Neurodegenerative diseases are a group of disorders characterized by neuronal loss and generally an accumulation of insoluble intracellular or extracellular material in certain brain regions. Most neurodegenera-tive disorders are of unknown etiology, affect the elderly, are progressive, and damage selected neuronal populations or brain regions. There are some inherited forms of these disorders; however, most are sporadic occurrences (idiopathic) with genetic predisposition, environmental factors, and aging contributing as risk factors.

The neurodegenerative disorders include (1) Alzheimer's disease, the most common cause of dementia, in which the neural injury is primarily in the hippocampus and cortex; (2) Parkinson's disease, a disabling motor impairment disorder due to the loss of nigrostriatal dopamine neurons; (3) Huntington's disease, a motor disease characterized by excessive and ab normal movements resulting from the loss of a specific subset of striatal neurons; (4) amyotrophic lateral sclerosis (ALS), in which progressive weakness and muscle atrophy are due to degeneration of spinal, bulbar, and cortical neurons. This chapter focuses on Parkinson's and Alzheimer's diseases, for which pharmacological intervention can alleviate the clinical symptoms. However, drugs used in the treatment of neurodegenerative disorders only treat symptoms and do not cure or alter the progression of the disease.


The classic publication in 1817 by James Parkinson defined the triad of distinguishing symptoms that bear his name; this movement disorder is known as Parkinson's disease or parkinsonism. It generally affects the elderly and is estimated to afflict more than 1% of individuals over the age of 65. A small subset of patients has familial forms of parkinsonism with an autosomal dominant pattern of inheritance. Genetic mutations in three proteins have been identified thus far. These genes encode for a-synuclein, a protein found in abundance in vesicles and synaptic regions, and for parkin and ubiquitin carboxy-terminal hydroxylase, both of which are involved with protein degradation.

Some forms of parkinsonism have been traced to specific entities, such as viral inflammation (e.g., the postencephalitic parkinsonism of the early 1900s), brain trauma, stroke, and poisoning by manganese, carbon monoxide, pesticide, or 1-methyl-4-phenyl,-1,2,3,6-tetra-hydropyridine (MPTP). Intoxication with MPTP, a byproduct of the synthesis of an illegal meperidine analogue, produces a condition closely resembling parkin-sonism, but there is little evidence that this or a similar toxin exists in the environment. However, the information from research with this toxin has provided important insight into mitochondrial function and has led to the theory that impairment of mitochondrial function (whether of genetic or toxin derivation) may be a relevant risk factor in Parkinson's disease.

Although the causes of some forms of parkinsonism are known, most cases are sporadic and are of unknown origin (idiopathic Parkinson's disease). The causes are likely multifactorial, with genetic predisposition, environmental toxins, and aging contributing to the initiation and progression of the disease. There is a progressive loss of dopamine neurons with age. Relatively smooth functioning of motor control is maintained until neuronal loss is such that it causes an 80% reduction of dopamine in the striatum. At this time, clinical symptoms appear and then worsen with increasing neuronal loss.

Another form of parkinsonism is drug-induced, that is, iatrogenic parkinsonism, which often is a complication of antipsychotic therapy, especially following the use of the butyrophenone and phenothiazine drug classes (see Chapter 34). Unlike idiopathic parkinson-ism, striatal content of dopamine is not reduced by administration of these drugs. In contrast, they produce a functional decrease in dopamine activity by blocking the action of dopamine on postsynaptic dopamine receptors.

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