An In-depth Analysis of Parkinson’s Disease: Etiological Mechanisms, Symptomatology, Diagnostic Criteria, and Current Therapeutic Modalities

Parkinson’s disease is a nervous system disease that affects movement. It develops gradually, sometimes starting with a tremor that is barely noticeable on one hand. It also causes stiffness and slow movement.

Man With Parkinson’s

Parkinson’s disease is a degenerative disease resulting from the slow, progressive death of neurons in the brain. Because the part of the brain affected by the disease plays an important role in controlling our movements, people with Parkinson’s disease gradually make stiff and uncontrollable movements. For example, it becomes difficult to bring a cup to the lips with precision and smoothness. Today, available treatments can reduce symptoms quite effectively and slow the progression of the disease. A person can live with Parkinson’s disease for many years.

Parkinson’s disease usually occurs between the ages of 50 and 70. The average age of onset of the disease in the US is 60. At first, the symptoms may be mistaken for normal aging, but as they get worse, the diagnosis becomes clearer.

When the first symptoms appear, an estimated 60% to 80% of dark matter nerve cells have already been destroyed. Thus, when symptoms appear, the disease has already progressed by an average of 5 to 10 years.

Worldwide, more than 300,000 people are diagnosed with the disease each year. The number of cases increases with age. An estimated 1 in 100 people are affected at age 65, and 2 in 100 people at age 70 and older. At the heart of the disease: a dopamine imbalance.

Nerve cells affected by Parkinson’s disease are located in an area called “dark matter” in the center of the brain. The cells in this area produce dopamine, a chemical messenger ( a neurotransmitter) that helps control movement but also acts on feelings of pleasure and desire. The death of the dark matter cells causes a shortage of dopamine, which leads to an increase in acetylcholine and glutamate (two other chemical messengers). This imbalance causes the occurrence of the disease symptoms, namely tremors, muscle stiffness, and the inability to perform certain movements. On the other hand, an excess of dopamine can cause symptoms associated with schizophrenia.

Causes

Dopamine Pathways Credit: Patrick J. Lynch

What causes the progressive loss of neurons in Parkinson’s disease remains unknown in most cases. Scientists agree that a combination of genetic and environmental factors plays a role, although these cannot always be clearly defined. The current consensus is that the environment plays a more important role than heredity, but that genetic factors would prevail when the disease occurs before age 50. Here are some of the environmental factors involved:

Early or prolonged exposure to chemical pollutants or pesticides, including herbicides and insecticides (e.g., rotenone).
MPTP, a drug that sometimes contaminates heroin, can suddenly cause a severe and irreversible form of Parkinson’s disease. This drug acts in the same way as a rotenone pesticide.
Carbon monoxide or manganese poisoning.

Researchers have also found that many changes occur in the brains of people with Parkinson’s disease, although the reasons for these changes have not been determined. These changes include:

The presence of Lewy bodies, which are substances present in brain cells (neurons). Researchers believe that these Lewy bodies play a toxic role in Parkinson’s disease.
The presence of alpha-synuclein in Lewy bodies. Although there are many substances present in Lewy’s bodies, scientists believe that alpha-synuclein is a protein that plays a harmful role when it is in an aggregated form that cannot be resolved by cells.

Possible evolution and complications

The progression of Parkinson’s disease varies from person to person. Parkinson’s disease is chronic and develops slowly, meaning that symptoms worsen over the course of several years.

Motor symptoms vary from person to person, as does the progression of Parkinson’s disease.

Some of these symptoms are more bothersome than others, depending on what a person normally does during the day.

Some people with PD live for many years with fewer disabling symptoms, while others develop motor difficulties more quickly.

Non-motor symptoms also vary from person to person and affect most people with PD, regardless of the stage of the disease. Some people with PD find that symptoms such as depression or fatigue interfere with their daily activities more than motor problems.

Parkinson’s disease is often accompanied by the following problems, which can be treated:

Difficulty in reasoning: The onset of cognitive problems usually occurs in the later stages of the disease. These cognitive problems do not respond very well to medication.
Mood disorders: People with PD may suffer from depression. With treatment for depression, it is easier to manage the other problems of Parkinson’s disease. Other disorders, such as anxiety or loss of motivation, may accompany depression.
Difficulty swallowing: The person has difficulty swallowing as his or her condition worsens. Slow swallowing can cause saliva to build up in the mouth.
Problems sleeping: People with Parkinson’s often have trouble sleeping. They often wake up at night, wake up early, or fall asleep during the day.
Incontinence: Parkinson’s disease can cause bladder weakness, resulting in an inability to control urine or difficulty urinating.
Constipation: Many people with Parkinson’s disease get constipated, mainly due to a slowed digestive tract.
Change in blood pressure: patients may experience dizziness, and lightheadedness (orthostatic hypotension).
Disturbances in the sense of smell: Difficulty recognizing or distinguishing specific odors.
Fatigue: Many patients feel tired, and the cause is not always known.
Pain: Many sufferers experience pain, either in specific areas of the body or throughout the body.
Sexual dysfunction: Some affected people report a decrease in sexual desire or performance.

Symptoms of Parkinson’s disease.

Symptoms related to motor function often occur asymmetrically, meaning they initially affect only one side of the body and then spread to both sides of the body after a few years.

Most common symptoms:

In 70% of cases, the first symptom consists of an uncontrollable rhythmic tremor of one hand, followed by tremors of the head and legs, especially at rest or in stressful situations. On the other hand, 25% of patients do not suffer from tremors.

Tremors that occur during an action, such as lifting an object, are not a sign of PD.

The tremor decreases and stops when the person moves and when the person sleeps.
Rigid, slow (bradykinetic) limbs, rigid, sudden movements that are difficult to initiate. As the disease progresses, there may be difficulty performing everyday tasks, such as buttoning clothes, tying shoelaces, picking up coins, walking, standing, or getting out of a car.
Parkinsonian gait: small, shuffling steps, with dragging feet, with little or no arm swing.
Loss of smell, sleep disturbances, and constipation, which may occur early in life.
Loss of balance, which may occur later in life.

Other symptoms, as applicable:

Depression and anxiety
Difficulty swallowing
Excessive salivation with difficulty holding saliva (drooling).
Very tight handwriting (micrographia), due to loss of dexterity.
A cranky voice, with an inarticulate voice, lacking expression and difficult to articulate.
Lack of facial expression, with a decrease or absence of blinking of the eyelids.
The presence of dandruff and greasy skin on the face.
Urinary incontinence
Confusion, memory loss, and other significant mental disturbances appear quite late in the course of the disease.
Difficulty in changing positions; it may be difficult to get out of bed or out of a chair, for example. And in some cases, it becomes impossible to move.

Parkinson’s syndrome or Parkinson’s disease?

Some people may experience symptoms that resemble Parkinson’s disease, but a diagnosis of Parkinson’s disease cannot be made. In fact, Parkinson’s disease accounts for 85% of cases in a group of diseases known as “Parkinson’s syndrome.” The latter is also manifested by movement disorders, but the physiology of the disease differs. In fact, Parkinson’s syndrome is usually caused by an imbalance in the cholinergic system (acetylcholine) rather than a dopamine deficit. Overall, some differences are apparent and treatment is not the same.

Conditions that can trigger Parkinson’s syndrome include brain damage from trauma or tumors, minor strokes, and taking certain medications to treat nausea, epilepsy, hypertension, or psychiatric disorders. A variety of unusual neurological conditions also manifest as Parkinson’s syndrome.

Diagnosis

There is no specific test to diagnose Parkinson’s disease. The neurologist diagnoses the disease based on the patient’s medical history, an examination for signs and symptoms, and a neurological examination.

The doctor may order tests, such as blood tests, to rule out other conditions that may cause these symptoms.

Imaging tests – such as an MRI or brain scan – may also be used to rule out other conditions. Imaging tests are not particularly helpful in diagnosing Parkinson’s disease.

In addition to a standard test, your doctor may give the person carbidopa-levodopa, a medication used to treat Parkinson’s disease. The person should receive a sufficient dose to see any benefit from the medication, as low doses given for a day or two are not sufficient. Significant improvement with this medication often confirms the diagnosis of Parkinson’s disease.

The diagnosis of Parkinson’s disease may take time. Doctors may recommend regular follow-up visits to assess the person’s condition and symptoms over time to diagnose Parkinson’s disease.

People at risk and risk factors for Parkinson’s disease.

People at risk:

The disease is more common in people over the age of 60.
Men are more often affected than women for unknown reasons.
A person who has a parent with the disease has a higher risk of developing the disease themselves. However, the genetic contribution would be especially important for those who develop the disease when they are young.

Risk factors

People with PD often experience periods of depression. Researchers are now investigating the hypothesis that depression is a predisposing factor for the disease. However, this has yet to be proven. It may be that for some it is just an early manifestation of the disease.

Prevention of Parkinson’s disease

There is no medically recognized way to prevent Parkinson’s disease. However, research shows the following.

Men who consume caffeinated beverages (coffee, tea, cola) in moderation (1 to 4 cups per day) may benefit from a protective effect against Parkinson’s disease, according to large cohort studies. A study in a Chinese population showed the same effect. However, the protective effect has not been as clearly demonstrated in women. Nevertheless, an 18-year cohort study showed that the risk of Parkinson’s disease decreased in coffee drinkers who did not take hormone replacement therapy during menopause. In contrast, the combined use of hormone replacement and caffeine would increase the risk.

Drinking one to four cups of green tea per day also appears to prevent Parkinson’s disease, an effect thought to be due at least in part to the caffeine contained in green tea. In men, the most effective doses are in the range of about 400 mg to about 2.5 g of caffeine per day or at least 5 cups of green tea per day.

In addition, people who are dependent on tobacco are less likely to be affected by Parkinson’s disease. According to a meta-analysis published in 2012, this risk is reduced by 56% in smokers compared to non-smokers. Nicotine stimulates the release of dopamine and thus compensates for the dopamine deficit found in patients. However, this benefit does not weigh against all the diseases that smoking can cause, including various cancers.

Several meta-analyses suggest that ibuprofen may be associated with a reduced risk of Parkinson’s disease. Data for other nonsteroidal anti-inflammatory drugs (NSAIDs) are conflicting, with some meta-analyses concluding that NSAIDs are associated with a lower risk of disease, while others report no significant association.

Medical treatments for Parkinson’s disease

Although there is no cure for Parkinson’s disease, symptoms can be reduced with medications and lifestyle measures. Symptoms are usually controlled quite successfully when treatment is well adapted to the course of the disease. Despite the anxiety and discouragement, the disease can cause, taking an active role in managing the disease makes it easier to live with.

Lifestyle

It is very important for the patient to stay active and exercise. Regular physical activity increases flexibility, balance, and coordination of the body and helps fight depression. Your doctor can suggest a specific exercise program, but any form of physical activity (walking, swimming, etc.) is beneficial.

Also, since people with PD are more prone to osteoporosis, it is advisable to perform exercises that strengthen the skeleton (lifting weights, walking, jogging, jumping in place, etc.). Similarly, you should regularly take a small “dose” of sunshine to counteract a possible deficiency of vitamin D, a common deficiency in PD. Vitamin D plays an essential role in bone health.

Allow yourself periods of relaxation. Practicing a relaxation technique, such as yoga or tai chi, or using massage therapy is important for stress reduction. For people with PD, stress increases the intensity of tremors.

Prevent falls. As the disease progresses, walking becomes more difficult. It is important to wear good shoes – avoid slippery soles – and practice long strides by elevating the legs. Gait training by a physical therapist is often recommended. To minimize the risk of falls, the patient’s space should be set up appropriately. For example, it is best to remove rugs, install grab bars near the toilet and bathtub, and handrails on stairs. An occupational therapy assessment is often required.

Food

To enhance the beneficial effects of levodopa, the physician may make certain dietary recommendations. For example, it is beneficial to consume most protein at the evening meal and to maintain a carbohydrate/protein ratio of 7:1 (7 g carbohydrate to 1 g protein). The vegetarian diet inherently provides such a carbohydrate/protein balance.
At the Mayo Clinic, they recommend a diet rich in fruits, vegetables, and whole grains because they provide natural antioxidants that protect against oxidative damage. These foods are also a good source of fiber, which promotes better intestinal transit. The consumption of saturated fats (red meat, dairy products, palm oil, coconut oil, etc.) should be reduced.

In the advanced stages of the disease, chewing is difficult, so it is important to take small bites.
To prevent constipation associated with PD, doctors recommend drinking plenty of water per day and eating enough fiber.

Social support

The use of a support person (a psychologist, psychotherapist, etc.) is often useful, even necessary, to manage the suffering from a chronic disease. Parkinson’s disease can be particularly difficult to manage because it attacks the biochemistry of the brain – which is often a great source of anxiety. You can also join a support group.

Medications

The appropriate time to start medication depends on several factors (age, lifestyle, the severity of symptoms, etc.) and is determined in consultation with the doctor. The prescribed medications are intended to relieve the symptoms of the disease, but cannot stop the progression of the disease. Finding the ideal treatment may take some time; it is recommended that you inform your doctor of any new symptoms that occur during treatment so that adjustments can be made.

Levodopa, or L-dopa, is a precursor to dopamine. In the brain, levodopa is converted to dopamine. It is often prescribed in combination with carbidopa or benserazide to enhance the effect or limit side effects (nausea, vomiting, dizziness on waking). Levodopa is particularly effective in reducing difficulty moving, tremors, and stiffness in the limbs. Because levodopa’s effectiveness declines over time it is often significantly less effective after 5 or 6 years that is why doctors usually wait until symptoms of the disease are severe before they prescribe it.

Dopamine agonists mimic the action of dopamine (bromocriptine, pergolide, pramipexole, and ropinirole are examples). These medications may be prescribed as soon as the diagnosis is made and may be combined with levodopa if the disease is in an advanced stage. These medications have levodopa-like side effects but can also cause compulsive behaviors (compulsive gambling, hypersexuality, compulsive shopping) in 7-13% of cases, according to some studies.

Monoamine oxidase B (MAOI B) inhibitors, such as selegiline and rasagiline, may be prescribed early in the course of the disease. They decrease the breakdown of natural dopamine and that formed from levodopa. In addition, they are thought to prevent the formation of free radicals and neurological toxins, thus protecting healthy cells. This protective effect has not yet been fully demonstrated. This class of drugs sometimes causes side effects, such as tremors and confusion. It has many interactions with other medications and natural health products.

Anticholinergics (benztropine, trihexyphenidyl) help reduce tremors in some people by restoring the balance between dopamine and acetylcholine in the brain. It is usually prescribed to younger patients in whom tremors are the dominant symptom. It is the oldest type of medication available to patients.

Catechol-O-methyltransferase (COMT) inhibitors prolong the effects of carbidopa-levodopa therapy by blocking the enzyme that breaks down levodopa. Tolcapone is prescribed only to people who do not respond to other therapies because it can cause liver damage. Entacapone (Comtan) does not cause this problem.

Amantadine, an antiviral drug originally developed to treat influenza, has shown positive effects in people with PD. Because this drug only slightly reduces symptoms, it is used in patients who are in the early stages of the disease. Its mechanism of action in the brain is not yet well understood. In combination with levodopa, amantadine may help reduce motor problems in advanced stages of the disease.

Levodopa and dopamine agonists can cause daytime drowsiness. Monitoring is necessary because some patients treated with these medications may feel drowsy during activities (e.g., driving).

In addition to medications used to reduce motor dysfunction, an antidepressant is sometimes prescribed. Several factors can lead to depression: living with a chronic degenerative disease, habitual tasks that become increasingly difficult, physiological changes that occur in the brain during the disease, and the side effects of certain medications.

Surgery

Brain surgery may be considered for patients with advanced disease whose symptoms no longer respond to levodopa.

Deep brain stimulation involves implanting electrodes in specific parts of the brain (thalamus, globus pallidus, and subthalamus). A stimulator then sends electrical pulses to reduce involuntary movements and tremors. However, this procedure does not reduce muscle stiffness, does not correct loss of voluntary movement, and has some potential for serious side effects.

Previously, procedures were done in the parts of the brain responsible for Parkinson’s symptoms: Pallidotomy (globus pallidus), Thalamotomy (thalamus), or Subthalamotomy (subthalamic nucleus). These very delicate brain surgeries are rarely performed nowadays.

Kinesiotherapy and speech therapy

Physiotherapy, which includes daily exercise, gymnastics, balance exercises, etc, and occupational therapy are indicated for functional rehabilitation and home adaptation. Speech therapy is used to treat dysarthria, a language expression disorder due to articulation difficulties.

Experimental treatments

Several innovative treatments are being studied, such as fetal dopamine cell transplantation and gene therapy, but these are experimental treatments and none of them are commonly practiced.

Our Expert’s Point of View

“Effective management of Parkinson’s disease requires a comprehensive understanding of its multifaceted neurological implications,” asserts Tampiwa Chebani MD of Gilmore Health. “Present-day therapeutic strategies, such as dopaminergic medications and deep brain stimulation, serve as pivotal tools in mitigating symptoms and enhancing the quality of life for patients. Concurrently, the exploration of non-motor symptoms, including cognitive and mood disturbances, is vital to fully apprehend the extensive impact of Parkinson’s disease. Notably, emerging research into the gut-brain axis provides intriguing insights, suggesting a potential interplay between gastrointestinal health and neurological manifestations in Parkinson’s disease. As the medical community advances, the optimization of available treatments and the steadfast commitment to patient-centered approaches will remain paramount, ensuring management strategies are both individualized and substantiated by evidence.”

References

National Institute on Aging. (n.d.). Parkinson’s Disease. Retrieved [insert date of retrieval], from https://www.nia.nih.gov/health/parkinsons-disease

Parkinson’s Foundation. (n.d.). What is Parkinson’s? Retrieved [insert date of retrieval], from https://www.parkinson.org/understanding-parkinsons/what-is-parkinsons