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Parkinson´s Disease

Parkinson´s Disease. Pekka Jäkälä, M.D., Ph.D. Department of Neuroscience and Neurology University and University Hospital of Kuopio, Finland. Outline:. Part A: Summary of Parkinson´s disease Part B: Molecular biology of Parkinson´s disease . PART A: Summary of Parkinson´s disease

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Parkinson´s Disease

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  1. Parkinson´s Disease Pekka Jäkälä, M.D., Ph.D. Department of Neuroscience and Neurology University and University Hospital of Kuopio, Finland

  2. Outline: • Part A:Summary of Parkinson´s disease • Part B:Molecular biology of Parkinson´s disease

  3. PART A:Summary of Parkinson´s disease • 1. History   • 2. Epidemiology • 3. Risk factors   • 4. Clinical features  • 5. Neuropathology   • 6. Functional neuroanatomy • 7. Neurochemistry   • 8. Therapy  • 9. Diagnosis  • 10. Summary

  4. History of Parkinson´s 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.

  5. 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 Alzheimer´s disease (AD).

  6. Incidence of PD Incidence / 100 000 Age

  7. Prevalence of PD Prevalence / 100 000 Age

  8. 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.

  9. 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.

  10. Clinical features of PD • Three cardinal symptoms: ®resting tremor ® bradykinesia (generalized slowness of movements) ® muscle rigidity

  11. 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.

  12. 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.

  13. 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.

  14. Lewy bodies

  15. 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.

  16. Lewy bodies

  17. 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.

  18. CORTEX + + STRIATUM D1 D2 D1 GPe SNc - SNr STN GPi + + THALAMUS NORMAL MOTORCONTROL Substantia nigra and the extrapyramidal system

  19. 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.

  20. Dopamine pathways in human brain

  21. Dopamine synthesis

  22. 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.

  23. 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).

  24. Inhibition of peripheral COMT by entacapone increases the amount of L-DOPA and dopamine in the brain andimproves the alleviation of PD symptoms.

  25. Therapy of PD: limitations of levodopa • Does not prevent the continuous degeneration of nerve cells in the subtantia nigra, the treatment being thereforesymptomatic.

  26. Therapy of PD: Other treatments • DA receptor agonists (bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) • Amantadine • Anticholinergics

  27. Diagnosis of PD • Anamnesis and clinical examination • No disease-specific biological marker available • Positron Emission Tomography (PET) or Single-photon Emission Computed Tomography (SPECT) with dopaminergic radioligands • Exclusion of several causes of secondary Parkinsonism

  28. Summary • 1-2 % of the general population over the age of 65 y • Lewy bodies and Lewy neurites particularly in the substantia nigra pars compacta dopaminergic neurons projecting to striatum • DA levels severely reduced in striatum. • Resting tremor, bradykinesia, muscle rigidity • Levodopa and other dopaminergic drugs • No treatment which would prevent the continuous degeneration of nerve cells in the substantia nigra and resulting striatal DA loss • No disease-specific biological marker

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