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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

Neuropathology 6. Diagnosis 10.PART A: Summary of Parkinson´s disease 1. Epidemiology 3. Neurochemistry 8. Risk factors 4. Clinical features 5. Summary © TND 2005 . History 2. Functional neuroanatomy 7. Therapy 9.

Charcot.”  The famous French neurologist.History of Parkinson´s disease (PD)  First described in 1817 by an English physician. further described the syndrome in the late 1800s. James Parkinson. © TND 2005 . in “An Essay on the Shaking Palsy.

 The second most common neurodegenerative disorder after Alzheimer´s disease (AD). © TND 2005 .Epidemiology of PD  The most common movement disorder affecting 1-2 % of the general population over the age of 65 years.

Incidence of PD Incidence / 100 000 Age © TND 2005 .

Prevalence of PD Prevalence / 100 000 Age © TND 2005 .

reason unknown. and in African-Americans. © TND 2005 . though a role for estrogen has been debated.Epidemiology of PD  May be less prevalent in China and other Asian countries.  Prevalence rates in men are slightly higher than in women.

iron). wood pulp mills. © TND 2005    .Risk factors of PD     Age . and steel alloy industries Race Life experiences (trauma. farming. metals (manganese. personality traits such as shyness and depressiveness)? An inverse correlation between cigarette smoking and caffeine intake in case-control studies. rural residence. emotional stress.the most important risk factor Positive family history Male gender Environmental exposure: Herbicide and pesticide exposure. well water.

Clinical features of PD  Three cardinal symptoms:  resting tremor  bradykinesia (generalized slowness of movements)  muscle rigidity © TND 2005 .

anteroflexed head. decreased blinking. slowed chewing and swallowing. shaving. usually asymmetric and most evident in one hand with the arm at rest. Bradykinesia: Difficulty with daily activities such as writing. Rigidity: Muscle tone increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints. and opening buttons. masked facies. using a knife and fork. stooped posture.Clinical features of PD  Resting tremor: Most common first symptom. and flexed knees and elbows. © TND 2005   .

© TND 2005 . and orthostatic hypotension. Dysfunction of the autonomic nervous system: Impaired gastrointestinal motility.   Cognitive impairment: Mild cognitive decline including impaired visual-spatial perception and attention. excessive head and neck sweating. and impaired concentration in most patients. bladder dysfunction.Additional clinical features of PD   Postural instability: Due to loss of postural reflexes. slowness in execution of motor tasks. sialorrhea. Depression: Mild to moderate depression in 50 % of patients. at least 1/3 become demented during the course of the disease.

round intracytoplasmic inclusions called lewy bodies and Lewy neurites.Neuropathology of PD    Eosinophilic. Inclusions particularly numerous in the substantia nigra pars compacta. © TND 2005 .Friedrich Lewy. First described in 1912 by a German neuropathologist .

Lewy bodies © TND 2005 .

© TND 2005 .

the hypothalamus. © TND 2005 . also found in the locus coeruleus. the cerebral cortex.  Confined largely to neurons. the olfactory bulb and the autonomic nervous system.Neuropathology of PD: Lewy bodies  Not limited to substantia nigra only. glial cells only rarely affected. motor nucleus of the vagus nerve. the nucleus basalis of Meynert.

Lewy bodies © TND 2005 .

One major function of the striatum is the regulation of posture and muscle tonus. returning it back to the cortex through the thalamus.  © TND 2005 .  Part of extrapyramidal system which processes information coming from the cortex to the striatum.Functional neuroanatomy of PD  Substantia nigra: The major origin of the dopaminergic innervation of the striatum.

Substantia nigra and the extrapyramidal system CORTEX + + STRIATUM D1 D2 D1 SNc GPe - SNr + STN + GPi THALAMUS NORMAL MOTOR CONTROL © TND 2005 .

Neurochemistry of PD  Late 1950s: Dopamine (DA) present in mammalian brain.   1960. and the levels highest within the striatum. © TND 2005 . 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 © TND 2005 .

Dopamine synthesis © TND 2005 .

levodopa).Therapy of PD: levodopa  Late 1950s: L-dihydroxyphenylalanine (L-DOPA. © TND 2005   . virtually all the patients benefit. First treatment attempts in PD patients with levodopa resulted in dramatic but short-term improvements. levodopa cornerstone of PD treatment. 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). took years before it become an established and succesfull treatment. Still today.

Therapy of PD: limitations of levodopa  Efficacy tends to decrease as the disease progresses. dyskinesias and neuropsychiatric problems). Chronic treatment associated with adverse events (motor fluctuations.  © 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 .

the treatment being therefore symptomatic. © TND 2005 .Therapy of PD: limitations of levodopa  Does not prevent the continuous degeneration of nerve cells in the subtantia nigra.

Therapy of PD: Other treatments  DA receptor agonists (bromocriptine. pramipexole. pergolide. cabergoline)   Amantadine Anticholinergics © TND 2005 . ropinirole.

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  .

bradykinesia. Resting tremor. 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 .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.