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Parkinson’s DiseaseINTRODUCTION
Parkinson’s disease is a neurodegenerative disorder of motor function due to loss of dopamine producing brain cells. Parkinson’s disease was discovered by British surgeon Dr. James Parkinson in 1817.

The cause of Parkinson’s disease is unknown, but researchers speculate that both genetic and environmental factors are involved. Dopamine is essential for movement as it acts as a transmitter for signals from the brain to other parts of the body.

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Parkinson’s disease is a progressive nervous system disorder that affects how the person moves, including how they speak and write. Symptoms develop gradually, and may start off with ever-so-slight tremors in one hand. People with Parkinson’s disease also experience stiffness and find they cannot carry out movements as rapidly as before – this is called bradykinesia. The muscles of a person with Parkinson’s become weaker and the individual may assume an unusual posture.

In the majority of cases, symptoms start to appear after the age of 50. However, in about 4% to 5% of cases the sufferer is younger than 40 years. When signs and symptoms develop in an individual aged between 21 and 40 years, it is known as Young-onset Parkinson’s disease. The youngest recorded case of Parkinson’s was a 12-year-old patient.

A person with Parkinson’s has abnormally low dopamine levels. Dopamine-generating cells, known as dopaminergic neurons (types of nerve cells) in the substantia nigra part of the brain have died. Experts do not know why these cells die. When dopamine levels are too low, people find it harder to get things done, to control their movements.

Dopamine levels progressively drop in patients with the disease, so their symptoms gradually become more severe.

Parkinsonism is a neurological syndrome characterized by tremor, rigidity, postural instability, and hypokinesia (decreased bodily movement).

Genes linked to the development of Parkinson’s are classified as either “‘causal genes” or “associated genes.”
Causal Genes
Causal genes are those which carry mutations that, when inherited, cause the disease. Parkinson’s caused by these mutations is very rare, accounting for only 1 or 2 percent of all patients. One example of a causal gene is SNCA, which encodes a protein called alpha-synuclein. At least five mutations of SNCA have been found to cause Parkinson’s. These mutations can be inherited and directly cause the disease.

Associated Genes
Mutations in associated genes do not directly cause Parkinson’s, but increase the risk of developing it. A person may have mutations in associated genes and never get Parkinson’s, but is more likely to develop it. The combined effect of associated genes and environmental factors may trigger the development of Parkinson’s.

Genes associated with Parkinson’s disease include PRKN, which codes for the parkin protein;,PINK1, which codes for a protein found in the heart and skeletal muscles; LRRK2, which codes for a brain protein called dardarin; and PARK7, which codes for a brain protein called DJ-1.

Mutations in certain genes, including GBA (which codes for an enzyme called glucocerebrosidase) and UCHL1 (which codes for an esterase enzyme), also appear to increase the risk of developing Parkinson’s.

The diagnosis is usually based on the person’s medical history and a physical examination that focuses on four common disease features: shaking or tremor, bradykinesia or slow movements, rigidity in the limbs or truck, and postural instability that makes walking and balance difficult (and causes falls).

Imaging tests, such as MRI, PET or DAT scans, may be performed to rule out other conditions that may cause symptoms similar to Parkinson’s, and blood tests taken for this same reason.

Levodopa Test
The doctor may ask the patient to take levodopa, a medication that temporally restores dopamine levels in the brain and is used to treat Parkinson’s. If the patient’s symptoms improve, the disease is likely.

There is no known cause of Parkinson’s disease although a family history of the disease will increase your risk. Researchers think environmental factors such as smoking, pollution, heavy metals, medications and illegal drugs may be responsible for the onset of the disease. Head trauma, brain inflammation, and stroke have also been associated with the disease.

There are certain genes which, when they become mutated, cause Parkinson’s disease. However, these mutated genes are very rare, except in cases where Parkinson’s runs in the family. There are also some gene variations which seem to slightly increase the risk of developing Parkinson’s.

Researchers think there are some environmental factors and toxins which may trigger Parkinson’s disease, although they feel the increased risk is small.

Presence of Lewy bodies in the brain
Changes happening within the brain may also be a trigger for Parkinson’s disease. Lewy bodies are proteins found in brain cells which are biomarkers of the disease and may hold the key to finding out the exact cause.

Alpha-synuclein in Lewy bodies
There are many different substances found in Lewy bodies, but scientists are focusing on alpha-synuclein proteins. Alpha-synuclein proteins don’t break down; they form clumps in the cells which are thought to contribute to the disease.

Stiff muscles
Most people with Parkinson’s have some rigidness that makes it hard to move parts of the body. That’s because your muscles can’t relax normally. This may also cause you pain.

This uncontrolled shaking usually starts in the hands and arms, although it can happen in the jaw or feet, too. You often notice your thumb and forefinger rubbing together, especially when you’re resting your hand or feeling stressed. In the beginning, tremor usually affects only one side of your body or one limb. Over time, the shaking may spread to other parts of your body, although not everyone gets tremor.

Slow movements
Actions like walking, getting out of bed, and even talking become harder and slower. Doctors call this bradykinesia. It happens because your brain’s signal to specific parts of the body slows down. Bradykinesia can give your face an expressionless, mask-like look.

Changes in walking
A common early sign is that your arm or arms stop swinging naturally when you walk. Your steps might become short and shuffling. You may have trouble walking around corners, or feel as if your feet are glued to the floor.

Parkinson’s is a progressive disorder, which means your symptoms get more serious over time. It can affect your movements as well as things like your vision, sleep, and mental health. A person with Parkinson’s can get different symptoms at different times than someone else with the same condition. They include:
•Trouble with balance
•Forward or backward lean that can cause falls
•Stooped posture, with bowed head and slumped shoulders
•Head shaking
•Memory problems
•Trouble peeing or pooping
•Skin problems, such as dandruff
•Difficulty swallowing and chewing
•Trouble having an erection or orgasm
•Lightheadedness or fainting when standing up
•Fear and anxiety
•Dementia, or trouble with thinking and reasoning
•Loss of smell
•Too much sweating
Non-Motor Symptoms
Almost everyone with Parkinson’s gets at least one of these. When severe, they’re more likely than motor issues to lead to a disability or make you move into a nursing home. These symptoms can show up almost any time, but they follow a general trend such as:
•Loss of smell
•Low blood pressure when you stand up
•Sleep issues
Pseudobulbar affect (PBA) is a condition characterized by frequent, uncontrollable outbursts of crying or laughing that do not match how the person actually feels. It can affect people with Parkinson’s disease as well as those with brain injury or other neurologic conditions. Crying appears to be a more common sign of PBA than laughing.

The sudden outbursts seen in PBA may be frequent and occur at any time with the affected person’s mood appearing normal between episodes. The condition often is mistaken for depression or bipolar disorder because of the intense emotions experienced. However, PBA episodes tend to be short in duration, while depression causes a persistent feeling of sadness. People with PBA often lack certain features of depression, such as sleep disturbances or a loss of appetite. But depression also is common among those who have pseudobulbar affect. It is speculated that many cases go unreported and undiagnosed due to a lack of awareness about the condition.

PBA happens when a nervous system disorder, such as Parkinson’s, affects the areas of the brain that control the expression of emotion, such as the prefrontal cortex. There also may be alterations in chemicals in the brain that contribute to the development of the condition. These alterations may disrupt brain signaling, triggering episodes the person affected cannot control.

Although the condition is not curable, it is treatable. There are various treatment options with differing side effects and limitations on their use (counterindications).

Stage 1
Stage 1 is the mildest form of Parkinson’s. At this stage, there may be symptoms, but they’re not severe enough to interfere with daily tasks and overall lifestyle. In fact, the symptoms are so minimal at this stage that they’re often missed. But family and friends may notice changes in your posture, walk, or facial expressions.

A distinct symptom of stage 1 Parkinson’s is that tremors and other difficulties in movement are generally exclusive to one side of the body. Prescribed medications can work effectively to minimize and reduce symptoms at this stage.

Stage 2
Stage 2 is considered a moderate form of Parkinson’s, and the symptoms are much more noticeable than those experienced in stage 1. Stiffness, tremors, and trembling may be more noticeable, and changes in facial expressions can occur.

While muscle stiffness prolongs task completion, stage 2 does not impair balance. Difficulties walking may develop or increase, and the person’s posture may start to change.

People at this stage feel symptoms on both sides of the body (though one side may only be minimally affected) and sometimes experience speech difficulties.

The majority of people with stage 2 Parkinson’s can still live alone, though they may find that some tasks take longer to complete. The progression from stage 1 to stage 2 can take months or even years. And there is no way to predict individual progression.

Stage 3
Stage 3 is the middle stage in Parkinson’s, and it marks a major turning point in the progression of the disease. Many of the symptoms are the same as those in stage 2. However, you’re now more likely to experience loss of balance and decreased reflexes. Your movements become slower overall. This is why falls become more common in stage 3.

Parkinson’s significantly affects daily tasks at this stage, but people are still able to complete them. Medication combined with occupational therapy may help decrease symptoms.

Stage 4
Independence separates people with stage 3 Parkinson’s from those with stage 4. During stage 4, it’s possible to stand without assistance. However, movement may require a walker or other type of assistive device.

Many people are unable to live alone at this stage of Parkinson’s because of significant decreases in movement and reaction times. Living alone at stage 4 or later may make many daily tasks impossible, and it can be extremely dangerous.

Stage 5
Stage 5 is the most advanced stage of Parkinson’s disease. Advanced stiffness in the legs can also cause freezing upon standing, making it impossible to stand or walk. People in this stage require wheelchairs, and they’re often unable to stand on their own without falling. Around-the-clock assistance is required to prevent falls.

Up to 30 percent of people at stage 4 and 5 experience confusion, hallucinations, and delusions. Hallucinations occur when you see things that aren’t there. Delusions happen when you believe things that aren’t true, even when you have been presented with evidence that your belief is wrong. Dementia is also common, affecting up to 75 percent of people with Parkinson’s. Side effects from medications at these later stages can often outweigh the benefits.

Parkinson’s disease can’t be cured, but medications can help control your symptoms, often dramatically. In some later cases, surgery may be advised.

Your doctor may also recommend lifestyle changes, especially ongoing aerobic exercise. In some cases, physical therapy that focuses on balance and stretching also is important. A speech-language pathologist may help improve your speech problems.

Medications help to manage problems with walking, movement and tremor. These medications increase or substitute for dopamine, a specific signaling chemical (neurotransmitter) in the brain.

People with Parkinson’s disease have low brain dopamine concentrations. However, dopamine can’t be given directly, as it can’t enter the brain.

There may be a significant improvement of the symptoms after beginning Parkinson’s disease treatment. Over time, however, the benefits of drugs frequently diminish or become less consistent, although symptoms usually can continue to be fairly well-controlled.

Medications doctor may prescribe include:
Levodopa, the most effective Parkinson’s disease medication, is a natural chemical that passes into the brain and is converted to dopamine.

Levodopa is combined with carbidopa (Rytary, Sinemet), which protects levodopa from premature conversion to dopamine outside the brain, which prevents or lessens side effects such as nausea.

Side effects may include nausea or lightheadedness (orthostatic hypotension).

After years, as the disease progresses, the benefit from levodopa may become less stable, with a tendency to wax and wane (“wearing off”).

Also, there may be experiences of involuntary movements (dyskinesia) after taking higher doses of levodopa. Te doctor may lessen the dose or adjust the times of the doses to control these effects.

Carbidopa-levodopa infusion.
The U.S. Food and Drug administration approved a drug called Duopa in 2015. This medication is made up of carbidopa and levodopa. However, it’s administered through a feeding tube that delivers the medication in a gel form directly to the small intestine.

Duopa is for patients with more advanced Parkinson’s who still respond to carbidopa-levodopa, but who have a lot of fluctuations in their response. Because Duopa is continually infused, blood levels of the two drugs remain constant.

Placement of the tube requires a small surgical procedure. Risks associated with having the tube include the tube falling out or infections at the infusion site.

Dopamine agonists
Unlike levodopa, dopamine agonists don’t change into dopamine. Instead, they mimic dopamine effects in the brain.

They aren’t as effective as levodopa in treating symptoms. However, they last longer and may be used with levodopa to smooth the sometimes off-and-on effect of levodopa.

Dopamine agonists include pramipexole (Mirapex), ropinirole (Requip) and rotigotine (given as a patch, Neupro). A short-acting injectable dopamine agonist, apomorphine (Apokyn), is used for quick relief.

Some of the side effects of dopamine agonists are similar to the side effects of carbidopa-levodopa, but also include hallucinations, sleepiness and compulsive behaviors such as hypersexuality, gambling and eating.
•MAO-B inhibitors. These medications include selegiline (Eldepryl, Zelapar) and rasagiline (Azilect). They help prevent the breakdown of brain dopamine by inhibiting the brain enzyme monoamine oxidase B (MAO-B). This enzyme metabolizes brain dopamine. Side effects may include nausea or insomnia.

When added to carbidopa-levodopa, these medications increase the risk of hallucinations.

These medications are not often used in combination with most antidepressants or certain narcotics due to potentially serious but rare reactions.
•Catechol-O-methyltransferase (COMT) inhibitors. Entacapone (Comtan) is the primary medication from this class. This medication mildly prolongs the effect of levodopa therapy by blocking an enzyme that breaks down dopamine.

Side effects, including an increased risk of involuntary movements (dyskinesias), mainly result from an enhanced levodopa effect. Other side effects include diarrhea or other enhanced levodopa side effects.

Tolcapone (Tasmar) is another COMT inhibitor that is rarely prescribed due to a risk of serious liver damage and liver failure.

•Anticholinergics. These medications were used for many years to help control the tremor associated with Parkinson’s disease. Several anticholinergic medications are available, including benztropine (Cogentin) or trihexyphenidyl.

However, their modest benefits are often offset by side effects such as impaired memory, confusion, hallucinations, constipation, dry mouth and impaired urination.

•Amantadine. Doctors may prescribe amantadine alone to provide short-term relief of symptoms of mild, early-stage Parkinson’s disease. It may also be given with carbidopa-levodopa therapy during the later stages of Parkinson’s disease to control involuntary movements (dyskinesias) induced by carbidopa-levodopa.

Side effects may include a purple mottling of the skin, ankle swelling or hallucinations.

Surgical procedures
•Deep brain stimulation. In deep brain stimulation (DBS), surgeons implant electrodes into a specific part of your brain. The electrodes are connected to a generator implanted in your chest near your collarbone that sends electrical pulses to your brain and may reduce your Parkinson’s disease symptoms.

Your doctor may adjust your settings as necessary to treat your condition. Surgery involves risks, including infections, stroke or brain hemorrhage. Some people experience problems with the DBS system or have complications due to stimulation, and your doctor may need to adjust or replace some parts of the system.

Deep brain stimulation is most often offered to people with advanced Parkinson’s disease who have unstable medication (levodopa) responses. DBS can stabilize medication fluctuations, reduce or halt involuntary movements (dyskinesias), reduce tremor, reduce rigidity, and improve slowing of movement.

DBS is effective in controlling erratic and fluctuating responses to levodopa or for controlling dyskinesias that don’t improve with medication adjustments.

However, DBS isn’t helpful for problems that don’t respond to levodopa therapy apart from tremor. A tremor may be controlled by DBS even if the tremor isn’t very responsive to levodopa.

Although DBS may provide sustained benefit for Parkinson’s symptoms, it doesn’t keep Parkinson’s disease from progressing.

Dopamine is an important neurotransmitter found naturally in the brain. Dopamine (and norepinephrine) belongs to a subcategory of monoamines called catecholamines. The chemical structure of dopamine is C8H11NO2 as is depicted in the picture above. The study of dopamine in methamphetamine use is very important as it is involved in the reinforcing effects of drug abuse. In general, dopamine is normally involved in many important functions such as mood, movement, and learning.
Dopaminergic neurons are involved in motor activity, in which dopamine is synthesized, stored and released to intersynaptic space. Dopamine is synthesized from the aminoacid tyrosine in two steps that occur in the cytosol:
(i) hydroxylation of tyrosine to l-dihydroxyphenylanaline(l-dopa), a reaction catalyzed by tyrosine hydroxylase (TH)
that requires oxygen and
(ii) decarboxylation of l-dopa to dopamine, a reaction catalyzed by aromatic amino acid decarboxylase (AADC) that generates CO2. Interestingly, dopamine synthesis does not result in dopamine accumulation in the cytosol as a consequence that TH and AADC are associated with the vesicular monoaminergic transporter-2 (VMAT-2) generating a complex where tyrosine is converted to l-dopa that immediately decarboxylated to dopamine.


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