Diseases and Disorders

Neuropharmacology of Parkinson’s Disease

Christian Gonzalez


Introduction

In 1817, six accounts of cases of a previously unclassified disease reported muscle paralysis, decreased strength, abnormal gaits and resting tremors in patients. Although these symptoms had been noticed centuries prior by accounts in Egypt and India, the observations described in “An Essay On Shaking Palsy” by the English surgeon James Parkinson were the first time that these symptoms were collectively classified as paralysis agitans {1}.  About fifty years later, French neurologist Jean-Martin Charcot conducted further empirical studies investigating the symptoms observed by Dr. Parkinson. Through his investigations, he made advances in understanding the condition by distinguishing between signs including rigidity and bradykinesia. Following his publications, Charcot prompted the renaming of paralysis agitans to Parkinson’s disease, after the condition’s original observer {2}. Now, two hundred years later, Parkinson’s disease is one of the most common neurodegenerative disorders, affecting over ten million people worldwide {3}. Characterized by slowly progressing motor symptoms and accompanying neurological difficulty, Parkinson’s disease noticeably impacts the lives of patients. Consequently, anxiety and depression are quite common in Parkinson’s disease. There is currently no cure and no known cause, though research is continually being carried out to develop novel pharmacological treatments to treat the pathology of Parkinson’s disease.

 

Overview and Symptoms

     Parkinson’s disease is a neurodegenerative disorder of the central nervous system that results in slowness of movement, muscle stiffness, resting tremors, and neurological difficulties specifically relating to memory and cognition. Typically, patients with Parkinson’s disease begin experiencing motor symptoms such as shaking and rigidity of movement before advancing to other physical symptoms such as difficulty thinking or behavioral issues. Collectively, the earliest prodromes of the condition are referred to as Parkinsonism [4]. This syndrome includes select motor symptoms such as bradykinesia and resting tremors, but excludes the other typical symptoms in Parkinson’s, specifically those later on in the pathology.  The neurological symptoms that patients experience such as memory loss, and in some cases dementia, are rarer in Parkinson’s disease in comparison to motor signs, but are increasingly prevalent during the later, more advanced, stages of the disease. As the disease progresses, other symptoms also become more prevalent, such as insomnia and depression [5].

 

Causes

    Parkinson’s disease is an idiopathic condition, meaning that there is currently no known cause of the disorder. The prevailing theory regarding the origins of Parkinson’s disease is that there are several contributing factors that impact disease incidence. Genetics is thought to play a significant role in the onset of Parkinson’s, as approximately 15% of all diagnosed patients have reported a family history of the disease [6]. Gene mutations are commonly observed in a large portion of Parkinson’s patients; specifically, five genes have had a strong enough correlation made to establish them as causal genes with which to diagnose the disease: alpha-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), and Leucine-rich repeat kinase 2 (LRRK2). SNCA was the first causal gene to be identified, and duplications of the gene are a frequent hereditary indicator of the presence of idiopathic Parkinson’s disease. Mutations in PARK2 have been associated with early-onset Parkinson’s disease, in addition to a slower pathological progression of the disease. PINK1 is also linked to early-onset Parkinson’s disease, and mutations in the gene have been verified to cause aggregations of abnormally folded proteins that result in cell apoptosis and mitochondrial dysfunction. In contrast to most of the other causal genes of Parkinson’s disease, LRRK2 is the only one that has been shown to be clinically involved in the etiology of late-onset Parkinson’s disease, rather than varieties that present themselves earlier on in the lives of patients. Besides genetics, environmental factors are being investigated for their role in the development of Parkinson’s disease. As of right now, no environmental facets have been shown to directly cause the disorder, but high levels of lead and exposure to pesticides have been shown to increase the chances of developing Parkinson’s disease [6].

 

Pathophysiology

    The pathology of Parkinson’s disease is considered to be caused by damage to an area in the cerebrum known as the basal ganglia. This cluster of cerebral nuclei deep within the brain functions normally by being intimately involved in control of voluntary motor movements, proper emotional management, and cognition. Specifically, dopaminergic neuronal cell death occurs in the portion of the basal ganglia known as substantia nigra (Latin for “Black substance”). During certain cases of the disease, upwards of 70% of neurons in the anterior portion of the substantia nigra can be affected. [7] Glial apoptosis in surrounding areas is also quite common, as is the presence of Lewy bodies. Lewy bodies are abnormal protein aggregations that gather in clusters inside the somata of neurons in the substantia nigra and the greater brainstem, often in places where neuronal death is most prevalent. This loss of dopamine-producing cells in the substantia nigra causes decreased brain activity and results in the symptoms of Parkinson’s disease such as hypokinesia (decreased movement) and cognitive issues.

Figure 1. Visual comparison between healthy and diseased Substantia nigra [8].

 

Diagnosis

    There are currently no tests specifically designed to diagnose Parkinson’s disease. Family histories of Parkinson’s disease and assessment of neurological health are the two most common diagnostic tools neurologists use when trying to reach an accurate diagnosis of the condition. Identifying whether or not a patient has mutations in causal genes of Parkinson’s is quite helpful during the diagnostic process, as is knowing if any relatives have been diagnosed with Parkinson’s disease. During a neurological examination, a neurologist will try to rule out the possibility of other diseases through evaluating the degree of motor and sensory impairment levels. It is also especially important to observe the gait of a patient to distinguish it from other movement disorders. To accomplish this, doctors sometimes conduct multidirectional walk tests to test the normality of their gait. Positron Emission Tomography (PET) may also be employed in diagnosis to identify decreased activity in the basal ganglia [9].

 

Pharmacotherapy

    Treatment for Parkinson’s disease involves a combination of therapy, drugs, and surgery. Occupational and physical therapy sessions can be effective in gait habilitation and improving how patients can perform tasks by teaching how to deal with symptoms. The most frequent surgery performed on patients with Parkinson’s disease is deep brain stimulation (DBS). During this procedure, areas of the basal ganglia such as the globus pallidus, thalamus, and subthalamic nucleus are targeted with electrical impulses generated by a neurostimulator in order to reversibly change brain activity in those regions to improve symptoms. Deep brain stimulation is only used if pharmacological treatments are ineffective in a patient. There are an array of medicines that can be prescribed to patients to manage their symptoms, but none are effective at altering the pathology or course of the disease. All of the pharmacotherapeutic drugs work differently, but the majority still work with the intent of modifying dopamine in some form. Doctors prescribe levodopa (L-DOPA) initially to treat a patient’s symptoms. This drug works by synthesizing dopamine to account for deficiencies in the neurotransmitter that occur in patients with Parkinson’s disease. Carbidopa is also sometimes used alongside L-DOPA to increase efficacy by enhancing L-DOPA and preventing nausea that is often experienced as a result of taking L-DOPA alone. When combined into one commercial drug, they are collectively referred to as sinemet. Dopamine agonists are a class of drugs that also mimic the effects of dopamine, and are thus also used when treating Parkinson’s disease with pharmacotherapy. In addition, MAO-B inhibitors and COMT inhibitors are used to help patients by blocking monoamine oxidase enzymes and the activity of catechol-O-methyl transferase, respectively. Amantadine is another dopamine promoter integrated into Parkinsonian drug treatment, but it is not as effective as other treatments as it is a weak NMDA receptor antagonist. Anticholinergics are also frequently prescribed to treat Parkinson’s disease, but unlike most other pharmacological treatments, this drug class acts on the neurotransmitter acetylcholine rather than dopamine [10].

 

Advocacy and Awareness

    If you would like to find out more information on how to get involved in helping patients with Parkinson’s disease, please contact the following organizations listed below.

National Parkinson Foundation - http://www.parkinson.org/get-involved

American Parkinson Disease Association - http://www.apdaparkinson.org/#

 

Image source: Wilkins Parkinson’s Foundation

http://www.wilkins-pf.org/pdtulip.php

 

Key Terms

James Parkinson - English surgeon who first described Parkinson’s disease

Jean-Martin Charcot- French neurologist who coined the term “Parkinson’s disease”; widely regarded as the founder of modern neurology

Bradykinesia - Slowness of movement observed in patients with Parkinson’s disease

Parkinsonism - Neurological syndrome similar to Parkinson’s disease characterized by motor symptoms such as bradykinesia, rigidity, and resting tremors

Alpha-synuclein (SNCA)- First causal gene to be associated with Parkinson’s disease

Parkin (PARK2)- Causal gene associated with early-onset Parkinson’s disease

PTEN-induced putative kinase 1 (PINK1)- Causal gene associated with early-onset Parkinson’s disease

Leucine-rich repeat kinase 2 (LRRK2)- Causal gene associated with late-onset Parkinson’s disease

Basal Ganglia - Cluster of nuclei deep within the brain involved in movement and motivation

Substantia Nigra - Midbrain structure that is important for movement and reward

Lewy Bodies - Protein aggregates that form in neurons of patients with Parkinson’s

Hypokinesia - Decreased movement observed in Parkinson’s disease

Positron Emission Tomography (PET)- Medical imaging technique used to study tissue functions with radioactive tracers

Deep brain stimulation (DBS) - Surgical procedure that provides therapeutic benefits to patients with movement diseases through transmitting electrical impulses to specific brain areas

Globus Pallidus- Subcortical nucleus in basal ganglia involved in voluntary movement control

Thalamus- Egg-shaped part of the brain involved in processing received sensory information

Subthalamic Nucleus- Subcortical nucleus in the basal ganglia whose function is unknown

Levodopa (L-DOPA) - Drug that can treat Parkinson’s through chemical synthesis of dopamine

Carbidopa- Drug that can treat Parkinson’s alongside Levodopa by synthesizing dopamine

Dopamine agonists - Drug class consisting of compounds that mimic the effects of dopamine

MAO-B inhibitors - Drug class consisting of chemicals that block monoamine oxidase enzymes

COMT inhibitors - Drug class consisting of medications that inhibit the activity of catechol-O-methyl transferase

Amantadine - Dopamine promoter drug that can treat Parkinson’s disease as well as the flu

Anticholinergics - Drug class that blocks the activity of the neurotransmitter acetylcholine


References


  1. Connolly, B. S., & Lang, A. E. (n.d.). Pharmacological treatment of Parkinson disease: a review. JAMA. https://www.ncbi.nlm.nih.gov/pubmed/24756517. Retrieved December 21, 2016.

  2. Bryant, M. S., Workman, C. D., & Jackson, G. R. (2015). Multidirectional walk test in individuals with Parkinson’s disease. International Journal of Rehabilitation Research, 38(1), 88-91. doi:10.1097/mrr.0000000000000091. Retrieved December 21, 2016

  3. Parkinson's Disease In-Depth Report. The New York Times (n.d.).http://www.nytimes.com/health/guides/disease/parkinsons-disease/print.html Retrieved December 21, 2016

  4. Davie, C. A. (2008). A review of Parkinson's disease . British Medical Bulletin, 86(1), 109-127. http://bmb.oxfordjournals.org/content/86/1/109.short. Retrieved December 21, 2016.

  5. Parkinson disease. (n.d.). Retrieved December 21, 2016, from https://ghr.nlm.nih.gov/condition/parkinson-disease Retrieved December 21, 2016

  6. Sveinbjornsdottir, S. (2016). Journal of Neurochemistry, 139(S1), 318-324. http://onlinelibrary.wiley.com/doi/10.1111/jnc.13691/abstract Retrieved December 21, 2016.

  7. Merello, M. (n.d.). Parkinson's Disease & Parkinsonism. Retrieved December 21, 2016, from http://www.movementdisorders.org/MDS/About/Movement-Disorder-Overviews/Parkinsons-Disease--Parkinsonism.htm

  8. Statistics on Parkinson's. (n.d.). Retrieved December 21, 2016, from http://www.pdf.org/en/parkinson_statistics Retrieved December 21, 2016

  9. Goetz, C. G. (2011). The History of Parkinson's Disease: Early Clinical Descriptions and Neurological Therapies. Cold Spring Harbor Perspectives in Medicine, 1(1). doi:10.1101/cshperspect.a008862. Retrieved December 21, 2016

  10. Parkinson, J. (2002). An Essay on the Shaking Palsy. The Journal of Neuropsychiatry and Clinical Neurosciences, 14(2), 223-236. doi:10.1176/jnp.14.2.223 Retrieved December 21, 2016

Christian Gonzalez

Christian Gonzalez


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