Parkinson's disease is a chronic, progressive and incurable disease of the central nervous system, making it one of the most common neurological conditions, second only to dementia. It affects walking, talking, writing and swallowing, and is characterised by involuntary movements, such as shaking, rigidity and difficulty walking. It can also include non-motor symptoms such as pain, sensory changes, gastrointestinal system changes, depression and problems with memory, thought and sleep. The condition is linked to an imbalance between two brain chemicals, or neurotransmitters: dopamine and acetylcholine. The destruction of cells in a tiny region of the brain called the substantia nigra leads to a lack of dopamine, which is important in the control of movement.
Dr James Parkinson’s seminal work, An Essay on the Shaking Palsy – the first complete medical description of the disease was published in 1817. The essay described the symptoms of six individuals as: involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace. (The name Parkinson's disease came into common usage in 1872.) Treatment in Parkinson’s day was radical. He advocated venesection, or bloodletting from the neck. This was followed by the application of substances to induce blistering of the skin and the insertion of small pieces of cork into these blisters to lead to pus discharge. Other dubious methods were recommended by French neurologist Jean-Martin Charcot in the later 19th century. These included rest and reduced stress, as well as experimental therapy in which rhythmic vibrations were delivered via a shaking chair and a Russian pulley and harness system designed to suspend the patient in mid-air and stretch the spinal cord.
The first drug treatments, hyoscyamine and other drugs made from the plant belladonna, were introduced by Charcot and his student Ordenstein in the 1860s. They led to unexpected, but mild, improvements in motor symptoms such as tremor, muscle rigidity and slowed movement. While the reason for their effectiveness wasn’t understood then, today it is known they block receptors for the neurotransmitter acetylcholine, which works in balance with dopamine – similar to a seesaw. Decreasing excessive activity of acetylcholine helps increase that of dopamine. Other early drug treatments included derivatives of ergot, a fungus that affects rye. Today we know these mimic the effects of dopamine in the brain and many of the modern dopamine-mimicking Parkinson’s drugs are based on these compounds. Hyoscyamine and other anti-cholinergic drugs would remain the primary means of treatment for the next 100 years.
The involvement of the substantia nigra of the brain was known since the late 19th and early 20th century. But it wasn’t until the discovery of dopamine’s role in the disease that drug therapy made significant progress following a discovery in the 1950s that dopamine was located primarily in a part of the brain called the striatum. This area is connected to the substantia niagra by a long nerve cell through which it releases dopamine into the striatum. In 1960, Herbert Ehringer and Oleh Hornykiewicz discovered that dopamine was depleted in the brain of those with the disease.
Dopamine itself is not able to cross the blood-brain barrier – a protective barrier that stops pathogens and other larger molecules from entering the brain through the blood. This means dopamine itself can’t be given as a medicinal treatment, since it will not be able to enter the brain. So in 1961, levodopa – a dopamine “precursor” that is transported across the blood brain barrier into the brain and converted into dopamine – was trialled for the first time with beneficial effects. Levodopa leads to significant improvements in motor symptoms in the majority of people. In some people in the early stages of Parkinson’s disease, it leads to virtually normal motor movement.
Today, levodopa remains the most effective and widely prescribed pharmacological treatment for the disease. It is often coupled with certain enzyme inhibitors, such as carbidopa (that stop the breakdown of levodopa prior to entering the brain), allowing more of it into the brain and increasing the amount of dopamine produced.
Unfortunately, levodopa becomes less effective over time as dopamine neurons continue to die in people with Parkinson’s, requiring higher doses of the drug. Prolonged use is also associated with significant side effects. These include severe dyskinesia (involuntary, erratic movements) and a wearing-off effect, in which patients become stiff and slow in between medication doses.
The wearing off effect may in part be addressed with slow-release forms of levodopa with carbidopa – such as Sinemet CR. This releases the drug over a longer period of time (four to six hours), leading to steadier levels of levodopa in the blood. But because of the slow release, the beneficial effects of Sinemet CR may take longer to come about.
Other drug treatments are derivates of ergot, a fungus that affects rye. from shutterstock.com
In 2015, the US Food and Drug Administration (FDA) approved Rytary, a drug that combines both immediate-release and extended-release levodopa beads to address this slow onset issue. However, this drug has not yet been approved for use in Australia.
For advanced Parkinson’s disease, a slow-release intestinal gel form of levodopa together with carbidopa, called Duodopa, may be administered directly into the small intestine via a surgically-implanted tube. Duodopa received approval in Australia by the Therapeutic Goods Administration in 2008 and has been covered by the Pharmaceutical Benefits Scheme since 2011.
This treatment, however, is only suitable in a relatively small number of patients in advanced stages of the disease. Surgery to implant the tube also comes with some risks, such as infection and bleeding, as well as potential clogging or dislodging of the tube over time.
Parkinson’s disease is the second most common neurodegenerative disease after dementia, affecting more than ten million people worldwide. While Parkinson’s primarily affects adults over the age of 55, 20% of those diagnosed with the condition are under 50 and 10% of cases occur in those under 40.
An Australian study in 2011 estimated that about one in 350 Australians had Parkinson's disease. By 2018, it was closer to one in 300, or approximately 80,000 people; among those over 70 years of age, 1 in 1,000 are afflicted. The estimated costs of Parkinson’s disease to the Australian economy add up to almost A$1.1 billion, a number that has almost doubled since 2005. The prevalence of the disease is estimated to double by 2030.
In the UK in 1994 it was estimated that the disease cost more than £3 billion a year for the 112,000 sufferers (namely £30,000 per year each).
Damaged brain cells emit chemical noise, rather than a series of appropriate chemical signals. The brain has to sift through the unclear message to identify genuine movement signals, which slows reaction time from the normal 80 milliseconds (ms) to more than 250 ms, characteristic of Parkinson's patients, and also results in false movement commands. Slow reaction time is one basis for diagnosing the severity of Parkinson's disease.
Researchers at the Mayo Clinic recently released the results of a 15-year study on Parkinson Disease, and out of 364 cases they studied, the found that 20% of these cases (73 people) the Parkinson's disease was the result of poisoning from pharmaceutical drugs.