Parkinson's Disease: Cause and Treatment

Parkinson disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic nigrostriatal neurons. It is named after James Parkinson, the English physician who described it as ‘Shaking Palsy’ in 1817.

PD is recognized as one of the most common neurological disorders, affecting approximately 1% of individuals older than 60 years. Common features include resting tremor, rigidity, bradykinesia, and postural instability. The incidence has been estimated to be 4.5-21 cases per 100,000 population per year. PD is about 1.5 times more common in men than in women. The incidence and prevalence of PD increase with age. The average age of onset is approximately 60 years. Onset in persons younger than 40 years is relatively uncommon. This disease is not contagious.

What happens?
The cause of PD is unknown although there are many theories. It is caused due to lack of dopamine in their brain (dopamine is a neurotransmitter that carries messages from one nerve cell to another) because the cells that manufacture this important chemical messenger have either been lost or blocked.

PD develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra. Approximately 60-80% of dopaminergic neurons are lost before clinical symptoms of PD emerge. Nerve cells in the substantia nigra send out fibers to the corpus stratia, gray and white bands of tissue located in both sides of the brain. There the cells release dopamine, an essential neurotransmitter. Loss of dopamine in the corpus striata is the primary defect in Parkinson's disease.

Dopamine is one of three major neurotransmitters known as catecholamines, which help the body respond to stress and prepare it for the fight-or-flight response. Loss of dopamine negatively affects the nerves and muscles controlling movement and coordination, resulting in the major symptoms characteristic of Parkinson's disease.
The disease process also may impair nerve endings in the heart that regulate the release of norepinephrine, a hormone that regulates blood pressure, pulse rate, perspiration, and other automatic responses to stress.

One theory concerning why these cells are destroyed states that as we age the liver loses its efficiency, and the cells are destroyed by the toxins that the less efficient liver can't filter out or detoxify. Others believe that environmental toxins such as pesticides or other chemicals and genetics play a part. Free radical damage may also play a part in Parkinson's as free radicals steal electrons allowing dopamine to be lost through oxidation.

The Biologic Factors:
Abnormal Apoptosis (Programmed Cell Death). Cells in the body are programmed to naturally die through a genetically regulated process called apoptosis. There is evidence that in PD, this process goes awry in nerve cells.

Proteins Involved in PD. Research suggests that three molecules are critical in the development of inherited PD: parkin, alpha synuclein (specifically alphaSp22), and ubiquitin, which all interact in the normal brain. AlphaSp22 is produced in the nerve cells involved with the dopamine pathway. Parkin normally causes alpha synuclein to bind with a molecule called ubiquitin, which then triggers apoptosis causing this compound to self-destruct. In many cases of inherited Parkinson's disease, however, parkin is abnormal and fails to bind alpha synuclein to ubiquitin. Apoptosis does not take place and, instead of dying, synuclein accumulates in Lewy bodies, deposits of fibrous tissue found in all patients with PD.

Lewy Bodies. Fibrous deposits known as Lewy bodies are the hallmark signs of Parkinson's disease. They are found in the substantia nigra, the place in the brain where dopamine is first released. It is not clear whether Lewy bodies are the major killers of the nerve cells or whether they are simply a byproduct of the degenerative process. They are found not only in the brains of patients with PD, but in rare cases, may show up in cells in other parts of the body (the heart, intestine), causing severe disabling symptoms. These substances are also present in other diseases that cause dementia, such as Alzheimer's, and can occur in people without neurologic symptoms.

Complex I and Oxygen Free Radicals. Some research has observed that certain Parkinson's patients have a 30% to 40% reduction in an enzyme called complex I. This enzyme is found in the mitochondria, structures in cells that generate energy. Some theories suggest that low amounts may make nerve cells vulnerable to the assault of oxygen free radicals (also called oxidants). Oxidants are unstable molecules that bind to other molecules in the body. The natural chemical processes in the body normally produce them. If the body is subjected to environmental stresses, however, they can be over-produced. And, in excess, they can damage any cell, including nerve cells in the brain, and even interferes with their DNA.

NMDA Receptors. Also of interest in PD are processes that occur in an area of the brain called the subthalamic nucleus. Here, receptors known as glutamate N-methyl-D-aspartate (NMDA) become persistently overexcited and produce high levels of calcium ions within brain cells. This in turn leads to a cascade of events that trigger oxygen-free radicals and cell damage.

Immune Factors and the Inflammatory Response. An over-responsive immune system triggered by initial damage may also play a role in developing PD. When the immune system becomes over-active, it produces excessive numbers of potent factors called cytokines (interleukin-1 and tumour necrosis factor), which cause inflammation and further injury in brain cells.

The Genetic Factors:
Specific genetic factors, most often detected in specific family groups appear to play a role only in early-onset PD. Defective genes that regulate the molecules alpha synuclein and parkin, may be responsible for a number of early-onset cases. For example, genetic abnormalities the alpha synuclein protein has been detected in some early-onset Parkinson's patients of European descent. The parkin gene may be the cause of many cases of early-onset Parkinson's in young adults. The role of genes in late-onset, the much more common form of the disorders, is not yet clear and appears to be weak. Still, some may be important. Research pinpoints the gene for the tau protein, which in its healthy state is important for the support structure in nerve cells that allows the flow of nutrients through them. A defective tau gene may increase susceptibility for idiopathic late-onset PD. Investigators have observed iron deposits in the brains of PD patients. Animal research suggests that genetic factors that impair iron metabolism may play a role in late-onset PD.

Environmental Assaults and Oxygen-Free Radicals:
Environmental toxins, infections, and other factors can provoke excessive production of oxygen free-radicals, damaging particles that may play a major role in the deterioration of nerve cells that lead to Parkinson's. Some evidence implicates pesticides and herbicides as important factors in many cases of PD. A higher incidence of parkinsonism has long been noted in people who live in rural areas, particularly those who drink well water or are agricultural workers. Studies suggest that rotenone, a common organic chemical in pesticides, which releases destructive oxidants are believed to target the dopamine nerve cells.

Intense exposure to other industrial chemicals and metals (manganese, copper, lead, iron, mercury, zinc, aluminum, and others) has also been linked with parkinsonism, which is often reversible. The role of long-term exposure in the development of PD is unclear.
Aging Process:

Majority of Parkinson's victims are above 60. Aging does appear to reduce the concentration of dopamine in structures called dopamine transporters, which carry the neurotransmitter back and forth between nerve cells.

The main symptoms of Parkinson’s disease are:
Shaking (muscle tremor) – though not always present, this is often the first sign of Parkinson’s disease. It often starts in the arms and may spread to the face, jaw and legs.
Stiffness (rigidity) – this makes the limbs feel weak and difficult to move. This may be intermittent or continuous. People with advanced Parkinson’s disease may lose use of the limb altogether.

Slowness – bradykinesia (slow movement) and akinesia (inability to move) are common in people with Parkinson’s disease. Walking may start with a hesitant step, followed by a shuffle without swinging the arms.

As the disease progresses, other symptoms that develop include:

Problems with posture and balance – people with Parkinson’s disease often stoop, fall forwards and lean to one side when sitting.

Bowel and bladder problems – constipation is very common and there may be a frequent urge to urinate.

Speech changes – the voice becomes weak, and weakness of the swallowing muscles may cause drooling.

Loss of facial expression – a mask-like appearance with loss of emotional expression gradually develops. Blinking and smiling are reduced.

Small writing – this commonly develops over time.

Anxiety and depression – this occurs in about a third of people with Parkinson’s disease.

Intellect – slowness of thought and memory problems can develop in the later stages.

Diagnosis
There is no single test for Parkinson's disease. Diagnosis is usually based on symptoms, and by ruling out other conditions that cause similar symptoms. This can often be done with an X-ray examination called computerised tomography (a CT scan), which is useful in detecting diseases that affect large areas of the brain. Then, if the symptoms are reduced by treatments given for Parkinson’s disease, this confirms the diagnosis.

Surgery
This is currently used as a last resort when drugs no longer give benefits. Electrodes guided by X-rays (stereotactic surgery) are used to destroy the tiny areas of the brain responsible for tremor and abnormal movements.

A device called a deep brain stimulator can also be used to give the same effect as stereotactic surgery, without destroying brain tissue.

Radio surgery is a new technique currently available at only a few specialist centers. It uses high energy radiation to focus on very precise areas of the brain.

A new treatment, where brain cells from human fetuses are transplanted into diseased areas of the brain, is at the experimental stage.

Other therapies
Other therapies that have a crucial role in managing and coping with Parkinson’s disease include physiotherapy, speech therapy, and occupational therapy. Staying active will help to maintain muscle tone and function. A doctor or physiotherapist can recommend an appropriate range of exercises and activities.

Living with Parkinson’s disease
A diagnosis of Parkinson’s disease can be very upsetting. However, most people remain reasonably active, and symptoms may progress no further than slight tremor. However, some people do become debilitated, needing help with washing, eating and dressing. With proper treatment, life expectancy for people with Parkinson’s disease can be normal.

There are six main groups of drugs:
Drugs which replace dopamine –they are combinations of levodopa – a drug which breaks down in the body to form dopamine, plus a chemical which ensures the optimum dopamine concentration in the brain. They are effective at treating symptoms, although there are some side effects. These include nausea, dizziness and constipation. Also, they can cause long term problems such as unwanted movements of the face and limbs (dyskinesia) and they may become less effective over time.

Drugs that mimic the action of dopamine – eg. bromocriptine. Using these early on in the course of Parkinson’s disease may delay the long-term problems of the dopamine replacement drugs. Side effects can include nausea and hallucinations.

Drugs which block the action of the brain chemical acetylcholine – eg benzhexol. These help to correct the balance between dopamine and acetylcholine. Side effects can include dry mouth and blurred vision. They are not usually used in people aged over 70 as they can cause memory loss, and urine retention in men.

Drugs that prevent the breakdown of dopamine – eg selegiline. Low blood pressure and irregular heartbeat are the most significant side effects.

COMT (catechol O-methyl transferase) inhibitors – eg tolcapone. This is a new class of drugs that stops the breakdown of dopamine. They are usually given when dopamine replacement drugs start to lose their effectiveness. They can affect liver function, so blood tests are needed for the first few months.

About one-third of Parkinson's disease sufferers eventually show signs of dementia. The disease lasts an average ten years and ultimately results in death usually by an infection or aspiration pneumonia.