Parkinson’s disease aetiology and treatment

Parkinson’s disease is a movement disorder of middle and old age that affects 1-2% of the elderly population. It is about 2.5 times more prevalent in males than females. The initial symptoms of Parkinson’s disease are mild, perhaps no more than a slight stiffness or tremor of the fingers. But these symptoms inevitably increase in severity with advancing years. The most common symptoms of the full-blown disorder are, tremor that is pronounced during inactivity but not during voluntary movement or sleep, muscular rigidity, difficulty initiating movement, slowness of movement, and a mask-like face. Pain and depression often develop before the motor symptoms become severe. What are the biological causes of this progressive neurological disorder? And how is it treated?

 Aetiology

Parkinson’s disease seems to have no single cause; faulty DNA, brain infections, stokes, tumors, traumatic brain injury, and neurotoxins have all been implicated in specific cases. However, in the majority of cases no cause is obvious, and there is no family history of the disorder. To date, mutations in the LRRK2 gene are the greatest genetic contributor to the disorder.

Parkinson’s disease is associated with widespread degeneration, but it is particularly severe in the substantia nigra; the midbrain nucleus whose neurons project via the nigrostriatal pathway to the striatum of the basal ganglia. Although dopamine is usually the major neurotransmitter released by most neurons of the substantia nigra, there is little dopamine in the substantial nigra and striatum of long term Parkinson’s patients.  Dopamine allows smooth, coordinated function of the body’s muscles and movement. Without an adequate supply of dopamine in the brain, a person experiences problems such as tremors, balance problems, and the inability to move quickly. When approximately 80% of the dopamine producing cells are damaged, these symptoms of Parkinson’s disease appear. Exactly why these brain cells waste away is unknown.

Neurons on the substantia nigra regulate motion via dopamine into the striatum. The striatum relays these messages to higher motion-controlling regions in the frontal lobe, the motor cortex.  The cortical regions ultimately dictate how the muscles behave. Two pathways have opposite net effects on thalamic target structures. Excitation of the direct pathway has the net effect of exciting thalamic neurons, which in turn make excitatory connections onto cortical neurons, and stimulate muscle movement. Excitation of the indirect pathway has the net effect of inhibiting thalamic neurons, rendering them unable to excite motor cortex neurons, which inhibits muscle movement. Function of the basal ganglia is related to a proper balance between these two pathways. Loss of these dopamine neurons in Parkinson’s disease causes poverty of movement, as the balance between direct pathway excitation of the cortex and indirect pathway inhibition of the cortex is tipped in favour of the indirect pathway, with a subsequent pathological global inhibition of motor cortex areas. Reduction of thalamic excitation interferes with the ability of the motor cortex to generate commands for voluntary movement.

Although the substantia nigra gets most of the publicity when Parkinson’s disease is discussed, researchers have discovered that some of the brain neurons that secrete norepinephrine die as well. This death may be responsible for disease symptoms such as digestive problems and a rapid drop in blood pressure when the person stands up after sitting or lying down (postural hypotension).

Autopsy often reveal clumps of proteins in surviving dopaminergic neurons of the substania nigra, called Lewy bodies. However, it is not known what the function of Lewy bodies is.

Treatment

Treatments either replenish dopamine or mimic the action of dopamine in the brain. Dopamine levels can be replenished with various medicines based on levodopa (L-dopa), a drug that is converted to dopamine in the brain. The symptoms of Parkinson’s disease can be alleviated by injections of L-dopa. However, L-dopa is not a permanent solution. It typically becomes less and less effective with continued use, until its side effects (e.g., involuntary movement) outweigh its benefits. There is currently no drug that will block the progressive development of Parkinson’s disease or permanently reduce the severity of its symptoms. Dopamine levels can also be increased by medicines called monamine oxidase B inhibitors which prevent dopamine from breaking down in the brain. Dopamine agonists (e.g. sifrol) can mimic the action of dopamine.

A controversial treatment for Parkinson’s disease has been deep brain stimulation. This treatment is a low intensity electrical stimulation which is continually applied to an area of the brain through a stereotaxically implanted electrode. The treatment of Parkinson’s disease by this method usually involves chronic bilateral electrical stimulation of a nucleus that lies just beneath the thalamus and is connected to the basal ganglia; the sub thalamic nucleus. High frequency electrical stimulation is employed, which blocks the function of the target structure, much as a lesion would. Once the current is turned on, symptoms are sometimes alleviated within minutes, but the effectiveness of deep brain stimulation slowly declines over the ensuing months. If the stimulation is turned off, the therapeutic improvements dissipate within an hour or two. Unfortunately, deep brain stimulation can cause side effects such as cognitive, speech, and gait problems.

In conclusion, the exact cause of Parkinson’s disease is unknown, although research points to a combination of biological and environmental factors. Biologically, the disorder results from a loss of cells in various parts of the brain, including the substatia nigra, which produces dopamine. Dopamine modulates circuit interactions which initiate or inhibit movement. Loss of dopamine causes neurons to fire without normal control, leaving patients less able to control their movement. L-dopa is used to alleviate the symptoms of Parkinson’s, although there is currently no drug which blocks the progressive development of the disorder.

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