Parkinson’s Disease

Parkinson’s disease is a progressive neurodegenerative disorder caused by a loss of dopamine (DA) neurons in the substantia nigra and the presence of Lewy bodies (eosinophilic cytoplasmic inclusions) in surviving DA neurons. The disease is characterized by resting tremor, bradykinesia (slowness), rigidity, and postural instability (impaired balance), the latter appearing late in the course of the disease. Long-term disability is typically related to worsening motor fluctuations and dyskinesias, dementia, or imbalance, and death results from the complications of immobility, including pulmonary embolism or aspiration pneumonia.

Although evidence implicates environmental and genetic factors in Parkinson’s disease, its etiology remains unknown. While the term Parkinson’s disease refers to the idiopathic disease, parkinsonism refers to disorders that resemble Parkinson’s disease but have a known cause and variable rates of progression and responses to drug therapy. These include encephalitis lethargica, multiple small strokes, and traumatic brain injury (pugilistic parkinsonism). In addition, parkinsonism can be induced by the long-term use of typical antipsychotic drugs and results from poisoning by manganese, carbon monoxide, or cyanide.

Parkinson’s disease is one of the few neurodegenerative diseases whose symptoms can be improved with drugs. In the late 1960s it was discovered that orally ingested 3,4-dihydroxy-phenylalanine (l-DOPA) improved symptoms dramatically. Primary treatments for Parkinson’s disease now include drugs that increase DA synthesis, decrease DA catabolism, and stimulate DA receptors; secondary compounds antagonize muscarinic cholinergic receptors, enhance DA release, and may antagonize N-methyl-d-aspartate (NMDA) glutamate receptors.

Alzheimer’s Disease

Alzheimer’s disease is a progressive dementing disorder resulting from widespread degeneration of synapses and neurons in the cerebral cortex and hippocampus as well as some subcortical structures. Its defining pathological characteristics are the presence of extracellular senile plaques and intracellular neurofibrillary tangles. The plaques in Alzheimer’s brain consist of an amyloid core surrounded by dystrophic (swollen, distorted) neurites and activated glia secreting a number of inflammatory mediators. The amyloid core consists of aggregates of a polymerized 40- to 42-amino acid peptide (Aβ) that is an alternate processing product of the transmembrane amyloid precursor protein and several accessory proteins. The neurofibrillary tangles are intracellular filaments composed of the microtubule associated protein tau, which is highly phosphorylated at unusual amino acid residues.

Both plaques and tangles are present in brain regions with the greatest degree of neuron and synapse loss and are largely absent from regions that are spared (e.g., cerebellum). Although the best correlate of the severity of dementia is synapse loss, the amount of neurofibrillary tangles appears more closely related to neuron loss than the amount of plaque pathology. The loss of these largely glutamatergic neurons intrinsic to the cortices is responsible for most clinical manifestations of Alzheimer’s disease.

While several neurotransmitter systems deteriorate in Alzheimer’s disease, one of the first and most pronounced reductions occurs within the acetylcholine (ACh) containing projections from the nucleus basalis in the basal forebrain to the cerebral cortex. The septo-hippocampal cholinergic pathway is similarly affected, whereas the

intrinsic striatal cholinergic system remains largely intact. Muscarinic cholinergic receptors in the cerebral cortex and hippocampus remain more or less intact, but nicotinic cholinergic receptors decline.

Current drug treatments for Alzheimer’s disease increase cholinergic transmission by the use of acetylcholinesterase (AChE) inhibitors and blocking the excitotoxic effects of glutamate at NMDA receptors with the antagonist memantine.

Patients with both Parkinson’s and Alzheimer’s diseases may manifest neuropsychiatric disturbances as a result of their primary disease, including psychoses, depression, anxiety, and agitation. These can be treated with the atypical antipsychotics, antidepressants, and anxiolytic compounds discussed in Chapters 29 to Chapters 31. A summary of the treatment of Parkinson’s and Alzheimer’s diseases is provided in the Therapeutic Overview Box.

Parkinson’s Disease Drugs

Current strategies for the treatment of Parkinson’s disease are directed at increasing dopaminergic activity in the striatum to compensate for the loss of nigrostriatal DA neurons (see Fig. 27-8). The major drugs used include compounds that increase the synthesis and decrease the catabolism of DA or directly stimulate DA receptors; secondary compounds block muscarinic cholinergic receptors, enhance DA release, and perhaps antagonize NMDA receptors.

Increased Dopamine Synthesis

l-DOPA was introduced for the treatment of Parkinson’s disease in 1970. It is the precursor of DA and crosses the BBB, whereas DA does not. l-DOPA increases DA synthesis but does not stop progression of the disease. When given alone, only 1% to 3% of an administered dose of l-DOPA reaches the brain; the rest is metabolized peripherally as shown in Figure 28-1. To prevent its peripheral metabolism and increase its availability to the brain, l-DOPA is administered with carbidopa, an aromatic l-amino acid decarboxylase inhibitor that does not cross the BBB. Carbidopa does not have any therapeutic benefit when used alone but increases the amount of l-DOPA available to the brain. However, as a consequence of peripheral inhibition of aromatic l-amino acid decarboxylase, more precursor is metabolized by plasma catechol-O-methyltransferase (COMT) producing 3-o-methyldopa. To overcome this, the COMT inhibitors tolcapone or entacapone are used in combination with l-DOPA/carbidopa. These compounds prolong the plasma t_1/2 of l-DOPA, increasing the time the drug is available to cross the BBB. They also prevent the buildup of 3-o-methyldopa, which competitively inhibits l-DOPA transport across the BBB. Entacapone does not cross the BBB, and its actions are limited to the periphery. However, tolcapone does cross the BBB and also prevents the formation of 3-o-methyldopa in brain and the catabolism of DA (Fig. 28-1).

FIGURE 28–1 Peripheral and central metabolism of l-DOPA and DA depicting the sites of action of enzyme inhibitors. AAAD, Aromatic l-amino acid decarboxylase; AD, aldehyde dehydrogenase; COMT, catechol-O-methyltransferase; MAO, monoamine oxidase.