Parkinson's Disease: A Comprehensive Overview

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Parkinson's disease (PD) is a progressive neurological disorder that primarily affects the motor system, leading to difficulties with movement, balance, and coordination. The primary cause of PD is the degeneration of dopamine-producing neurons in the substantia nigra, a region in the midbrain. Dopamine is a neurotransmitter essential for controlling movement and emotional responses. The loss of dopamine results in the characteristic symptoms of Parkinson's disease.

Causes

The exact cause of Parkinson's disease is still not fully understood, but it is believed to involve a combination of genetic and environmental factors:

1. Genetic factors: Researchers have identified specific gene mutations that can increase the risk of developing PD. However, these cases are relatively rare, accounting for approximately 10-15% of all PD cases.
2. Environmental factors: Exposure to certain toxins or chemicals, such as pesticides or heavy metals, has been linked to an increased risk of PD. Additionally, head injuries and certain infections might also contribute to the development of the disease.

Symptoms

The symptoms of Parkinson's disease can be classified into two categories: motor symptoms and non-motor symptoms.

Motor symptoms

1. Tremors: Involuntary, rhythmic shaking that usually begins in one hand and may progress to other parts of the body.
2. Rigidity: Stiffness or inflexibility of the muscles, leading to difficulties in movement and a decreased range of motion.
3. Bradykinesia: Slowness of movement, causing difficulties in initiating and completing everyday tasks.
4. Postural instability: Impaired balance and coordination, increasing the risk of falls.

Non-motor symptoms

1. Sleep disturbances
2. Cognitive changes, such as memory problems or dementia
3. Mood disorders, including depression and anxiety
4. Gastrointestinal issues, like constipation
5. Autonomic dysfunction, affecting blood pressure, sweating, and bladder control

Diagnosis

There is no specific test for Parkinson's disease. Diagnosis is typically based on a combination of the patient's medical history, a physical examination, and the presence of characteristic motor symptoms. In some cases, neuroimaging techniques (such as MRI or PET scans) or other tests may be used to help rule out other conditions with similar symptoms.

Treatment

While there is no cure for Parkinson's disease, various treatments can help manage the symptoms and improve the quality of life for people with PD:

1. Medications: The most common treatment involves medications that increase dopamine levels in the brain, such as levodopa or dopamine agonists. Other drugs may be used to manage non-motor symptoms or to alleviate side effects of dopaminergic medications.
2. Deep brain stimulation (DBS): In some cases, a surgical procedure called deep brain stimulation may be recommended. DBS involves implanting electrodes into specific areas of the brain and connecting them to a device that sends electrical impulses to help control motor symptoms.
3. Physical, occupational, and speech therapies: These therapies can help maintain mobility, improve coordination, and address speech or swallowing difficulties.
4. Lifestyle modifications: Regular exercise, a balanced diet, and stress management techniques can help improve overall well-being and may help slow the progression of the disease.

Prognosis

The progression of Parkinson's disease varies widely among individuals. Some people may experience only mild symptoms for many years, while others may develop more severe disability. In general, the severity of symptoms tends to worsen over time. However, with appropriate management and treatment, many people with PD can maintain a good quality of life for many years after diagnosis.

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Topic Highlights:-

1. Parkinson's disease is a chronic and progressive neurodegenerative disorder.
2. It affects the neurons situated in the area of brain that controls movements.
3. The symptoms result from a decrease in dopamine levels.
4. This animation provides an illustrated insight into what causes Parkinson's disease, classical symptoms of Parkinson's disease, the pathophysiology of the disease, disease diagnosis, and treatment.

Transcript:-
Parkinson’s disease is a chronic progressive and degenerative disease affecting the neurons in the area of the brain which control muscle movement. The disease worsens gradually over time leading to disability.

Symptoms of Parkinson’s disease in the initial phase are subtle and progress gradually. The initial phase may last for a very long time before the disease deteriorates further. As the disease progresses, the classic symptoms of Parkinson’s appear- tremors, rigidity and slowing of movements or bradykinesia.

Dopaminergic neurons of the substantia nigra are destroyed in Parkinson’s disease, which results in a decrease in the secretion of the neurotransmitter dopamine. This presentation focuses on causes, symptoms, diagnosis and treatment of Parkinson’s disease.

Parkinson's disease is a neurodegenerative disease causing motor function disorders that occur as a result of disturbances in the region of the brain that plays a crucial role in regulating smooth motor functions.

Neurological syndromes are exhibited in some combination of the following: resting tremors, rigidity, bradykinesia and loss of postural reflexes. Parkinson’s disease is more common in older people, the cause of which is not known.

Although practically the entire brain contributes to body movements, any voluntary movement of the body involves the motor cortex and numerous other neural systems and their sensory-motor coordination.

The primary motor cortex is located in the frontal lobe together with the secondary motor cortices. The secondary motor cortices consist of the posterior parietal cortex, the premotor cortex and the supplementary motor area (SMA) involved in the planning, coordination and execution of voluntary movement.

The basal ganglia at the base of the cerebrum and in the upper brainstem, buried deep inside the cortex, include the striatum and the substantia nigra. The caudate nucleus, putamen, globus pallidus and subthalamic nucleus (STN) receive information from several different regions of the cerebral cortex. The caudate nucleus and putamen form part of the neuronal structure called striatum. The basal ganglia plays an important role in coordinating voluntary movement using the direct and indirect pathways. The caudate receives the information from the associated cortices that control motor areas in the frontal lobe, while the diverse sensory information is received by the putamen. Together with the substantia nigra the basal ganglia controls voluntary movement.

The substantia nigra is located in the mesencephalon or the midbrain. The axons leaving this area innervate the major input structures of the basal ganglia. It is also the site for synthesis of the neurotransmitter dopamine. The strong input signals for movement emanate from the dopaminergic neurons in the substantia nigra. The two types of dopamine receptors-- the excitatory D1 and the inhibitory D2 receptors provide the balance of starting and stopping a movement.

The basal ganglia and cerebellum work in close coordination with each other and also with the motor cortex. The cerebellum usually sends out excitatory signals whereas the basal ganglia send out inhibitory signals. The cerebellum plays a role in motor coordination in both the acceleration and the braking phases of body movements.

Movement is facilitated by the direct pathway. When input from the cortex reaches the striatum, and the dopamine from the substantia nigra reach the D1 receptors, the GABAergic neurons inhibit the GPi which in turn sends inhibitory signals to the thalamus.

With GPi inhibited, the motor thalamus, relieved from inhibition, provides the frontal cortex with the appropriate motor programs for the desired movement. The motor cortex then triggers upper motor neurons to signal the lower motor neurons to perform the movement. The sensory feedback then enables actual execution of the movement.

The indirect pathway inhibits unwanted movements. Nullifying the disinhibitory actions of the direct pathway and restoring the inhibition of the motor thalamus stop the movement. The subthalamic nucleus (STN) that is responsible for this is under inhibition by the external segment of the Globus pallidus or GPe. This happens when the inhibition is lifted and the STN excites the inhibitory GPi that brings the motor thalamus to its original state. The STN also excites the substantia nigra, which also inhibits the motor thalamus. These actions of STN in influencing both substantia nigra and the GPi serve to halt the movement.

Normally excitatory and inhibitory signals balance each other in such a way that the body is able to carry out smooth and coordinated movements.

In Parkinson’s disease the dopaminergic neurons projecting from the substantia nigra to the putamen portion of striatum are destroyed. The symptoms appear when the cells become impaired and die. The symptoms are due to the decrease in dopamine levels, which occur due to the decreased number of substantia nigra neurons.

This results in the abnormal activity in the putamen, causing the primary features of the disease. When substantia nigra projections to the putamen are impaired, the globus pallidus interna and subthalamic nucleus begin to function abnormally resulting in the insufficient control of motor functions by the brain.

Parkinson’s disease is caused by a loss of striato-nigral dopaminergic cells but it is not known why this occurs. It is believed that environment and genetics play a role. Certain medications, toxins and other diseases can produce symptoms similar to Parkinson’s disease and this is known as secondary Parkinsonism, which may be reversible.

Symptoms of Parkinson’s disease may be subtle in the initial phase of the disease. They may include tremors, mumbling speech, difficulty in getting up from a chair or turning in bed, cramped handwriting or slowed walking. The typical clinical features of Parkinson’s disease are a rest tremor, rigidity, and bradykinesia, or slowness in the execution of movement. The resting tremor often increases with walking and decreases with posture holding or action. The tremor is asymmetrical and affects the hands and legs. Victims also show signs of smaller writing. Non-motor symptoms such as memory difficulties, bladder disturbance, and depression are also seen.

The diagnosis relies entirely on clinical judgment and depends upon a careful history and examination of the patient. Neurological examinations are carried out and the changes in gait, handwriting, facial expressions, difficulty in getting up from a chair, walking, etc. are observed.

There is no known drug treatment to retard the progression of the pathophysiology of Parkinson's disease. The current aim of treatment is to manage the symptoms to help the patient continue his/her day-to-day activities. The doctor may choose a single medication or combine two or three depending on the individual case.

Levodopa is the most powerful medication used for treating Parkinson’s disease. Dopamine cannot be given to patients of Parkinson’s disease, as it is unable to cross the blood-brain barrier. Levodopa is a precursor of dopamine and is itself inactive. It is converted to dopamine by the action of an enzyme, called dopa decarboxylase. Levodopa can cross the blood-brain barrier and is converted to dopamine within the brain and the rest of the body. Peripheral metabolism of Levodopa is undesirable as this leads to a number of adverse effects including vomiting and low blood pressure.

Decarboxylase inhibitors that prevent metabolism of Levodopa to dopamine outside the brain enhance the efficacy of Levodopa. These drugs by themselves have no effect on the symptoms of Parkinson’s disease. But when given along with Levodopa they block the enzyme dopa decarboxylase in all the sites except the brain, as they are unable to penetrate the blood brain barrier. This means that only Levodopa which enters the brain is metabolized to dopamine. Two such dopa decarboxylae inhibitors are Carbidopa and Benserazide.

Another group of drugs commonly used to treat Parkinson’s disease are Dopamine agonists, which stimulate the brain dopamine receptors. Examples are bromocriptine, ropinirole, pergolide and pramipexole.

Levodopa and dopamine are metabolized by two enzymes, mono-amine oxidase type B (MAO-B), and catechol-O-methyl-transferase (COMT). Action of these enzymes outside the blood-brain barrier decreases levels of Levodopa entering the brain. Therefore these enzymes are inhibited so that there is a more stable and constant supply of Levodopa, which makes its beneficial effects last longer.

MAO-B inhibitors and COMT inhibitors, which inhibit these enzymes, are used to treat Parkinson’s disease. These inhibitors allow a larger amount of Levodopa to reach the brain, which raises dopamine levels.

Selegiline is an MAO-B inhibitor, which may be used alone or in conjunction with other dopaminergic drugs. Tolcapone and Entacapone are COMT inhibitors, which by themselves cannot help alleviate the symptoms of Parkinson’s disease but must be combined with Levodopa and carbidopa.

Amantidine was originally developed as an antiviral drug. It has a mild anti-Parkinsonian effect and may be useful to treat Levodopa induced dyskinesias (abnormal involuntary movements and postures.)

Anticholinergics may help in controlling tremor. Examples are Trihexyphenidyl, Benztropine and Orphenadrine. They may also help in controlling salivation and drooling.

Surgery was the primary for treatment of Parkinson’s disease until the advent of Levodopa. Now surgical procedures are recommended for patients who have developed severe motor complications. Surgery may involve transplantation of fetal dopaminergic cells, selective destruction of certain parts of the brain (eg. Pallidotomy) or deep brain stimulation. The role of surgery remains uncertain and is probably only appropriate for a small number of patients.