Parkinson’s disease: Early signs, causes, and risk factors

Parkinson’s disease is a neurologic disorder and one of the primary sources of disability.

The second most common neurodegenerative disease is Parkinson’s disease, right after Alzheimer’s disease.  The typical onset of Parkinson’s disease is between 55 and 65 years. In general, about 0.3% of the population is affected by this disease.

Parkinson’s disease occurs more in men than in women. Also, it is more frequent in white people than those of Asian and African descent.

The earliest changes resulting from changes in a few brain regions such as basal ganglia, olfactory tubercule are motor impairment, called parkinsonism.

So, these changes include: 

• paucity 
  
  
• slowness of movement
  
  
• muscle stiffness
  
  
• tremor at rest.

Mostly, these problems are caused by degeneration in substancia nigra. It is a group of pigmented nuclei in the midbrain and brainstem responsible for the production of dopamine. 

Consequently, part of the brain which receives dopamine as a messenger can’t work properly.

What Is Parkinson’s Disease?

Parkinson’s disease is one of the most frequent degenerative diseases which primarily affects the specific area in the brain. Parkinson’s disease affects millions worldwide.

It’s a disease that affects multiple organs such as the brain, gut, olfactory system (smell).

Further, parkinson’s disease is the most common type of parkinsonism. Manifestations of Parkinsonism is rest tremor, rigidity, bradykinesia (slow motion), and postural imbalance and instability.

Although the exact cause of Parkinson’s disease is not still clear, it is confirmed that the main underlying mechanism is lack of dopamine. 

Is Parkinson Inherited?

The specific cause of Parkinson’s disease is unknown. However, it’s assumed that factors such as environmental add to genetic predisposition or susceptibility.

More and more evidence emerges that environmental and genetic factors have a positive effect on occurring of Parkinson’s disease.

Moreover, these factors lead to an abnormal form of normal protein α-synuclein. Abnormal α-synuclein leads to cell death or can promote this effect.

The onset of the disease can be categorized as:

• juvenile – below 21-year-old
  
  
• early – 21-50 years
  
  
• late – above 60 years

The juvenile form is rare and usually familiar. It’s often associated with a parkin gene mutation, and because of that has an atypical presentation. Most of the patients with juvenile form have a first or second-degree relative.

It’s important to know that 10-15% of patients with Parkinson’s disease have a first or second-degree relative. Moreover, first-degree relatives have a two-fold higher risk of getting this disease.

In the early and late-onset form, the positive family history is not so much important.

Further, advances in genetic and research provide much more in-depth insight into our genes. A considerable number of genetic mutations have been found to affect the occurrence of Parkinson’s disease. 

Some of the genes which participate in the onset of the disease are:

• LRRK2 – produce protein “dardin” for which can cause tremor
  
  
• SNCA – lead to abnormal protein α-synuclein which could lead to oxidative stress in brain cells and destroy them
  
  
• Parkin – characterized by early-onset and slow-progressive symptoms

These genes are responsible for dopamine secretion, enzymes activation, development of certain brain structures, receptors in the brain.

As previously mentioned, these genes and environmental factors may interact and create a positive background for the onset of Parkinson’s disease.

Risk Factors for Parkinson Disease

A family history of Parkinson’s disease is a very important risk factor for developing this disease. Several studies found a higher correlation between depression and the development of Parkinson’s disease.

This implies that depression is either a risk factor or one of the first early symptoms in patients with this disease. Similarly, constipation is a risk factor or one of the earliest symptoms.

Pesticides are also at the top of the list of risk factors. 

Pesticides interfere with brain chemistry, which is the reason why they might lead to Parkinson’s disease.

Another potential risk factors which should be more examined are:

• Trauma of the brain
  
  
• Reduced intake of dietary and sun-light vitamin D
  
  
• History of migraine
  
  
• Living in urban and rural areas
  
  
• Exposure to copper, manganese, lead
  
  
• Obesity
  
  
• Diabetes

Moreover, some data suggest that mortality (death rate) is higher among people with higher socioeconomic status and occupations. But, in people with low socioeconomic status, mortality is lower.

The prevalence (commonness) of cancers in patients with Parkinson’s disease is quite low. 

However, there is evidence that a history of melanoma and prostate cancer is connected with increased risk for Parkinson’s disease and vice versa.

What Causes Parkinson’s Disease?

The underlying mechanism of the onset of Parkinson’s disease is very complex. The leading cause of the disease is the lack of neurotransmitter dopamine.

Dopamine is the neurotransmitter (the substance secreted by nerve cells) produced in a part of the brain called substancia nigra. 

As dopamine has an effect not only in the brain but also in the gut, this leads to a number of symptoms.

Moreover, dopamine depletion from basal ganglia results in significant disruptions in the connections to the thalamus and motor cortex. This causes parkinsonism signs such as bradykinesia.

To understand the mechanism, we will explain some basic anatomy of the brain and its function:

Basal ganglia – this is a group of different structures in the brain. Basal ganglia include:

• Substancia nigra
  
  
• Striatum (caudate and putamen)
  
  
• Globus palidus
  
  
• Subthalamic nuclei

Thalamus (the main relay station – most of the nerves cross here)

The functions of basal ganglia and its structures are extremely important for our function. 

Basal ganglia controls:

• Motor control
  
  
• Motor learning
  
  
• Executive functions
  
  
• Emotional behaviors
  
  
• Reward and reinforcement role
  
  
• Addictive behaviors
  
  
• Habit formation

Oxidative Hypothesis and Proteins

When cells in substancia nigra where dopamine neurons are located start to die, dopamine levels decrease.

Dopamine is one of the main messengers in our brain and body, and it has many functions.

 It has the role of messenger, which tells another part of the body that you want to make a movement with your body. 

As dopamine plays a role in the movement, a lack of this neurotransmitter leads to motor symptoms such as 

• tremors (shaking)
  
  
• bradykinesia – slow movements

In the substancia nigra, the part which produces dopamine, eventually, there is an accumulation of α-synuclein, famous as Lewy bodies.

This continuous accumulation of Lewy bodies has adverse effects not only on motor function but also on memory. 

Therefore, this accumulation leads to Lewy bodies dementia. Parkinson’s disease dementia is one of the prevalent symptoms in this disease, especially in the late stage.

Although the exact mechanism of degeneration in Parkinson disease is not fully understood, it probably involves interaction and synergistic effects of:

• genetic factors 
  
  
• abnormalities in immune response
  
  
• oxidative stress 
  
  
• inflammation
  
  
• lack of enzymes
  
  
• other factors

Besides dopamine, in Parkinson’s disease, non-dopaminergic neurons probably have a role. 

This non-dopaminergic involvement can explain non-motor symptoms such as:

• depression
  
  
• cognitive 
  
  
• sleep disturbance

Moreover, autonomic function (sexual function, blood pressure) is also affected. The oxidative hypothesis suggests that free radicals such as hydrogen peroxide damage nerve cells.

During dopamine metabolism, free radicals are a side product. 

Glutathione clear free radicals. However, if hydrogen peroxide is not cleared properly, it can accumulate and lead to the formation of reactive hydroxyl radicals that can interact with cells and destroy them.

In Parkinson’s disease, levels of glutathione are reduced. This, therefore, suggests a lower level of protection from free radicals.

What are the Symptoms of Parkinsons Disease?

Early signs of Parkinson’s disease

So, the most prominent early symptoms and signs of Parkinson’s disease are: 

Tremor – it is a rest tremor (shaking of the body in the rest). This means that tremor is most visible when the tremulous part of the body is supported by gravity. More precisely, when there is no purposeful activity. The tremor decreases with the beginning of some action.A tremor in Parkinson’s disease can often be intermittent. Moreover, tremor at the early phase of the disease can be subtle and hard to notice. However, as the disease progresses, it becomes obvious.

Bradykinesia – is a generalized slowness of movement. It occurs in the early stage of the disease in around 80% of patients. It is the main cause of disability.Patients often have problems to describe bradykinesia. Most common words are “weakness,” “incoordination,” and “tiredness.”

The most common complaints when walking are dragging legs shorter (shuffling) steps, feeling of unsteadiness, difficulty while standing up from a chair or getting out from car occur.

Moreover, the characteristic manifestation of the disease in these patients is gait freezing and festation – an irresistible impulse to take much quicker and shorter steps and thereby adopt an unwillingly a running pace


Rigidity – this is increased resistance to passive movement. As previous signs and symptoms, usually at first occur at one side, often on the same side as tremor. Cogwheel and lead-pipe rigidity are characteristic of Parkinson’s disease.

Postural instability – due to impaired spinal reflex, feeling of instability, and imbalance occur. These lead to a tendency to fall, which could cause serious injuries.

Late signs of Parkinson’s disease

Parkinson’s disease dementia – is also known as Lewy bodies dementia. It is a late-stage symptom. Parkinson’s disease dementia is subcortical dementia, which leads to psychomotor retardation and alteration of personality and memory impairment. They wrongly precipitate space (dimensions) that can’t retrieve memory and execute functions.

Psychosis and hallucinations – although all types of hallucinations can emerge, visual hallucinations are the most common. Paranoid delusion such as that somebody is stilling money from the patient, intruders living in the house, spousal infidelity are the most common.

Mood disorders – the most common are depression and anxiety. Depression often presents a loss of joy interest in daily activities and sadness.

Other non-motor symptoms are:

• Constipation
  
  
• Sleep disturbance – insomnia, daytime sleepiness
  
  
• Orthostatic hypotension – drop of blood pressure when getting up
  
  
• Sexual difficulties – can range from lack of activity to hypersexuality
  
  
• Dysphagia – difficult swallowing
  
  
• Loss of smell
  
  
• Pain

What are the Stages of Parkinsons Disease?

Stage 1 – this is the initial stage. Symptoms are mild and mostly to not interfere with daily life and activities. Usually, the most common involuntary movement symptom is tremor at this stage. 

Also, walking and posture disturbance can occur as well as changes in facial expression (mask).

Stage 2 – movement symptoms are worsening. Tremor and rigidity are becoming bilateral. Walking disturbance and characteristic posture becoming obvious.

Stage 3 – previous symptoms progress. Falls are common. The disease starts to interfere with daily activities considerably.

Stage 4 – disease limits most of the activities. Patients can stand alone. However, they will usually require support to walk. The person at this stage is unable to live alone.

Stage 5 – the most advanced phase of the disease. Motor symptoms severely limit of Parkinson’s patients. The person is bedridden and requires full healthcare. 

At this stage, psychosis can start. Non-motor symptoms can dominate besides motor.

How is Parkinsons Disease Diagnosed?

Diagnosing Parkinsons disease is not easy. Until now, there is no specific analysis that makes the diagnosis of Parkinson much harder.

Diagnosis of Parkinsons disease is based on clinical features observed from the neurologic examination and taking the patient’s history. 

Therefore, the diagnosis is clinical. To make the diagnosis, following signs must be present:

• Bradykinesia
  
  
• Tremor
  
  
• Rigidity

At least bradykinesia must be present so the doctor can consider Parkinson’s disease.

Additionally, the response to dopaminergic therapy is also one of the features which support this diagnosis. 

Other features that add on to Parkinson’s disease are unilateral onset, rest tremor.

It is vital to examine in detail patients and take a medical history. Many drugs can cause parkinsonism. 

Note that parkinsonism is not the same as Parkinson’s disease. 

The cause of Parkinsons disease is a lack of dopamine in substancia nigra.

Parkinsonism can occur after taking certain drugs such as:

• typical antipsychotics (haloperidol, chlorpromazine, promethazine, etc)
  
  
• atypical antipsychotics (risperidone, olanzapine, aripiprazole)
  
  
• antiemetics (metoclopramide, clebopride)
  
  
• calcium-channel blockers (flunarizine, cinnarizine)

What are the Treatment Options?

So, there are a few treatment options for Parkinsons disease.

• Levo-dopa and Carbi-dopa – is also famous as L-dopa. As in Parkinson’s disease, there is a lack of produced dopamine; the aim is to give the person more dopamine. This drug has side effects such as nausea, vomiting, and more significant effects of this medication taken alone last very short.
  
  

• COMT inhibitors – this drug prevents degradation of L-dopa in the intestine. In our intestines, there is enzyme catechol-o-methyl-transferase, which causes degradation of L-dopa.  Because of that, COMT inhibitors suppress that enzyme, and more of L-dopa is absorbed.
  
  

• Deep Brain Stimulation – this is a surgical procedure in which neurosurgeon places the wire and electrode in the specific areas in the brain stimulation certain parts of the brain. Which parts doctor swill stimulate depends on which symptoms we try to mitigate. Deep brain stimulation is a technique that has a high percentage of success in these patients and leads to significant improvement.

How to Cope with Parkinsons disease?

• Exercise: Exercise is one of the best ways to work on and improve your strength and balance. More importantly, exercise decreases tremors. It also improves coordination, flexibility, memory, and reduce the risks from falls. The exercise also mitigates depressive and anxiety symptoms. Further, a study conducted on people with Parkinson’s disease showed that 2.5 hours a week improved the movements and slowed the cognitive decline in this group.
  
  

• Diet: A healthy and balanced diet can help with constipation. High fiber intake is the best non-medical way to prevent and regulate constipation.  Still, the Mediterranean diet is one of the healthiest diets. This is because it reduces the risk of cardiovascular disease, diabetes, and improve wellbeing.
  
  

• Sleep: Regular sleeping is also very important. While sleeping, our bodies rest and conserve and generate energy. During sleeping, our pineal gland secretes the hormone melatonin, which has many physiological effects.
  
  

• Prevent falls: Preventing falls, which are common complications of Parkinsons disease, is important. Thus, it is essential to talk with your doctor and physiotherapist to ensure that therapy is optimal.
  
  

• Comfort: Make your living place as most comfortable as it can be for your situation. It is good advice to install grabs and bars so you can always hold on something.
  
  

• Driving: Don’t drive and try to be aware of your limitations. This is because driving with Parkinsons disease even in early-stage can be dangerous. Always seek for help whenever necessary.

Conclusion

Above all, parkinsons disease is not a fatal disease. However, it is a neurodegenerative disease that causes the total debilitation of a person. 

Therefore, early diagnosis may benefit as in that way; therapy can be started as soon as possible. The disease usually progresses over 15 years.

Progression is highly individual. Some patients can have only mild tremors after 20 years, while some can be bedridden after 10 years. .