It is characterised by the loss of A9 dopaminergic neurons in the substantia nigra pars compacta (SNpc) area of the midbrain. Loss of these neurons leads to a decrease in the dopamine supply to their projection zones.

The underlying process for the observed cell death in this area is not yet known. It has, however, been shown that a build-up of Lewy Bodies could be, in part, responsible. Lewy Bodies are an aggregation of proteins that cause the normal cellular functions to be impaired or even stop completely. Symptoms of PD appear slowly over time, with the first symptom usually being a gait disturbance or a difficulty in writing.

1. Parkinson’s Dease in a Nutshell

Clinically, PD manifests as bradykinesia (slowness of movement), cogwheel rigidity, a resting tremor, as well as progressive depression and dementia. The symptoms often appear on one side of the body first, before progressing to affect both sides.

The symptoms can vary day by day: PD sufferers often report having “good” and “bad” days.

The umbrella term for this collection of symptoms is called “Parkinsonism”. However, just over 85% of people with Parkinsonism actually suffer from PD. The other 15% include rarer disorders such as Multiple Systems Atrophy, amongst others.

FUN FACTS & STATS:

• Men are at (slightly) higher risk of developing disease than women
• Disease is more prevalent amongst those that drink well water 
• Welding is an occupational hazard with 10 fold increased risk of developing the disease
• Smoking is linked with a decreased risk
• Caffeine intake is also linked with decreased risk of developing PD

PD has an effect on the motor circuits deep in the centre of the brain. These areas are collectively called the basal ganglia. In PD, the SNpc (marked in dark blue) is destroyed, and therefore, its connection to the striatum is severed, and the fallout of this changed circuitry is what causes the symptoms classically described as PD.

2. What causes Parkinson’s Disease?

PD is often split into genetic and non-genetic subtypes. However, in reality, this is a spectrum and most cases will have both genetic and non-genetic components. There have been many arguments in the field of neurology for whether PD is caused by nature or nurture. Whilst purely genetic and purely sporadic variants can be observed, a majority of PD cases are believed to be a result of both processes.

Genetic Parkinson’s Disease
There are a number of genes that have been identified in PD. A mutation in a gene Alpha-synuclein was the first to be implicated, with the dosage of this gene shown to be inversely proportionate to the age of PD onset. Therefore, the more active this gene is, the younger you are likely to be when you develop PD. Tirades of other genes such as Parkin, DJ1, LRRK2, PINK1 + UCH-L1 are also involved in a minor way.

However, these genes are still being studied and their exact functions and role in the progression of PD are yet to be discovered.

Sporadic Parkinson’s Disease
It is estimated that 85-90% of PD cases have non-genetic components of the disease (hence sporadic). Current theories of the cause vary, with no unanimous agreement, but the prevailing theory is that of oxidative stress.

Oxidative Stress (Free Radical) Theory
The SNpc of the midbrain is especially rich in substances such as neuromelanin, iron and dopamine. All of these substances increase the levels of oxidative stress. Indeed, post mortem studies of PD sufferers show increased levels of lipid peroxidations, which suggests increased levels of oxidative stress.  MAO activity increases with age and glutathione peroxidase activity decreases, this, collectively, leads to the increased free radical damage.

It would follow that, since the oxidative stress can be reduced by antioxidants, their supplementation (e.g. by administering vitamin E) should slow down the progression of the disease. Unfortunately, no such effect has been shown. This could hint that the oxidative stress is secondary to an unknown primary process.

3. How can we treat Parkinson’s?

There is currently no known cure for PD. Therefore, the available treatments target the reduction or relief of symptoms. The effectiveness of these treatments can vary significantly between patients. If medication fails, PD sufferers can undergo neurosurgical procedures to lesion an area or insert a Deep Brain Stimulator (DBS). The goal of these surgeries is to reduce symptoms, and not to cure the disease.

Medical Treatments
The current first-line treatment for PD is the Anti-Parkinson medication L-Dopa. This is a dopamine substitute that aims to replace the loss of signalling molecules, caused by the death of the dopamine neurons in the midbrain. L-Dopa can also be given in conjunction with Carbidopa, which is known as Sinemet.

If this medication is not effective, a dopamine agonist is used such as Requip, NeuPro or Mirapex. These are molecules that resemble dopamine but have a slightly different structure. There are a number of other medications used to relieve symptoms of PD such as COMT inhibitors. It has been shown that over time, these medications become progressively less effective and can even produce further motor complications.

Surgical Treatments
It is currently estimated that between 1-10% of PD patients would benefit from a neurosurgical treatment. There are two major types of neurosurgical procedures for PD: lesioning and DBS.

Lesioning surgeries involve making a precise damage in an area of the brain, with the goal of reducing the symptoms of PD. Although many lesioning surgeries have now been replaced by DBS, some are still performed in the countries where this is not available. Thalamotomy (selective lesioning in the thalamus) and Palamotomy (selective lesioning in the globus pallidus) are still regularly performed in the UK in specialised neurosurgical units.

The DBS can be thought of as a pacemaker for the brain. Treatment-resistant PD can be managed this way with promising results. The procedure involves placing an electrode into the subthalamus, thalamus or globus pallidus. A small electric current stimulates the local neurons in order to correct the abnormal circuitry. Following this, a permanent electrode is fitted under general anaesthetic, and connected to a pulse generator.

4. Current research and future treatment

The ultimate aim of PD research is, obviously, to discover a cure. Currently, we are only able to treat the symptoms of the disease, as we still do not completely understand what causes these specific neurons to die. Despite this, a number of future treatments are currently being investigated and trialled, with the aim of slowing down the progression of the disease, stopping it in its tracks or even undoing damage that is already done. Progress in this field is slow, but has made a number of leaps forward in recent years.

Removing the underlying cause
As our knowledge of the causa efficiens of the pathology is still incomplete, it is safe to say that the new targets for treatment will become clear as research elucidates more and more of the picture.

Currently, we know that there is a genetic component in some PD patients. Therefore, a keen area of interest is gene therapy.
Gene therapy and gene editing have been hinted as a way of stopping any further damage from taking place; this can be done by using a reprogrammed virus to remove or turn off genes that are linked to PD, such as alpha-synuclein. This is currently being trialled in humans and results are promising.

However, this treatment is not particularly focused as it affects the whole body, despite the disease being localised in a very specific place. The side effects of the treatment in other areas of the body could be significant, so the challenge going forward is to target this therapy effectively.

Notwithstanding the promising results, a vast majority of PD patients have a non-genetic component, and therefore would not benefit from a gene-based therapy.

Keeping the cells alive
All cells in the body receive a complex cascade of “survive” and “die” signals all the time. When the “die” signals outweigh the “survive” signals, the cell dies. A promising area of research is to increase the “survive” signals, so that they outweigh the “die”, meaning that the dopamine cells will survive and not cause the classical symptoms of PD.

Neuroprotective factors such as Brain-Derived Neurotrophic Factor (BDNF), Glial-Cell-Line Derived Neurotrophic Factor (GDNF) can be used to boost survival signals. GDNF is currently in clinical trials.

Replacing the Lost Cells
Another key area of research is to simply replace the neurons that are lost with new cells. Stem cells gained traction in research as they can become any cell in the body. We can currently create dopamine neurons using these stem cells, which could then be transplanted into the midbrain of PD patients.

There is no saying, though, whether or not transplanted cells will survive. The microenvironment caused the death of the original cells, so it’s logical that the newly transplanted cells would eventually die, too. Also, neurons cannot survive by themselves. There is a complex interaction with the surrounding microarchitecture as well as support cells called Glia.

Therefore, a successful transplantation would require not only new neurons, but also the support cells and matrix to enable them to thrive.

Embryonic Stem Cells (ESCs) can be used to create new neurons. There would, however, be an issue of an immune rejection, as the immunological profiles of the donor and recipient would not match and, therefore, any patient undergoing a transplant would have to take antirejection medication for the rest of their lives.

However, in 2007 a new method of creating stem cells was discovered. Called induced pluripotent stem cells (iPSCs), these can be created in a lab from any cell in an individual’s body and therefore would be a match immunologically.

The issue surrounding these cells is that they are hard to make in large numbers, and methods for producing the desired cell type are currently slow and very inefficient. Although this is still in the research and development phase, it is thought to be a promising treatment of the future.

It is foreseeable to me, that the first neurodegenerative disease to be cured using a stem cell or gene-based therapy will be PD. When this will happen, nobody knows. However, given the progress made in the last 10 years alone, it is hard not to be positive for what the future will bring.

Written by Dr Matt Kobetić