Parkinsonism ?...

[신상훈]

Idiopathic parkinsonism or Lewy body PD

 Secondary (symptomatic) parkinsonism

Preview of Understanding Parkinson's Disease

The essential cause is not known. Clues are available from studies of the distribution of the disease, that is, who is affected, where and in what circumstances. These show associations that don’t prove a cause, but lead to the investiga- tion of possible causal or contributory factors, which may play a part in causing the illness. I have already mentioned that it is relatively common – perhaps as many as 100,000 patients are affected in the UK at any one time – that men and women are equally affected, and that no race is immune. It is not related to any particular job and is clearly a physical disease of the brain, which is not caused by stress, anxiety, emotional or family upsets. Extensive searches for a viral or bacterial cause have proved negative, so the disease is not infectious.

Nerve cells in the brain are affected

In patients with Parkinson’s disease, there is disease or degeneration of the so-called basal ganglia in the deeper grey matter of the brain, particularly of that part known as the substantia nigra.

The substantia nigra, which connects with the striatum (caudate nucleus and globus pallidus), contains black pigmented cells and, in normal individuals, produces a number of chemical transmitters, the most important of which is dopamine. Transmitters are chemicals that transmit, that is, pass on, a message from one cell to the next, either stimulating or inhibiting the function concerned; it is like electricity being the transmitter of sound waves in the radio. Other transmitters include serotonin, somatostatin and noradrenaline. In Parkinson’s disease, the basal ganglia cells produce less dopamine, which is needed to transmit vital messages to other parts of the brain, and to the spinal cord, nerves and muscles.

The basal ganglia, through the action of dopamine, are responsible for planning and controlling automatic movements of the body, such as pointing with a finger, pulling on a sock, writing or walking. If the basal ganglia are not working properly, as in Parkinson’s disease patients, all aspects of movement are impaired, resulting in the characteristic features of the disease – slowness of movement, stiffness and effort required to move a limb and, often, tremor.

Dopamine levels in the brain’s substantia nigra do normally fall with ageing. However, they have to fall to one-fifth of normal values for the symptoms and signs of parkinsonism to emerge.

In Parkinson’s disease, there is degeneration of the substantia nigra which produces the chemical dopamine deep inside the brain.

An important balance

Normally, there is a balance between dopamine and another neurotransmitter – the transmitter of nerve impulses – called acetylcholine. Acetylcholine is present in many areas of the brain and plays a part in normal memory recording and recall. As dopamine is depleted, there is a relative excess of acetylcholine. Thus two of the main groups of drugs used to treat Parkinson’s disease are dopamine drugs (levodopa and its preparations Madopar and Sinemet) and drugs designed to restore the balance by diminishing the acetylcholine – anticholinergics (for example, benzhexol [Artane], orphenadrine [Disipal] and benztropine [Cogentin]).

How do the nerve cells send messages?

The diagram on page 6 shows how the nerve cells or neurons in the basal ganglia release packages of the dopamine, transmit it down its main wire or axon, and how this sprouts into receptors of the next nerve cells and transmits the message and nerve impulse further down the line. You can imagine this process carried out by millions of neurons at the same time, forming a network of activity which puts BT and other telephone networks to shame.

Current ideas about the cause of Parkinson’s disease suggest a predisposition that makes certain people more vulnerable to some (unidentified) environmental toxic agents. Why cells die in the substantia nigra of Parkinson’s disease patients is unknown. This important group of cells shows three changes:

1. Evidence of the release of oxygen compounds by cells which act as a stress that damages cells (oxidative stress), and depletion of a chemical called reduced glutathione.
2. High levels of iron.
3. A deficiency of an essential component of all cells (mitochondrial complex I) that normally controls oxidative reactions; these last involve the release of oxygen compounds which act as stress causing damage to the cells.
4. Which of these is the primary event, causing secondary changes culminating in death of the nigral cells, is not known. In people with Lewy bodies in their brains but before the development of symptoms of parkinsonism, the substantia nigra shows a comparable loss of reduced glutathione and, possibly, a reduction of complex I activity. Lewy bodies are small areas in nerve cells (inclusions) present in practic- ally every case. They are pink acidophilic (acid-loving) blobs, and show a central core with a peripheral halo. As they may be signs of very early disease, before definite signs emerge, these various abnormalities provide a new focus for the development of future treatments.

Various parts of the nervous system combine to generate movement. Nerve impulses start in the cortex, pass through the basal ganglia, brain stem and spinal cord, and finally pass through the peripheral nerves which actually control muscles.

Receptors are important

The receptors are most important. Some drugs can block the receptors, and if they are taken for a long period they block the passage of dopamine in the nerve cells and their connect- ing network of axons. The nerve impulses so essential for normal movements are therefore reduced. This is the basis of the drug-induced parkinsonism I shall describe next.

Ageing and heredity

Although Parkinson’s disease is not caused by the normal ageing process that affects all our brains, just as it does other organs, the incidence of the disease does increase as we get older. The possible role of a genetic abnormality and of hereditary transmission is one of the fertile areas for present and future research. A weak link has been found between Parkinson’s disease and Alzheimer’s disease, but genetic studies have ruled out any important connection. Nor do the results support any role for genetic factors in the dementia sometimes associated with Parkinson’s disease. A family history is obtained in five to ten per cent of patients, but studies on twins suggest that hereditary factors are relatively unimportant. It may be that affected relatives share some environmental agent or are genetically vulnerable to it. What this environmental factor might be, we do not know.

Dopamine is released from storage granules in the nerve cell, and travels down the axon across the synaptic knob to dopamine receptors at the next nerve cell.

KEY POINTS

1. The cause of Parkinson’s disease is unknown
2. Research has shown that pigment-containing cells in the deep part of the brain that produce dopamine and other important chemicals degenerate and die. This, in turn, affects the working of other parts of the brain, the spinal cord, nerves and muscles involved in movement
3. When the chemical dopamine is depleted, there is a relative excess of the chemical acetylcholine

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If you, or a close relative or friend, suffer from Parkinson’s disease, this book is written for you. It is aimed to help you understand the symptoms and disabilities caused by the disease and to suggest what you can do for yourself, as well as how doctors can treat the condition.

Great progress has been made in our understanding of this disorder, bringing new hope to sufferers. Medical science has developed a range of treatments which can control the symptoms and allow as normal a life as possible.

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Professor Tony Schapira is Professor of Clinical Neurosciences and a consultant neurologist with considerable experience in treating patients with Parkinson's disease. He has a particular interest in the cause of the disease and in helping to develop new treatments.

Is there any treatment?
 

At present, there is no cure for PD, but a variety of medications provide dramatic relief from the symptoms.  Usually, patients are given levodopa combined with carbidopa.  Carbidopa delays the conversion of levodopa into dopamine until it reaches the brain.  Nerve cells can use levodopa to make dopamine and replenish the brain's dwindling supply.  Although levodopa helps at least three-quarters of parkinsonian cases, not all symptoms respond equally to the drug. Bradykinesia and rigidity respond best, while tremor may be only marginally reduced. Problems with balance and other symptoms may not be alleviated at all.  Anticholinergics may help control tremor and rigidity.  Other drugs, such as bromocriptine, pramipexole, and ropinirole, mimic the role of dopamine in the brain, causing the neurons to react as they would to dopamine.  An antiviral drug, amantadine, also appears to reduce symptoms.  In May 2006, the FDA approved rasagiline to be used along with levodopa for patients with advanced PD or as a single-drug treatment for early PD. 

In some cases, surgery may be appropriate if the disease doesn't respond to drugs. A therapy called deep brain stimulation (DBS) has now been approved by the U.S. Food and Drug Administration. In DBS, electrodes are implanted into the brain and connected to a small electrical device called a pulse generator that can be externally programmed. DBS can reduce the need for levodopa and related drugs, which in turn decreases the involuntary movements called dyskinesias that are a common side effect of levodopa. It also helps to alleviate fluctuations of symptoms and to reduce tremors, slowness of movements, and gait problems. DBS requires careful programming of the stimulator device in order to work correctly.

What is the prognosis?
 

PD is both chronic, meaning it persists over a long period of time, and progressive, meaning its symptoms grow worse over time.  Although some people become severely disabled, others experience only minor motor disruptions. Tremor is the major symptom for some patients, while for others tremor is only a minor complaint and other symptoms are more troublesome.  No one can predict which symptoms will affect an individual patient, and the intensity of the symptoms also varies from person to person. At nanotech a 70 year old lady who use to cry at home was eval‎uated, she could not bend down and pray before Allah. She cried in the clinic that she wants to bow down and pray. It took us a week and with the help of God she is Bowing down in Mecca these days.Nanotech a world leader in anti ageing treatments.

What research is being done?
 

We are using electrical stimulation with nanaotechnology and electropolation to help parkinson patients.