课件：帕金森病PD.ppt

Parkinsons Disease,Zhanglu M.D. Ph.D. Department of Neurology,Outline:,Part A: Summary of Parkinsons disease Part B: Molecular biology of Parkinsons disease,PART A: Summary of Parkinsons disease 1. History 2. Epidemiology 3. Risk factors 4. Clinical features 5. Neuropathology 6. Functional neuroanatomy 7. Neurochemistry 8. Therapy 9. Diagnosis 10. Summary,History of Parkinsons disease (PD) First described in 1817 by an English physician, James Parkinson, in “An Essay on the Shaking Palsy.” The famous French neurologist, Charcot, further described the syndrome in the late 1800s.,History,James Parkinson (1755-1824), while best remembered for the disease state named after him by Charcot, was a man of many talents and interests.,Publishing on chemistry, paleontology and other diverse topics, he was, early in his career, a social activist championing the rights of the disenfranchised and poor. His efforts in this area were enough to result in his arrest and appearance before The Privy Council in London on at least one occasion. In collaboration with his son, who was a surgeon, he also offered the first description, in the English language, of a ruptured appendix.,AN ESSAY ON THE SHAKING PALSY CHAPTER I DEFINITION-HISTORY-ILLUSTRATIVE CASES SHAKING PALSY. (Paralysis Agitans.),Monograph by James Parkinson 1817,James Parkinson,History of Parkinsons Disease,His small but famous publication, “Essay on the Shaking Palsy“, appeared in 1817, 7 years before his death in 1824.,The clinical description of 6 patients was a remarkable masterpiece testifying to his prodigious powers of observation for most of the 6 were never actually examined by Parkinson himself; rather, they were simply observed walking on the streets of London.,Epidemiology of PD The most common movement disorder affecting 1-2 % of the general population over the age of 65 years. The second most common neurodegenerative disorder after Alzheimers disease (AD).,Incidence of PD,Age,Incidence / 100 000,Prevalence of PD,Age,Prevalence / 100 000,Epidemiology of PD,May be less prevalent in China and other Asian countries, and in African-Americans. Prevalence rates in men are slightly higher than in women; reason unknown, though a role for estrogen has been debated.,Risk factors of PD Age - the most important risk factor Positive family history Male gender Environmental exposure: Herbicide and pesticide exposure, metals (manganese, iron), well water, farming, rural residence, wood pulp mills; and steel alloy industries Race Life experiences (trauma, emotional stress, personality traits such as shyness and depressiveness)? An inverse correlation between cigarette smoking and caffeine intake in case-control studies.,Etiology of Parkinsons Disease,Degeneration of the substantia nigra (with Lewy bodies ?),Parkinsons disease,PARK-1 (a-Synuclein),PARK-2 (Parkin),mitochondrial dysfuction ?,oxidative stress ?,genetic susceptibilies Debrisoquin hydroxylase ?,PARK- 5 (Ubiquitin C terminal hydrolase L1),Toxins? (MPTP, Rotenone),Neuroinflammation ?,Infection,PARK- 4 (3x a-Synuclein),PARK- 7 (DJ1),Parkinsons Disease,The basal ganglia, through the action of dopamine, are responsible for planning and controlling automatic movements of the body, such as pointing with a finger, pulling on a sock, writing or walking. If the basal ganglia are not working properly, as in Parkinsons disease patients, all aspects of movement are impaired, resulting in the characteristic features of the disease slowness of movement, stiffness and effort required to move a limb and, often, tremor.,Clinical features of PD,Three cardinal symptoms: resting tremor bradykinesia (generalized slowness of movements) muscle rigidity,Clinical features of PD Resting tremor: Most common first symptom, usually asymmetric and most evident in one hand with the arm at rest. Bradykinesia: Difficulty with daily activities such as writing, shaving, using a knife and fork, and opening buttons; decreased blinking, masked facies, slowed chewing and swallowing. Rigidity: Muscle tone increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints; stooped posture, anteroflexed head, and flexed knees and elbows.,Additional clinical features of PD Postural instability: Due to loss of postural reflexes. Dysfunction of the autonomic nervous system: Impaired gastrointestinal motility, bladder dysfunction, sialorrhea, excessive head and neck sweating, and orthostatic hypotension. Depression: Mild to moderate depression in 50 % of patients. Cognitive impairment: Mild cognitive decline including impaired visual-spatial perception and attention, slowness in execution of motor tasks, and impaired concentration in most patients; at least 1/3 become demented during the course of the disease.,Clinical Stage,Parkinsons Disease,Neuropathology of PD Eosinophilic, round intracytoplasmic inclusions called lewy bodies and Lewy neurites. First described in 1912 by a German neuropathologist - Friedrich Lewy. Inclusions particularly numerous in the substantia nigra pars compacta.,Lewy bodies,Neuropathology of PD,What feature have you observed?,Asymmetric lesions,Neuropathology of PD: Lewy bodies Not limited to substantia nigra only; also found in the locus coeruleus, motor nucleus of the vagus nerve, the hypothalamus, the nucleus basalis of Meynert, the cerebral cortex, the olfactory bulb and the autonomic nervous system. Confined largely to neurons; glial cells only rarely affected.,Lewy bodies,Functional neuroanatomy of PD Substantia nigra: The major origin of the dopaminergic innervation of the striatum. Part of extrapyramidal system which processes information coming from the cortex to the striatum, returning it back to the cortex through the thalamus. One major function of the striatum is the regulation of posture and muscle tonus.,Substantia nigra and the extrapyramidal system,Neurochemistry of PD Late 1950s: Dopamine (DA) present in mammalian brain, and the levels highest within the striatum. 1960, Ehringer and Hornykiewicz: The levels of DA severely reduced in the striatum of PD patients. PD symptoms become manifest when about 50-60 % of the DA-containing neurons in the substantia nigra and 70-80 % of striatal DA are lost.,Dopamine pathways in human brain,Dopamine synthesis,Therapy of PD: levodopa Late 1950s: L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of DA that crosses the blood-brain barrier, could restore brain DA levels and motor functions in animals treated with catecholamine depleting drug (reserpine). First treatment attempts in PD patients with levodopa resulted in dramatic but short-term improvements; took years before it become an established and succesfull treatment. Still today, levodopa cornerstone of PD treatment; virtually all the patients benefit.,SINEMET (CARBIDOPA-LEVODOPA) DESCRIPTION SINEMET* (Carbidopa-Levodopa) is a combination of carbidopa and levodopa for the treatment of Parkinsons disease and syndrome.,/neuro/mod6/carb.html,Therapy of PD: limitations of levodopa Efficacy tends to decrease as the disease progresses. Chronic treatment associated with adverse events (motor fluctuations, dyskinesias and neuropsychiatric problems).,Inhibition of peripheral COMT by entacapone increases the amount of L-DOPA and dopamine in the brain and improves the alleviation of PD symptoms.,Therapy of PD: limitations of levodopa Does not prevent the continuous degeneration of nerve cells in the subtantia nigra, the treatment being therefore symptomatic.,Therapy of PD: Other treatments DA receptor agonists (bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) Amantadine Anticholinergics,Treatment of Parkinsons Disease: Monoamine Oxidase Inhibitors (MAOIs),As shown above, monoamine oxidase is an enzyme that catalyzes the destruction of primary amines (such as dopamine,norepinephrine, seritonin) and secondary amines. The type B isoform of MAO (MAO-B) is primarily responsible for metabolism of dopamine.,Metabolism of Dopamine via Monoamine Oxidase (MAO),Inhibitor of MAO-B,Selegiline (l-deprenyl, Eldepryl or Anipryl veterinary) is a drug used for the treatment of early-stage Parkinsons disease and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor.,In late stage Parkinsons Disease, Selegiline is usually added to levodopa to prolong and enhance its effect,Metabolism of Dopamine via Catachol-O-Methyl Transferase (COMT),Inhibitors of COMT,Entacapone,Tolcapone,Inhibitors of COMT,Entacapone is marketed by Novartis as Comtan in the US Stalevo is a combination of Levodopa, Carbidopa, and Entacapone,Summary of the Treatment of Parkinsons Disease,Endorphin,Endorphins (or more correctly Endomorphines) are endogenous opioid biochemical compounds. They are peptides produced by the pituitary gland and the hypothalamus in vertebrates, and they resemble the opiates in their abilities to produce analgesia and a sense of well-being. In other words, they might work as “natural pain killers.“ Using drugs may increase the effects of the endorphins.,Serotonin,Although the CNS contains less than 2% of the total serotonin in the body, serotonin plays a very important role in a range of brain functions. It is synthesized from the amino acid tryptophan. Within the brain, serotonin is localised mainly in nerve pathways emerging from the raphe nuclei, a group of nuclei at the centre of the reticular formation in the Midbrain, pons and medulla. These serotonergic pathways spread extensively throughout the brainstem, the cerebral cortex and the spinal cord.,In addition to mood control, serotonin has been linked with a wide variety of functions, including the regulation of sleep, pain perception, body temperature, blood pressure and hormonal activity. Outside the brain, serotonin exerts a number of important effects, particularly involving the gastrointestinal and cardiovascular systems.,Serotonin,In the central nervous system, serotonin is believed to play an important role in the regulation of body temperature, mood, sleep, vomiting, sexuality, and appetite. Low levels of serotonin have been associated with several disorders, namely clinical depression, obsessive-compulsive disorder (OCD), migraine, irritable bowel syndrome, tinnitus, fibromyalgia, bipolar disorder, and anxiety disorders. If neurons of the brainstem that make serotoninserotonergic neuronsare abnormal, there is a risk of sudden infant death syndrome (SIDS) in an infant.,Serotonin,Understanding Serotonin,Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, 5-HT reuptake transporter, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), cocaine, tric