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In conjunction with the World Parkinson's Disease Day which was around last week on 11th of April, I have decided to write an article about the disease which has affected millions worldwide. 11th of April was chosen as the date of honour in regards of James Parkinson 's birthday, who is the first person to describe about the disease in his 1817 Essay on the Shaking Palsy. This is a progressive disease that mainly affects our motor system with some neuropsychiatric elements embedded in it.

Michael J Fox , the star of the classic “Back to the Future” film series was diagnosed with Parkinson’s disease when he was just 30 years old. He hid his diagnosis for years and took on several acting roles in the brief time he thought he still had. 7 years later, the Canadian native decided to announce to the whole world that he was affected by the condition. Fox told the famous Today’s show “I thought it was a mistake. I got a couple of second opinions and third opinions, it is a degenerative, progressive disease. You can’t say, ‘You can expect this henceforth.’ Plus, there’s shame in illness”. Soon after that, Fox founded The Michael J. Fox Foundation for further research in the disease.

The next famous person who was diagnosed with Parkinson’s disease is none other than the world’s famous boxer, Muhammad Ali . In 1984 he was affected with the condition, and that was three years after he stopped boxing. The doctors related his Parkinson’s disease to the years of brain injury that has been facing during boxing. “I might die tomorrow, I might die next week. I don’t know when I’ll die”, words from the legendary boxer. He died in 2016, which was 32 years after the diagnosis has been given.

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Well, there are many other notable people or celebrities with Parkinson’s disease including the America’s first Attorney General – Janet Reno, creator of the Peanut’s comic strip – Charles M Schulz , Grammy Award winner – Linda Ronstandt , and others. That shows how common is the disease.

Parkinson’s disease is the most common cause of Parkinsonism. The latter term describes the symptoms of resting tremor, rigidity, bradykinesia and postural instability. The pathogenesis of this disease is not well understood until the early 20th century. During the ancient time, the Mucuna pruriens plant was used to treat Parkinsonism. It was later found that the plant contains Levodopa, a precursor to Dopamine. Dopamine plays a huge role in the symptoms caused by Parkinson’s disease.

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Anatomically, the pathology lies in the basal ganglia. Basal ganglia is a group of subcortical nuclei located in the base of the forebrain. This part of the brain has extensive connections with the cerebral cortex, thalamus, brainstem and other brain regions.

What’s the function of this basal ganglia?

WikimediaCommons (Basal Ganglia)
They involve in control of voluntary movements, learning, routine behaviours such as teeth grindings, eye movements, cognitions and even emotions. Basal ganglia is also referred as the extra pyramidal system.
The components of basal ganglia:
• Dorsal Striatum (caudate nucleus and putamen)
• Ventral Striatum (nucleus accumbens and olfactory tubercle)
• Globas pallidus
• Ventral Pallidum
• Substantia nigra
• Subthalamic nucleus

To understand further about the pathways, bear in mind that there’s 5 types of Dopaminergic receptors, D1-D5. D1 and D2 are highly available in the dorsal/motor striatum and they play a huge role causing Parkinson symptoms. D1 receptors are involved in the direct pathway via dopamine’s excitatory responses. D2 receptors are related to the indirect pathway which contributes to the dopamine’s inhibitory responses. Hence, both receptors produce different outcomes. D3, D4, and D5 are more localized in the mesolimbic/emotional part of the brain as well as the hippocampus/hypothalamus.

How Parkinson does affects the brain?

The left image depicts the pathways of neurotransmission of a normal person. The red arrow indicates suppression/inhibition and the blue arrow shows stimulation/excitation. There are three main substances involved: Glutamate, Dopamine and GABA. Glutamate is excitatory, which means they stimulate the receptor. GABA is inhibitory, which means they inhibit the receptors. Dopamine has both effects, which depends on the receptors that they target.
The right image explains how does the disease affects the pathway. There’s dopamine deficiency in the nigrostriatal pathway (substantia nigra to striatum), which causes hypersensitivity on D1 and D2 receptors. Since less dopamine travels from the substantia nigra to the D1 receptors in the striatum, the D1 will suppress the subthalamic nucleus and thus suppress the thalamus by inhibiting the GABA pathway (from striatum to globus pallidus).

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This will lead to fewer signals sent to the cerebral cortex, which contributes to our motor movements. The D2 receptors are affected too, which leads to the chain of reactions that affects the internal globus pallidus, and finally the thalamus. This will then contribute to the symptoms as they send lesser signals to the cerebral cortex.
In Parkinson’s disease, the dopamine-producing neurons are approximately 100, 000 instead of 550, 000 in a normal person. It is related to a combination of impaired degradation of proteins, intracellular protein accumulation and aggregation, oxidative stress, mitochondrial damage, inflammatory cascades and apoptosis. The brain too has the ability to compensate with this error. The surviving neurons increase the synthesis of dopamine and increases the afferent to the dendrites of the dopaminergic neurons. There is increase of D2 receptors synthesis in this process as well. Rapid communication via gap junctions which connects the pathways, are increased too. Nevertheless, when the compensatory mechanisms are inadequate in supporting the loss of dopamine, the symptoms arises.

So what are the cardinal features of Parkinson’s disease?

• Tremor – the tremor is often describes as “pill rolling”. As you are trying to role a pill or a small marble via your index finger and thumb. The tremor is much significant at rest in comparison to other disease. The frequency of the tremor is between 3 to 7Hz

• Bradykinesia – It means “generalize slowness of movements”. The slowness often begins at the distal fingers and they have difficulties in buttoning shirt, tying shoelaces, typing and lifting coins. They also have small handwritings, the symptom is called as micrographia. Micro = Small, Graphia = Writings

pixabay (Cogwheel)

• Rigidity – People with Parkinson exhibits rigidity on their muscles. Their muscle movements are stiff. There are two types of rigidity, namely the cogwheel type and the lead-pipe type. Cogwheel rigidity, as the name implies, implies the pattern of rigidity to have both the resistant and relaxation properties. Try pulling your car’s handbrake. It has the same cogwheel rigidity feel. Lead pipe rigidity is defined as the tonic resistance throughout the entire range of movement. It means that if we move someone’s forearm with Parkinson’s disease, the resistance is throughout the entire motion which is different as compared to the Cogwheel type.

Non-motor symptoms:

• Cognitive function and dementia
• Psychosis and hallucinations
• Mood disorders such as depression and anxiety
• Sleep disturbances
• Fatigue

All anti-parkisonian medications causes psychotic symptoms such as hallucinations and delusions. How?

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In general, Parkinson’s main feature is the lacking of dopamine production in the basal ganglia. Drugs to treat Parkinson’s disease are often brewed to bring up the Dopamine level. The symptoms are alleviated with the increase of Dopamine. High Dopamine level could lead to Psychosis as it is a well-known fact that most anti-psychotic medications inhibits the dopamine receptors. Hence, it is postulated that Psychosis could arise from increase in the brain’s dopamine level.

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Pharmacological agents used in Parkisonism attempt to restore the dopaminergic activity with levodopa and dopamine agonists. The other alternative and yet only complementary approach is by restoring the balance between cholinergic and dopaminergic influences in the basal ganglia with anti-muscarinic/cholinergic agents. The other drugs used are to disrupt the dopamine’s degradation process so that there will be more dopamine available. These drugs increase the lifespan of Dopamine. Dopamine does not cross the blood brain barrier, thus giving raw Dopamine to the individual does not increase the concentration of Dopamine in the basal ganglia of the brain.

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1. Levodopa
   • Levodopa is the immediate precursor (or let’s simply say the original state of Dopamine). Levodopa does enter the blood brain barrier where it is changed to Dopamine via the action of Dopamine Decarboxylase (an enzyme). Unfortunately, only 1-3% of Levodopa enters the brain as most of it will be degraded before it travels to the brain. Hence it must be given in large amount if used alone.
   • GI effects: Levodopa might trigger the chemoreceptors of the brainstem and triggers vomiting.
   • Cardiovascular effects: Since the levodopa is converted into Dopamine peripherally, it can be further converted to adrenaline and noradrenaline. The latter two substances can affect their respective receptors in the other parts of the body which can cause tachycardia, atrial fibrillation, and hypertension.
   • Behavioural effects: Since more dopamine is in the brain now, it can trigger the other receptors which can cause depression, anxiety, nightmares, euphoria, and personality changes. I have explained about the psychosis part earlier.

2. Dopamine Receptor Agonists (Bromocriptine, Pergolide, Pramipexole, Ropinirole)
   • They act directly on the dopamine receptors and does not require enzymatic conversions to be effective. Furthermore, they have no potential toxic metabolites such as the problems that could arise from excessive peripheral levodopa.

3. Monoamine Oxidase Inhibitors (Selegiline, Rasagiline)
   • Dopamine is degraded via the monoamine oxidase pathway or the catechol-o-methyltransferase (COMT) pathway. Hence by giving the Monoamine Oxidase Inhibitor, there will be more circulating dopamine. It further prolongs the effect of Levodopa.

4. Catechol-O-MethylTransferase (COMT) Inhibitors (Tolcapone, Entacapone)
   • Same mechanism as MAOis as they inhibit the degradation of Dopamine.

5. Amantadine
   • It is an antiviral agent that exhibit anti-parkisonism properties. It has been reported that it antagonizes the effects of adenosine at adenosine A2A receptors, which are receptors that may inhibit D2 receptors function.

6. Anti-Cholinergic (Benztropine, Procyclidine, Trihexyphenidyl)
   • These agents may improve tremor and rigidity of Parkinsonism but have little effects on bradykinesia.

7. B- Blockers (Propranolol)
   • This drug can reduce tremors. Propranolol reduces the tremor’s amplitude.

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Facts about Parkinson

• Approximately 10 million people worldwide are suffering from the disease
• Men are 1.5 times more likely to have Parkinson’s disease than females
• About 60 000 Americans are diagnosed with the condition each year
• Around 1 in 20 people are diagnosed under the age of 40, pretty young huh.
• Symptoms usually occur after 50 years old
• The average cost of the medication is 2.5k USD per year, the Parkinson-related surgery can cost up to 100k USD.

Parkinson's disease is a serious and debilitating condition. Although it does not cause death directly, it does affect one's social life extensively. This disease affects the individual's quality of life and usually they are unable to continue with their careers after being diagnosed with the disease. Let's not forget about the financial burden that it might cause to the affected person. With that, thank you for reading :)

Side note: Please read !
I am representing the National University of Malaysia in an idea challenge (MIIC - Medical Innovation Idea Challenge) which is to be held on this Saturday (21st April 18). For your information, this research is very useful to identify dead bodies in any major disasters. This innovation brings a great impact to the society. In order for us to win this challenge, we need your help and support by JUST LIKING the youtube video. It accounts for about 20% of our total score and many other universities managed to assemble more "likes" than us and I think we can do better. Thank you for the support :)

#voteforcoldjustice

References

1. Katzung et al. Basic & Clinical Pharmacology .Singapore: McGrawHill, 2012. Print
2. Etiology and Pathogenesis of Parkinson disease. Up To Date. Retrieved on April 18, 2018, from https://www.uptodate.com/contents/etiology-and-pathogenesis-of-parkinson-disease
3. Clinical Manifestation of Parkinson disease. Up To Date. Retrieved on April 18, 2018, from https://www.uptodate.com/contents/clinical-manifestations-of-parkinson-disease?topicRef=4906&source=related_link
4. Parkinson Disease Statistics. Parkinson's News Today. Retrieved on April 18, 2018, from https://parkinsonsnewstoday.com/parkinsons-disease-statistics/
5. 10 facts about Parkinson's Disease. OrionPharma. Retrieved on April 18, 2018, from http://www.orionpharma.co.uk/Products-and-Services-Orion/Parkinsons-disease/10-facts-about-Parkinsons-disease/
6. World's Parkinson Disease Day. Days of the Year. Retrieved on April 18, 2018, from https://www.daysoftheyear.com/days/world-parkinsons-disease-day/
7. Basal Ganglia. Wikipedia. Retrieved on April 18, 2018, from https://en.wikipedia.org/wiki/Basal_ganglia
8. #UniteForParkinsons. ParkinsonsUK. Retrieved on April 18, 2018, from https://www.parkinsons.org.uk/get-involved/world-parkinsons-day-2018
9. 7 Celebrities with Parkinson's Disease. Healthline. Retrieved on April 18, 2018, from https://www.healthline.com/health/celebrities-parkinsons#1