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The Pathology of Parkinson’s Disease

By Keionna Newton

Parkinson’s disease (PD) is a progressive, aging-related neurodegenerative disease first described in Western medicine in 1817 by James Parkinson (Goetz, 2011). Second only to Alzheimer’s disease, PD is one of the most common neurodegenerative diseases in the United States. The National Institute of Neurological Disorders and Stroke (NINDS) estimates that there are 500,000 patients currently living with the disease. A study supported by the Parkinson’s Foundation found that nearly 90,000 people in the U.S. are diagnosed with PD each year (Parkinson’s Foundation, 2024). Given that the biggest risk factor for developing PD is age, as most people are diagnosed after the age of 60, the Parkinson’s Foundation Prevalence Project estimates that approximately 1.2 million people will be living with PD in the U.S. by the year 2030. Like most pathologies, PD is a complex, multifaceted disease with a variety of genetic and environmental factors that contribute to its development and progression. So, where are we now in our current understanding of PD?

The Etiology of PD

PD is characterized by resting tremors, bradykinesia (i.e., slowness of movement), muscle rigidity, and a shuffling gait (Tsalenchuk et al., 2023). There are also potential disturbances in cognition, mood, and sensory experiences. These symptoms can include anxiety, depression, apathy, sleep disturbances, dementia, hallucinations/delusions, and even changes in vision and loss of smell (Parkinson’s Foundation, 2024). The primary pathological marker of PD is the death of dopamine-producing neurons in a part of the brain known as the Substantia Nigra pars compacta (SNpc), leading to an overall reduction in dopamine (Giguere et al., 2018). Dopamine is an important chemical produced in the brain that controls things like learning, emotional responses, and movement. The reduction of dopamine in the SNpc, a brain region involved in regulating things like motor control and cognition, ultimately leads to the movement disturbances observed in PD patients (Giguere et al., 2018). As PD progresses, Lewy bodies form inside of neurons in the SNpc, as well as other brain regions (Spillantini et al., 1998). Lewy bodies are inclusions inside cells that consist of aggregated, misfolded proteins known as alpha-synuclein (α-syn) and are a common pathological feature of many neurodegenerative diseases (Marotta et al., 2021; Spillatini et al., 1998).  

PD is characterized by resting tremors, bradykinesia (i.e., slowness of movement), muscle rigidity, and a shuffling gait

PD: Nature and Nurture Influences

In the advent of improved genetic testing and sequencing technologies, several major gene mutations have been identified and implicated in PD. The LRRK2 gene is the most frequent cause of familial (i.e., inherited) PD and late-onset PD, defined as PD diagnosed after 50 years of age (Cherian & Divya, 2020; Ferguson et al., 2016). In contrast, patients with mutations to the SNCA gene tend to have early-onset (i.e, before the age of 50 years) PD, but progress more rapidly than those with LRRK2 gene mutations (Polymeropoulos et al., 1996). Additionally, mitochondrial dysfunction has also been implicated in the development of PD (Inamdar et al., 2007). Mitochondria are small organelles inside cells and are often known as the “powerhouse of the cell” in that they provide metabolic energy for the cell. Research suggests genetic mutations in mitochondrial genes lead to a breakdown in cell metabolism in PD (Inamdar et al., 2007). However, the genetic, familial forms of PD only represent a small fraction (~15% of cases) of those diagnosed with PD (Tran et al., 2020). Most people that are diagnosed with PD present with the sporadic, non-inherited form of PD and have no known family history of the disease, with 85% of people presenting with this form of PD (Tran et al., 2020). Research has indicated a positive correlation between PD and certain environmental risk factors including exposure to pesticides, consumption of low-fat dairy products, traumatic brain injury, and exposure to heavy metals (Tsalenchuk et al., 2023).

The Gut-Brain Connection in PD

In the 1980s, researchers found α-syn deposits in the gastrointestinal tracts of PD patients (Wakabayaski et al., 1988). Later autopsy studies performed on PD patients led to the development of a hypothesis that stated that the gut-to-brain propagation of α-syn via the vagus nerve was the main cause of sporadic PD (Braak et al., 2003). Since then, there have been numerous clinical and preclinical studies demonstrating the role for dysregulation of the gut microbiome in PD patients. One study has shown that conditions like “leaky gut,” where the intestinal tract is more permeable and inflamed, seem to be more common in people with PD compared to the average population, further suggesting a gut-brain axis correlation in the disease (Forsyth et al., 2011). 

… several major gene mutations have been identified and implicated in PD. The LRRK2 gene is the most frequent cause of familial (i.e., inherited) PD and late-onset PD…

Treatment for PD Patients 

With such a devastating disease on the rise, what treatments are currently available for those already living with PD? Below are some common treatment options:

  1. Levodopa (L-DOPA): Levodopa is a precursor to dopamine and is prescribed by doctors in the form of oral tablets as a replacement agent for dopamine to treat the motor symptoms of PD (Parkinson’s Foundation, 2024).
  2. Deep brain stimulation (DBS): In DBS, an electrode is surgically implanted into a specific region of the patient’s brain and electrical impulses are sent into the brain which has been shown to drastically reduce the motor symptoms of PD (Parkinson’s Foundation, 2024). Improvements in non-motor symptoms such as sleep disturbances and pain have also been observed after DBS surgery (Parkinson’s Foundation, 2024). There are three main target regions in the brain that have been approved by the FDA for DBS surgery which include the subthalamic nucleus (STN), globus pallidus interna (GPi), and pedunculopontine nucleus. However, which of these specific brain regions to target is tailored to the specific patient’s case, with the most common target regions being the STN and GPi (Parkinson’s Foundation, 2024). Despite the emerging benefits, due to the invasiveness of this treatment strategy, it is typically reserved for patients with more advanced forms of PD who are not responsive to traditional treatments (i..e, L-DOPA treatment).
  3. Virtual reality simulations: A novel and exciting treatment option that has emerged in our new age of technology is the use of immersive virtual reality video games to treat patients with mild-to-moderate PD. One study of 41 participants, all aged 65 and older, provided an immersive exercise experience for PD patients (Campo-Prieto et al., 2021). There were four different exercise training environments patients could choose from, all with a focus of making quick motor responses to various stimuli in the VR game. The VR games were focused on continuous movement of the entire body, including focus on improving joint range, muscle strength, endurance, and muscle power (Campo-Prieto et al., 2021). VR Participants showed significant improvements in their gait, balance, handgrip strength, and cognition.

Exercising regularly is an important way to reduce your risk for a wide array of diseases, and it is known to especially help in the case of movement disorders like Parkinson’s

Preventive Strategies for PD

With all the complex, multifaceted risk factors involved in the development and progression of PD, what can we do to help mitigate risk? Below are some known approaches that anyone can take to help reduce their risk against PD: 

  1. Consume a Healthy Diet: Research shows that eating a healthy diet, eliminating processed foods, and limiting consumption of low-fat dairy products can lower your risk of developing a host of diseases, including PD (Hughes et al., 2017). Maintaining a healthy diet also goes hand-in-hand with creating a healthy gut microbiome which is another important factor to consider in light of the evidence on the connection between gut dysfunction and PD (Forsyth et al., 2011).
  2. Engage in Exercise: Exercising regularly is an important way to reduce your risk for a wide array of diseases, and it is known to especially help in the case of movement disorders like Parkinson’s. The Parkinson’s Foundation states that for PD patients specifically, exercise routines should include aerobic activity, strength training, balance, agility, multitasking training, and flexibility training. Patients who exercised for at least 2.5 hours per week earlier on in their diagnosis showed an improvement in their quality of life compared to those who started exercising later on in their disease progression (Parkinson’s Foundation, 2024).
  3. Consume Coffee Regularly: Interestingly, recent research has found that consumption of coffee is negatively correlated with developing PD (Hong et al., 2020). This has been corroborated by many studies, though the reasons are still somewhat unclear. Many studies speculate it is the caffeine component itself that has disease-modifying capabilities, and those who regularly consume coffee (defined as 2.5mg/kg of body weight, or roughly 2 cups of coffee per day) are at lower risk for developing PD than those who do not (Ren & Chen, 2020; Ascherio et al., 2003; Ascherio et al., 2004; Fujimaki et al., 2018; Wikoff et al., 2017). 

Although we are still in the early stages of understanding all of the mechanisms that go into the development of Parkinson’s disease, a plethora of exciting new research holds a mountain of promise. We are now on the horizon of understanding the nature and nurture components of PD development. Novel treatment advancements and methods for reducing risk of developing PD will only continue to grow as we make new strides with our technology.

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Written by Keionna Newton
Illustrated by Vidya Saravanapandian
Edited by Alli Lindquist, Gabrielle Sarlo, and Daniel Janko

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Campo-Prieto, P., Rodríguez-Fuentes, G., & Cancela-Carral, J. M. (2021). Can Immersive Virtual Reality Video games Help Parkinson’s Disease Patients? A case study. Sensors21(14), 4825. 

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Author

  • Keionna Newton

    Keionna is currently pursuing her PhD in Neuroscience in the lab of Dr. Lindsay De Biase at UCLA. She graduated from the University of Washington in 2021 where she used mouse models to investigate the cellular and molecular mechanisms of stress, pain, and addiction, with particular focus on kappa opioid receptors. Now at UCLA, Keionna’s research is focused on understanding how microglia modulate dopamine neuron circuitry in health and disease. Outside of the lab, Keionna enjoys hiking, backpacking, painting, reading books, and playing her guitar.

Keionna Newton

Keionna is currently pursuing her PhD in Neuroscience in the lab of Dr. Lindsay De Biase at UCLA. She graduated from the University of Washington in 2021 where she used mouse models to investigate the cellular and molecular mechanisms of stress, pain, and addiction, with particular focus on kappa opioid receptors. Now at UCLA, Keionna’s research is focused on understanding how microglia modulate dopamine neuron circuitry in health and disease. Outside of the lab, Keionna enjoys hiking, backpacking, painting, reading books, and playing her guitar.