1. PARKINSON’S
DISEASE
Prepared by:
Tayseer J. M. Afifi

2. JAMES PARKINSON

3. HEADINGS Disease Definition Pathology Classification Causes
Signs and Symptoms
Diagnosis, Prevention and Management
Research

4. Disease Definition

5. Disease Definition
Parkinson's disease is a progressive disorder of the nervous system that affects movement. It develops gradually, sometimes starting with a barely noticeable tremor in just one hand. But while a tremor may be the most well-known sign of Parkinson's disease, the disorder also commonly causes stiffness or slowing of movement.
In the early stages of Parkinson's disease, your face may show little or no expression, or your arms may not swing when you walk. Your speech may become soft or slurred. Parkinson's disease symptoms worsen as your condition progresses over time.

6. Disease Definition
In 2013, PD was present in 53 million people and resulted in about 103,000 deaths globally. Parkinson's disease typically occurs in people over the age of 60, of which about one percent are affected. Males are more often affected than females.

7. Pathology

8. Pathology, Anatomical The most affected area is the Basal Ganglia.
Basal Ganglia is innervated by dopaminergic system.
The main cell death is in the substantia nigra, specifically the ventral part of the pars compacta.

9. Pathology, Anatomical
The histopathology of the substantia nigra and several other brain regions shows neuronal loss and Lewy bodies in many of the remaining nerve cells. Neuronal loss is accompanied by death of astrocytes (star-shaped glial cells) and activation of the microglia (another type of glial cell). Lewy bodies are a key pathological feature of PD.
First picture: A Lewy body (stained brown) in a brain cell of the substantia nigra in Parkinson's disease. The brown colour is positive immunohistochemistry staining for alpha-synuclein.
Second picture: A. Schematic initial progression of Lewy body deposits in the first stages of Parkinson's disease, as proposed by Braak and colleagues B. Localization of the area of significant brain volume reduction in initial PD compared with a group of participants without the disease in a neuroimaging study, which concluded that brain stem damage may be the first identifiable stage of PD neuropathology
199 years of Parkinson disease - what have we learned
and what is the path to the future?
Schulz JB, Hausmann L, Hardy J.
1 Oct. 2016

10. Pathology, Pathophysiology
The primary symptoms of Parkinson's disease result from greatly reduced activity of dopamine-secreting cells caused by cell death in the pars compacta region of the substantia nigra.
There are five major pathways in the brain connecting other brain areas with the basal ganglia.
 motor, oculo-motor, associative, limbic and orbitofrontal circuits

11. Pathology, Pathophysiology
Scientifically, the motor circuit has been examined the most intensively.

12. Pathology, Pathophysiology
Low levels of dopamine function
Pathology, Pathophysiology
Basal ganglia exert inhibition on motor system.
Hypokinesia: overall reduction in motor output.
Prevent activity at inappropriate time.
Drugs: excessive dopamine activity
A decision to perform a particular action.
High levels of dopamine facilitate release of inhibition.
Inhibition is reduced, thereby releasing it for activation.
Dyskinesia: activation at inappropriate time.

13. Pathology, Brain Cell Death
Abnormal accumulation of α-synuclein*.
Bound to ubiquitin.
Accumulation inside neurons – Lewy Bodies.
Appear in olfactory bulb, medulla oblongata and  pontine tegmentum.
Develop until reach midbrain, substantia nigra and neocortex.
* α-synuclein is a protein that is abundant in the human brain. Smaller amounts are found in the heart, muscles, and other tissues. 
* In the brain, α-synuclein is found mainly at the tips of nerve cells (neurons) in specialized structures called presynaptic terminals.
* α-synuclein interacts with phospholipids and proteins. Presynaptic terminals release chemical messengers, called neurotransmitters, from compartments known as synaptic vesicles. The release of neurotransmitters relays signals between neurons and is critical for normal brain function.
* Studies suggest that it plays a role in maintaining a supply of synaptic vesicles in presynaptic terminals by clustering synaptic vesicles. 
* α-synuclein may also help regulate the release of dopamine,.

14. Pathology, Brain Cell Death
Events in alpha synuclein
Toxicity.
α-Synuclein and neuronal
cell death.
Cookson M.
4 April 2009

15. The Central Panel
Monomeric α-synuclein is natively unfolded but can also bind to membranes in an α-helical form.
Unfolded monomer can aggregate first into small oligomeric stabilized by β-sheet-like interaction.
Deposition of α-synuclein into pathological structures such as Lewy bodies.

16. The Left Side
Electrical activity in neurons stimulates polo-like kinase 2 (PLK2),
Phosphorylation of α-synuclein at Ser-129.
Truncation through proteases such as calpains, and nitration, probably through nitric oxide (NO). Present during inflammation.
Modify synuclein such that it has a higher tendency to aggregate.

17. The Right Side
Proposed cellular targets for α-synuclein mediated toxicity
ER-golgi transport, synaptic vesicles, mitochondria and lysosomes.
Each has detrimental effects.

18. Astrocytes Role in Parkinson: A Double-Edged Sword
Experimental models in PD. Many molecules are currently used in cellular and animal models of PD, including pesticides as paraquat or rotenone and neurotoxins such as 6-OHDA and MPP+. Paraquat, 6-hydroxydopamine (6-OHDA) and MPP+ easily cross cell membrane through the dopamine transporter (DA) thus inducing the formation of α-synuclein aggregates and mitochondrial impairment with the subsequent production of ROS and quinones. Compounds, as rotenone, are extremely hydrophobic and penetrate easily the cellular membrane of neurons and astrocytes. Rotenone may promote processes such as the formation of α-synuclein aggregates, and the genetic activation through the nuclear translocation of NF-κB. Additionally, as an inhibitor of mitochondrial complex I, rotenone causes the impairment of ATP, the generation of ROS and the release of proapoptotic molecules, such as cytochrome c that activate caspase 9, which trigger caspases 3, 6 and 7, and induce apoptosis.
Astrocytes Role in Parkinson: A Double-Edged Sword
Cabezas R, Avila M, Torrente D, Santos R, Morales L, Gonzalez J and Barreto G
May 15, 2013

19. Classification

20. Multiple System Degeneration
Classification
Parkinsonian syndromes can be divided into four subtypes, according to their origin:
Primary or idiopathic
Secondary or acquired
Hereditary
Multiple System Degeneration

21. Life is just about
Chances…

22. Causes

23. Causes Environmental Factors Head injuries.
Rural environment. (Well’s water)
Pesticide exposure. ( chlorpyrifos, organochlorines)
Herbicides. (ziram)
Heavy metals exposure.
U.S. Army helicopter spraying Agent Orange over
Vietnamese agricultural land during the Vietnam war.

24. Causes Genetic Factors
15% of individuals with PD have a first- degree relative who has the disease.
5% of people have forms of the disease that occur because of a mutation of one of several specific genes.
These genes code for alpha-synuclein (SNCA) are parkin, leucine-rich repeat kinase 2 (LRRK2), DJ-1 and ATP13A2.
Parkin crystal structure
Classification of Parkinson's Disease Genotypes in Drosophila Using Spatiotemporal Profiling of Vision.
24 Nov. 2015
West R. Elliott C. & Wade A.

25. Causes Genetic Factors
Mutations in genes including SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD. Mutations in GBA are known to cause Gaucher's disease.
Mutations in LRRK2 are the most common known cause of familial and sporadic PD.

26. Causes Genetic Factors
Several Parkinson-related genes are involved in the function of lysosomes, organelles that digest cellular waste products. It has been suggested that some forms of Parkinson may be caused by lysosome dysfunctions that reduce the ability of cells to break down alpha-synuclein.
Pharmacological LRRK2 kinase inhibition induces LRRK2
Protein destabilization and proteasomal degradation.
23 Sep. 2016

27. Signs and Symptoms

28. Signs and Symptoms Motor Tremor. Hypokinesia. Rigidity.
Postural instability.
Voice disorders.
Mask-like face expression.
Small handwriting.

29. Signs and Symptoms Neuropsychiatric
Neuropsychiatric disturbances can range from mild to severe, including:
Speech.
Cognition.
Mood.
Behavior.
Thought.

30. Signs and Symptoms Others
In addition to cognitive and motor symptoms, PD can impair other body functions, including:
Insomnia.
Autonomic nervous system. (orthostatic hypotension)
Oily skin.
Excessive sweating.
5. Urinary incontinence.
6. Altered sexual function.
7. Constipation.
8. Gastric dysmotility.
9. Double vision.
10. Paresthesia.

31. Diagnosis,
Prevention &
Management

32. Diagnosis Medical History. Neurological examination.
CT and MRI brain scan.
Finding of Lewy bodies.
Response to treatment.
NO LAB TESTS.

35. Prevention Exercise in middle age. Caffeine consumption.
Tobacco smoke. (dopamine stimulant)
Antioxidants. (vitamin C & D)
Protective role of estrogens and anti- inflammatory.

36. Management There is no cure for Parkinson’s disease.
Medications, surgery and multidisciplinary management can provide relief from the symptoms.
Management is determined by the stage of disease:
Initial stage.
Second stage.
Final stage.

37. Management Medication. Levodopa.
Dopamine agonist. (bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergo line, apomorphine and lisuride)
MAO-B inhibitors. (safinamide, selegiline and rasagiline)
Pharmacological treatment of PD
Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration.
6 Oct. 2016

38. Management
Surgery.
The number of operations declined since the discovery of Levodopa. But the great improvement in surgical techniques led to again use of surgery. Surgery for PD is divided into two main groups:
Lesional.
Deep Brain Stimulation (DBS).
Placement of an electrode into the brain.
The head is stabilized in a frame for
stereotactic surgery.
Genetic and Clinical Predictors of Deep Brain Stimulation
in Young-Onset Parkinson's Disease.
3 Sep. 2016

39. Management Rehabilitation. Regular physical activities.
Speech practice.

40. Management
Rehabilitation.
Live positively
You con do it…

41. Management Palliative Care.
Palliative care is specialized medical care for people with serious illnesses, including Parkinson's. The goal of this specialty is to improve quality of life for both the person suffering from Parkinson's and the family by providing relief from the symptoms, pain, and stress of illnesses.

42. Management Palliative Care.
Palliative care specialists can help with physical symptoms.
People with Parkinson's may have many difficult decisions to make as the disease progresses such as wishes for feeding tube, non-invasive ventilator, and tracheostomy; wishes for or against cardiopulmonary resuscitation; and when to use hospice care.

43. Research

44. Research Animal Models. Gene Therapy. Neuroprotective Treatment.
Neural Transplant.

46. Doughnut Which protein does accumulate in Parkinson’s?
Which one of brain areas is mostly affected? And what is the name of dead cells area?
Which gene is the most mutated frequently?

47. QUESTIONS

48. THANK YOU