Parkinson's disease an overview

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
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 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.

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).

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.

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.

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: 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 CORTEX SNc GPe GPi STN SNr THALAMUS STRIATUM D1 D1 D2 +  + + + NORMAL MOTOR CONTROL

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.

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 P D 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

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

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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Parkinson's disease an overview

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