Parkinson's Disease

Parkinson's disease (PD) is considered a hypokinetic movement disorder, as it results in a fundamental slowing of movement. It is most often idiopathic and the result of a degenerative process which leads to depletion of dopaminergic neurons. Both medical and surgical treatments work by relieving the symptoms caused by this loss of dopamine. Future therapies of PD will be geared at halting disease progression.

The hallmark symptoms of PD include resting tremor, rigidity, and bradykinesia, as well as postural and gait disturbances. The tremor is often described as “pill-roll-ing” and gait as shuffling. Other symptoms include:

• Poverty and slowness of movement (including face, i.e. masked facies)
• Stooped posture
• Reduced blink rate, impaired upgaze
• Difficulty with alternating movements, micrographia
• Hypophonia, speech hurried and monotonous
• Drooling, dysphagia, constipation
• Dementia in 10 percent, depression

Dyskinesias (i.e. hyperkinetic involuntary movements) are often present in PD; however, these movements are a result of medications and not of PD itself.

Parkinson's disease is generally idiopathic, though other etiologies including familial, post-encephalitic, drug-induced, and Parkinson's Plus syndromes have been described. The onset generally occurs between 30–80 years of age with a peak between 50–70 years. The diagnosis is based on history and neurological [Page 1339]exam. PD is a degenerative process marked by a decrease in dopaminergic neurons in the basal ganglia. The basal ganglia (BG) are located in the telencephalon and consist of four interconnected nuclei: the striatum, globus pallidus (GP), substantia nigra (SN) and subthalamic nucleus (STN). The striatum is the main input of the BG; the internal segment of the GP (Gpi) and the pars reticulata of the SN (SNr) are the output nuclei.

Output occurs either via a direct or an indirect pathway. In the direct pathway, the striatum projects to the GPi and SNr. In the indirect pathway, the striatum projects to the external segment of the globus pallidus, then to the STN, and ultimately to the GPi and SNr. The neurons involved in the direct pathway express the D1 subtype of the dopamine receptor (primarily excitatory), and in the indirect pathway express the D2 subtype of the dopamine receptor (primarily inhibitory). Both the direct and indirect pathways inhibit the thalamus, the relay station for sensory information en route to the cerebral cortex. In PD, the disruption of the motor circuit of this basal ganglia-thalamo-cortical network results in changes in neuronal rates of firing and activity patterns.

The pathologic hallmark of PD is the loss of dopaminergic neurons in the SN with deposition of eosinophilic cytoplasmic inclusions called Lewy bodies. In normal aging, there are 425,000 of these dopaminergic neurons at age 20 and 200,000 at age 80. In PD, cell counts decrease to 100,000 and the SN appears pale and gliotic. The clinical symptomatology of PD results when dopamine loss exceeds approximately 60 percent. Dopamine denervation also results in a series of events within the basal ganglia that impairs its ability to appropriately interact with the rest of the nervous system. Medical treatment of PD is geared at replenishing dopamine.

Medications often significantly relieve the majority of PD symptoms. Most commonly, treatment is with levodopa, a dopamine precursor, which is effective in 75 percent of PD patients. Levodopa is most beneficial in the treatment of bradykinesia and rigidity, and is given with carbidopa, a peripheral decarboxylase inhibitor, which limits its peripheral breakdown and thus increases the amount of drug which reaches the BG. However, over time the efficacy of levodopa may wane, requiring increased doses which often lead to the development of dyskinesias and motor fluctuations.

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