From AU Science Wiki
Jump to: navigation, search


Given the obvious symptoms associated with Parkinson disease, such as tremor and imbalance, it seems unusual that the first description of the disease did not appear until 1817. The disease is named for the man who originally described it in 1817. James Parkinson was a British physician who described the symptoms of six of his patients. He originally called this disease paralysis agitans, which is latin for "shaking palsy."

Many researchers propose the idea that the disease was uncommon before the industrial revolution. It is thought that the appearance of Parkinson's may be related to the presence of an environmental toxin released as a byproduct from machines and other technology. Also, the higher occurance of the disease may be related to longer life spans that people today experience. Now people are able to reach an age when the physical effects of Parkinson disease become more apparent.


Parkinson's Disease has four major symptoms:

  1. tremor or trembling in hands, arms, legs, jaw, and face
  2. rigidity, or stiffness in the limbs or trunk
  3. bradykinesia, or slowness of movement
  4. postural instability, or impaired balance and coordination

Parkinson's disease normally effects people over the age of 50 and symptoms occur gradually and get greater with time. However, some peoples symptoms may progress faster than others. When they symptoms start, they don't normally have a great effect on a person's everyday life. But as they symptoms progress, they produce a large interference on people's daily activities.

Some other symptoms people with Parkinson's might experience are depression or other emotional changes; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions. However, Parkinson's disease can not be diagnosed through a blood or lab test but only through look at a person's medical history and a neurological examination. This means the disease can be hard to diagnose accurately.


Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons, or dopamine releasing neurons, in the area of the brain called the substantia nigra (Burch and Sheerin 2005). The substantia nigra is a dark gray nucleus pigmented with melanin and is the motor region where inhibitory signals (dopamine) are relayed to the thalamus and basal nuclei. It is situated between the peduncles and tegmentum (Saladin 2007) making up part of the mesencephalon. Before any further description of PD can be made, a review of the motor functions of the thalamus and the basal nuclei is essential.

The thalamus constitutes to the majority of the diencephalon and is the center where cerebral cortex communication occurs with the brain. Nearly all sensory input such as taste, smell, hearing, equilibrium, pain, vision and pressure must pass through the filtering thalamus. More importantly to Parkinson’s disease, this is the area of the brain that has a large role in dispatching signals from the cerebellum to the cerebral cortex, and provides feedback loops between the cerebral cortex and the basal nuclei (Saladin 2007). As a result, motor signals are controlled and regulated by this system of relay.

Furthermore, basal nuclei are a group of subcortical tissue that also controls voluntary skeletal movements (Burch and Sheerin 2005). It consists of the striatum, globus pallidus externa and interna, subthalamic nucleus, substantia nigra pars compacta and reticularis. While having no direct connections with the descending spinal cord, feedback loops are formed from the cortex to the thalamus, and back to the cortex (Burch and Sheerin 2005). In other words, the basal nuclei will receive input from both the substantia nigra and from the motor areas of the brain, and consequently return signals back to these locations.

In Parkinson’s, the neurons of the substantia nigra have degraded so there is no neurotransmission of dopamine to the neurons of the basal ganglia (Landes 2003). Therefore, antagonistic inhibition does not occur, and the excitation of both agonist and antagonist muscles compete which produces dykinesia, a common symptom of PD (Saladin 2007).

Please refer to the following diagrams:

Normal v. Parkinson's human midbrain

Lewy Bodies in Substantia Nigra

Destruction of the Substantia Nigra

PET Scan indicating decreased levels of dopamine activity in PD patients

A 140 amino acid protein known as α-synuclein protein is believed to have a major role in the degradation of dopaminergic neurons. A mutation in α-synuclein produces a toxic effect where the protein misfolds and aggregates improperly (Cardoso et al.2005). Monomers of the mutated α-synuclein can form β pleated sheets called protofibrils, which in turn form fibrils to finally create a cytoplasmic proteinaceous inclusion called a Lewy body (Moore et al. 2005). Lewy bodies have been found in high concentration among PD patients, and its toxic properties have been linked to the death of neurons. Moore et al. (2005) believe that protofibrils of α-synuclein will cause improper permeability of a neuron’s membrane which could somehow contribute to its collapse. α-synuclein can also alter the amount of dopamine synthesized in the neuron by decreasing the activity of tyrosine hydroxylase, the enzyme responsible for hydroxylating Tyrosine to 3,4-dihydroxyphenylalanine, or L-Dopa (Voet and Voet 2004). The precursor to dopamine, L-Dopa, is then decarboxylated to yield dopamine. α-synuclein also has the potential to regulate synaptic vesicle reuptake of the neurotransmitter dopamine.

Moreover, mutations in genes encoding for UCHL1, parkin, DJ-1 and PINK1 can lead to oxidative stress and mitochondrial dysfunction, other possible causes of PD (Cardoso et al. 2005). Because all aerobic organisms undergo oxidative and reduction reactions, free radicals are constantly being produced. The older a person’s age, the more oxidative stress that person has experienced. PD patients, normally aged 50 years or older, are prone to changes in dopamine metabolism.

Mitochondrial dysfunction also may have a leading role in PD because of its capability to produce free radicals. Impairment in the electron chain transport and Co-enzyme Q10, a free radical consumer, may contribute to free radical damage of dopaminergic pathways.


For the treatment of Parkinson's disease there are two main types of therapy. These are drug therapy and brain surgery. As most of the symptoms of Parkinson's come from decreased levels of dopamine in the brain, many of the pharmaceutical solutions include drugs that increase the dopamine levels in the brain. A logical solution to the problem might be to introduce more dopamine into their system. This tactic although logical will not work because dopamine cannot be absorbed through the blood stream. The drugs used to treat Parkinson's disease are referred to as antiparkinson drugs. These drugs work by temporarily restoring dopamine in the brain or closely mimic dopamine’s actions.

According to Burch and Sheerin (2005) and the Parkinson's Disease Foundation, the following treatments for Parkinson's Disease can be summarized:

Drug Therapy

Levodopa- Currently the most frequently used drug to treat PD and is used concurrently with a dopa-decarboxylase inhibitor. By itself, dopamine is ineffective because it cannot cross the blood-brain barrier, however, L-Dopa is and will later be decarboxylated by aromatic amino acid decarboxylase to activate it (Voet and Voet 2004). But with the proliferation and uncertainty of motor symptoms, Levodopa may become counterproductive. 70-80% of PD patients receive this treatment and report significant temporary improvements in their symptoms (1).

Dopamine antagonists- Apomorphine, administered subcutaneously, Bromocriptine, Pergolide, Pramipexole and Ropinirole works on post-synaptic dopamine receptors. They generally excite areas of the brain where dopamine is received so that the receptors believe they have received dopamine (1).

Catechol-o-methyltransferase (COMT) inhibitors- Entacapone and Tolcapone are drugs used to prevent enzymatic degradation of dopamine and Levodopa. As a result, the time of Levodopa’s effectiveness is considerably lengthened.

Anticholinergic drugs- Relatively ineffectual, Benzotropine mesylate and Trihexyphenidyl HCL are used to control mild tremors. These drugs will balance out acetylcholine and dopamine production to control muscle contractions.

Amantadine- The newest drug therapy for PD. It will act on N-methyl-D-aspartate (NMDA) receptors to signal more dopamine release by neurons. Currently, dyskinesia is treated with Amantadine.


Thalamotomy- A surgically invasive procedure where specific parts of the thalamus are destroyed. Patients report improvements in tremors but not bradykinesia or rigidity.

Pallidotomy- Tiny electrodes are placed in globus pallidus interna to destroy malfunctioning neurons. It can be useful in the sustainment of rigidity, dyskinesia and tremor.

Deep Brain Stimulation- Electrodes are used to promote inhibition in the thalamus, globus pallidus interna and subthalamus nucleus. Subthalamus nuclear stimulation has reported the most success in reducing rigidity and bradykinesia (>80%).

New Treatments

MAO-B inhibitors- Selegiline or Deprenyl is believed to slow down the loss of dopamine. MAO-B enzyme will toxically degrade Levodopa and dopamine, and these drugs will oxidize the MAO-B enzyme rendering it useless.

Stem Cell Therapy- Presently a politically controversial topic. Stem cells may be implanted into PD patients and differentiated to produce dopamine. Early tests report that grafted stem cells have improved PD symptoms and have shown long term survival.


Parkinson's is both chronic and progressive. This means it persists over a long period of time and the symptoms get worse. Even though this is so, symptoms might never disrupt a patient's daily life. However, some symptoms cause them to become severely disabled.

Parkinson’s disease is by no means a fatal disease, but is a progressive one. Patients with PD can live up to 20 or more years, and the mortality rate of PD patients compared to non-PD patients of the same age and sex is 1.6 times higher (Hauser 2006). Death from PD usually results from illnesses coexisting with PD or physical injuries suffered from falling.

PD affects approximately 1.5 million Americans and 1% of the population over 65 (Hauser 2006). Mild or early PD symptoms typically are well controlled with medications and are effective for several years. However, after years of treatment, patients may begin to build tolerance for the drugs and containment of symptoms could only last a few hours.

Two scales can be used to monitor a patient’s progression with PD, with or without treatment, over the years—the Hoehn and Yahr scale and the Unified Parkinson’s Disease Rating Scale (UPDRS).

Current Research

Levodopa and STN Stimulation

The most notable signs of Parkinson’s disease are the debilitating physical motor symptoms that inflict patients over time. Little attention has been paid to treating the nonmotor symptoms of this disease such as depression or changes in behavior. Research by Funkiewiez et al. in 2006 investigated just this when it compared the effects of Levodopa and subthalamic nucleus (STN) stimulation on the nonmotor aspects to PD. Cognition, behavior and mood were all assessed during controlled experiments with or without drugs, and with or without STN stimulation. As previously discussed, Levodopa is a proven dopaminergic medication influencing motor responses; however, apart from its motor effects, Levopoda alters nonmotor activity as well. In addition, this study also investigates the efficacy of STN stimulation on motivation, fatigue, anxiety, depression and apathy.

The following neuropsychological tests were conducted on 22 PD patients four times (twice on and off Levodopa before surgery, and twice 3 months after STN surgery with no drug):

Planning Task in which the patient had to look at an arrangement of balls in pockets and copy that arrangement with another set of pockets and balls. The level of difficulty became increasingly harder.

Reversal/Extinction Task where the patient received points for choosing one stimulus while holding back response to another. Once the patient received a certain score, the conditions changed such that the patient now could only receive points by responding to both stimuli instead of choosing one and refraining from the other,

Apathy scale of 14 questions. A score of 14 or more out of the possible 42 would categorize the patient as apathetic.

Back Depression Inventory where patients answered a series of questions about how they felt in the past two weeks.

The results of these tests were contradicting in that while STN stimulation significantly improved cognitive and behavior functions such as planning and reversal/extinction, Levodopa seemed to impede some performance on the series of task, particularly the extinction part of the reversal/extinction test. Despite these disparities, both Levodopa and STN stimulation improved the patient’s feeling of well being. STN stimulation also reduced depression while increasing apathy.

Possible hypothesis for these results are that Levodopa will affect more structures than STN stimulation, such as the motor striatum, frontal cortex, hippocampus, amygdala, globus pallidus, thalamus and STN. Funkiewiez et al. also believes that Levodopa has a more potent effect on the dopamine systems potentially causing problems with dopaminergic overdose than does STN stimulation.

The conclusions of this research are that STN stimulation has opposite effects to that of Levodopa. While the former shows improvement in cognitive abilities, the latter will worsen performance on some planning and performance tasks. Both, however, proved equally as effective in altering mood, depression, increasing motivation, and decreasing fatigue and anxiety.

Molecules to Medicine

As previously described research into this disease often deals with the synthesis of molecules that can increase the dopamine levels within the patient. This often proves difficult because it has been proven that dopamine cannot cross the blood brain barrier. Many examinations of brains from PD patients demonstrate neuronal cell loss, especially in dopamine-rich pigmented neurons. There is also evidence that shows the modern treatments are difficient in nature. This is because current medical and surgical therapies for PD are symptomatic and lack significant disease-modifying effect.

The most recent advances in available medical therapies in the United States have revolved around prolonging the effect of levodopa through the use of COMT inhibition and by changing the availability and formulation of older medications such as selegiline and apomorphine. Despite this there seems to be no cure for the disease in sight. Many of the current modes of treatment deal with developing new molecules that will ease the symptoms of PD and not actually cure the disease.

Surgical DBS is perhaps the most influential development in symptomatic PD therapy since Levodopa. In this procedure, an electrode is inserted through the skull to reach and stimulate the globus pallidus, subthalamic nucleus (STN), or ventral intermediate thalamus. A pacemakerlike device is implanted and connected to the electrode through wires buried beneath the skin. The results of this therapy can be quite marked and include the reduction of “off ” time, increased “on” time. This is also just a treatment into relieving the symptoms of the disease instead of searching for the cure.

The current research in PD is often related to prolonging the life of the patient and decreasing the symptoms of the disease. These methods are just temporary however because despite the best efforts of doctors this disease will eventually overcome the drug therapys. As for the cure current research is faced towards fixing the mitochondrial complex dysfunction and cell replacement. These two methods are both prominent area's of study.

Additional Information

National Parkinson Foundation

National Institute of Neurological Disorders and Stroke

Parkinson Disease Foundation

Michael J. Fox on Stem Cell Research


Burch D., and F. Sheerin. 2005. Parkinson's Disease. Lancet 365:622-627.

Cardoso S.M, P.I Moreira , P. Agostinho, C. Pereira, and C.R Oliveira. 2005. Neurodegenerative Pathways in Parkinson's Disease:Therapeutic Strategies. CNS & Neurological Disorders 4,405-419.

Funkiewiez, A., C. Ardouin, R. Cools, P. Krack, V. Fraix, A. Batir, S. Chabardes, A. Benabid, T. Robbins, and P. Pollak. 2006. Effects of Levodopa and Subthalamic Nucleus Stimulation on Cognitive and Affective Functioning in Parkinson’s Disease. Movement Disorder Society 21:1656-1662.

Hauser, R. 2006. Long term care of Parkinson's Disease. Geriatrics 14-20.

Moore DJ, A.B West, V.L Dawson, and T.M Dawson. Molecular Pathophysiology of Parkinson's Disease. Annual Review Neuroscience 28:57-87.

Saladin, K.S. 2007. Anatomy and Physiology: The Unity of Form and Function, 4th edition. WCB McGraw-Hill.

Savitt, Joseph M. 2006. Diagnosis and treatment of Parkinson disease: molecules to medicine. Journal of Clinical Investigation

Voet D., and J. Voet. 2004. Biochemistry: Biomolecules, Mechanisms of Enzyme Action, and Metabolism. Philadelphia, John Wiley & Sons, Inc.

Dopamine and Parkinson's. Eureka Landes Bioscience Book Collection. 2005. Landes Bioscience

National Institute of Neurological Disorders and Stroke. (2006).NINDS Parkinson's Disease Information Page. Retrieved November 29, 2006

Return to Bio 225 Collaborative Projects