Parkinson’s disease is a progressive neurodegenerative disease marked by the motor and non-motor features. The term parkinsonism describes a set of symptoms that pertain to motor features of Parkinson’s disease namely:
• Muscular rigidity
Parkinson’s disease was first described by Dr. James Parkinson in 1817. It was then termed as ‘shaking palsy.’ In 19th century, Jean-Martin Charcot refined the description of the disease and identified its prominent symptoms.
The most prominent symptom of Parkinson’s is uncontrolled tremors in the limb and difficulty in making normal movement which come under motor symptoms of the disease. This occurs primarily due to loss of neurons (brain cells) about the motor function; called striatal dopaminergic neurons.
However, the presence of non-motor symptoms indicates that other neurons may be affected as well. Non-motor symptoms include depression, the decline in cognitive function and sleep disorders.
The progressive nature of Parkinson’s disease makes it a significant burden on patients, family, and caregivers.
End stage disease could give rise to serious complications. Available treatment focuses mainly on symptom management.
What is Parkinsonism?
Parkinsonism refers to the set of motor symptoms seen in Parkinson’s disease. Disorders in which ‘parkinsonism’ is prominent are known as Parkinsonian disorders.
Table of Contents
- 1 What is Parkinsonism?
- 2 How common is Parkinson’s?
- 3 What are the stages of Parkinson’s disease?
- 4 What are the symptoms of Parkinson’s disease?
- 5 Causes: How does one get Parkinson’s?
- 6 Parkinson’s Pathophysiology Explained
- 7 What is the treatment available for Parkinson’s disease?
- 8 Conclusion
Some Parkinsonian diseases have a specific cause such as a genetic mutation whereas some may be chronic with an unknown cause. Some can be caused by toxins, metabolic disturbances or even drugs.
Degenerative Parkinsonian diseases can be inherited or sporadic, but both are characterised by damage to neurons.
Multiple system atrophy is a condition characterised by alpha-synuclein aggregate (an abnormal protein accumulation that leads to neuronal damage) that affects not only the nigrostriatal pathway as observed in Parkinson’s disease, but also other pathways in the brain.
Progressive supranuclear palsy or ‘parkinsonism-plus’ disorder is a degenerative parkinsonian disorder which involves the accumulation of tau protein, and unlike classic Parkinson’s disorders, it presents with other symptoms such as eye movement disorder and dementia.
However, the term ‘parkinsonism-plus’ is now confusing since even patients with Parkinson’s disease present symptoms that are not characteristic of Parkinson’s disease.
A non degenerative cause of the Parkinsonian disorder is ‘Vascular Parkinsonism’ which is a cerebrovascular disease. It presents with classical Parkinson’s symptoms in addition to strokes and blockage of blood supply to the brain.
Idiopathic Parkinson’s disease is when no known cause of Parkinson’s is known.
How common is Parkinson’s?
Parkinson’s disease affects around 1 million people in the US alone. Around 1% of the individuals above the age of 60 years suffer from Parkinson’s while the statistics rise to 1-3% above the age of 80 years.
Approximately the ratio of males versus females affected by Parkinson’s disease is 3:2. This is the difference is attributed to the protection of estrogen which helps delay damage to striatal dopaminergic neurons.
What are the stages of Parkinson’s disease?
The onset of Parkinson’s like symptoms leads to its classification as:
• Early onset Parkinson’s: below the age of 49years
• Middle onset Parkinson’s: around 50-69 years
• Late onset Parkinson’s: above 70 years
Parkinson.org describes 5 stages of Parkinson’s disease :
• Stage 1– Symptoms may not be significant enough to interfere with daily life. Tremors may occur on one side only. Changes in walking or posture may not be visible to observers.
• Stage 2– Symptoms worsen with significant tremors, difficulty in walking and poor posture; thus interfering with daily activities.
• Stage 3– This is mid stage of the disease where loss of balance and falls may occur. The individual is independent, but certain activities such as eating may be hampered.
• Stage 4– Symptoms are severe, and one may not be able to walk without assistance.
• Stage 5– This is the most advanced stage where the patient is bedridden, may experience hallucinations, psychosis and other non motor symptoms. Assistance in every activity is required.
What are the symptoms of Parkinson’s disease?
As mentioned previously, Parkinson’s main motor features include:
• Resting tremor
• “Cogwheel” rigidity
• Postural instability
Resting tremor is when your hand or limb experiences involuntary action even when you haven’t moved your hand. Around 2/3 of the patients diagnosed with Parkinson’s disease present with this initial symptom.
It may be mild and intermittent in fashion and is measured at a level of 4-6 Hz. Resting tremors may affect the hand, lower limbs, toes, and jaws. Stressful conditions may worsen the tremor.
Also, the presence of tremors is linked with the age; onset of tremors may be twice as common in patients above 64 years of age than younger patients (less than 45 years of age).
The second major symptom is bradykinesia. It is characterised by reduction in speed, gait and repetitive action with involuntary movements. This symptom is generally observed after onset of tremors.
Bradykinesia may cause difficulty in starting a movement and some individuals may even experience immobility. ‘Freezing’ episodes may also occur at advanced stages of the disease.
The third feature cogwheel rigidity is resistance to passive motion and increased muscle tone. It is evidenced by jerky movements and tension in the muscle. The last symptom is postural instability which can cause loss of balance and increase the risk of fall.
Difficult in handwriting and speech may also be observed.
Non-motor symptoms include:
• Sense of smell is impaired
• Sleep disorders
• Cognitive decline
• Medication induced psychosis
Depression and anxiety are symptoms that occur before motor features of Parkinson’s disease. Depression, anxiety, dopamine dysregulation syndromes and personality syndromes may occur at later stages of the disease.
Cognitive deficits, dementia, cognitive impairment (reduced attention, memory, etc) may also occur. This may even occur as a result of overdosing on dopaminergic medications. Parkinsonian dementia may occur later in the disease or with progressing age as a result of Lewy body and even amyloid accumulation.
Those who experience motor features earlier in the disease, experience faster disease progression. Individuals may also experience dementia. Other complications may arise at later stages such as immobility, pneumonia, pulmonary embolism, etc.
Causes: How does one get Parkinson’s?
Research has identified various factors that could cause Parkinson’s disease.
Parkinson’s disease could be inherited. Studies have identified certain gene loci that could contribute to the development of ‘sporadic’ Parkinson’s.
Mutations in tau, alpha synuclein, semaphoring 5A, fibroblast growth factor 20 and nuclear receptor related 1 genes increase the risk of developing Parkinson’s disease.
Mutations in Parkin gene is the most common genetic cause of early onset Parkinson’s. Less than 1% of the individuals suffering from early onset Parkinson’s demonstrate DJ-1 mutations and behavioural and psychiatric features are common in the case of such mutations.
Mutations in PINK-1 is observed in patients with early onset Parkinson’s as early as 35 years, with slow disease progression and response to treatment. Mutations in each of these genes fuel oxidative stress which contributes to the progression of the disease.
Certain toxins have been discovered which if mistakenly injected produce symptoms similar to Parkinson’s disease. These include 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat, maneb, and epoxomicin.
Identification of these toxins suggests that Parkinson’s could be triggered by exposure to environmental toxins.
The brain comprises of phospholipids and polyunsaturated fatty acids which are susceptible to oxidation. Damage to dopaminergic neurons leads to production of reactive oxygen species and reactive nitrogen species.
Each cell produce these agents, but a perfect balance is maintained which does not allow them to be overproduced or accumulate.
However, in Parkinson’s disease this balance is hampered. Concentration of polyunsaturated fatty acids is decreased and markers of oxidative damage are increased in Parkinson’s disease.
Even DNA is susceptible to oxidative damage. Levels of antioxidant enzymes are also hampered in Parkinson’s disease. Excessive activation of glial cells ( a type of immune cells in the brain) also leads to the production of agents that cause oxidative damage.
Loss of neurons triggers inflammation in the brain in Parkinson’s disease. Microglia is type of immune cells present in brain and spinal cord. In the case of death of neurons, the microglia is activated and began to accumulate in these sites.
Dopamine metabolism leads to excessive production of reactive oxygen species that contribute to oxidative damage and lead to loss of brain cells. Further disruption of cellular respiration leads to an imbalance of calcium and iron which further promote oxidative damage in the disease.
Few studies suggest that aging is genetically programmed in humans and children of long lived parents are protected from neurodegenerative disorders. This may suggest that aging can activate genes related to development of Parkinson’s in few individuals.
Parkinson’s Pathophysiology Explained
Dopamine is one of the neurotransmitters that the nerve and brain cells require to communicate with each other. As research uncovers various roles of dopamine, one of the main functions it is involved in is maintaining voluntary movement.
Basal ganglia is a part of the brain that is essentially involved in motor function and control. Parkinson’s disease is characterised by damage to this area of the brain and loss of dopaminergic function. This leads to diminished motor activity.
Apart from basal ganglia, neurons in other parts of the brain are also damaged such as in thalamus and cortex, which is why Parkinsonism is considered as a disease of a distributed brain network.
There is a progressive degeneration of such dopaminergic neurons in the striatal pathway which leads to loss of dopaminergic function. Individuals experience motor symptoms only after 50 to 80% of the neurons are damaged.
There are 2 types of dopamine receptors: D1 (excitatory) and D2 (inhibitory) that control motor function. The basal ganglia is a part of a larger circuit that involves thalamus and cortex.
Loss of dopamine function leads to increased activity in smaller circuits of the brain that are involved in motor function. This leads to dysfunction of another neurotransmitter GABA which inhibits the activity of thalamus.
In turn, the thalamus fails to activate the frontal cortex which leads to reduced motor function.
Another important aspect of Parkinson’s disease is the formation of Lewy bodies. Lewy bodies are aggregates of proteins, lipids, etc. These Lewy bodies are formed in the dopaminergic neurons.
These Lewy bodies are formed to due to aggregates of alpha synuclein protein. Genetic mutations cause these aggregates. Lewy bodies lead to formation of lesions that progress neurodegeneration.
Presence of Lewy bodies is also associated with Parkinson’s dementia. However some studies suggest that Lewy bodies may be present in the normal elderly population who may not present with Parkinson’s disease.
Inflammation in Parkinson’s disease also contributes to the progression of the disease.
The presence of non motor symptoms indicates that other neurotransmitter systems are also affected by this disease. Neurons dealing with other functions such as vision and smell are also damaged in Parkinson’s disease.
Lewy body formation in parts of the brain other than striatum nigra, also contributes to non motor symptoms of Parkinson’s.
What is the treatment available for Parkinson’s disease?
Treatment strategies for Parkinson’s disease are mainly targeted at reducing motor symptoms. Herein we will be going through different strategies employed to treat Parkinson’s.
Treatment of motor symptoms
Levodopa is the main medication used to treat Parkinson’s disease. However, it can cause complications such as fluctuations and dyskinesia which is why clinicians are debating on the appropriate time to start Levodopa therapy.
The addition of carbidopa (dopa decarboxylase inhibitor) to levodopa enhances its therapeutic benefits and reduces the adverse effects.
Most patients are taking levodopa experience motor complications after 5 year treatment. Another common issue with levodopa therapy is that there is a delay in response even after taking the appropriate dose of levodopa.
These issues are tackled by reducing the dosage of levodopa or adding other drugs to combat drug induced motor complications or even surgery.
Catechol-O-Methyl transferase (COMT) inhibitors such as entacapone are also prescribed. COMT is an enzyme that degrades neurotransmitters like dopamine and epinephrine.
Dopamine agonists are also used as the first line of treatment instead of levodopa, because of the motor complications associated with levodopa. These medications activate the nerve cells in the absence of dopamine.
Overall protection of the brain as a whole is also a part of Parkinson’s treatment. Antioxidants may be prescribed to prevent progression of the disease.
Agents that deal with neurotransmitter systems other than dopamine such anti-glutamatergic drugs, anticholinergic drugs are administered to reduce motor complications.
Parkinson’s disease leads to loss of neurotrophic factors- biological agents produced by the body to support growth and development of brain and nerve cells. Nerve growth factor, brain-derived neurotrophic factor, and glial-derived neurotrophic factor (GDNF) has been found to benefit in Parkinson’s.
Anti-inflammatory agents may help reduce inflammation in the brain. Also, therapies are being designed to prevent Lewy body formation.
Neuropsychiatric symptoms treatment
Neuropsychiatric symptoms are treated separately. Depression and anxiety occur mostly during the periods when there a resistance to dopamine treatment and Parkinson’s symptoms develop.
Therefore the first line of treatment involves modulating dopamine treatment. Other medications utilised to treat these conditions is tricyclic antidepressants and SSRIs. Anti-anxiety medications such as pregabalin or venlafaxine may be prescribed.
In severe cases, Electroconvulsive therapy may be necessary. Dopamine agonists and psychostimulants may be prescribed to treat fatigue. Antipsychotic medications are prescribed to treat hallucinations and psychosis in Parkinson’s disease.
However, these symptoms need to be treated carefully since addition or withdrawal of these medications may worsen symptoms of the disease or increase adverse events.
Deep brain stimulation is found to improve the quality of life and reduce motor complications in advanced Parkinson’s disease patients.
It is a surgical procedure which involves implanting a neurostimulator; this neurostimulator provides electrical impulses which help reduce tremor and motor complications in Parkinson’s.
Stem cell therapy for Parkinson’s disease has been investigated since the 1980s.
Transcranial magnetic stimulation is a relatively new therapy that involves placing a coil near the head and provides electromagnetic waves to stimulate the brain. This helps in reducing motor symptoms of Parkinson’s disease.
It has been around 200 years since Parkinson’s disease was first discovered, but research community is still struggling with understanding the disease as a whole and designing a full proof treatment.
Given the fact that as much as 1-3% of the elderly population suffers from Parkinson’s disease, more focus is required regarding prevention of Parkinson’s disease and educating people about the disease and prevention strategies.