Parkinson’s Disease: Key Factors And Diagnosis

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Introduction

Have you ever wondered what it would be like to be physically impaired? There are plenty of conditions that involve movement issues. One condition is Parkinson’s disease (PD). Famous icons, such as Michael J. Fox and Muhammad Ali have been diagnosed with the condition and have helped the public in some way regarding the disease. Michael J. Fox has created a foundation for the disease in which he informs the public on PD; what it is, new research, and it is open for donations to help further PD research. Muhammad Ali helped establish a center, the Muhammad Ali Parkinson’s Disease Center, in 1997 to help patients with PD.

PD is a disorder of the central nervous system that affects movement and some non-movement areas of the body. PD is known to be progressive and gets worse over time. It is found to affect more than 1 million people in the U.S.; 1 out of every 100 people above the age of 55 (Zigmond and Burke, 2002). Throughout this paper, I will be discussing the disease from the anatomical and physiological level to what goes wrong with the functions of these structures and the factors that cause dysfunction. You will also read about how the disease is diagnosed and what treatments are offered to PD patients. Towards the end of this paper, there will be information regarding the most recent PD research and what its results are.

Anatomy and Physiology of PD

PD is a progressive neurodegenerative disorder that attacks the central nervous system (CNS). The main area of destruction is in the basal ganglia. The basal ganglia are a group of nuclei located deep and in the central of the base of the forebrain. These nuclei have connections with the cerebral cortex, thalamus, substantia nigra, and other areas of the brain. The substantia nigra is an important structure involved with the disease. The substantia nigra is known as a melanin-containing nucleus in the ventral midbrain. This structure contains neurons that synthesize dopamine, a neurotransmitter connected to the progression of the disease. Dopamine plays a key role in the control of movements from the signals it sends to the striatum. The largest nuclear complex of the basal ganglia is the striatum. The striatum is composed of the caudate nucleus and putamen (Parkinson’s – Anatomy, Pathology, Prognosis and Diagnosis). The diagrams below show where these main structures involved in PD are located in the brain.

Physiology

The striatum receives input from the cerebral cortex and the dopaminergic neurons from substantia nigra pars compacta. The cerebral cortex delivers excitatory input while the dopaminergic (DA) neurons deliver inhibitory and excitatory input. These inputs are then received by spiny projection neurons that project directly inside and outside of the globus pallidus. These structures have a system that work together to perform involuntary and voluntary movements, as well as some behaviors and emotions. “Their vast system of communication allows the involvement with a variety of functions, including automatic and voluntary motor control, procedural learning related to routine behaviors and emotional functions. The association with other cortical areas ensures smoothly orchestrated movement control and motor behavior” (Parkinson’s – Anatomy, Pathology, Prognosis and Diagnosis).

Pathophysiology

A person with Parkinson’s disease has different physiology in the anatomical structures mentioned above. Patients with PD will have a wide variety of dysfunction beyond motor control disabilities since so many structures are involved. They are at increased risk of having cognitive and psychiatric dysfunctions (Zigmond and Burke, 2002). Not every person with PD has the same pathology, symptoms, or progression of the disease. The next paragraph will talk about what happens during DA neuron loss in patients with PD.

The basal ganglia will become over or under stimulated when dopamine receptors from the striatum are not properly stimulated. Mildly affected PD patients will lose up to 60 percent of DA neurons when degeneration begins. This accounts for the almost 80 percent of DA loss in the striatum (Zigmond and Burke, 2002) PD symptoms such as tremor, slowness of movement, stiffness, and balance problems occur once 80 percent of neurons dies. Shutdown of motion and rigidity is caused by the subthalamic nucleus becoming overactive and acting as a brake on the internal globus pallidus (GPi). A decrease in thalamus output occurs when the GPi is overstimulated. This decrease in thalamus output causes tremor. “Although there are several groups of dopaminergic neurons in the central nervous system (CNS), it is the loss of DA cells in the SNpc that is believed to account for all of the motor manifestations of PD” (Zigmond and Burke 2002).

The substantia nigra pars compacta (SNpc) DA neurons are not the only ones involved in the disease. The presence of Lewy bodies (LB) is another pathological hallmark of PD. Lewy bodies are tiny, eosinophilic clumps that are abnormally accumulated by the alpha-synuclein protein (Shahmoradian, et al. 2019). The most recent hypothesis in PD research states that the basis of LB are B-sheet rich amyloid fibrils that were transformed by abnormal oligomers (Shahmoradian, et al. 2019). It has been found that there is severe loss of pigmented neurons in the ventral-lateral tier of the substantia nigra. This neuron loss is in the presence of Lewy bodies and Lewy neurites in certain regions of the nervous system (Halliday, Lees, and Stern 2011). These eosinophilic inclusions are normally noticed in the brain regions with the most neuron loss in PD. Some examples of these regions include the brainstem, substantia nigra, and the cortex. When LB attack the brainstem, it will cause symptoms such as constipation, depression, and sleep disorders. Motor control symptoms such as tremor, slowness, and stiffness will occur when LB are present in the substantia nigra. Beyond the brainstem, LB can also affect the cortex and cause cognitive problems. Cognitive functions, such as, planning, multitasking, ordering, navigating, and memory can be affected. When memory is affected by LB it is referred to as Parkinson’s disease dementia (Gilbert 2018).

Etiology

In the 20th century, heritability was not thought to be a factor of the disease; only environmental factors were the cause (Moore, et al. 2005). Today the genesis of Parkinson’s disease is unknown, but gene mutations and environmental factors are considered causative factors (Bhat, et al. 2018).

Gene Mutations

About twenty percent of PD cases are presumed to be genetic (Bhat, et al. 2018). Out of ten distinct genetic loci associated with PD, only four have been discovered to have mutations which cause familial forms of PD (Moore, et al. 2005). Familial forms of PD are present in patients who have a mutation in their genes which are either hereditary or sporadic. New studies have reported there are mutations in five of these genes. Familial cases of Parkinson’s disease can be caused by mutations in the LRRK2 (leucine-rich repeat kinase 2), PARK 7 (Parkinsonism Associated Deglycase), PRKN (Parkin RBR E3 Ubiquitin Protein Ligase), PINK 1 (PTEN-induced putative kinase 1), or SNCA (alpha-synuclein) (Bhat, et al. 2018). Some of these gene mutations may also play a role in cases that are not inherited. Alterations in some genes, such as GBA (glucocerebrosidase) and UCHL1 (Ubiquitin C-Terminal Hydrolase L1), modify the risk of developing the disease at a higher rate in some families. It has been found that individuals with GBA-related PD are prone to showing signs of changes at an earlier age than non GBA-related PD patients (Bhat, et al 2018). According to the U.S. National Library of Medicine governmental website, “It is not fully understood how genetic changes cause Parkinson’s disease or influence the risk of developing the disorder” (Parkinson’s disease). Although it is not fully understood, it does appear that gene mutations get in the way of the cell’s that break down unwanted proteins in DA neurons. This causes the accumulation of undegraded proteins which leads to the degeneration of DA neurons.

Environmental factors

[bookmark: _Hlk22131561]Many environmental factors have been linked to the progression or increased risk of developing Parkinson’s disease. Some environmental factors include pesticides, lack of vitamin D, lack of exercise, and head injuries (Parkinson’s Disease and Environmental Factors 2014). There are several animal and human studies that provide evidence that link pesticide exposure to PD. Organochlorine insecticides are found to be most commonly related to the disease. These chemicals are found in pesticides like DDT and dieldrin. DDT is used for mosquito control and dieldrin is used for termites (Parkinson’s Disease and Environmental Factors 2014). Researchers have investigated the role of vitamin D deficiency in the development of PD because majority PD patients lack vitamin D. “NIEHS in-house researchers have show that there is at least one more reason to exercise on daily basis—it may protect against Parkinson’s disease” (Parkinson’s Disease and Environmental Factors 2014). Middle aged people who engage in moderate to high intensity exercise daily have shown to be at a lower risk of getting Parkinson’s. Another causative factor of PD could be from head injuries. A head injury can cause inflammation of the brain and oxidative stress which may play a role in neuronal degeneration and PD. Many studies have looked at the link of head injuries to PD and have found that this association may be affected by genetic factors. Researchers have found that the Parkinson’s gene, SNCA, could modify the link between head injury and PD (Parkinson’s Disease and Environmental Factors 2014).

Diagnosis

There is no specific test to diagnose a person with Parkinson’s disease, but there are other ways to diagnose the disease. Diagnosis of PD can be determined by a trained neurologist. The doctor will diagnose the disease based on medical history, a review of symptoms, and a neurological and physical exam. The physician will only consider the disease if the patient displays two out of the four major symptoms: tremor, postural instability, rigidity, and bradykinesia (slowness of movement). If a patient shows these signs, then the doctor will determine his/her level of certainty through the patient’s medical history and examinations. (Diagnosing Parkinson’s).

It can be hard to determine a diagnosis on just symptoms and medical history, so biological markers are used. Biological markers are used to determine individuals with a high risk of developing PD and to monitor the progression of the disease. “Markers such as cerebrospinal fluid tests, non-motor clinical symptoms of PD, and several imaging modalities are used as early diagnostic measures of PD” (Bhat, et al. 2018). Cerebrospinal fluid tests take a sample of cerebrospinal fluid to test for conditions that affect the brain and spinal cord. Non-motor symptoms of PD include depression, anxiety, irritability, cognitive difficulties, and hallucinations. Examples of some neuroimaging used to measure changes in PD patients are magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). An MRI can be used to look for structural changes to the substantia nigra, a SPECT is used to find functional changes and loss of DA neurons in the nigrostriatal pathway, and a PET scan can be used to find low levels of dopamine in a PD brain. Once a person is diagnosed with PD, they will be monitored by their specialist to determine the disease’s progression. The degrees of progression are categorized into three subtypes: mild, moderate, and advanced. There are scales used to measure the progression. Mild symptoms include movement problems on one side of the body, body posture and facial expression changes, and slight difficulty in walking. Moderate symptoms include movement problems on both sides of the body, impaired balance and coordination, and freezing episodes. Advanced symptoms include impaired cognition, significant difficulty in walking, and dependence on others. These scales that measure PD progression are called, “The United Parkinson’s Disease Rating Scale” and “Hoehn and Yahr scale” (Bhat, et al. 2018).

References

Bhat, et al. (24 July 2018). Parkinson’s Disease: Cause factors, measurable indicators, and early diagnosis. Retrieved from https://www.sciencedirect.com/science/article/pii/S0010482518302701?via%3Dihub
Diagnosing Parkinson’s: American Parkinson Disease Assoc. (2019). Retrieved from https://www.apdaparkinson.org/what-is-parkinsons/diagnosing/
Halliday, Lees, and Stern. (2011) Milestones in Parkinson’s Disease—Clinical and Pathological Features. Retrieved from https://www.wileyonlinelibrary.com
Gilbert, R. (2018, May 15). Lewy Bodies, Dementia, and Parkinson’s – What Does it all Mean? Retrieved October 15, 2019, from https://www.apdaparkinson.org/article/understanding-parkinsons-disease-dementia-lewy-bodies/
Moore, et al. (25 Jan 2005). Molecular Pathophysiology of Parkinson’s Disease. Retrieved from http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.321.4079&rep=rep1&type=pdf
Parkinson’s – Anatomy, Pathology, Prognosis and Diagnosis. (n.d.). Retrieved from https://www.physio-pedia.com/Parkinson’s_-_Anatomy,_Pathology,_Prognosis_and_Diagnosis
Parkinson disease – Genetics Home Reference – NIH. (n.d.). Retrieved from https://ghr.nlm.nih.gov/condition/parkinson-disease.
Parkinson’s Disease and Environmental Factors: NIH. (Feb. 2014) Retrieved from https://www.niehs.nih.gov/health/materials/parkinsons_disease_and_environmental_factors_508.pdf
Shahmoradian, et al. (July 2019). Lewy Pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nature Neuroscience. Retrieved from https://doi.org/10.1038/s41593-019-0423-2
Zigmond, M. J., & Burke, R. E. (2002). PATHOPHYSIOLOGY OF PARKINSON’S DISEASE. Retrieved from https://acnp.org/wp-content/uploads/2017/11/C123_1781-1794.pdf

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