brain that is affected in Parkinson's disease, to better understand how current medication and surgical therapies work and how future curative treatments will be employed.

Parkinson's Disease's Effects on the Brain

In the brain, nuclei or groups of brain cells (from the substantia nigra, striatum, globus pallidus, subthalamic nucleus, and thalamus) connect to one another and to the part of the brain that controls motor function, the motor cortex. In order for normal movement of the arms and legs to occur, a series of electrical circuits must be fired in a specific pattern and frequency between all of these parts of the brain or nuclei. When one part of this system malfunctions, as it does in Parkinson's disease, then the entire system is affected. In Parkinson's disease, it's the substantia nigra compacta (SNc) that appears to malfunction. The end result of the loss of dopamine cells in the SNc is inhibition or dampening of the electrical signals to the motor cortex.

This part of the brain has so many connections-with motor, sensation, and thinking functions and even the brain stem-that it's thought that the many varied presentations of Parkinson's disease and the many motor and cognitive symptoms of the disease are the result of damage to the various connections. While the mechanism is not truly understood, this damage to the brain's circuitry results in motor symptoms of Parkinson's disease such as bradykinesia, tremors, and rigidity. Medications and surgical treatments available today attempt to restore normal dopamine activity and function of this motor circuit to allow return of normal motor skills.

The Lewy Body

The Lewy body is a clump of proteins that can be found within the cytoplasm of certain brain cells, typically in people with Parkinson's disease. Lewy bodies are not normally found in brain cells, although rarely they may be seen in small numbers in the brain of an elderly person who has not been diagnosed with Parkinson's disease. There is also a rare disorder, Diffuse Lewy Body Disease, where Lewy bodies are widespread throughout the brain. But the presence of Lewy bodies, when they are primarily found in dopamine cells in the SNc, is considered diagnostic of Parkinson's disease. The proteins that make up the core of the Lewy body are alpha-synuclein and ubiquitin ligase. These proteins are important in normal cellular function. Ubiquitin ligase is an important enzyme that breaks down abnormally large proteins similar to a garbage disposal, and alpha-synuclein appears to be important in the normal folding of cell proteins. Hence abnormal functioning of these proteins may lead to abnormal folding and clumping of proteins and subsequent cell death. It is not known whether the Lewy body is a by-product of cell death or whether it might cause cell death, but researchers agree that the more we learn about the Lewy body, the more we will learn about what causes Parkinson's disease.

Dopamine in Parkinson's Disease

In the normal adult brain there are 400,000 dopamine neurons in the SNc. The dopamine neurons in the SNc release dopamine to stimulate dopamine receptors on nerves in the motor pathway. Dopamine is made by a series of biochemical steps and is also degraded by two main enzymes, MAO and COMT. After 60 to 70 percent of these cells are lost, the motor symptoms of Parkinson's disease develop. As the dopaminergic neurons continue to die off, the motor symptoms gradually and slowly worsen over years. The medications used to treat Parkinson's disease may be dopamine (carbidopa/levodopa is a precursor to dopamine, meaning it is converted by enzymes into dopamine), look like dopamine (dopamine agonists), or act on the enzymes that metabolize dopamine (MAO and COMT inhibitors). So the key to Parkinson's treatment is to restore dopamine activity to normal levels through medica-tions, or through surgery to help restore the brain's electrical signal processing.

THE PREVALENCE OF PARKINSON'S DISEASE

The incidence of a disease is defined as the number of new cases of a disorder diagnosed during a specific period, such as a year, in a defined population, such as people living in a specific geographic region or of a specific race. The prevalence of a disease is defined as the total number of persons with the disease at a fixed point in time. Prevalence is easier to measure than incidence, and both are used to report the frequency of a disease and to study and identify risk factors for that illness. In the United States, over one million people are estimated to have Parkinson's disease. The prevalence is estimated to be as high as 1 in 100 persons over 60 years of age. The median age of onset of Parkinson's disease is between 55 and 60 years, and 10 to 15 percent of patients are diagnosed before age 40, which is considered young-onset Parkinson's disease. The disease is not necessarily a disease of the elderly, but because it is a progressive illness that is more common in older people, as the population itself ages, the number of persons with Parkinson's disease is on the rise. Parkinson's disease affects both men and women, but tends to be slightly more common in men. All cultures and races appear to be affected by Parkinson's disease; however the exact incidence and prevalence among cultures varies somewhat.

THE STAGES OF PARKINSON'S DISEASE

Parkinson's disease is a slowly progressive illness. That means it tends to worsen over many years-ten to thirty-so that the person who has Parkinson's disease will over time notice more difficulty with motor function, such as increasing tremors, more difficulty with fine motor coordination, walking and balance, and possibly more muscle stiffness. Not everyone progresses at the same rate, but in general, the disease progresses slowly, meaning that a person with Parkinson's does not rapidly decline in his or her motor function.

The symptoms usually start on one side of the body (either left or right) and over the course of many years will usually begin to affect the other side. Many patients may have had minor symptoms for five to ten years before being diagnosed. While the fact that the disease is progressive is daunting, the good news is that as the motor symptoms become more pronounced, the currently available treatments-such as medications, surgical procedures, and alternative therapies-can dramatically improve these symptoms. It is imperative to understand that the proper treatment of Parkinson's disease should be a dynamic and ongoing process that will require frequent visits to a Parkinson specialist and other health care providers and will involve periodic adjustments of medications as well as other therapies, such as nutrition, exercise, physical therapy, occupational therapy, speech therapy, massage, and possibly neurosurgery.

There are five stages of Parkinson's disease that have been defined and are outlined below. These definitions are used primarily by Parkinson specialists, often for selecting and following patients that are involved in clinical studies on Parkinson's disease.

It is important to realize that most people who are being treated properly do not progress to Stage IV and very rarely do people progress to Stage V. In addition, a person with Parkinson's disease may have symptoms and a physical examination that, early in the day, before the medication has taken effect, may define his or her status as Stage III, but after the medicine starts working, the patient's status may jump down to Stage II, so the stage can vary within hours or over the course of a day. Persons with Parkinson's disease who are undertreated or improperly treated can enjoy significant improvement with proper therapy, especially with medications and surgery. Some practitioners report seeing patients go from a Stage IV or V without medication down to Stage II or III after being put on correct medicine. This means that people who could not walk without assistance and needed help with virtually everything, such as dressing, feeding, and bathing, can, within several weeks of starting proper medication, walk again and take care of themselves without help.

Continues...

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Excerpted from What Your Doctor May Not Tell You About Parkinson's Disease by Jill Marjama-Lyons and Mary J. Shomon Copyright © 2003 by Jill Marjama-Lyons, M.D. and Mary J. Shomon. Excerpted by permission.
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