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Pathophysiology of Parkinson's Disease

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So this is part two of my research into cognitive impairments. In this section, I will cover the pathophysiology of parkinson's disease as well its treatment using deep brain stimulation.

Motivations

So why am I addressing parkinsons? Well parkinsons is the 2nd most common neurodegenerative disease behind Alzheimer’s with 6 million cases globally or roughly 1 in every 1000 people. Initially I didn't know much about parkinsons or its characteristics. However, I took an interest in this disease after realising that Muhammad Ali actually had it. And actually reading into it a little, I became subtly curious about the disease, hence I decided to commit the second part of this series to detail what I have discovered about Parkinson's Disease.

Mechanism of parkinson's

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So let's start from the ground up by defining Parkinsons. Parkinson's disease (PD) is a neurodegenerative disorder characterised by a loss of dopaminergic neurons in the substantial night (basal ganglia). This induces severe motor and non- motor dysfunction, such as akinesia, tremors, rigidity, postural instability, cognitive impairment and depression. This is however a non exhaustive list as the impacts of neurodegeneration vary depending on individual characteristics.

These impacts manifests in movement disorders which is the hallmark of parkinson's such as :

  1. "Shuffling gait" where the individual is only able to take small steps, in a hunched over position with little arm movement during walking.

  2. Difficulty turning where the individual can walk but has trouble changing direction or rotating his body.

  3. Freezing where the individual feels upon random movements such as getting up from a chair or walking through a door. 

  4. Impaired ocular movement where the individual lacks control over where they look

  5. Dystopia which is the spasmodic twisting of the neck. 

Knowing this, the next logical line questioning would be to ask how. What is the biology behind this disease which causes the presenting symptoms and impacts. To understand this we must study the distinctive pathology of PD. Well PD is not caused by any one specific reason. Rather, it's progression is of a multifactorial nature, meaning its progression from early to mid to late stages is determined by multiple factors.
The first factor are clumps of misfolded proteins called alpha-synuclein in neurons, most commonly lawyers bodies. The alpha-synuclein forms oligomers/fibrils that are toxic to neurons hence leading to death of brain cells and neurodegeneration. 
Neurodegeneration may be further expedited by an impairment of certain mitochondria processes. Hence proper neuron functions cannot be sustained due to energy restrictions which leads to cellular death overtime.
The third contributing factor are cells in the brain called "microglia". These cells take up cellular debris and alpha-synuclein from the loss of dopaminergic neurons which triggers an immune response that damages more neurons in brain tissue.
Lastly, although this is purely conjectural at this point in time, the transmission of alpha-synuclein between neurons at synapses facilitates progression of parkinson's. 
Hence depending how many of these factors the person has, this would affect the speed of PD progression in an individual and their presenting symptoms.

Stage progression of Parkinson's

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The stage life progression of parkisons can be best represented in the image below. The initial 10 to 20 year before the appearance of any symptoms is known as the prodromal phase. During this period, the inidividual will be largely unaffected by the disorder and will likely not notice that they are pre-symptomatic for PD. 

Upon the onset of non-motor symptoms, the patients overall well being will see a downward trend, soon after moto symptoms will set in such as Akinesia, rigidity and tremors. This period is of roughly 10 years is known as the early stage of PD. During both the early and Prodromal stage, DBS and or dopamine medication will be highly effective in abating movement symptoms, providing the patient with an addition few hours of good movement control everyday.

This gradually loses its effectiveness as PD progresses to its mid stages where Axial deformities, Dysphagia and Postural Instability begin to take hold. 

In the final stages of PD, both DBS and medications would cease being effective. 

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Older treatment methods

Older treatment methods were based on the theory that since Parkinson's was caused by a loss of dopaminergic neurons, proving dopamine medication would help treat the symptoms.

Giving some background information, the basal ganglia in the brain is responsible for the secretion of dopamine. Insufficient levels of dopamine can be seen id the normally when the normally "blackish" substantia nigra turns grey in colour. 

To abate certain symptoms of neurodegeneration, a dopamine precursor (L-Dopa) is prescribed that passes through the blood brain barrier and is taken up by dopaminergic neurons that convert the L-Dopa to dopamine, increasing their dopamine production and storage. However this is a temporary solution as overtime, Dystopia (involuntary, erratic writhing movements of appendages) will set in again as an enzyme is produced to metabolise the L-Dopa before it can be converted to dopamine. Hence dosage would have to be progressively increased which increases risks on the patient. This may be circumvented using either Carbidopa to inhibit the metabolism of L-Dopa or Amantadine to enhance L-Dopa receptors.

Deep Brain Stimulation (DBS)

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A relatively new concept that may not be known to most, deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of neurotransmitters aka "brain pacemakers'' which sends electrical impulses through implanted electrodes for the treatment of symptoms of movement disorders, obsessive compulsive disorder and epilepsy. Which will be discussed in detail on a separate independent write up. The electrodes are inserted near the thalamus region of the brain, targeting the globulus pallidus and subthalamic nucleus. (Essential the thalamus and hippocampus)
After insertion, the voltage, length and frequency of electrical impulses can be remotely controlled by the individual to suit their needs and condition. It is important to note however that though DBS treats the symptoms of parkinson's, it does not prevent the progression of neurodegeneration.
Initially developed as an alternative treatment for PD, it is now widely accepted in the medical world as an effective treatment of movement disorder by reducing the "tremors" seen in patients thereby improving their quality of life

Mechanism of DBS

Currently, the mechanism behind DBS underlying effectiveness is yet to be scientifically established, but there are 3 presenting action mechanisms which the most likely explanation.

Inhibition,  Excitation, Disruption.

  1. DBS inhibits local neuronal elements

    1. This theory is supported by the fact that the most common recorded effects of DBS was a reduction of firing rates of neighbouring neurons but not a complete cessation of neuron firing.

    2. This leads scientists to believe that the electrical impulses from DBS inhibits neuron activity hence reducing the tremors like movements in individuals

  2. DBS disrupts abnormal information flow 

    1. This is based on the theory that the electrical impulses created by the neurostimulator activates axon terminals in specific regions of the brain to release large amounts of neurotransmitters that disrupts the transmission of electrical signals hence dissociating the inputs and outputs

  3. DBS excites local neuronal elements 

    1. Suprathreshold DBS induces spikes in the axons but not cell bodies.

References

  1. A, schematic figure of the rate model of parkinson's ... (n.d.). Retrieved February 17, 2022, from https://researchgate.net/figure/A-Schematic-figure-of-the-rate-model-of-Parkinsons-disease-The-major-nuclei-of-the_fig1_8219740

  2. C;, S.-B. E. R. J. R. B. C. M. (n.d.). A firing rate model of Parkinsonian deficits in interval timing. Brain research. Retrieved February 17, 2022, from https://pubmed.ncbi.nlm.nih.gov/16413510/

  3. Causes. Parkinson's Foundation. (n.d.). Retrieved February 17, 2022, from https://www.parkinson.org/Understanding-Parkinsons/Causes

  4. Chiken, S., & Nambu, A. (2016, June). Mechanism of deep brain stimulation: Inhibition, excitation, or disruption? The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. Retrieved February 17, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871171/

  5. Dadabhoy, D. S. (2021, December 6). Top tips: Parkinson's disease. Guidelines in Practice. Retrieved February 17, 2022, from https://www.guidelinesinpractice.co.uk/neurology-/top-tips-parkinsons-disease-/453543.article

  6. Deep brain stimulation for parkinson’s disease | singhealth. (n.d.). Retrieved February 17, 2022, from https://www.singhealth.com.sg/news/medical-news-singhealth/parkinson-disease-deep-brain-stimulation

  7. EN;, H. T. M. C. J. J. E. (n.d.). Mechanisms of deep brain stimulation. Journal of neurophysiology. Retrieved February 17, 2022, from https://pubmed.ncbi.nlm.nih.gov/26510756/

  8. Holtzheimer, P. E., & Mayberg, H. S. (2011). Deep brain stimulation for psychiatric disorders. Annual review of neuroscience. Retrieved February 17, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413475/

  9. Kouli, A. (2018, December 21). Parkinson's disease: Etiology, neuropathology, and pathogenesis. Parkinson's Disease: Pathogenesis and Clinical Aspects [Internet]. Retrieved February 17, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK536722/

  10. MediLexicon International. (n.d.). Dopamine and parkinson's disease: What to know. Medical News Today. Retrieved February 17, 2022, from https://www.medicalnewstoday.com/articles/dopamine-parkinsons#parkinsons-disease

  11. NatureVideoChannel. (2019, December 16). Understanding parkinson's disease. YouTube. Retrieved February 17, 2022, from https://www.youtube.com/watch?v=ckn9zybpYZ8

  12. Smith, Y. (2021, February 3). What does deep brain stimulation involve? News. Retrieved February 17, 2022, from https://www.news-medical.net/health/What-does-deep-brain-stimulation-involve.aspx

  13. U.S. Department of Health and Human Services. (n.d.). Deep Brain Stimulation (DBS) for the treatment of parkinson's disease and other movement disorders. National Institute of Neurological Disorders and Stroke. Retrieved February 17, 2022, from https://www.ninds.nih.gov/About-NINDS/Impact/NINDS-Contributions-Approved-Therapies/DBS

  14. U.S. Department of Health and Human Services. (n.d.). Parkinson's disease. National Institute on Aging. Retrieved February 17, 2022, from https://www.nia.nih.gov/health/parkinsons-disease

  15. Wikimedia Foundation. (2022, January 11). Pathophysiology of parkinson's disease. Wikipedia. Retrieved February 17, 2022, from https://en.wikipedia.org/wiki/Pathophysiology_of_Parkinson's_disease

  16. Wikimedia Foundation. (2022, January 31). Deep Brain stimulation. Wikipedia. Retrieved February 17, 2022, from https://en.wikipedia.org/wiki/Deep_brain_stimulation#Adverse_effects

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