Curing Parkinson’s – a review
Posted by Science Oxford on December 1, 2011 | comments
Talk reviewed by Blanka Collis, a Science Oxford volunteer and postdoctoral scientist at the University of Oxford.
On 24th November, Professor Tipu Aziz of Oxford University came to talk at Science Oxford and took the audience on a journey exploring Parkinson’s disease (PD), what we understand about its causes and the treatments through the years.
Parkinson’s disease (not known under that name at the time, of course) was first diagnosed by James Parkinson in 1817 and described as paralysis agitans (shaking palsy). There are four basic characteristic symptoms of PD and these are tremors (the earliest and most common symptom), rigidity, akinesia (slowness of movement) and postural instability. It was Jean-Martin Charcot who, in the 1890s, differentiated the tremor caused by shaking palsy from that caused by multiple sclerosis by looking at how an ostrich feather moved when held by patients with the two different disorders. He also coined the name “Parkinson’s disease” in honour of the Englishman who first described it, and introduced the first drug of a kind, the belladonna herb. This was used in royal courts to dilate pupils of women to make them look beautiful but it was observed that a dry mouth was one of the side effects of its use. With this in mind, PD patients were treated with belladonna to control their drooling, and surprisingly tremors were also reduced. This was because belladonna contains an anticholinergic, which blocks acetylcholine receptors in the nervous connections of the brain, thus preventing muscle contractions being triggered. However, apart from belladonna, the only form of treatment, until 1969, was surgery.
No one really knew at the time what caused PD. Initially, it was thought to be a psychogenic disorder, caused by an event in a patient’s life. It was much later that a young Austrian scientist, Oleh Hornykeiwicz, showed that PD was caused by the loss of a pigment in the brain and linked with missing dopamine, eventually leading to the development of L-Dopa as by George Cotzias, still the most commonly used treatment for PD to date. But let’s take a step back to the surgery that was used to treat patients prior to this discovery in 1969. When Prof Aziz recounted the type of surgery that was performed on many of the patients, there were collective intakes of breath from the audience.
One of the ways of treating PD involved opening up the skull and then effectively sucking out part of the patient’s brain to remove the motor cortex. Whilst this often led to loss of the tremor, the treatment increased the risk of epilepsy. Rather than taking out large chunks of the brain, a positive development involved selective destruction of parts of the brain with electrodes. To help with this process, a way of mapping the brain was developed, first based on experiments in monkeys, allowing the use of something called stereotactic surgery to target particular areas of the brain for electrode stimulation. In another rather dramatic treatment, Leslie Oliver would take a scalpel to the spinal cord– after 6 months of paralysis, some of the patients regained their movement and had lost the tremor! Russell Mayer, as late as the 1950s, used a technique to incise the cortex and suck part of it out, leaving 30% of patients dead. However, those who survived and hadn’t suffered from epilepsy had lost their tremor. The lack of any other treatment meant that such a drastic procedure was a viable option at the time.
Not all was bad though as these rather experimental treatments did lead to increased knowledge about PD and its causes. Irving Cooper’s surgical technique involved making an incision in the side of the patient’s head, and cutting at the interface between the spinal cord and the brain. By mistake, he cut the anterior choroidal artery once and found that this resulted in reduction of the tremor, rigidity and paralysis in the subject. By careful experimentation in monkeys, he showed that this artery supplied the thalamus and, together with work showing that slow destruction of a part of the brain called the palladum improved the rigidity and tremors, this suggested a signalling link between the palladum and thalamus. Since controlled lesioning of the thalamus led to improvement in the tremor and rigidity of patients, with only a 1% death rate, the number of thalamothomies in treating PD rose steadily. Nevertheless, although rigidity and tremor were improved, the patients remained slow moving and immobile, still suffering from akinesia.
This is where treatment was at in 1969, when seminal work was presented by George Cotzias at the 3rd international congress of PD in Edinburgh which suggested that treatment with L-Dopa, a metabolic precursor of dopamine, the molecule missing in PD patients, could restore patients to a relatively healthy state, with a reduction in tremors and rigidity and an improvement in movement speed. In the 1970s, the case of the frozen addicts led to the discovery of a compound called MPTP, which induced Parkinson’s like symptoms in users. The compound was discovered by Barry Kidston, a graduate student chemist who made a concoction with MPTP as a major impurity and when he self-injected this, he developed symptoms of PD. Crucially, his symptoms were successfully treated with L-Dopa, and after his death 18 months later (of a cocaine overdose), an autopsy showed that the brain changes that had occurred were uncannily like those of PD patients.
A key contribution of MPTP to the field was the development of an animal model of PD as injection of monkeys with MPTP led to a Parkinson’s like state, which could be successfully cured by administration of L-Dopa. Using this and a variety of approaches, including the use of 2-deoxyglucose uptake, researchers showed that the subthalamic nucleus (STN), a type of pacemaker, was involved in PD, and that in patients with the disease the reduction in dopamine led to an overactive STN. Using this knowledge, subthalamic nucleotomy (using a heated needle to lesion the STN) or poisoning the STN was proposed as a treatment for PD, but was a rather risky procedure so not many were referred for it. However, it was then shown that stimulating nerve cells in the STN using electrodes to knock out the pacemaker function of the STN led to a marked improvement in PD.
Stimulation of the STN is called deep brain stimulation (DBS) and involves insertion of a wire into the STN, with a connected pacemaker under the skin delivering electric shocks at regular intervals aiming to provide stimulation only when it is needed and stop any tremors occurring before they begin. Prof Aziz was one of the surgeons involved in the development of the technique in its early days. So far 60,000 people have undergone DBS, and Prof Aziz showed us recordings of patients pre- and post-operation, demonstrating major improvements in their mobility, tremors and rigidity. He did point out that whilst DBS may help to treat the major issues with PD, other symptoms such as excessive sweating and progressive cognitive problems may remain an issue, meaning that patients probably still need to keep taking drugs to control the disease. And of course, the procedure is a very expensive one, so PD patients generally have to wait until their quality of life starts deteriorating significantly before becoming eligible for DBS surgery.
Prof Aziz rounded off his talk with a discussion of possible future technologies of treating PD. One of these could depend on the use of stem cells for the brain to effectively repair itself. As explained, this might involve harvesting some cells from the olfactory node (an organ at the top end of your nose, pretty much the most accessible part of the brain) and growing these in culture whilst “teaching them” to express dopamine, the chemical missing in the STN. Once these cells are capable of expressing dopamine, they could be injected into the diseased area (i.e. STN) to replace the non-functioning cells. Another approach could involve the use of viral vectors to enable gene therapy to restore the production of dopamine in defective cells. Indeed, several of these are currently in clinical trials and include AAV-GAD, a treatment to increase the production of a neurotransmitter called GABA in STN cells, ProSavin, attempting to restore dopamine production, and Neurtutin, with promising results for some of these treatments.
The talk was rounded off with a lively Q&A discussion, with much interest and participation from the audience, showing there is certainly a keen interest in Prof Aziz’s research area! If you’ve missed the talk, you can watch a pre-talk interview with Prof Aziz here, and the webcast of the talk is available here.
What do you think?