Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e

Chapter 22: Treatment of Central Nervous System Degenerative Disorders

David G. Standaert; Erik D. Roberson

INTRODUCTION

Neurodegenerative disorders are characterized by progressive and irreversible loss of neurons from specific regions of the brain. Prototypical neurodegenerative disorders include Parkinson disease (PD) and Huntington's disease (HD), where loss of neurons from structures of the basal ganglia results in abnormalities in the control of movement; Alzheimer's disease (AD), where the loss of hippocampal and cortical neurons leads to impairment of memory and cognitive ability; and amyotrophic lateral sclerosis (ALS), where muscular weakness results from the degeneration of spinal, bulbar, and cortical motor neurons.

As a group, these disorders are relatively common and represent a substantial medical and societal problem. They are primarily disorders of later life, developing in individuals who are neurologically normal, although childhood-onset forms of each of the disorders are recognized. PD is observed in more than 1% of individuals over the age of 65 (Tanner, 1992), whereas AD affects as many as 10% of the same population (Evans et al., 1989). HD, which is a genetically determined autosomal dominant disorder, is less frequent in the population as a whole but affects, on average, 50% of each generation in families carrying the gene. ALS also is relatively rare but often leads rapidly to disability and death (Kurtzke, 1982).

Currently available therapies for neurodegenerative disorders alleviate the disease symptoms but do not alter the underlying neurodegenerative process. Symptomatic treatment for PD, where the neurochemical deficit produced by the disease is well defined, is, in general, relatively successful, and a number of effective agents are available. The available symptomatic treatments for AD, HD, and ALS are much more limited in effectiveness. On the horizon are pharmacological treatments aimed at preventing or retarding progression of neurodegeneration. A wide range of such disease-modifying approaches hold the promise to transform the approach to both the diagnosis and the treatment of neurodegenerative disorders.

SELECTIVE VULNERABILITY AND NEUROPROTECTIVE STRATEGIES

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Selective Vulnerability. A striking feature of neurodegenerative disorders is the exquisite specificity of the disease processes for particular types of neurons. For example, in PD there is extensive destruction of the dopaminergic neurons of the substantia nigra, whereas neurons in the cortex and many other areas of the brain are unaffected. In contrast, neural injury in AD is most severe in the hippocampus and neocortex, and even within the cortex, the loss of neurons is not uniform but varies dramatically in different functional regions (Arnold et al., 1991). Even more striking is the observation that in HD the mutant gene responsible for the disorder is expressed throughout the brain and in many other organs, yet the pathological changes are most prominent in the neostriatum (Landwehrmeyer et al., 1995). In ALS, there is loss of spinal motor neurons and the cortical neurons that provide their descending input (Tandan and Bradley, 1985). The diversity of these patterns of neural degeneration suggests that the process of neural injury results from the interaction of genetic and environmental influences with the intrinsic physiological characteristics of the affected populations of neurons. The intrinsic factors may include susceptibility to excitotoxic injury, regional variation in capacity for oxidative metabolism, and the production of toxic free radicals as by-products of cellular metabolism. New neuroprotective agents may target the factors that convey selective vulnerability.

Genetics and Environment. Each of the major neurodegenerative disorders may be familial in nature. HD is exclusively familial; it is transmitted by autosomal dominant inheritance, and the molecular mechanism of the genetic defect has been defined. Nevertheless, environmental factors importantly influence the age of onset and rate of progression of HD symptoms. PD, AD, and ALS are mostly sporadic without clear pattern of inheritance. But for each there are well-recognized genetic forms. For example, there are both dominant (α-synuclein, LRRK2) and recessive (parkin, DJ-1, PINK1) gene mutations that may give rise to PD (Farrer, 2006). In AD, mutations in the genes coding for the amyloid precursor protein (APP) and proteins known as the presenilins (involved in APP processing) lead to inherited forms of the disease (Selkoe and Podlisny, 2002). Mutations in the gene coding for copper-zinc super-oxide dismutase (SOD1) account for about 2% of the cases of adult-onset ALS (Boillée et al., 2006). Several other less common mutations have also been described.

In addition to these monogenic forms of neurodegenerative disease, there are also genetic risk factors that influence the probability of disease onset and modify the phenotype. For example, the apolipoprotein E (apo E) genotype constitutes an important risk factor for AD. Three distinct isoforms of this protein exist. Although all isoforms carry out their primary role in lipid metabolism equally well, individuals who are homozygous for the apoE4 allele ("4/4") have a much higher lifetime risk of AD than do those homozygous for the apoE2 allele ("2/2"). The mechanism by which the apoE4 protein increases the risk of AD is not exactly known. ApoE4 probably has multiple effects, some of which are mediated through altering β-amyloid (Aβ) aggregation or processing, and some of which that are Aβ-independent (Mahley et al., 2006).

Environmental factors including infectious agents, environmental toxins, and acquired brain injury have been proposed in the etiology of neurodegenerative disorders. The role of infection is best documented in the cases of PD that developed following the epidemic of encephalitis lethargica (Von Economo's encephalitis) in the early part of the 20th century. Most contemporary cases of PD are not preceded by encephalitis, and there is no convincing evidence for an infectious contribution to HD, AD, or ALS. Traumatic brain injury has been suggested as a trigger for neurodegenerative disorders, and in the case of AD there is some evidence to support this view (Cummings et al., 1998). At least one toxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), can induce a condition closely resembling PD (Langston et al., 1983). More recently, evidence has linked pesticide exposure with PD (Costello et al., 2009). Exposure of soldiers to neurotoxic chemicals has been implicated in ALS (as part of "Gulf War syndrome") (Golomb, 2008). While these examples illustrate the potential of environmental factors to influence neurodegenerative disease, it is clear that the causes identified so far are too few to account for more than a small minority of the cases. Further progress in understanding the causes of neurodegenerative disorders will require a deeper understanding of the interactions between genetic predisposition and environmental factors, an area that is just beginning to be explored.

Common Cellular Mechanisms of Neurodegeneration. Despite their varied phenotypes, the neurodegenerative disorders share some common features. For example, misfolded and aggregated proteins are found in every major neurodegenerative disorder: alpha-synuclein, in PD; amyloid-β (Aβ) and tau in AD; huntingtin in HD; and SOD and TDP-43 in ALS. The accumulation of misfolded proteins may result from either genetic mutations producing abnormal structure, or from impaired cellular clearance. Age-related decline in the ability to clear misfolded proteins may be an important predisposing factor, and strategies to augment the clearance of misfolded proteins are being studied as potential therapies.

The term excitotoxicity describes the neural injury that results from the presence of excess glutamate in the brain. Glutamate is used as a neurotransmitter by many different neural systems and is believed to mediate most excitatory synaptic transmission in the mammalian brain (see Table 14–3). Although glutamate is required for normal brain function, the presence of excessive amounts of glutamate can lead to excitotoxic cell death (see Figure 14–13). The destructive effects of glutamate are mediated by glutamate receptors, particularly those of the N-methyl-D-aspartate (NMDA) type. Excitotoxic injury contributes to the neuronal death that occurs in acute processes such as stroke and head trauma (Choi and Rothman, 1990). The role of excitotoxicity is less certain in the chronic neurodegenerative disorders; nevertheless, regional and cellular differences in susceptibility to excitotoxic injury, conveyed, e.g., by differences in types of glutamate receptors, may contribute to selective vulnerability. This has led to the development of glutamate antagonists as neuroprotective therapies, with two such agents (memantine and riluzole, described later) currently in clinical use.

Aging is associated with a progressive impairment in the capacity of neurons for oxidative metabolism, perhaps in part because of a progressive accumulation of mutations in the mitochondrial genome. A consequence of impaired oxidative capacities is the production of reactive compounds such as hydrogen peroxide and oxygen radicals. Unchecked, these reactive species can lead to DNA damage, peroxidation of membrane lipids, and neuronal death. This has led to pursuit of drugs that can enhance cellular metabolism (such as the mitochondrial cofactor coenzyme Q₁₀) and anti-oxidant strategies as treatments to prevent or retard degenerative diseases (Beal, 2005).

Parkinson Disease (PD)

Clinical Overview. Parkinsonism is a clinical syndrome consisting of four cardinal features:

bradykinesia (slowness and poverty of movement)
muscular rigidity
resting tremor (which usually abates during voluntary movement)
an impairment of postural balance leading to disturbances of gait and falling

The most common form of parkinsonism is idiopathic PD, first described by James Parkinson in 1817 as paralysis agitans, or the "shaking palsy." The pathological hallmark of PD is the loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta, with the appearance of intracellular inclusions known as Lewy bodies. Progressive loss of dopamine (DA) containing neurons is a feature of normal aging; however, most people do not lose the 70-80% of dopaminergic neurons required to cause symptomatic PD. Without treatment, PD progresses over 5-10 years to a rigid, akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. The availability of effective pharmacological treatment has radically altered the prognosis of PD; in most cases, good functional mobility can be maintained for many years. Life expectancy of adequately treated patients is increased substantially, but overall mortality remains higher than that of the general population. In addition, while DA neuron loss is the most prominent feature of the disease, the disorder affects a wide range of other brain structures, including the brainstem, hippocampus, and cerebral cortex (Braak and Del Tredici, 2008). This pathology is likely responsible for the "non-motor" features of PD, which include sleep disorders, depression, and memory impairment. As treatments for the motor features have improved, these non-motor aspects have become important sources of disability for patients (Langston, 2006).

It is important to recognize that several disorders other than idiopathic PD also may produce parkinsonism, including some relatively rare neurodegenerative disorders, stroke, and intoxication with DA-receptor antagonists. Drugs that may cause parkinsonism include antipsychotics such as haloperidol and thorazine (Chapter 16) and anti-emetics such as prochloperazine and metoclopramide (Chapter 46). Although a complete discussion of the clinical diagnosis of parkinsonism exceeds the scope of this chapter, the distinction between idiopathic PD and other causes of parkinsonism is important because parkinsonism arising from other causes usually is refractory to all forms of treatment.

Pathophysiology. The dopaminergic deficit in PD arises from a loss of the neurons in the substantia nigra pars compacta that provide innervation to the striatum (caudate and putamen). The current understanding of the pathophysiology of PD is based on the finding that the striatal DA content is reduced in excess of 80%. This paralleled the loss of neurons from the substantia nigra, suggesting that replacement of DA could restore function (Cotzias et al., 1969; Hornykiewicz, 1973). These fundamental observations led to an extensive investigative effort to understand the metabolism and actions of DA and to learn how a deficit in DA gives rise to the clinical features of PD. We now have a model of the function of the basal ganglia that, while incomplete, is still useful.

Dopamine Synthesis, Metabolism, and Receptors. DA, a catecholamine, is synthesized in the terminals of dopaminergic neurons from tyrosine and stored, released, and metabolized by processes described in Chapter 13 and summarized in Figure 22–1. The actions of DA in the brain are mediated by a family of DA-receptor proteins. Two types of DA receptors were identified in the mammalian brain using pharmacological techniques: D₁ receptors, which stimulate the synthesis of the intracellular second messenger cyclic AMP; and D₂ receptors, which inhibit cyclic AMP synthesis as well as suppress Ca²⁺ currents and activate receptor-operated K⁺ currents. More recently, genetic studies revealed at least five distinct DA receptors (D₁-D₅) (Chapter 13). All the DA receptors are G protein–coupled receptors (GPCRs) (Chapter 3). The D₁ and D₅ proteins have a long intracellular carboxy-terminal tail and are members of the class defined pharmacologically as D₁; they stimulate the formation of cyclic AMP and phosphatidyl inositol hydrolysis. The D₂, D₃, and D₄ receptors share a large third intracellular loop and are of the D₂ class. They decrease cyclic AMP formation and modulate K⁺ and Ca²⁺ currents. Each of the five DA receptor proteins has a distinct anatomical pattern of expression in the brain. The D₁ and D₂ proteins are abundant in the striatum and are the most important receptor sites with regard to the causes and treatment of PD. The D₄ and D₅ proteins are largely extrastriatal, whereas D₃ expression is low in the caudate and putamen but more abundant in the nucleus accumbens and olfactory tubercle.

Neural Mechanism of Parkinsonism. Considerable effort has been devoted to understanding how the loss of dopaminergic input to the neurons of the neostriatum gives rise to the clinical features of PD (for review, see Albin et al., 1989; Mink and Thach, 1993; and Wichmann and DeLong, 1993). The basal ganglia can be viewed as a modulatory side loop that regulates the flow of information from the cerebral cortex to the motor neurons of the spinal cord (Figure 22–2). The neostriatum is the principal input structure of the basal ganglia and receives excitatory glutamatergic input from many areas of the cortex. Most neurons within the striatum are projection neurons that innervate other basal ganglia structures. A small but important subgroup of striatal neurons consists of interneurons that connect neurons within the striatum but do not project beyond its borders. Acetylcholine (ACh) and neuropeptides are used as transmitters by these striatal interneurons.

The outflow of the striatum proceeds along two distinct routes, termed the direct and indirect pathways. The direct pathway is formed by neurons in the striatum that project directly to the output stages of the basal ganglia, the substantia nigra pars reticulata (SNpr) and the globus pallidus interna (GPi); these, in turn, relay to the ventroanterior and ventrolateral thalamus, which provides excitatory input to the cortex. The neurotransmitter of both links of the direct pathway is γ-aminobutyric acid (GABA), which is inhibitory, so that the net effect of stimulation of the direct pathway at the level of the striatum is to increase the excitatory outflow from the thalamus to the cortex. The indirect pathway is composed of striatal neurons that project to the globus pallidus externa (GPe). This structure, in turn, innervates the subthalamic nucleus (STN), which provides outflow to the SNpr and GPi output stage. As in the direct pathway, the first two links—the projections from striatum to GPe and GPe to STN—use the inhibitory transmitter GABA; however, the final link—the projection from STN to SNpr and GPi—is an excitatory glutamatergic pathway. Thus, the net effect of stimulating the indirect pathway at the level of the striatum is to reduce the excitatory outflow from the thalamus to the cerebral cortex.

The key feature of this model of basal ganglia function, which accounts for the symptoms observed in PD as a result of loss of dopaminergic neurons, is the differential effect of DA on the direct and indirect pathways (Figure 22–3). The dopaminergic neurons of the substantia nigra pars compacta (SNpc) innervate all parts of the striatum; however, the target striatal neurons express distinct types of DA receptors. The striatal neurons giving rise to the direct pathway express primarily the excitatory D₁ dopamine receptor protein, whereas the striatal neurons forming the indirect pathway express primarily the inhibitory D₂ type. Thus, DA released in the striatum tends to increase the activity of the direct pathway and reduce the activity of the indirect pathway, whereas the depletion that occurs in PD has the opposite effect. The net effect of the reduced dopaminergic input in PD is to increase markedly the inhibitory outflow from the SNpr and GPi to the thalamus and reduce excitation of the motor cortex.

There are several limitations of this model of basal ganglia function (Parent and Cicchetti, 1998): The anatomical connections are considerably more complex than envisioned originally. In addition, many of the pathways involved use not just one, but several neurotransmitters. For example, the neuropeptides substance P and dynorphin are found predominantly in striatal neurons making up the direct pathway, whereas most of the indirect pathway neurons express enkephalin. These transmitters are expected to have slow modulatory effects on signaling, in contrast to the rapid effects of glutamate and GABA, but the functional significance of these modulatory effects remains unclear. Nevertheless, the model is useful and has important implications for the rational design and use of pharmacological agents in PD. First, it suggests that to restore the balance of the system through stimulation of DA receptors, the complementary effect of actions at both D₁ and D₂ receptors, as well as the possibility of adverse effects that may be mediated by D₃, D₄, or D₅ receptors, must be considered. Second, it explains why replacement of DA is not the only approach to the treatment of PD. Drugs that inhibit cholinergic receptors have long been used for treatment of parkinsonism. Although their mechanisms of action are not completely understood, their effect is likely mediated at the level of the striatal projection neurons, which normally receive cholinergic input from striatal cholinergic interneurons. Only few clinically useful drugs for parkinsonism are presently available based on actions through GABA and glutamate receptors, even though both have crucial roles in the circuitry of the basal ganglia. However, they represent a promising avenue for drug development (Hallet and Standaert, 2004).

Figure 22–1.

Dopaminergic nerve terminal. Dopamine (DA) is synthesized from tyrosine in the nerve terminal by the sequential actions of tyrosine hydrolase (TH) and aromatic amino acid decarboxylase (AADC). DA is sequestered by VMAT2 in storage granules and released by exocytosis. Synaptic DA activates presynaptic autoreceptors and postsynaptic D1 and D2 receptors. Synaptic DA may be taken up into the neuron via the DA and NE transporters (DAT, NET), or removed by postsynaptic uptake via OCT3 transporters. Cytosolic DA is subject to degradation by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) in the neuron, and by catechol-O-methyl tranferase (COMT) and MAO/ALDH in non-neuronal cells; the final metabolic product is homovanillic acid (HVA). See structures in Figure 22-4. PH, phenylalanine hydroxylase.

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Figure 22–2.

Schematic wiring diagram of the basal ganglia. The striatum is the principal input structure of the basal ganglia and receives excitatory glutamatergic input from many areas of cerebral cortex. The striatum contains projection neurons expressing predominantly D₁ or D₂ dopamine receptors, as well as interneurons that use ACh as a neurotransmitter. Outflow from the striatum proceeds along two routes. The direct pathway, from the striatum to the substantia nigra pars reticulata (SNpr) and globus pallidus interna (GPi), uses the inhibitory transmitter GABA. The indirect pathway, from the striatum through the globus pallidus externa (GPe) and the subthalamic nucleus (STN) to the SNpr and GPi, consists of two inhibitory GABAergic links and one excitatory glutamatergic projection (Glu). The substantia nigra pars compacta (SNpc) provides dopaminergic innervation to the striatal neurons, giving rise to both the direct and indirect pathways, and regulates the relative activity of these two paths. The SNpr and GPi are the output structures of the basal ganglia and provide feedback to the cerebral cortex through the ventroanterior and ventrolateral nuclei of the thalamus (VA/VL).

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Figure 22–3.

The basal ganglia in Parkinson disease. The primary defect is destruction of the dopaminergic neurons of the SNpc. The striatal neurons that form the direct pathway from the striatum to the SNpr and GPi express primarily the excitatory D₁ DA receptor, whereas the striatal neurons that project to the GPe and form the indirect pathway express the inhibitory D₂ dopamine receptor. Thus, loss of the dopaminergic input to the striatum has a differential effect on the two outflow pathways; the direct pathway to the SNpr and GPi is less active (structures in purple), whereas the activity in the indirect pathway is increased (structures in red). The net effect is that neurons in the SNpr and GPi become more active. This leads to increased inhibition of the VA/VL thalamus and reduced excitatory input to the cortex. Light blue lines indicate primary pathways with reduced activity. (See legend to Figure 22–2 for definitions of anatomical abbreviations.)

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Treatment of Parkinson Disease

Commonly used medications for the treatment of PD are summarized in Table 22–1.

Table 22-1Commonly Used Medications for the Treatment of Parkinson Disease

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Table 22-1 Commonly Used Medications for the Treatment of Parkinson Disease

AGENT

TYPICAL INITIAL DOSE

DAILY DOSE RANGE

COMMENTS

Levodopa Formulations

Carbidopa/levodopa

25 mg carbidopa + 100 mg levodopa ("25/100" tablet), 2-3x daily

200-1200 mg levodopa

Carbidopa/levodopa sustained-release

50 mg carbidopa + 200 mg levodopa ("50/200 sustained-release" tablet) 2x daily

200-1200 mg levodopa

Bioavailability 75% of immediate-release form

Carbidopa-levodopa orally disintegrating tablets (parcopa)

25 mg carbidopa + 100 mg levodopa ("25/100" tablet), 2-3x daily

200-1200 mg levodopa

COMT Inhibitors

Entacapone

200 mg with each dose of levodopa/carbidopa

600-2000 mg

Tolcapone

100 mg with carbidopa/levodopa

100-300 mg

May be hepatotoxic. Use only in patients not responding satisfactorily to other treatments. Requires monitoring of liver function

Carbidopa/levodopa/ entacapone

12.5 mg carbidopa + 50 mg levodopa + 200 mg entacapone (stalevo 50), 3x daily

150-1200 mg levodopa

DA Agonists

Apomorphine

2 mg subcutaneous

6-18 mg subcutaneous

Trimethobenzamide is used to reduce nausea when initiating therapy

Bromocriptine

1.25 mg

2.5-15 mg daily

Ergot; long-term use is associated with cardiac valve fibrosis

Pramipexole

0.125 mg 3x daily

1.5-4.5 mg

Ropinirole

0.25 mg 3x daily

1.5-24 mg

Ropinirole sustained-release

2 mg per day

2-24 mg

MAO Inhibitors

Rasagiline

1 mg daily

0.5-1 mg

Selegiline

5 mg 2x daily

2.5-10 mg

Other Medications

Trihexyphenidyl HCl

1 mg 2x daily

2-15 mg

Amantadine

100 mg 2x daily

100-200 mg

Levodopa. Levodopa (l-DOPA, larodopa, L-3,4-dihydroxyphenylalanine), the metabolic precursor of DA, is the single most effective agent in the treatment of PD. Levodopa is itself largely inert; both its therapeutic and adverse effects result from the decarboxylation of levo-dopa to DA. When administered orally, levodopa is absorbed rapidly from the small bowel by the transport system for aromatic amino acids. Concentrations of the drug in plasma usually peak between 0.5 and 2 hours after an oral dose. The t_1/2 in plasma is short (1-3 hours). The rate and extent of absorption of levodopa depends on the rate of gastric emptying, the pH of gastric juice, and the length of time the drug is exposed to the degradative enzymes of the gastric and intestinal mucosa. Competition for absorption sites in the small bowel from dietary amino acids also may have a marked effect on the absorption of levodopa; administration of levodopa with high-protein meals delays absorption and reduces peak plasma concentrations. Entry of the drug into the CNS across the blood-brain barrier also is mediated by a membrane transporter for aromatic amino acids, and competition between dietary protein and levodopa may occur at this level. In the brain, levodopa is converted to DA by decarboxylation primarily within the presynaptic terminals of dopaminergic neurons in the stratium. The DA produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or metabolized by the actions of MAO and catechol-O-methyltransferase (COMT) (Figure 22–4).

Figure 22–4.

Metabolism of levodopa (l-DOPA). ALDH, aldehyde dehydrogenase; COMT, catechol-O-methyltransferase; DβH, dopamine β-hydroxylase; AADC, aromatic l-amino acid decarboxylase; MAO, monoamine oxidase.

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In clinical practice, levodopa is almost always administered in combination with a peripherally acting inhibitor of aromatic l-amino acid decarboxylase, such as carbidopa or benserazide (available outside the U.S.), drugs that do not penetrate well into the CNS. If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites so that relatively little unchanged drug reaches the cerebral circulation and probably <1% penetrates the CNS. In addition, DA release into the circulation by peripheral conversion of levodopa produces undesirable effects, particularly nausea. Inhibition of peripheral decarboxylase markedly increases the fraction of administered levodopa that remains unmetabolized and available to cross the blood-brain barrier (Figure 22–5) and reduces the incidence of GI side effects.

Figure 22–5.

Pharmacological preservation of l-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-O-methyltransferase (COMT) (such as tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of levodopa (l-DOPA) and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AADC, aromatic l-amino acid decarboxylase; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; MAO, monoamine oxidase; 3MT, 3-methoxyltyramine; 3-O-MD, 3-O-methyl DOPA

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In most individuals, a daily dose of 75 mg carbidopa is sufficient to prevent the development of nausea. For this reason, the most commonly prescribed form of carbidopa/levodopa (sinemet, atamet, others) is the 25/100 form, containing 25 mg carbidopa and 100 mg levodopa. With this formulation, dosage schedules of three or more tablets daily provide acceptable inhibition of decarboxylase in most individuals. Occasionally, individuals will require larger doses of carbidopa to minimize gastrointestinal side effects, and administration of supplemental carbidopa (lodosyn) may be beneficial. Carbidopa/ levodopa is also available in an orally disintegrating tablet (parcopa). This may be useful in patients with swallowing difficulty, although it is important to note that levodopa is not absorbed through the oral mucosa, and must still be delivered to the small intestine for absorption. Thus, the time to onset of action of PARCOPA is not appreciably different from that of standard oral formulations.

Levodopa therapy can have a dramatic effect on all the signs and symptoms of PD. Early in the course of the disease, the degree of improvement in tremor, rigidity, and bradykinesia may be nearly complete. In early PD, the duration of the beneficial effects of levodopa may exceed the plasma lifetime of the drug, suggesting that the nigrostriatal DA system retains some capacity to store and release DA. A principal limitation of the long-term use of levodopa therapy is that with time this apparent "buffering" capacity is lost, and the patient's motor state may fluctuate dramatically with each dose of levodopa, a condition described as motor complications of levodopa. A common problem is the development of the "wearing off" phenomenon: each dose of levodopa effectively improves mobility for a period of time, perhaps 1-2 hours, but rigidity and akinesia return rapidly at the end of the dosing interval. Increasing the dose and frequency of administration can improve this situation, but this often is limited by the development of dyskinesias, excessive and abnormal involuntary movements. Dyskinesias are observed most often when the plasma levodopa concentration is high, although in some individuals dyskinesias or dystonia may be triggered when the level is rising or falling. These movements can be as uncomfortable and disabling as the rigidity and akinesia of PD. In the later stages of PD, patients may fluctuate rapidly between being "off," having no beneficial effects from their medications, and being "on" but with disabling dyskinesias, a situation called the on/off phenomenon.

Recent evidence has indicated that induction of motor complications may be the result of an active process of adaptation to variations in brain and plasma levodopa levels. This process of adaptation is apparently complex, involving not only alterations in the function of DA receptors but also downstream changes in the postsynaptic striatal neurons, including modification of NMDA glutamate receptors (Hallett and Standaert, 2004). When levodopa levels are maintained constant by intravenous infusion, dyskinesias and fluctuations are greatly reduced, and the clinical improvement is maintained for up to several days after returning to oral levodopa dosing (Mouradian et al., 1990). A sustained-release formulation consisting of carbidopa/levodopa in an erodable wax matrix (sinemet cr) has been marketed in an attempt to produce more stable plasma levodopa levels than can be obtained with oral administration of standard carbidopa/levodopa formulations. This formulation is helpful in some cases, but absorption of the sustained-release formulation is not entirely predictable. Other approaches to more continuous delivery of levodopa, including gel and transdermal formulations, are under study.

An important unanswered question regarding the use of levodopa in PD is whether this medication alters the course of the underlying disease or merely modifies the symptoms. A recent randomized trial has provided evidence that levodopa does not have an adverse effect on the course of the underlying disease, but has also confirmed that high doses of levodopa are associated with early onset of dyskinesias (Fahn et al., 2004). Most practitioners have adopted a pragmatic approach, using levodopa only when the symptoms of PD cause functional impairment and other treatments are inadequate or not well tolerated.

In addition to motor complications and nausea, several other adverse effects may be observed with levodopa treatment. A frequent and troubling adverse effect is the induction of hallucinations and confusion, especially in elderly patients or in patients with preexisting cognitive dysfunction. This adverse effect often limits the ability to treat parkinsonian symptoms adequately. Conventional antipsychotic agents, such as the phenothiazines, are effective against levodopa-induced psychosis but may cause marked worsening of parkinsonism, probably through actions at the D₂ DA receptor. An alternative approach has been to use "atypical" antipsychotic agents (Chapter 16). However, not all of these are equally useful in this setting, and some of the "atypical" agents may nevertheless worsen PD symptoms. The two drugs which appear to be most effective and best tolerated in patients with advanced PD are clozapine and quetiapine (Friedman and Factor, 2000).

Peripheral decarboxylation of levodopa and release of DA into the circulation may activate vascular DA receptors and produce orthostatic hypotension. Administration of levodopa with nonspecific inhibitors of MAO, such as phenelzine and tranylcypromine, markedly accentuates the actions of levodopa and may precipitate life-threatening hypertensive crisis and hyperpyrexia; nonspecific MAO inhibitors always should be discontinued at least 14 days before levodopa is administered (note that this prohibition does not include the MAO-B subtype-specific inhibitors selegiline and rasagiline (azilect), which, as discussed later, are often administered safely in combination with levodopa). Abrupt withdrawal of levodopa or other dopaminergic medications may precipitate the neuroleptic malignant syndrome of confusion, rigidity, and hyperthermia, a potentially lethal adverse effect.

Dopamine-Receptor Agonists. An alternative to levodopa is the use of drugs that are direct agonists of striatal DA receptors, an approach that offers several potential advantages. Since enzymatic conversion of these drugs is not required for activity, they do not depend on the functional capacities of the nigrostriatal neurons. The DA receptor agonists in clinical use have durations of action substantially longer than that of levodopa; they are often used in the management of dose-related fluctuations in motor state, and may be helpful in preventing motor complications. Finally, it has been suggested that DA receptor agonists may have the potential to modify the course of PD by reducing endogenous release of DA as well as the need for exogenous levodopa, thereby reducing free radical formation.

Two orally administered DA receptor agonists are commonly used for treatment of PD: ropinirole (requip) and pramipexole (mirapex).

These agents are better tolerated and have largely replaced the older agents (e.g., bromocriptine, pergolide), which have to be titrated more slowly. Pergolide was withdrawn from the U.S. market in 2007 because of cardiac valve fibrosis. Ropinirole and pramipexole have selective activity at D₂ class sites (specifically at the D₂ and D₃ receptor) and little or no activity at D₁ class sites. Both are well absorbed orally and have similar therapeutic actions. Like levodopa, they can relieve the clinical symptoms of PD. The duration of action of the DA agonists (8-24 hours) often is longer than that of levodopa (6-8 hours), and they are particularly effective in the treatment of patients who have developed on/off phenomena. Ropinirole is also available in a once-daily sustained release formulation (requip xl), which is more convenient and may reduce adverse effects related to intermittent dosing. Both pramipexole and ropinirole may produce hallucinosis or confusion, similar to that observed with levodopa, and may cause nausea and orthostatic hypotension. They should be initiated at low dose and titrated slowly to minimize these effects. The DA agonists, as well as levodopa itself, are also associated with fatigue and somnolence. The somnolence in some cases may be quite severe, and several instances of sudden attacks of irresistible sleepiness leading to motor vehicle accidents have been reported (Frucht et al., 1999). Although an uncommon complication, it is prudent to advise patients of this possibility and to switch to another agent when somnolence is an issue.

Apomorphine. Apomorphine (apokyn) is a dopaminergic agonist that can be administered by subcutaneous injection. It has high affinity for D₄ receptors; moderate affinity for D₂, D₃, D₅, and adrenergic α_1D, α_2B, and α_2C receptors; and low affinity for D₁ receptors. Apomorphine has been used in Europe for many years and is FDA-approved as a "rescue therapy" for the acute intermittent treatment of "off" episodes in patients with a fluctuating response to dopaminergic therapy.

Apomorphine has the same side effects as discussed earlier for the oral DA agonists. In addition, apomorphine is highly emetogenic and requires pre- and post-treatment anti-emetic therapy. Oral trimethobenzamide (tigan), at a dose of 300 mg three times daily, should be started 3 days prior to the initial dose of apomorphine and continued at least during the first 2 months of therapy. Profound hypotension and loss of consciousness have occurred when apomorphine was administered with ondansetron; hence, the concomitant use of apomorphine with antiemetic drugs of the 5-HT₃ antagonist class is contraindicated. Other potentially serious side effects of apomorphine include QT prolongation, injection-site reactions, and the development of a pattern of abuse characterized by increasingly frequent dosing leading to hallucinations, dyskinesia, and abnormal behavior. Because of these potential adverse effects, use of apomorphine is appropriate only when other measures, such as oral DA agonists or COMT inhibitors, have failed to control the "off" episodes. Apomorphine therapy should be initiated with a 2-mg test dose in a setting where the patient can be monitored carefully. If tolerated, it can be titrated slowly up to a maximum dosage of 6 mg. For effective control of symptoms, patients may require three or more injections daily.

Catechol-O-Methyltransferase (COMT) Inhibitors. Drugs for the treatment of PD include inhibitors of the enzyme COMT, which, together with MAO, metabolizes levodopa and DA. COMT transfers a methyl group from the donor S-adenosyl-L-methionine, producing the pharmacologically inactive compounds 3-O-methyl DOPA (from levodopa) and 3-methoxytyramine (from DA; Figure 22–5). When levodopa is administered orally, nearly 99% of the drug is metabolized and does not reach the brain. Most is converted by aromatic l-amino acid decarboxylase (AADC) to DA, which causes nausea and hypotension. Addition of an AADC inhibitor such as carbidopa reduces the formation of DA but increases the fraction of levodopa that is methylated by COMT. The principal therapeutic action of the COMT inhibitors is to block this peripheral conversion of levodopa to 3-O-methyl DOPA, increasing both the plasma t_1/2 of levodopa as well as the fraction of each dose that reaches the CNS.

Two COMT inhibitors presently are available for this use in the United States, tolcapone (tasmar) and entacapone (comtan). In double-blind clinical trials, both agents significantly reduced the "wearing off" symptoms in patients treated with levodopa/carbidopa (Parkinson Study Group, 1997). The two drugs differ only in their pharmacokinetic properties and adverse effects: tolcapone has a relatively long duration of action, allowing for administration two to three times a day, and appears to act by both central and peripheral inhibition of COMT. Entacapone has a short duration of action (2 hours) and usually is administered simultaneously with each dose of levodopa/carbidopa. The action of entacapone is attributable principally to peripheral inhibition of COMT. The common adverse effects of these agents are similar to those of levodopa/carbidopa alone and include nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations. An important adverse effect associated with tolcapone is hepatotoxicity. Up to 2% of the patients treated have increased serum alanine aminotransferase and aspartate transaminase; and at least three fatal cases of fulminant hepatic failure in patients taking tolcapone have been observed, leading to addition of a black box warning to the label. At present, tolcapone should be used only in patients who have not responded to other therapies and with appropriate monitoring for hepatic injury. Entacapone has not been associated with hepatotoxicity and requires no special monitoring. Entacapone also is available in fixed-dose combinations with levodopa/carbidopa (stalevo).

Selective MAO-B Inhibitors. Two isoenzymes of MAO oxidize monoamines. While both isoenzymes (MAO-A and MAO-B) are present in the periphery and inactivate monoamines of intestinal origin, the isoenzyme MAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of DA in the brain. Two selective MAO-B inhibitors are used for the treatment of PD: selegiline (eldepryl, emsam, zelapar) and rasagiline (azilect). When used at recommended doses, these agents selectively inactivate MAO-B through irreversible inhibition of the enzyme (Elmer and Bertoni, 2008). Both agents exert modest beneficial effects on the symptoms of PD. The basis of this efficacy is presumed to be the inhibition of breakdown of DA in the striatum. Unlike nonspecific inhibitors of MAO (such as phenelzine, tranylcypromine, and isocarboxazid), selective MAO-B inhibitors do not substantially inhibit the peripheral metabolism of catecholamines and can be taken safely with levodopa. These agents also do not exhibit the "cheese effect," the potentially lethal potentiation of catecholamine action observed when patients on nonspecific MAO inhibitors ingest indirectly acting sympathomimetic amines such as the tyramine found in certain cheeses and wine.

Selegiline has been used for many years as a symptomatic treatment for PD and is generally well tolerated in younger patients with early or mild PD. In patients with more advanced PD or underlying cognitive impairment, selegiline may accentuate the adverse motor and cognitive effects of levodopa therapy. Metabolites of selegiline include amphetamine and methamphetamine, which may cause anxiety, insomnia, and other adverse symptoms. Recently, selegiline has become available in an orally disintegrating tablet (zelepar) as well as a transdermal patch (emsam). Both of these delivery routes are intended to reduce hepatic first-pass metabolism and limit the formation of the amphetamine metabolites.

Unlike selegiline, rasagiline does not give rise to undesirable amphetamine metabolites. In randomized controlled clinical trials, rasagiline monotherapy was effective in early PD. Adjunctive therapy significantly reduced levodopa-related "wearing off" symptoms in advanced PD.

A consequence of the inhibition of MAO-B in the brain is a reduction in the overall catabolism of DA, which may reduce the formation of potentially toxic free radicals. This observation has led to studies which have examined the question of whether MAO-B inhibition can alter the rate of neurodegeneration in PD. The potential protective role of selegiline in idiopathic PD was evaluated in several multicenter randomized trials; although there was some evidence supporting a neuroprotective effect, the outcomes were obscured by the difficulty of distinguishing long-term neuroprotective effects from short-term symptomatic effects (Parkinson Study Group, 1993; Yacoubian and Standaert, 2008). A more recent study, using a different design, has produced more convincing data suggesting a neuroprotective effect of rasagiline (Olanow, 2008).

Although selective MAO-B inhibitors are generally well tolerated, drug interactions can be troublesome. Similar to the nonspecific MAO inhibitors, selegiline can lead to the development of stupor, rigidity, agitation, and hyperthermia when administered with the analgesic meperidine. Although the mechanics, of this interaction is uncertain, selegiline or rasagiline should not be given in combination with meperidine. Adverse effects have been reported from co-administration of MAO-B inhibitors with tricyclic antidepressants or with serotonin-reuptake inhibitors. However, interactions with antidepressants are uncommon, and many patients do take these combinations of medications without apparent adverse interaction; nonetheless, concomitant administration of selegiline or rasagiline with serotonergic drugs should be done with caution, especially in patients on high doses of serotonin-reuptake inhibitors.

Muscarinic Receptor Antagonists. Antagonists of muscarinic acetylcholine receptors were used widely for the treatment of PD before the discovery of levodopa. The biological basis for the therapeutic actions of anticholinergics is not completely understood. They may act within the neostriatum through the receptors that normally mediate the response to intrinsic cholinergic innervation of this structure, which arises primarily from cholinergic striatal interneurons. Several muscarinic cholinergic receptors have been cloned (Chapters 9 and 14); like the DA receptors, these are GPCRs. Five subtypes of muscarinic receptors exist. All five subtypes are probably present in the striatum, although each one has a distinct distribution (Hersch et al., 1994). Anticholinergic drugs currently used in the treatment of PD include trihexyphenidyl (2-4 mg three times per day), benztropine mesylate (1-4 mg two times per day), and diphenhydramine hydrochloride (25-50 mg three or four times per day). Diphenhydramine also is a histamine H₁ antagonist (Chapter 32).

All of these drugs have relatively modest antiparkinsonian activity and are only used in the treatment of early PD or as an adjunct to dopamimetic therapy. Adverse effects result from their anticholinergic properties. Most troublesome are sedation and mental confusion. Other side effects are constipation, urinary retention, and blurred vision through cycloplegia. All anticholinergic drugs must be used with caution in patients with narrow-angle glaucoma (Chapter 65).

Amantadine. Amantadine (symmetrel), an antiviral agent used for the prophylaxis and treatment of influenza A (Chapter 58), has antiparkinsonian activity. Amantadine appears to alter DA release in the striatum, has anticholinergic properties, and blocks NMDA glutamate receptors. However, it is not well understood which of amantadine's pharmacological effects are responsible for its antiparkinsonian actions. In any case, the effects of amantadine in PD are modest. It is used as initial therapy of mild PD. It also may be helpful as an adjunct in patients on levodopa with dose-related fluctuations and dyskinesias. The antidyskinetic properties of amantadine have been attributed to actions at NMDA receptors (Hallett and Standaert, 2004), although the closely related NMDA receptor antagonist memantine (discussed later) does not seem to have this effect.

Amantadine is usually administered at a dose of 100 mg twice a day and is well tolerated. Dizziness, lethargy, anticholinergic effects, and sleep disturbance, as well as nausea and vomiting, have been observed occasionally, but even when present, these effects are mild and reversible.

Neuroprotective Treatments for Parkinson Disease. It would be desirable to identify a treatment that modifies the progressive degeneration that underlies PD rather than simply controlling the symptoms. Current research strategies are based on the disease mechanisms described earlier (e.g., energy metabolism, oxidative stress, environmental triggers, and excitotoxicity) and on discoveries related to the genetics of PD (Yacoubian and Standaert, 2008). Several studies have examined the potential neuroprotective effects of existing medications. In a randomized controlled trial, levodopa did not worsen the disease state. Some benefits persisted for several weeks after treatment was stopped, but whether this was truly a "neuroprotective" effect remains uncertain (Fahn et al., 2004).

Two trials have attempted to examine the effect of pramipexole or ropinirole on neurodegeneration in PD (Parkinson Study Group, 2002; Whone et al., 2003). Both trials observed that in patients treated with either one of these agonists, there was a reduced rate of loss of markers of dopaminergic neurotransmission measured by brain imaging compared with a similar group of patients treated with levodopa. These intriguing data should be viewed cautiously, particularly because there is considerable uncertainty about the relationship of the imaging results techniques used and the true rate of neurodegeneration (Albin and Frey, 2003).

Inhibition of MAO-B in the brain reduces the overall catabolism of DA, which may decrease the formation of potentially toxic free radicals and consequently the rate of neurodegeneration in PD. The protective role of selegiline in idiopathic PD was evaluated in several multicenter randomized trials. Unfortunately, distinguishing long-term neuroprotective effects from short-term symptomatic effects was difficult in the earlier studies (Parkinson Study Group, 1993; Yacoubian and Standaert, 2008). A different study design showed more convincingly a neuroprotective effect of rasagiline (2008).

Another strategy under study is the use of compounds that augment cellular energy metabolism such coenzyme Q10, a cofactor required for the mitochondrial electron-transport chain. A small study has demonstrated that this drug is well tolerated in PD and has suggested that coenzyme Q10 may slow the course of the disease (Shults et al., 2002). A much larger study is in progress. Therapies directly targeting the molecules which are implicated in the pathogenesis of PD are still in a nascent stage, and may require unconventional delivery strategies such as gene therapy (Lewis and Standaert, 2008).

Clinical Summary. Pharmacological treatment of PD should be tailored to the individual patient. Drug therapy is not obligatory in early PD; many patients can be managed for a time with exercise and lifestyle interventions. For patients with mild symptoms, MAO-B inhibitors, amantadine, or (in younger patients) anticholinergics are reasonable choices. In most patients, treatment with a dopaminergic drug, either levodopa or a DA agonist, is eventually required. Large controlled clinical trials provide convincing evidence for a reduced rate of motor fluctuation in patients in which DA agonists are used as initial treatment. This benefit was, however, accompanied by an increased rate of adverse effects, especially somnolence and hallucinations (Parkinson Study Group, 2000; Rascol et al., 2000). Practitioners prefer DA agonist as initial therapy in younger patients in order to reduce the occurrence of motor complications. In older patients or those with substantial comorbidity, levodopa/ carbidopa is generally better tolerated.

ALZHEIMER'S DISEASE (AD)

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Clinical Overview. The brain region most vulnerable to neuronal dysfunction and cell loss in AD is the medial temporal lobe, including entorhinal cortex and hippocampus. Typical early AD symptoms are due to dysfunction of these structures resulting in anterograde episodic memory loss: repeated questions, misplaced items, missed appointments, and forgotten details of daily life. A typical patient presents with memory dysfunction that is noticeable by the patient and/or family members, but not severe enough to impair daily function. Because current diagnostic criteria for AD require the presence of dementia (i.e., cognitive impairments sufficient to reduce function), these patients are generally given a diagnosis of mild cognitive impairment (MCI). Patients with MCI progress at a rate of about 10% per year to AD (Petersen et al., 2005), although not all MCI patients will develop AD. The decline in both cognitive and functional capacity follows a course of gradual but relentless progression in AD, spreading to involve other cognitive domains including visuospatial and executive function. The later stages of the disease are characterized by increasing dependence and progression toward the akinetic-mute state that typifies end-stage neurologic disease. Death, most often from a complication of immobility such as pneumonia or pulmonary embolism, usually ensues within 6-12 years of onset.

At present, the diagnosis of AD is based on the clinical assessment of the patient. Structural neuroimaging and appropriate laboratory tests are used to exclude other disorders that may mimic AD. In the near future, laboratory measures to specifically identify AD, including analysis of biomarkers such as CSF or serum factors, genetic testing, and molecular or functional neuroimaging, are likely to be incorporated into AD diagnostic criteria to enhance the sensitivity of diagnosis, especially at early stages of the disease (Dubois et al., 2007). A direct antemortem confirmatory test currently does not exist.

Genetics. Mutations in three genes have been identified as causes of autosomal dominant, early-onset AD: APP, which encodes amyloid-β precursor protein, and PSEN1 and PSEN2, encoding presenilin 1 and 2. All three genes are involved in the production of amyloid-β peptides (Aβ). Aβ is generated by sequential proteolytic cleavage of APP by two enzymes, β-secretase and γ-secretase; the presenilins form the catalytic core of γ-secretase. The genetic evidence, combined with the fact that Aβ accumulates in the brain in the form of soluble oligomers and amyloid plaques, and is toxic when applied to neurons, forms the basis for the amyloid hypothesis of AD pathogenesis (Tanzi and Bertram, 2005).

Autosomal-dominant cases of AD are quite rare, but there is also a significant genetic component to the more common, sporadic, late-onset cases of AD. Many genes have been identified as having alleles that increase AD risk (Bertram et al., 2007). By far the most important of these is APOE, which encodes the lipid carrier protein apolipoprotein E (apoE) (Raber et al., 2004). Individuals inheriting the ∊4 allele of APOE have a more than 3-fold higher risk of developing AD. While they make up less than one-fourth of the population, they account for more than half of all AD cases. Several clinical trials have shown a different response rate between apoE4-carriers and noncarriers, suggesting an important potential pharmacogenetic influence of apoE genotype on the choice of therapy. However, at this point genetic testing for apoE status is not a routine part of the clinical evaluation for AD.

Pathophysiology. The pathological hallmarks of AD are amyloid plaques, which are extracellular accumulations of Aβ, and intracellular neurofibrillary tangles composed of the microtubule-associated protein tau (Figure 22–6). While the development of amyloid plaques is an early and invariant feature of AD, tangle burden accrues over time in a manner that correlates more closely with the development of cognitive impairment. The current consensus is that Aβ accumulation is an upstream event that triggers tau pathology, resulting in impaired neuronal function and cell loss. In autosomal dominant AD, Aβ accumulates due to mutations that cause its overproduction. The cause of high cerebral Aβ levels in late-onset sporadic AD is unclear but is likely caused by impaired clearance rather than overproduction.

Aggregation of Aβ is an important event in AD pathogenesis. While plaques consist of highly ordered fibrils of Aβ, it appears that soluble Aβ oligomers, perhaps as small as dimers, are more highly pathogenic. Tau also aggregates to form the paired helical filaments that make up neurofibrillary tangles. Post-translational modifications of tau including phosphorylation, proteolysis, and other changes cause loss of tau's normal functions and increase its propensity to aggregate. Mechanisms by which Aβ and tau induce neuronal dysfunction and death may include direct impairment of synaptic transmission and plasticity, excitotoxicity, oxidative stress, and neuroinflammation. The factors underlying the selective vulnerability of particular cortical neurons to the pathological effects of AD are not known.

Neurochemistry. The most striking neurochemical disturbance in AD is a deficiency of acetylcholine. The anatomical basis of the cholinergic deficit is atrophy and degeneration of subcortical cholinergic neurons, particularly those in the basal forebrain (nucleus basalis of Meynert) that provide cholinergic innervation to the cerebral cortex. The selective deficiency of ACh in AD, as well as the observation that central cholinergic antagonists such as atropine can induce a confusional state that bears some resemblance to the dementia of AD, has given rise to the "cholinergic hypothesis," which proposes that a deficiency of ACh is critical in the genesis of the AD symptoms (Perry, 1986). Although viewing AD as a "cholinergic deficiency syndrome" akin to the "dopaminergic deficiency syndrome" of PD provides a useful framework, it is important to note that the deficit in AD is far more complex. AD involves multiple neurotransmitter systems, including glutamate, 5-HT, and neuropeptides, and there is destruction of not only cholinergic neurons but also the cortical and hippocampal targets that receive cholinergic input.

Figure 22–6.

Molecular and cellular processes presumed to participate in AD pathogenesis. (From Roberson ED, Mucke L. 100 years and counting: Prospects for defeating Alzheimer's disease. Science, 2006, 314:781–784. Reprinted with permission from AAAS.)

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Treatment of Alzheimer's Disease

At present, no disease-modifying therapy for AD is available. While aggressive attempts to develop drugs targeting Aβ, tau, apoE, and other molecules involved in AD pathogenesis are underway (Roberson and Mucke, 2006), current treatment is aimed at alleviating symptoms.

Treatment of Cognitive Symptoms. Augmentation of the cholinergic transmission is currently the mainstay of AD treatment. Three drugs, donepezil, rivastigmine, and galantamine, are widely used for this purpose; a fourth, tacrine, was the first drug approved to treat AD but is rarely used now because it has much more extensive side effects compared to the newer agents (Table 22–2). All four agents are reversible antagonists of cholinesterases, enzymes that act to limit cholinergic neurotransmission by catalyzing the cleavage of acetylcholine in the synaptic cleft into choline and acetate (Chapter 10). Cholinesterase inhibitors are the usual first-line therapy for symptomatic treatment of cognitive impairments in mild or moderate AD. These agents have a beneficial, albeit quite modest, effect on cognition in clinical AD studies (Birks, 2006). They are also widely used to treat other neurodegenerative diseases with cholinergic deficits, including dementia with Lewy bodies (Bhasin et al., 2007) and vascular dementia (Kavirajan and Schneider, 2007). In addition, they are sometimes used in MCI, where they may also have symptomatic benefit but do not slow the conversion to AD (Raschetti et al., 2007). The drugs are usually well tolerated, with the most common side effects being GI distress, muscle cramping, and abnormal dreams. Because of their cholinergic and potentially vagotonic properties, they should be used with caution in patients with bradycardia or syncope.

Table 22-2Cholinesterase Inhibitors Used for the Treatment of Alzheimer's Disease

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Table 22-2 Cholinesterase Inhibitors Used for the Treatment of Alzheimer's Disease

DONEPEZIL

RIVASTIGMINE

GALANTAMINE

TACRINE^a

Brand name

Aricept

Exelon, generic

Razadyne, generic

Cognex

Enzymes inhibited^b

AChE

AChE, BuChE

AChE

AChE, BuChE

Mechanism

Noncompetitive

Competitive

Noncompetitive

Typical maintenance dose^c

10 mg once daily

9.5 mg/24h (transdermal)

8-12 mg twice daily (immediate-release)

20 mg, four times daily

3-6 mg twice daily (oral)

16-24 mg/day (extended-release)

FDA-approved indications

Mild–severe AD

Mild–moderate AD,

Mild–moderate AD

Mild–moderate PDD^d

Metabolism^e

CYP2D6, CYP3A4

Esterases

CYP2D6, CYP3A4

CYP1A2

^a Tacrine was the first cholinesterase inhibitor approved for the treatment of AD, but is now rarely used because of hepatotoxicity and adverse effects.

^bAChE (acetylcholinesterase) is the major cholinesterase in the brain; BuChE (butyrylcholinesterase) is a serum and hepatic cholinesterase that is upregulated in AD brain. ^c Typical starting doses are one-half of the maintenance dose and are given for the first month of therapy. ^d PDD, Parkinson disease dementia. ^e Drugs metabolized by CYP2D6 and CYP3A4 are subject to increased serum levels when co-administered with drugs known to inhibit these enzymes, such as ketoconazole and paroxetine. Similarly, tacrine levels are increased by co-administration with the CYP1A2 inhibitors theophylline, cimetidine, and fluvoxamine.

Memantine (namenda) is used either as an adjunct or an alternative to cholinesterase inhibitors in AD, and is also commonly used to treat other neurodegenerative dementias. Memantine is a noncompetitive antagonist of the NMDA-type glutamate receptor. It interacts with the Mg²⁺ binding site of the channel to prevent excessive activation while sparing normal function (Lipton, 2007). Memantine significantly reduces the rate of clinical deterioration in patients with moderate to severe AD (Raina et al., 2008). Whether this is due to a true disease-modifying effect, possibly reduced excitotoxicity, or to a symptomatic effect of the drug is unclear. Adverse effects of memantine include headache or dizziness, but are usually mild and reversible. The drug is excreted by the kidneys, and dosage should be reduced in patients with severe renal impairment.

Treatment of Behavioral Symptoms. In addition to cognitive decline, behavioral and psychiatric symptoms in dementia (BPSD) are common, particularly in middle stages of the disease. These symptoms, including irritability and agitation, paranoia and delusional thinking, wandering, anxiety, and depression, are a major source of caregiver distress and often precipitate nursing home placement. Treatment can be difficult, and non-pharmacological approaches should generally be first-line (Beier, 2007; Sink et al., 2005).

A variety of pharmacological options are also available. In addition to their effects on cognitive measures, both cholinesterase inhibitors and memantine reduce some BPSD (Maidment et al., 2008; Trinh et al., 2003). However, their effects are modest, and they do not treat some of the most troublesome symptoms, such as agitation (Howard et al., 2007). Furthermore, because most AD patients are already treated with these drugs, other options are often needed when behavioral symptoms emerge.

Atypical antipsychotics, such as risperidone, olanzapine, and quetiapine (Chapter 16), are the most efficacious therapy for agitation and psychosis in AD. Risperdone and olanzapine are effective, but their use is often limited by adverse effects, including parkinsonism, sedation, and falls (Schneider et al., 2006). In addition, the use of atypical antipsychotics in elderly patients with dementia-related psychosis has been associated with a higher risk of stroke and overall mortality (Douglas and Smeeth, 2008; Schneider et al., 2005), leading the FDA to order inclusion of a boxed warning in the prescribing information for all drugs in this class. Unfortunately, there are few effective alternatives.

Mood stabilizers (Chapter 16) have been the focus of several trials for BPSD. Carbamazepine has shown some benefit in small trials but carries numerous risks in the elderly, especially the potential for drug-drug interactions. There is little evidence of benefit from valproic acid. Lithium is of considerable interest given its ability to inhibit glycogen synthase kinase, which is implicated in AD pathogenesis, but clinical trial results are limited and concerns persist about the narrow therapeutic window in elderly patients. Benzodiazepines (Chapter 17) can be used for occasional control of acute agitation, but are not recommended for long-term management because of their adverse effects on cognition and other risks in the elderly population. The typical antipsychotic haloperidol (Chapter 16) may be useful for aggression, but sedation and extrapyramidal symptoms limit its use to control of acute episodes.

Antidepressants (Chapter 15) can be useful for BPSD, particularly when depression or anxiety contribute. Because of the adverse anticholinergic effects of tricyclic agents, serotonergic antidepressants are favored. These agents are generally well tolerated. Trazodone has modest benefits, but for the most part, selective serotonin reuptake inhibitors (SSRIs) are the preferred class of drugs.

Clinical Summary. The typical AD patient presenting in early stages of disease should probably be treated with a cholinesterase inhibitor. Patients and families should be counseled that a realistic goal of therapy is to induce a temporary reprieve from progression, or at least a reduction in the rate of decline, rather than long-term recovery of cognition. As the disease progresses, memantine can be added to the regimen. Behavioral symptoms are often treated with a serotonergic antidepressant or, if they are severe enough to warrant the risk of higher mortality, an atypical antipsychotic. Eliminating drugs likely to aggravate cognitive impairments, particularly anticholinergics, benzodiazepines, and other sedative/hypnotics, from the patient's regimen is another important aspect of AD pharmacotherapy.

HUNTINGTON'S DISEASE (HD)

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Clinical Features. HD is a dominantly inherited disorder characterized by the gradual onset of motor incoordination and cognitive decline in midlife. Symptoms develop insidiously, either as a movement disorder manifest by brief, jerk-like movements of the extremities, trunk, face, and neck (chorea) or as personality changes or both. Fine-motor incoordination and impairment of rapid eye movements are early features. Occasionally, especially when the onset of symptoms occurs before age 20, choreic movements are less prominent; instead, bradykinesia and dystonia predominate. As the disorder progresses, the involuntary movements become more severe, dysarthria and dysphagia develop, and balance is impaired. The cognitive disorder manifests first as slowness of mental processing and difficulty in organizing complex tasks. Memory is impaired, but affected persons rarely lose their memory of family, friends, and the immediate situation. Such persons often become irritable, anxious, and depressed. Less frequently, paranoia and delusional states are manifest. The outcome of HD is invariably fatal; over a course of 15-30 years, the affected person becomes totally disabled and unable to communicate, requiring full-time care; death ensues from the complications of immobility (Shoulson, 1992).

Pathology and Pathophysiology. HD is characterized by prominent neuronal loss in the striatum (caudate/putamen) of the brain (Vonsattel et al., 1985). Atrophy of these structures proceeds in an orderly fashion, first affecting the tail of the caudate nucleus and then proceeding anteriorly from mediodorsal to ventrolateral. Other areas of the brain also are affected, although much less severely; morphometric analyses indicate that there are fewer neurons in cerebral cortex, hypothalamus, and thalamus. Even within the striatum, the neuronal degeneration of HD is selective. Interneurons and afferent terminals are largely spared, whereas the striatal projection neurons (the medium spiny neurons) are severely affected. This leads to large decreases in striatal GABA concentrations, whereas SST and DA concentrations are relatively preserved (Ferrante et al., 1987).

Selective vulnerability also appears to underlie the most conspicuous clinical feature of HD, the development of chorea. In most adult-onset cases, the medium spiny neurons that project to the GPi and SNpr (the indirect pathway) appear to be affected earlier than those projecting to the GPe (the direct pathway; Figure 22–5) (Albin et al., 1992). The disproportionate impairment of the indirect pathway increases excitatory drive to the neocortex, producing involuntary choreiform movements (Figure 22–7). In some individuals, rigidity rather than chorea is the predominant clinical feature; this is especially common in juvenile-onset cases. Here, the striatal neurons giving rise to both the direct and indirect pathways are impaired to a comparable degree.

Genetics. HD is an autosomal dominant disorder with nearly complete penetrance. The average age of onset is between 35 and 45 years, but the range varies from as early as age 2 to as late as the middle 80s. Although the disease is inherited equally from mother and father, more than 80% of those developing symptoms before age 20 inherit the defect from the father. This is an example of anticipation, or the tendency for the age of onset of a disease to decline with each succeeding generation, which also is observed in other neurodegenerative diseases with similar genetic mechanisms. Known homozygotes for HD show clinical characteristics identical to the typical HD heterozygote, indicating that the unaffected chromosome does not attenuate the disease symptomatology. Until the discovery of the genetic defect responsible for HD, de novo mutations causing HD were thought to be unusual; but it is now clear that the disease can arise from unaffected parents, especially when one carries an "intermediate allele," as described in the next paragraph.

The discovery of the genetic mutation responsible for HD was the product of an arduous 10-year, multi-investigator collaborative effort. In 1993, a region near the end of the short arm of chromosome 4 was found to contain a polymorphic (CAG)_n trinucleotide repeat that was significantly expanded in all individuals with HD (Huntington's Disease Collaborative Research Group, 1993). The expansion of this trinucleotide repeat is the genetic alteration responsible for HD. The CAG repeat is unstable, and may expand during the DNA synthesis associated with meiosis. This is particularly common during spermatogenesis, and accounts for the phenomenon of anticipation. The range of CAG repeat length in normal individuals is between 9 and 34 triplets, with a median repeat length on normal chromosomes of 19. The repeat length in HD varies from 40 to over 100. Repeat lengths of 35-39 represent intermediate alleles; some of these individuals develop HD late in life, whereas others are not affected. Repeat length is correlated inversely with age of onset. The younger the age of onset, the higher the probability of a large repeat number. This correlation is most powerful in individuals with onset before age 30; with onset above age 30, the correlation is weaker. Thus, repeat length cannot serve as an adequate predictor of age of onset in most individuals. Several other neurodegenerative diseases also arise through expansion of a CAG repeat, including hereditary spinocerebellar ataxias and Kennedy's disease, a rare inherited disorder of motor neurons.

Selective Vulnerability. The mechanism by which the expanded trinucleotide repeat leads to the clinical and pathological features of HD is unknown. The HD mutation lies within a large gene (10 kilobases) designated IT15. It encodes a protein of approximately 348,000 DA. The trinucleotide repeat, which encodes the amino acid glutamine, occurs at the 5′5' end of IT15 and is followed directly by a second, shorter repeat of (CCG)_n that encodes proline. The protein, named huntingtin, does not resemble any other known protein, and the normal function of the protein has not been identified. Mice with a genetic knockout of huntingtin die early in embryonic life, so it must have an essential cellular function. It is thought that the mutation results in a gain of function—that is, the mutant protein acquires a new function or property not found in the normal protein. The nature of the function gained remains uncertain, although some evidence points to effects on cellular energy metabolism and gene transcription (Imarisio, 2008).

Figure 22–7.

The basal ganglia in Huntington's disease. HD is characterized by loss of neurons from the striatum. The neurons that project from the striatum to the GPe and form the indirect pathway are affected earlier in the course of the disease than those which project to the GPi. This leads to a loss of inhibition of the GPe. The increased activity in this structure, in turn, inhibits the STN, SNpr, and GPi, resulting in a loss of inhibition to the VA/VL thalamus and increased thalamocortical excitatory drive. Structures in purple have reduced activity in HD, whereas structures in purple have increased activity. Light blue line indicate primary pathways of reduced activity. (See legend to Figure 22–2 for definitions of anatomical abbreviations.)

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Treatment of Huntington's Disease

Symptomatic Treatment. Treatment for symptomatic HD emphasizes the selective use of medications (Shoulson, 1992). None of the currently available medications slows the progression of the disease. HD patients are frequently very sensitive to side effects of medications. Treatment is needed for patients who are depressed, irritable, paranoid, excessively anxious, or psychotic. Depression can be treated effectively with standard antidepressant drugs with the caveat that drugs with substantial anticholinergic profiles can exacerbate chorea. Fluoxetine (Chapter 15) is effective treatment for both the depression and the irritability manifest in symptomatic HD. Carbamazepine (Chapter 21) also has been found to be effective for depression. Paranoia, delusional states, and psychosis are treated with antipsychotic drugs, but usually at lower doses than those used in primary psychiatric disorders (Chapter 16). These agents also reduce cognitive function and impair mobility and thus should be used in the lowest doses possible and should be discontinued when the psychiatric symptoms resolve. In individuals with predominantly rigid HD, clozapine, quetiapine (Chapter 16), or carbamazepine may be more effective for treatment of paranoia and psychosis.

The movement disorder of HD per se only rarely justifies pharmacological therapy. For those with large-amplitude chorea causing frequent falls and injury, tetrabenazine (xenazinenitoman) has recently become available in the U.S. for the treatment of chorea associated with HD. Tetrabenazine, and the related drug reserpine, are inhibitors of the vesicular monoamine transporter 2 (VMAT2), and cause presynaptic depletion of catecholamines. Tetrabenazine is a reversible inhibitor; inhibition by reserpine is irreversible and may lead to long-lasting effects. Both drugs may cause hypotension and depression with suicidality; the shorter duration of effect of tetrabenazine greatly simplifies the clinical management. Antipsychotic agents also can be used, but these often do not improve overall function because they decrease fine motor coordination and increase rigidity. Many HD patients exhibit worsening of involuntary movements as a result of anxiety or stress. In these situations, judicious use of sedative or anxiolytic benzodiazepines can be very helpful. In juvenile-onset cases where rigidity rather than chorea predominates, DA agonists have had variable success in the improvement of rigidity. These individuals also occasionally develop myoclonus and seizures that can be responsive to clonazepam, valproic acid, and other anticonvulsants (Chapter 21).

Clinical Summary. HD is an autosomal dominant disorder caused by mutations in the IT15 gene that encodes huntingtin. The gene defect leads to progressive motor and cognitive symptoms. At present there is no effective treatment for the primary disorder, although antidepressant and antipsychotic medications may be useful to control specific symptoms and catecholamine depleting agents may be useful to control the motor features of the disease.

AMYOTROPHIC LATERAL SCLEROSIS (ALS)

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Clinical Features and Pathology. ALS (or Lou Gehrig's disease) is a disorder of the motor neurons of the ventral horn of the spinal cord (lower motor neurons) and the cortical neurons that provide their afferent input (upper motor neurons). The disorder is characterized by rapidly progressive weakness, muscle atrophy and fasciculations, spasticity, dysarthria, dysphagia, and respiratory compromise. Sensory, autonomic, and oculomotor function is generally spared. While it was previously thought that higher cortical function was also unaffected, many ALS patients exhibit behavioral changes and cognitive dysfunction, and there is clinical, genetic, and neuropathological overlap between ALS and frontotemporal dementia spectrum disorders (Strong et al., 2009). ALS usually is progressive and fatal. Most patients die of respiratory compromise and pneumonia after 2-3 years, although some individuals have a more indolent course and survive for many years. The pathology of ALS corresponds closely to the clinical features: There is prominent loss of the spinal and brainstem motor neurons that project to striated muscles (although the oculomotor neurons are spared), as well as loss of the large pyramidal motor neurons in layer V of motor cortex, which are the origin of the descending corticospinal tracts.

Etiology. About 10% of ALS cases are familial (FALS), usually with an autosomal dominant pattern of inheritance. Most of the mutations responsible have not been identified, but an important subset of FALS patients are families with a mutation in the gene for the enzyme SOD1 (Rosen et al., 1993). Mutations in this protein account for about 20% of cases of FALS. Most of the mutations are alterations of single amino acids, but more than 30 different alleles have been found in different kindreds. Transgenic mice expressing mutant human SOD1 develop a progressive degeneration of motor neurons that closely mimics the human disease, providing an important animal model for research and pharmaceutical trials. Interestingly, many of the mutations of SOD1 that can cause disease do not reduce the capacity of the enzyme to perform its primary function, the catabolism of superoxide radicals. Thus, as may be the case in HD, mutations in SOD1 may confer a toxic "gain of function," the precise nature of which is unclear.

More recently, mutations in the TARDBP gene encoding TAR DNA-binding protein (TDP-43) and in the FUS/TLS gene have been identified as causes of FALS (Lagier-Tourenne and Cleveland, 2009). Both TDP-43 and FUS/TLS bind DNA and RNA, and regulate transcription and alternative splicing.

More than 90% of ALS cases are sporadic. Of these, a few are caused by de novo mutations in SOD1, TDP-43, FUS/TLS, or other genes, but for the majority of sporadic cases the etiology remains unclear. Possible pathogenic mechanisms underlying sporadic ALS include autoimmunity, excitotoxicity, free radical toxicity, and viral infection (Rothstein, 2009), although none is well supported by available data. There is evidence that glutamate reuptake may be abnormal in the disease, leading to accumulation of glutamate and excitotoxic injury (Rothstein et al., 1992). The only currently approved therapy for ALS, riluzole, is based on these observations (Brooks, 2009).

Treatment of Als

Riluzole. Riluzole (2-amino-6-[trifluoromethoxy]benzothiazole; RILUTEK) is an agent with complex actions in the nervous system (Doble, 1996; Zarate and Manji, 2008).

Riluzole is absorbed orally and is highly protein bound. It undergoes extensive metabolism in the liver by both CYP–mediated hydroxylation and glucuronidation. Its t_1/2 is about 12 hours. In vitro studies have shown that riluzole has both presynaptic and postsynaptic effects. It inhibits glutamate release, but it also blocks postsynaptic NMDA- and kainate-type glutamate receptors and inhibits voltage-dependent Na⁺ channels. Some of the effects of riluzole in vitro are blocked by pertussis toxin, implicating the drug's interaction with an as yet-unidentified G protein–coupled receptor (GPCR). In clinical trials riluzole has modest but genuine effects on the survival of patients with ALS.

Meta-analyses of the available trials indicate that riluzole extends survival by 2-3 months (Miller et al., 2007). The recommended dose is 50 mg twice daily, taken 1 hour before or 2 hours after a meal. Riluzole usually is well tolerated, although nausea or diarrhea may occur. Rarely, riluzole may produce hepatic injury with elevations of serum transaminases, and periodic monitoring of these is recommended. Although the magnitude of the effect of riluzole on ALS is small, it represents a significant therapeutic milestone in the treatment of a disease refractory to all previous treatments.

Symptomatic Therapy of ALS: Spasticity. Spasticity is an important component of the clinical features of ALS and the feature most amenable to present forms of treatment. Spasticity often leads to considerable pain and discomfort and further reduces mobility, which already is compromised by weakness. Spasticity is defined as an increase in muscle tone characterized by an initial resistance to passive displacement of a limb at a joint, followed by a sudden relaxation (the so-called clasped-knife phenomenon). Spasticity results from loss of descending inputs to the spinal motor neurons, and the character of the spasticity depends on which nervous system pathways are affected (Sheean, 2008). Whole repertoires of movement can be generated directly at the spinal cord level; it is beyond the scope of this chapter to describe these in detail. The monosynaptic tendon-stretch reflex is the simplest of the spinal mechanisms contributing to spasticity. Primary Ia afferents from muscle spindles, activated when the muscle is stretched rapidly, synapse directly on motor neurons going to the stretched muscle, causing it to contract and resist the movement. A collateral of the primary Ia afferent synapses on a "Ia-coupled interneuron" that inhibits the motor neurons innervating the antagonist of the stretched muscle, allowing contraction of the muscle to be unopposed. Upper motor neurons from the cerebral cortex (the pyramidal neurons) suppress spinal reflexes and the lower motor neurons indirectly by activating the spinal cord inhibitory interneuron pools (Figure 22–8).

Figure 22–8.

Monosynaptic muscle stretch reflex with descending control via inhibitory interneurons. Primary Ia afferents (green) from muscle spindles, activated when the muscle is stretched rapidly, synapse directly on motor neurons (blue) going to the stretched muscle, causing it to contract and resist the movement. Pyramidal upper motor neurons (aqua) from the cerebral cortex suppress spinal reflexes and the lower motor neurons indirectly by activating the spinal cord inhibitory interneuron pools (red). When the pyramidal influences are removed, the reflexes are released from inhibition and become more active, leading to hyperreflexia and spasticity. Baclofen acts to restore the lost inhibition by stimulating postsynaptic GABA receptors. Tizanidine acts presynaptically to stimulate GABA release from spinal cord inhibitory interneuron.

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The pyramidal neurons use glutamate as a neurotransmitter. When the pyramidal influences are removed, the reflexes are released from inhibition and become more active, leading to hyperreflexia. Other descending pathways from the brainstem, including the rubro-, reticulo-, and vestibulospinal pathways and the descending catecholamine pathways, also influence spinal reflex activity. When just the pyramidal pathway is affected, extensor tone in the legs and flexor tone in the arms are increased. When the vestibulospinal and catecholamine pathways are impaired, increased flexion of all extremities is observed, and light cutaneous stimulation can lead to disabling whole-body spasms. In ALS, pyramidal pathways are impaired with relative preservation of the other descending pathways, resulting in hyperactive deep-tendon reflexes, impaired fine motor coordination, increased extensor tone in the legs, and increased flexor tone in the arms. The gag reflex often is overactive as well.

The best agent for the symptomatic treatment of spasticity in ALS is baclofen (lioresal), a GABA_B receptor agonist. Initial doses of 5-10 mg/day are recommended, which can be increased to as much as 200 mg/day if necessary. If weakness occurs, the dose should be lowered. Alternatively, baclofen can be delivered directly into the space around the spinal cord using a surgically implanted pump and an intrathecal catheter. This approach minimizes the adverse effects of the drug, especially sedation, but it carries the risk of potentially life-threatening CNS depression. Moreover, abrupt withdrawal of intrathecal baclofen can cause rebound spasticity, rhabdomyolitis, multi-organ failure, and even death. Intrathecal baclofen should be used only by physicians trained in delivering chronic intrathecal therapy.

Tizanidine (zanaflex) is an agonist of α₂ adrenergic receptors in the CNS. It reduces muscle spasticity and is assumed to act by increasing presynaptic inhibition of motor neurons. Tizanidine is primarily used in the treatment of spasticity in multiple sclerosis or after stroke, but it also may be effective in patients with ALS. Treatment should be initiated at a low dose of 2-4 mg at bedtime and titrated upward gradually. Drowsiness, asthenia, and dizziness may limit the dose that can be administered. Benzodiazepines (Chapter 17) such as clonazepam (klonipin) are effective antispasticity agents, but they may contribute to respiratory depression in patients with advanced ALS. Dantrolene (dantrium) also is approved in the U.S. for the treatment of muscle spasm. In contrast to the other agents discussed, dantrolene acts directly on skeletal muscle fibers, impairing Ca²⁺ release from the sarcoplasmic reticulum. Because it can exacerbate muscular weakness, it is not used in ALS but is effective in treating spasticity associated with stroke or spinal cord injury and in treating malignant hyperthermia (Chapter 8). Dantrolene may cause hepatotoxicity, so it is important to monitor liver associated enzymes before and during therapy with the drug.

Clinical Summary. ALS is a progressive degenerative disease of spinal motor neurons leading to weakness and eventually paralysis. It is the most rapidly progressive of the common neurodegenerative disorders and often is fatal within 2-3 years of onset. The only therapy established to alter the course of ALS is the drug riluzole, which acts through inhibition of glutamate release as well as other mechanisms. The effect of this treatment is modest, prolonging survival by a few months.

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Chapter 22: Treatment of Central Nervous System Degenerative Disorders

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INTRODUCTION

SELECTIVE VULNERABILITY AND NEUROPROTECTIVE STRATEGIES

Parkinson Disease (PD)

Figure 22–1.

Figure 22–2.

Figure 22–3.

Treatment of Parkinson Disease

Figure 22–4.

Figure 22–5.

ALZHEIMER'S DISEASE (AD)

Figure 22–6.

Treatment of Alzheimer's Disease

HUNTINGTON'S DISEASE (HD)

Figure 22–7.

Treatment of Huntington's Disease

AMYOTROPHIC LATERAL SCLEROSIS (ALS)

Treatment of Als

Figure 22–8.

BIBLIOGRAPHY

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