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Parkinson´s Disease Pekka Jäkälä, M.D., Ph.D. Department of Neuroscience and Neurology University and University Hospital of Kuopio, Finland © TND 2005 Outline: Part A: Summary of Parkinson´s disease Part B: Molecular biology of Parkinson´s disease © TND 2005 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 © TND 2005 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. © TND 2005 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). © TND 2005 Incidence / 100 000 Incidence of PD Age © TND 2005 Prevalence / 100 000 Prevalence of PD Age © TND 2005 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. © TND 2005 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. © TND 2005 Clinical features of PD Three cardinal symptoms: resting tremor bradykinesia (generalized slowness of movements) muscle rigidity © TND 2005 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. © TND 2005 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. © TND 2005 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. © TND 2005 Lewy bodies © TND 2005 © TND 2005 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. © TND 2005 Lewy bodies © TND 2005 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. © TND 2005 Substantia nigra and the extrapyramidal system CORTEX + + STRIATUM D1 D2 D1 GPe SNc - SNr STN + GPi + THALAMUS NORMAL MOTOR CONTROL © TND 2005 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. © TND 2005 Dopamine pathways in human brain © TND 2005 Dopamine synthesis © TND 2005 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. © TND 2005 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). © TND 2005 Inhibition of peripheral COMT by entacapone increases the amount of L-DOPA and dopamine in the brain and improves the alleviation of PD symptoms. © TND 2005 Therapy of PD: limitations of levodopa Does not prevent the continuous degeneration of nerve cells in the subtantia nigra, the treatment being therefore symptomatic. © TND 2005 Therapy of PD: Other treatments DA receptor agonists (bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) Amantadine Anticholinergics © TND 2005 Diagnosis of PD Anamnesis and clinical examination No disease-specific biological marker available Positron Emission Tomography (PET) or Singlephoton Emission Computed Tomography (SPECT) with dopaminergic radioligands Exclusion of several causes of secondary Parkinsonism © TND 2005 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 © TND 2005