Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II

chapter 22
Treatment of Central Nervous System Degenerative Disorders

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 disease (HD), where loss of neurons from structures of the basal ganglia results in abnormalities in the control of movement; Alzheimer 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. Currently available therapies for neurodegenerative disorders alleviate the disease symptoms but do not alter the underlying neurodegenerative process.


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. 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. In ALS, there is loss of spinal motor neurons and the cortical neurons that provide their descending input. The diversity of these patterns of neural degeneration suggests that the process of neural injury results from the interaction of genetic and environmental influences.

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. 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. Mutations in the gene coding for copper-zinc superoxide dismutase (SOD1) account for about 2% of the cases of adult-onset ALS. There are also genetic risk factors that influence the probability of disease onset and modify the phenotype. For example, the apolipoprotein E (apoE) 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”).

Environmental factors including infectious agents, environmental toxins, and acquired brain injury have been proposed in the etiology of neurodegenerative disorders. Traumatic brain injury has been suggested as a trigger for neurodegenerative disorders. At least one toxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), can induce a condition closely resembling PD. More recently, evidence has linked pesticide exposure with PD. Exposure of soldiers to neurotoxic chemicals has been implicated in ALS (as part of “Gulf War syndrome”).

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.

The term excitotoxicity describes the neural injury that results from the presence of excess glutamate in the brain. Glutamate is used as a neurotransmitter to mediate most excitatory synaptic transmission in the mammalian brain (see Table 14–1). The presence of excessive amounts of glutamate can lead to excitotoxic cell death (see Figure 14–8). 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. 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 2 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 with consequent production of reactive compounds such as hydrogen peroxide and oxygen radicals. 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 antioxidant strategies as treatments to prevent or retard degenerative diseases.


CLINICAL OVERVIEW. Parkinsonism is a clinical syndrome with 4 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 to 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. A loss of 70-80% of these dopamine-containing neurons accompanies 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. This pathology is likely responsible for the “non-motor” features of PD, which include sleep disorders, depression, and memory impairment.

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 chlorpromazine (see Chapter 16) and antiemetics such as prochlorperazine and metoclopramide (see Chapter 46). 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%, with a parallel loss of neurons from the substantia nigra, suggesting that replacement of DA could restore function. 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, reaccumulated, and metabolized by processes described in Chapter 13 and summarized in Figure 22–1. The actions of DA in the brain are mediated by DA receptor, of which there are 2 broad classes. D1 and D2, with 5 distinct subtypes, D1-D5 (see Figure 13–6). All the DA receptors are G protein–coupled receptors (GPCRs). Receptors of the D1 group (D1 and D5 subtypes) couple to Gs and thence to activation of the cyclic AMP pathway. The D2 group (D2, D3, and D4 receptors) couple to Gi to reduce the adenylyl cyclase activity and voltage-gated Ca2+ currents while activating K+ currents (see Chapters 3 and 13 for details). Each of the 5 DA receptors has a distinct anatomical pattern of expression in the brain (see Figure 13–6). 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.


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 transferase (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.

NEURAL MECHANISM OF PARKINSONISM: A MODEL OF BASAL GANGLIA FUNCTION. 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. 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).


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 2 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 2 inhibitory GABA-ergic links and 1 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 2 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).

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 2 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. The first 2 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).


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 2 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.)

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. The anatomical connections are considerably more complex and many of the pathways involved use several neurotransmitters. Nevertheless, the model is useful and has important implications for the rational design and use of pharmacological agents in PD.


Table 22–1 summarizes commonly used medications for the treatment of PD.

Table 22–1

Commonly Used Medications for the Treatment of Parkinson Disease


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.

The effects of levodopa result from its decarboxylation 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 h after an oral dose. The t1/2 in plasma is short (1-3 h). 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. 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 is mediated by a membrane transporter for aromatic amino acids. In the brain, levodopa is converted to DA by decarboxylation primarily within the presynaptic terminals of dopaminergic neurons in the striatum. 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). AADC, aromatic L-amino acid decarboxylase; ALDH, aldehyde dehydrogenase; COMT, catechol-O-methyltransferase; DβH, dopamine-β-hydroxylase; MAO, monoamine oxidase.

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 COMT (e.g., tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of 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-OMD, 3-O-methyl DOPA.

A daily dose of 75 mg carbidopa is generally 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 3 or more tablets daily provide acceptable inhibition of decarboxylase in most individuals.

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. With long-term levodopa therapy, the “buffering” capacity is lost, and the patient’s motor state may fluctuate dramatically with each dose of levodopa, producing the 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 h, 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. 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 (the on/off phenomenon). A sustained-release formulation consisting of carbidopa/levodopa in an erodable wax matrix (SINEMET CR) is helpful in some cases, but absorption of the sustained-release formulation is not entirely predictable.

Does levodopa alter the course of the underlying disease or merely modify 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. 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.

A frequent and troubling adverse effect is the induction of hallucinations and confusion, especially in elderly patients or in patients with preexisting cognitive dysfunction. 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 (see Chapter 16). The 2 drugs that are most effective and best tolerated in patients with advanced PD are clozapine and quetiapine. 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 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)]. 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. 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. 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). 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 h) often is longer than that of levodopa (6-8 h), 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. Practitioners prefer a 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.

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 α1D, α2B, and α2C receptors; and low affinity for D1 receptors. Apomorphine 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 the oral DA agonists. Apomorphine is highly emetogenic and requires pre- and posttreatment antiemetic therapy. Oral trimethobenzamide (TIGAN), at a dose of 300 mg 3 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 3 or more injections daily.

CATECHOL-O-METHYLTRANSFERASE INHIBITORS. When levodopa is administered orally, most is converted by aromatic L-amino acid decarboxylase (AADC) to DA (seeFigure 22–5), 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. COMT inhibitors block this peripheral conversion of levodopa to 3-O-methyl DOPA, increasing both the plasma t1/2 of levodopa as well as the fraction of each dose that reaches the CNS.

The COMT inhibitors tolcapone (TASMAR) and entacapone (COMTAN) reportedly reduce significantly the “wearing off” symptoms in patients treated with levodopa/carbidopa. The 2 drugs differ only in their pharmacokinetic properties and adverse effects: tolcapone has a relatively long duration of action, and appears to act by both central and peripheral inhibition of COMT. Entacapone has a short duration of action (2 h) and principally inhibits peripheral COMT. Common adverse effects of these agents include nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations. An important adverse effect associated with tolcapone is hepatotoxicity. At least 3 fatal cases of fulminant hepatic failure in patients taking tolcapone have been observed, leading to addition of a black box warning to the label. 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. Entacapone also is available in fixed-dose combinations with levodopa/carbidopa (STALEVO).

SELECTIVE MAO-B INHIBITORS. Two isoenzymes of MAO oxidize catecholamines: MAO-A and MAO-B. MAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of DA in the brain. Selective MAO-B inhibitors are used for the treatment of PD: selegiline (ELDEPRYL, EMSAM, ZELAPAR) and rasagiline (AZILECT). These agents selectively and irreversibly inactivate MAO-B. Both agents exert modest beneficial effects on the symptoms of PD. The basis of this efficacy is, presumably, inhibition of breakdown of DA in the striatum.

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 is generally well tolerated in younger patients for symptomatic treatment of 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. Selegiline has become available in an orally disintegrating tablet (ZELAPAR) 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. Rasagiline monotherapy is effective in early PD. Adjunctive therapy with rasagiline significantly reduces levodopa-related “wearing off” symptoms in advanced PD. 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, although uncommon, have been reported from coadministration of MAO-B inhibitors with tricyclic antidepressants or with serotonin-reuptake inhibitors.

MUSCARINIC RECEPTOR ANTAGONISTS. Antimuscarinic drugs currently used in the treatment of PD include trihexyphenidyl and benztropine mesylate, as well as the antihistaminic diphenhydramine hydrochloride, which also interacts at central muscarinic receptors. The biological basis for the therapeutic actions of muscarinic antagonists 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.

These drugs have relatively modest antiparkinsonian activity and are used only 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. All anticholinergic drugs must be used with caution in patients with narrow-angle glaucoma (see Chapter 64). The pharmacology and signaling mechanisms of muscarinic receptors are thoroughly covered in Chapter 9.

AMANTADINE. Amantadine (SYMMETREL), an antiviral agent used for the prophylaxis and treatment of influenza A (see Chapter 58), has antiparkinsonian activity. Amantadine appears to alter DA release in the striatum, has anticholinergic properties, and blocks NMDA glutamate receptors. 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. 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, these effects are mild and reversible.

NEUROPROTECTIVE TREATMENTS FOR PARKINSON DISEASE. 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. In a recent study, rasagiline has been reported to have a neuroprotective effect. 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.

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. 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.


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 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, although not all MCI patients will develop AD. Gradual but relentless progression in AD involves 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.

GENETICS. Mutations in 3 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 3 genes are involved in the production of amyloid-β peptides (Aβ). Aβ is generated by sequential proteolytic cleavage of APP by 2 enzymes, βsecretase 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. Many genes have been identified as having alleles that increase AD risk. By far the most important of these is APOE, which encodes the lipid carrier protein apoE. Individuals inheriting the ε4 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.

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. 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. In autosomal dominant AD, Aβ accumulates due to mutations that cause its 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. Posttranslational 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.

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. The selective deficiency of ACh in AD and the observation that central cholinergic antagonists (e.g., atropine) can induce a confusional state resembling the dementia of AD, have given rise to the “-cholinergic hypothesis” that a deficiency of ACh is critical in the genesis of the AD symptoms. AD, however, is complex and also 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.


At present, no disease-modifying therapy for AD is available; 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, is rarely used now because of its extensive side effects compared to the newer agents (Table 22–2). All 4 agents are reversible antagonists of cholinesterases (seeChapter 10). Cholinesterase inhibitors are the usual first-line therapy for symptomatic treatment of cognitive impairments in mild or moderate AD. They are also widely used to treat other neurodegenerative diseases with cholinergic deficits, including dementia with Lewy bodies and vascular dementia. The drugs are usually well tolerated, with the most common side effects being GI distress, muscle cramping, and abnormal dreams. They should be use with caution in patients with bradycardia or syncope.

Table 22–2

Cholinesterase Inhibitors Used for the Treatment of Alzheimer Disease


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. Memantine significantly reduces the rate of clinical deterioration in patients with moderate to severe AD. Adverse effects of memantine include mild headache or dizziness. 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 include irritability and agitation, paranoia and delusional thinking, wandering, anxiety, and depression. Treatment can be difficult, and nonpharmacological approaches should generally be first-line.

A variety of pharmacological options are also available. Both cholinesterase inhibitors and memantine reduce some BPSD. However, their effects are modest, and they do not treat some of the most troublesome symptoms, such as agitation. Atypical antipsychotics, such as risperidone, olanzapine, and quetiapine (see Chapter 16), are the most efficacious therapy for agitation and psychosis in AD. Risperidone and olanzapine are effective, but their use is often limited by adverse effects, including parkinsonism, sedation, and falls. 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. Benzodiazepines (see 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 (see Chapter 16) may be useful for aggression, but sedation and extrapyramidal symptoms limit its use to control of acute episodes. Antidepressants (see Chapter 15) can be useful for BPSD, particularly when depression or anxiety contribute. 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.


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. 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. 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.

PATHOLOGY AND PATHOPHYSIOLOGY. HD is characterized by prominent neuronal loss in the striatum (caudate/putamen) of the brain. 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. 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 somatostatin and DA concentrations are relatively preserved.

Selective vulnerability also appears to underlie 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; see Figure 22–2). The disproportionate impairment of the indirect pathway increases excitatory drive to the neocortex, producing involuntary choreiform movements (Figure 22–6). 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.


Figure 22–6 The basal ganglia in Huntington 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 that 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 red have increased activity.Light blue lines indicate primary pathways of reduced activity. (See legend to Figure 22–2 for definitions of anatomical abbreviations.)

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. Known homozygotes for HD show clinical characteristics identical to the typical HD heterozygote, indicating that the unaffected chromosome does not attenuate the disease symptomatology.

A region near the end of the short arm of chromosome 4 contains a polymorphic (CAG)n trinucleotide repeat that is significantly expanded in all individuals with HD. The expansion of this trinucleotide repeat is the genetic alteration responsible for HD. 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 length is correlated inversely with age of onset of HD. The younger the age of onset, the higher the probability of a large repeat number. 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 ~348,000 Da. The trinucleotide repeat, which encodes the amino acid glutamine, occurs at the 5′ end of IT15 and is followed directly by a second, shorter repeat of (CCG)n that encodes proline. The protein,huntingtin, does not resemble any other known protein, and the normal function of the protein has not been identified.


SYMPTOMATIC TREATMENT. None of the currently available medications slows the progression of the disease.

Symptomatic 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 (see Chapter 15) is effective treatment for both the depression and the irritability manifest in symptomatic HD. Carbamazepine (see 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 (see 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 (see Chapter 16), or carbamazepine may be more effective for treatment of paranoia and psychosis.

Tetrabenazine (XENAZINE, NITOMAN) is available for the treatment of large-amplitude 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. 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 (see Chapter 21).


ALS (or Lou Gehrig 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. Many ALS patients exhibit behavioral changes and cognitive dysfunction, and there is clinical, genetic, and neuropathological overlap between ALS and frontotemporal dementia spectrum disorders. ALS usually is progressive and fatal. Most patients die of respiratory compromise and pneumonia after 2-3 years, although some survive for many years.

ETIOLOGY. About 10% of ALS cases are familial (FALS), usually with an autosomal dominant pattern of inheritance. An important subset of FALS patients are families with a mutation in the gene for the enzyme SOD1. Mutations in this protein account for about 20% of cases of FALS. 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. 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. There is evidence that glutamate reuptake may be abnormal in the disease, leading to accumulation of glutamate and excitotoxic injury. The only currently approved therapy for ALS, riluzole, is based on these observations.


Riluzole. Riluzole (2-amino-6-[trifluoromethoxy] benzothiazole; RILUTEK) is an agent with complex actions in the nervous system.

Riluzole is absorbed orally and is highly protein bound. It undergoes extensive metabolism in the liver by both CYP–mediated hydroxylation and glucuronidation. Its t1/2 is 12 h. 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. The recommended dose is 50 mg twice daily, taken 1 h before or 2 h 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. Meta-analyses of the available clinical trials indicate that riluzole extends survival by 2-3 months. 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 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.

Baclofen. The best agent for the symptomatic treatment of spasticity in ALS is baclofen (LIORESAL), a GABAB receptor agonist. Initial doses of 5-10 mg/day are recommended, which can be increased to as much as 200 mg/day if necessary. 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.

Tizanidine. Tizanidine (ZANAFLEX) is an agonist of α2 adrenergic receptors in the CNS. It reduces muscle spasticity, probably 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.

Other Agents. Benzodiazepines (see Chapter 17) such as clonazepam (KLONOPIN) are effective antispasticity agents, but they may contribute to respiratory depression in patients with advanced ALS.

Dantrolene (DANTRIUM), approved in the U.S. for the treatment of muscle spasm, is not used in ALS because it can exacerbate muscular weakness. Dantrolene acts directly on skeletal muscle fibers, impairing Ca2+ release from the sarcoplasmic reticulum. It is effective in treating spasticity associated with stroke or spinal cord injury and in treating malignant hyperthermia (see Chapter 11). Dantrolene may cause hepatotoxicity, so it is important to monitor liver associated enzymes before and during therapy with the drug.