Parkinson's Spectrum Diseases

Parkinson's and diseases within this spectrum are primarilly movement disorders. Parkinson's Disease (PD) is otherwise known as "primary Parkinsonism". This classically means that there is no underlying cause but currently defines the disease when the neurodegeneration is not caused by a systemic cause.

 Parkinson's Disease

Most PD symptoms are motor in nature. They include tremor, rigidity, bradykinesia and postural instability. Bradykinesia is defined by a slowness in the execution of movement, with postural instability leading to impaired balance. The rigidity associated with Parkinson's Disease refers to an increased muscle tone and stiffness. Tremor is increased at rest and reduced with movement. The above symptoms are the most well defined and characterised symptoms.

These symptoms are caused by decreased motor stimulation of the motor cortex by the basal ganglia. This occurs as a result of insufficient dopamine production in the dopaminergic neurons of the brain. Specifically PD s associated with loss of dopaminergic cells in the substantia nigra. The loss of dopamine results in inactivation of the direct signalling pathway of motor control. This pathway includes the caudate and the putamen.

 A diagram showing the inputs resulting in the control of motor coordination. Because of neuronal death in the substantia nigra there is an inhibition of thalamic outputs due to an upregulation of the inhibitory pathway associated with the nucleus subthalamus.

http://en.wikipedia.org/wiki/Image:DA-loops_in_PD.jpg - under Creative Commons licence.

This above diagram displays the pathways of a Parkinson's sufferer (right) displayed next to the neural pathways in a healthy brain. Blue arrows define excitatory pathways and red arrows inhibitory pathways. The thickness of the arrow corresponds to the strength of input. The reduced pathway shown coming from the substantia nigra of the mesencephalon results in upregulation of the pathway from the nucleus subthalamus. The result of this process is the inhibition of the pathway from the thalamus which is crucial for control of movement.

A coronal slice through the brain showing extensive degeneration in the area of the substantia nigra. 

http://www.flickr.com/photos/26016306@N03/2477391485/in/set-72157604968285412/ - under Creative Commons licence

In the above photo the substantia nigra is the darker area towards the middle of the brain slice. It is known as the substantia nigra because of the darker colour. It shows the holes and marks associated with Parkinson's neurodegeneration.

Treatment of Parkinson's Disease

In common with the vast majority of neurodegenerative disorders current treatment of PD is no more than supportive. Drug treatment focuses on increasing dopamine levels inside the nigrostriatal pathway; there is no current method of preventing neuronal death in the substantia nigra.

The first-line drug for PD is a pro-drug known as L-Dopa. As dopamine cannot cross the blood brain barrier, this drug is taken and metabolised to dopamine within the body. This is a very inefficient drug with only ~1-5% of the drug entering into dopaminergic neurons. Because of this it is often given with drugs that support it's action.

An example of a type of drug used to support L-Dopa are dopa decarboxylase inhibitors. These act by preventing the metabolism of L-Dopa before it has reached the dopaminergic neurons. An example of this type of drug is Carbidopa.

Another drug which supports L-Dopa is tolcapone. This inhibits the COMT enzyme, which degrades catecholamines. The action of a COMT inhibitor prevents the breakdown of dopamine and leads to more sustained L-Dopa activity. These drugs cannot be used too extensively as they lead to liver damage.

Possible Future Treatments

Stem cell and gene therapy is widely touted as being a future cure for Parkinson's Disease. This involves the implantation of undifferentiated cells which differentiate into dopaminergic neurons. The toxic compound MPTP induced Parkinsonism in a group of drug addicts who consumed an improperly produced synthetic opiate. This was cured in two of seven cases by a graft of embryonic stem cells. However this drug only lead to one incident of cell death, not a continuouing and progressive degeneration.

There is a school of thought that because stem cell therapy does not prevent the progressive element of neurodegeneration it can never be a wholly effective treatment. Other ideas of novel treatments for PD include the implantation of electrodes in the subthalamic region of the brain in order to produce a form of deep brain stimulation. Another option is gene therapy. A gene coding for GDNF production would be inserted into the genome of a nigrostriatal neuron resulting in an increase in L-Dopa synthesis.

Other Conditions with Parkinsonism

As many antipsychotic drugs achieve their mechanism by reducing dopamine levels they can sometimes induce Parkinson's-like symptoms by lowering the amount of dopamine in the nigrostriatal pathway. Dementia with Lewy Bodies can also have motor symptoms. Wilson's disease is a symdrome in which copper deposits build up in a patient's body. This can also cause symptoms within the Parkinsonian spectrum, as copper accumulates in neuronal tissue.

Huntington's Disease has motor components and is characterised by accumulation of a protein known as huntingtin. It is characterised by slow, random movements known as chorea. Unlike many diseases outlined on this website it is autosomally inherited in a dominant fashion.