A Tour around Parkinson's Disease

(Date of publication 28 November 2005)

The characteristic appearance and movement of a patient with advanced Parkinson's Disease are succinctly summed up in this drawing, which illustrates the stooped and rigid posture, shuffling gait, tremor, and constant movement of the thumb and forefinger described as 'pill-rolling'. The face often becomes expressionless and mask-like – just compare a photograph of Muhammad Ali in his prime with one taken earlier this year.

The common symptoms are described more extensively on this page. Most sufferers experience a slight tremor in one hand or foot in the early stages of the disease which is termed a 'resting tremor', because the limb trembles when the muscles are relaxed but becomes steady as soon as the person begins an action. As the condition progresses, movements become slower and/or incomplete, difficult to initiate and inclined to stop suddenly. This is termed bradykinesia, and it is often accompanied by impaired balance and co-ordination, which increases the likelihood of falling.

In most cases the cause of Parkinson's Disease is unknown (idiopathic), but many researchers believe that several factors may be involved, including free radicals, accelerated ageing, environmental toxins and genetic predisposition. The average age of onset is 60, the condition being rare in people under 30, and the risk increases with age. Men are affected slightly more frequently than women. Symptoms result from the death of dopamine-secreting (dopaminergic) cells in the substantia nigra and locus coerulus of the brain, but only appear once 50%-60% of these neurones have been lost and the amount of dopamine present has dropped by more than 80%. The loss of cells appears to be associated with an abnormal accumulation of the protein alpha-synuclein in the damaged cells, forming Lewy bodies.

The substantia nigra is situated in the midbrain (see this labelled photograph for its precise location) and has two subdivisions: the pars compacta and the pars reticulata. Neurones in the pars compacta are depleted in Parkinson's patients; the function of these cells is unknown, but current research suggests they are involved in learning to predict behaviour that will lead to a reward. Pathological changes to these cells are also thought to play a part in schizophrenia.

Treatment relies mainly on replacing the lost dopamine with levodopa (L-DOPA), a precursor which is converted to dopamine in the brain, or by administering dopamine agonists. If your biochemistry is up to it(!), the conversion of the amino acid tyrosine to L-DOPA, thence to dopamine and finally to noradrenaline, is described on this University of Toledo site. It points out that L-DOPA is used therapeutically because – unlike dopamine – it can cross the blood-brain barrier, and that decarboxylase inhibitors such as carbidopa are often given at the same time, to increase the level of circulating L-DOPA and decrease the side effects associated with peripheral dopaminergic activity.

The pharmacological treatment of Parkinson's Disease is covered quite comprehensively in this article from The Pharmaceutical Journal. One major problem is that the beneficial effects of L-DOPA tend to diminish over a period of months or years and the patient then experiences fluctuations in response, which can switch dramatically between gross involuntary movements (dyskinesias) and a frozen, immobile state. Dopamine agonists may be used as initial treatment or as adjunctive therapy, but they are generally less potent than L-DOPA and less well tolerated. A relatively recent development has been the introduction of catechol-o-methyl transferase (COMT) inhibitors, which prolong the effectiveness of L-DOPA by preventing its breakdown.

Owing to the shortcomings of medical therapy, there has been a resurgence of interest in surgical treatment. The procedures most commonly carried out are pallidotomy and deep brain stimulation (DBS). In pallidotomy, stereotactic surgery is used to destroy tissue in the ventromedial portion of the globus pallidus. Magnetic resonance imaging or computer axial tomography is used to locate the exact position of the target and the patient remains conscious throughout the operation. In the great majority of patients, the symptoms – including tremor, rigidity and bradykinesia – are effectively abolished. Deep brain stimulation involves positioning an electrode in the thalamus or globus pallidus and connecting it to a radiofrequency stimulator which is implanted in the chest wall. The device is switched on (and off) by passing a magnet over it, and tremor is successfully controlled in more than 80% of patients. However, it does not affect bradykinesia, rigidity or other symptoms. This technique is now considered the surgical treatment of choice because it is more effective, safer and less destructive than other methods.

However, in the future the preferred method may be the implantation of cells directly into the brain. Researchers in Israel recently demonstrated that when human embryonic stem cells are transplanted into the brains of rats with Parkinson's Disease, some develop into dopaminergic nerve cells and the rats' functioning improves. Also, it is now possible to grow large numbers of fully mature brain cells in the laboratory. At the same time our understanding of the disease mechanism is growing. Only this month an Australian team announced that dopamine can cause oxidation of alpha-synuclein, changing the protein's structure and making it toxic to dopaminergic neurones, while duplication of the alpha-synuclein gene has been linked to familial forms of Parkinson's Disease. Both approaches hold the promise of a novel treatment......but which will be first?

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