پارکینسون

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MOLECULAR PATHOLOGY OF PARKINSON’S DISEASE(PD) 

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CEREBRUM touch vision hearing, speech reasoning, rotons, eaming fie control rt BRAIN STEM ray center comectng the movements cerebrum and ereblm to the spina cordbreting, ear rate, body temperate CEREBELLUM eat ate, body temperature, Coordinate musde vate and sep yl digestion, rmoverens, maintain sneezing coughing vomiting, posture, and balance ‘iting, and swallowing 

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Cerebrum 

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Brain Stem 

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Cerebellum Cerebellum 

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History First Desciption of Parkinson’s disease. Surgeon Geologist Palaeontologist He is best known for his 1817 work, An Essay on the Shaking Palsy, in which he was the first to describe "paralysis agitans", a condition that would later be renamed Parkinson's disease by Jean-Martin Charcot. Dr. James Parkinson 

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Jean-Martin 01 » Neurologist and professor of anatomical pathology. ° Charcot's primary focus was neurology. He named and was the first to describe’ multiple sclerosis. © Charcot's name is associated with many diseases and conditions including: ° Charcot's artery (lenticulostriate artery) ° Charcot's joint (diabetic arthropathy) © Charcot's disease (amyotrophic lateral sclerosis, the most-common subtype of motor neurone disease—also known as Lou Gehrig's disease.) ۶ Charcot-Marie-Tooth disease (peripheral muscular atrophy), named with Pierre Marie and Howard Henry Tooth. ° Charcot-Wilbrand syndrome (visual! agnosia and loss of ability to revisualise images), named with Hermann Wilbrand. 

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Jean-Martin 01 » Charcot's intermittent hepatic fever (intermittent pain, intermittent fever, intermittent jaundice, and loss of weight) ° Charcot-Bouchard aneurysms (tiny aneurysms of the penetrating branches of middle cerebral artery in hypertensives), named with Charies-Joseph Bouchard, © Charcot's triad of acute cholangitis (right upper quadrant pain, jaundice, and fever) © Charcot's triad of multiple sclerosis (nystagmus, intention tremor, and dysarthria) » Charcot-Leyden crystals due to the lysis of eosinophils in cases of allergic diseases, named with Ernst Viktor von Leyden. » Souques-Charcot geroderma: a variant of Hutchinson-Gilford disease, named with lexandre-Achille Souques.4 ° Charcot-Gombault necrosis: a biliary infarct, named with Alber’ Gombault. 

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What is Parkinson? It is neurodegenerative disorder characterized by the progressive loss of the Dopaminergic neurons in the substantia nigra pars compacta which innervates the dorsal striatum. PARKINSON’S DISEASE 

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Epidemiology ° Parkinson's disease (PD) affects 1-2 per 1000 of the population at any time. ° PD prevalence is increasing with age and PD affects 1% of the population above ۱۱1۱19 ۱۱۱ ۱۱۱۱۱۳ عا فاك ۱۱۱۷ 

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Symptoms SYMPTOMS OF PARKINSON'S ‘Tremor of the head ‘Swallowing Indistinct problems speech Weight Hand loss tremors The inclination of Stiffness of muscles the head and body Difficulty in movement Constipation, urinary incontinence 

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Clinical Presentation ° Bradykinesia (akinesia) ° This is a lack or difficulty in initiating voluntary muscle movement & in advanced stages is characterized by ‘frozen” muscle. ° Muscular rigidity ° This is usually of the plastic type i.e. it gives way in series of jerks. ° Resting tremor ° Repetitive muscle activity usually worse when the patient at rest. ° An impairment of postural balance leading to disturbances of gait and falling. ° Parkinsonian patients also display depressed mood and cognitive deficit. ° Secondary characteristics ° Impaired speech - muscle weakness - autonomic hyperactivity eg. Salivation. 

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Famous people with PD Cassius Marcellus Clay Jr.(.Muhammad Ali clay) ۱ « 

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Pathophysiology ° Parkinson disease is caused by the death of the nerve cells in the substantia nigra, which produce the neurotransmitter dopamine. ° Without dopamine, the brain is unable to transmit messages between nerve cells, resulting in a decrease in muscle function. © When 80% of dopamine producing cells are damaged, the symptoms of Parkinson disease start to appear. 

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Diagnosis © + The patient has BRADYKINESIA, Plus One or More © Classic Rest Tremor Muscular ° Rigidity Postural Instability ° without other explanation. © © CE-Computed Tomography ° ¢ MRI-Magnetic Resonance Imaging Axial T2 MR images compare normal midbrain with parkinson disease"s midbrain. Second image shows blurring and thinning of pars compacta. Subsequently, the red nuclei and substantia nigra are almost touching. 

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Pathogenesis ° 1. Oxidative Stress ° Neurons depends on oxidative metabolism for survival in which shows production of reactive compound such as H2O2and oxiradicals is may lead to cell death. © 2. Apoptosis ° It is a process of programmed cell death. It often associated with excitotoxicity. -Genetics. ° 4, Enviromental Triggers. Infectious agent © + Environmental Toxins © + Acquired brain injury 

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Stages The Staves ot Parkinson's Disease 3 4 5 ل 00 مهو ‎balance, Pent) bound or‏ ‎bed-ridden‏ ال ماه ۷/۵۵۵۱ تن ۳ ۵ Apomorphine HCI: A Promising Drug to Help Parkinson's Patients draws ‎and Mechanisms» Acessories ond Accouterments‏ موف ‎A Colrfl Pos * Side fects‏ + ‎+ Recommendations for Use felis era ne ‏حمستس موده لومس سارحو واه‎ ‎ 

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Lewy Bodies are abnormal aggregations of protein that develop inside nerve cells They are identified under the microscope when histology is performed on the brain. Lewy bodies may be found in the brainstem (within the substantia nigra) or within the cortex. 

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ETIOLOGIC FACTORS Aging ° The possible role of aging in the pathogenesis of PD is suggested by its usual occurrence in late middle age, and by marked increases in its prevalence at older ages. ° The possible contribution of age to the expression of the disease is further supported by early studies showing a loss with age of striatal DA .and DA of cells in the SN. ° For example, although the number of dopaminergic terminals appears to decrease with age, this takes place with a different temporal and spatial pattern than occurs in PD .The loss of SN neurons in aging is linear and predominantly in the dorsal tier of the SNpc, whereas in PD it is ° exponential and predominantly in the lateral ventral tier .In addition, the SN in PD contains numerous reactive microglia, which are much less frequent in agematched control brains, indicating an active destructive process that is not present in the normal aged brain. ° Thus, whereas there is no question that increased age is a risk factor for PD, it remains unclear what precise role aging plays in pathogenesis. 

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Synuclein Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. >is abundant in the brain while smaller amounts are found in the heart, muscle, and other tissues. en the brain, alpha-synuclein is found mainly at the tips of nerve cells (neurons) in specialized structures called presynaptic terminals. °It is predominantly expressed in the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum. It is predominantly a neuronal protein, but can also be found in the neuroglial cells. °In rare cases of familial forms of Parkinson's disease, there is a mutation in the gene coding for alpha-synuclein. Five point mutations have been identified thus far: A537T,A30P'E46K, H50Q, and G51D. 

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Parkinson’s disease is the second most prevalent neurodegenerative disorder. Clinically, this disease is characterized by bradykinesia, resting tremors, and rigidity due to loss of dopaminergic neurons within the substania nigra section of the ventral midbrain. In the normal state, release of the neurotransmitter dopamine in the presynaptic neuron results in signaling in the postsynaptic neuron through D1- and D2-type dopamine receptors. D1 receptors signal through G proteins to activate adenylate cyclase, causing cAMP formation and activation of PKA. D2-type receptors block this signaling by inhibiting adenylate cyclase. Parkinson’s disease can occur through both genetic mutation (familial) and exposure to environmental and neurotoxins (sporadic). Recessively inherited loss-of-function mutations in parkin, DJ-1, and PINK1 cause mitochondrial dysfunction and accumulation of reactive oxidative species (ROS), whereas dominantly inherited missense mutations in a-synuclein and LRRK2 may affect protein degradation pathways, leading to protein aggregation and accumulation of Lewy bodies. Mitochondrial dysfunction and protein aggregation in dopaminergic neurons may be responsible for their premature degeneration. Another common feature of the mutations in a-synuclein, Parkin, DJ-1, PINK1, and LRRK2 is the impairment in dopamine release and dopaminergic neurotransmission, which may be an early pathogenic precursor prior to death of dopaminergic neurons. Exposure to environmental and neurotoxins can also cause mitochondrial functional impairment and release of ROS, leading to a number of cellular responses including apoptosis and disruption of protein degradation pathways. There is also an inflammatory component to this disease, resulting from activation of microglia that cause the release of inflammatory cytokines and cell stress. This microglia activation causes apoptosis via the JNK pathway and by blocking the Akt signaling pathway via REDD1