The goal of treatment is improvement of the motor, autonomic, and cognitive symptoms of the disease. The treatment generally consists of medication along with physical, occupational, and speech therapy. Neurosurgical procedures are mostly reserved for intractable cases (see below). Pharmacotherapy is palliative, not curative. It is begun when the patient has trouble carrying out the activities of daily living and is prescribed, not according to a uniform pattern, but in relation to the needs of the individual patient.

■ Symptomatic Treatment

Dopaminergic agents. Levodopa is actively absorbed in the small intestine and rapidly distributed throughout the body (especially to skeletal muscle). Amino acids compete with the levodopa transport system at the blood-brain barrier. A decarboxylase inhibitor that does not penetrate the blood-brain barrier (benserazide or carbidopa) is administered together with levodopa to prevent its rapid breakdown in the peripheral circulation. Once it reaches the brain, levodopa is decarboxylated to dopamine, which is used for neurotransmission in the striatum. After it has been released from the presynaptic terminals of dopaminergic neurons in the striatum and exerted its effect on the postsynaptic terminals, it is broken down by two separate enzyme systems (deamination by monoamine oxidase type B, MAO-B; methylation by cate-chol-O-methyltransferase, COMT). Levodopa effectively reduces akinesia and rigidity, but has only a mild effect against tremor. Its long-term use is often complicated by motor fluctuations, dyskinesia, and psychiatric disturbances. Dopamine agonists (DAs) mimic the function of dopamine, binding to dopamine receptors. Their interaction with D, and D2 receptors is thought to improve motor function, while their interaction with D3 receptors is thought to improve cognition, motivation, and emotion. Long-term use of DAs is less likely to cause unwanted motor side effects than long-term use of levodopa. Commonly used DAs include bromocriptine (mainly a D2 agonist), lisuride (mainly a D2 agonist), and pergolide (a D,, D2, and D3 agonist). Apomorphine, an effective D, and D2 agonist, can be given by subcutaneous injection, but its effect lasts only about , hour. Other, recently in troduced dopamine agonists are ropinirol and pramipexol (D2 and D3), cabergoline (D2), and a-dihydroergocryptine (mainly D2). Selegiline inhibits MAO-B selectively and irreversibly (^ reduced dopamine catabolism ^ increase in striatal dopamine concentration). En-tacapone increases the bioavailability of levodopa via peripheral inhibition of COMT. Nondopaminergic agents. Anticholinergic agents (biperidene, bornaprine, metixene, trihexy-phenidyl) act on striatal cholinergic inter-neurons. Budipine can relieve tremor (risk of ventricular tachycardia ^ ECG monitoring). Glutamate antagonists (amantadine, memantine) counteract increased glutamatergic activity at the N-methyl-D-aspartate (NMDA) glutamate receptor in the indirect pathway.

■ Transplant Surgery

Current research on intrastriatal transplantation of stem cells (derived from fetal tissue, from umbilical cord blood, or from bone marrow) seems promising.

■ Stereotactic Neurosurgical Procedures, Deep Brain Stimulation (for abbreviations, see p. 210)

These procedures can be used when PD becomes refractory to medical treatment. Pal-lidotomy (placement of a destructive lesion in the GPi) derives its rationale from the observed hyperactivity of this structure in PD. Deep brain stimulation requires bilateral placement of stimulating electrodes in the GPi or STN. High-frequency stimulation by means of a subcu-taneously implanted impulse generator can improve rigor, tremor, akinesia, and dyskinesia.

A genetic predisposition for the development of PD has been postulated. Mutations in the genes for a-synuclein (AD), parkin (AR), and ubiquitin C-terminal hydrolase L1 (UCHL1; AD) have been found in pedigrees affected by the rare autosomal dominant (AD) and autosomal recessive (AR) familial forms of PD.

Glial cell

DOPAC (dihydroxyphenylacetic acid)

Dopamine reabsorption-

Dopamine release Presynaptic terminal

Phenylalanine + Tyrosine L-Dopa+ Dopamine t mSpu~

Phenylalanine Tyrosine hydroxylase hydroxy-lase m

Transport protein -Dopamine vesicle -Striatal dopaminergic synapse (schematic)

Speech therapy

3-0-methyldopamine (converted to homo-vanillic acid)

Glial cell

Dopamine Transport

3-0-methyldopamine (converted to homo-vanillic acid)

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