NEUROBIOLOGY AND PATHOPHYSIOLOGY

Although the actual cause of Parkinson’s disease remains undetermined, advances have been made in understanding of the neuropathology of parkinsonism, the central control of movement, and the role of neurotransmitters in motor control and extrapyramidal function. The classic motor signs of Parkinson’s disease occur when there is a 60% to 80% loss of dopamine in the basal ganglia. The cause of the loss can vary with the patient, however.

Lewy bodies are neuron inclusion bodies found in the brains of patients with idiopathic Parkinson’s disease and some other neurologic disorders. These inclusion bodies contain α-synuclein, ubiquitin, and in some cyclin-dependent kinase 5 (cdk5) and leucine-rich repeat kinase 2 (LRRK2).⁷ The role of α-synuclein has been associated with synapses and nuclei (“sy” + “nuclei” + “n”), cell membrane, mitochondrial membranes, and possibly reuptake transporters.² Excess formation of α-synuclein is termed a synucleinopathy. Ubiquitin is associated with the ubiquitin-proteasome catabolic system involved with removal of damaged or misfolded proteins (e.g., synuclein). The cdk5 enzyme has a role in regulating microtubular structural proteins that mediate neuronal function. The accumulation of cdk5 also may contribute to inflammatory changes in the brain.¹⁷ LRRK2 has been found in some genetic Parkinson’s disease cases in Asia. Lewy bodies decrease neuron survival of the affected cells, which may trigger increased microglial mediated inflammation and cell destructive activity.⁵²

By studying the pattern of α-synuclein inclusions, it has been observed that the common sporadic form of Parkinson’s disease starts in the brainstem and olfactory tract before motor symptoms appear. The most sensitive neurons apparently are small neurons with long axons, typical of catecholamine and other autonomic neurons. Early damage occurs in the dorsal motor nucleus of the vagus, spinal cord,¹¹ and olfactory neurons. Prodromal autonomic and olfactory symptoms coincide with the development and spread of α-synuclein accumulations. As the disorder progresses, the lesions ascend to involve brainstem, thalamus, basal ganglia, limbic, and finally cortical structures.¹⁰ When sufficient damage to dopamine cells occurs, clinical motor signs become evident. The overt symptoms generally progress over 10 to 20 years and may terminate in severe invalidism. Life expectancy is reduced because of the usual complications associated with long-term invalidism. There is growing interest in developing neuroprotective treatments that might be useful before these debilitating changes occur.

Hereditary Parkinson’s diseases are familial disorders usually seen in patients younger than 50 years old. Most of the known genetic differences that predispose to Parkinson’s disease are associated with changes in α-synuclein, ubiquitin-proteosome, or mitochondrial function; the number of possibilities continues to increase with further research (Table 15-1). Autosomal dominant loci tend to induce the disease, whereas recessive factors often contribute to expression but may not act alone. Mutations that affect the function of dopamine neurons can cause Parkinson’s symptoms directly, whereas in other cases Lewy bodies are conspicuous and may lead to subsequent damage of the dopamine cells.

Environmentally induced Parkinson’s disease is a result of a toxic agent from the environment or brain trauma that damages the basal ganglia. A dramatic upsurge of interest in environmental factors as a cause for Parkinson’s disease occurred when several young drug abusers developed severe parkinsonian symptoms after self-administering a drug that they thought was a heroin analogue. The compound, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was a by-product of a faulty synthesis of the opiate analgesic alphaprodine. Later work established that the chemical causing the toxicity was actually 1-methyl-4-phenylpyridinium (MPP+), a metabolite of MPTP. MPP+ toxicity stems from its transportation into cells by catecholamine reuptake transporters and subsequent interference with mitochondrial energy production. Acute MPP+ selectively destroys dopamine neurons in the substantia nigra, and this replicates many of the motor disorders of Parkinson’s disease, although not the synucleinopathy.⁴ In some models, chronic or continuous MPTP administration can compromise the ubiquitin-proteasome system and can lead to the accumulation of α-synuclein.²⁴ MPTP-induced damage is reduced in α-synuclein knockout mice, suggesting that these inclusions may potentiate the toxin’s damage.⁴⁰

Various environmental agents may contribute to the development of Parkinson’s disease, and various pyridines are present in the environment in insecticides, herbicides, and contaminants. The insecticides rotenone and paraquat (structurally related to MPP+) have been found to produce a Parkinson-like syndrome in rats.⁵¹ Antipsychotic drugs often produce reversible Parkinson-like signs. The antipsychotic agent haloperidol is metabolized to a pyridinium metabolite that increases oxidative damage in experimental animals,³⁹ raising the possibility of irreversible damage. Mitochondrial respiratory complexes may be compromised by MPP+, and mitochondrial complex 1 has been found to be prone to functional compromise. It is unclear whether mitochondrial disorders are a feature of idiopathic Parkinson’s disease, however.³⁶ Another important environmental toxin is the metal manganese, and miners and users of some manganese products may develop secondary Parkinson’s disease.

Changes in Brain Function in Parkinson’s Disease

Motor function in the spinal cord and trigeminal nucleus is directly controlled by motor regions of the cerebral cortex. A model of basal ganglia function is shown in Figure 15-1. Motor activity in the cerebral cortex is stimulated by thalamocortical input, which is modulated by many factors, including sensory feedback, memory readout, and emotional response. The basal ganglia modulate the thalamocortical processing through a γ-aminobutyric acid (GABA)–mediated inhibitory input derived from the substantia nigra pars reticulata and the internal part of the globus pallidus, nuclei whose functions seem to be similar and for this discussion are referred to as the basal ganglia thalamic inhibitor (BGTI). The output of the BGTI is influenced by two pathways within the basal ganglia, the direct and indirect. The direct pathway generally inhibits the BGTI and disinhibits the thalamic drive and increases motor activity. The indirect pathway, involving excitatory input from the subthalamic nucleus, inhibits movement by facilitating BGTI outflow.

FIGURE 15-1 Movement controlled by the cortex under the influence of the thalamus and basal ganglia. The thalamus relays excitatory input to the cortex. Glutamatergic cortical fibers project to the striatum, activating GABAergic neurons. The GABAergic output from the basal ganglia is funneled through the basal ganglia thalamic inhibitor (BGTI), which exerts an inhibitory action on the thalamus. By the direct pathway, cortical input inhibits the BGTI and disinhibits the thalamus output. The indirect pathway, involving the globus pallidus externus (GPe) and the subthalamic nucleus (ST), is complex but generally leads to an increase in inhibitory output from the BGTI. Excitatory D₁ dopamine receptors are believed to modulate the output of the direct pathway, whereas inhibitory D₂ receptors modulate the output of the indirect pathway. Dopamine neuron cell bodies are located in the substantia nigra pars compacta (SNc). Acetylcholine (ACh) is found in large interneurons within the striatum and opposes the effects of dopamine. GABA, γ-Aminobutyric acid.

Dopamine from the substantia nigra pars compacta (SNc) innervates the direct and indirect pathways in the striatum.⁴ In the direct pathway, it acts on D₁ receptors, which increase GABA inhibition of the BGTI. In the indirect pathway, dopamine acts on D₂ receptors, which inhibit GABA outflow to the indirect pathway. In the case of Parkinson’s disease, a loss of dopamine neurons from the SNc leads to dysregulation of the indirect pathway by the subthalamic nucleus, producing activation of the BGTI and inhibition of movement (bradykinesia or akinesia). Damage anywhere in these loops may result in localized motor abnormalities such as dystonias. Parallel cortico–basal ganglia–thalamic circuits are proposed that subserve aspects of executive and emotional thinking, which may help explain some of the psychiatric symptoms (e.g., depression, hallucinations) observed in some patients with Parkinson’s disease.^47,54

The tremor associated with Parkinson’s disease has been more difficult to explain. Research has suggested that the interaction between the subthalamic nucleus and the external segment of the globus pallidus may be one source of tremor. Other studies suggest a role for the thalamus in tremor generation. Tremors may also represent a dysregulation of the communication between the cerebellum and basal ganglia and other parts of the brain. Other research has found a relationship between acetylcholine, norepinephrine, or serotonin^18,25 levels and tremors.

Parkinson’s tremors predominate when the patient is resting, whereas cerebellar loop damage tremors predominate during movements. Cortical-striatal-thalamic loops, impaired in Parkinson’s disease, are associated with deficits in internally guided motor activity—difficulty with volitional behavior. A second motor control circuit, the cerebellar-thalamic-cortical loop, is thought to be more important for reacting to externally guided behavior. Evidence has accumulated more recently that these systems communicate at many levels—cortical,⁴⁶ thalamic,³⁷ and midbrain.³

Hints for a role of the cerebellum in Parkinson’s disease include the observation that patients can sometimes initiate blocked motor behaviors when presented with externally applied cues, such as an external target to guide a foot to initiate walking. In addition, patients with Parkinson’s disease freeze in conjunction with certain external stimuli, such as passing through a doorway. Functional brain imaging suggests that the cerebellum is hyperactive in patients with Parkinson’s disease and possibly trying to compensate for the basal ganglia deficiency.^20,42

Although Parkinson’s disease is primarily associated with movement problems, there may be additional changes. Responses to sensory stimuli, measured in the basal ganglia, tend to have large receptive fields. This tendency suggests that the basal ganglia may participate in poorly localized sensations such as pain.⁶⁰ As noted earlier, changes in olfaction and pain are early signs of the disorder. Pain sensation may be altered in Parkinson’s disease, including reductions in discriminative, affective, and cognitive dimensions.¹⁴ Patients differ on the direction of the sensory changes. In some cases, pain responding may be reduced, whereas in others diffuse and annoying spontaneous pains may be present, often associated with muscle pain. The basal ganglia may participate in the actions of opiates because the globus pallidus is rich in opiate receptors.⁶

Neuroprotection

Neuroprotective strategies for the treatment of Parkinson’s disease have evolved from theories regarding the cause of the disease. The free radical hypothesis is based on the concept that free radicals (generated from oxidative reactions) react with membrane lipids and cause lipid peroxidation, cell injury, and subsequent cell death. Mitochondrial damage and inhibition of oxidative phosphorylation also occur as a result of free radical attack.⁹ Figure 15-2 illustrates the relationship between dopamine metabolism and the generation of reactive oxygen species. In addition, the damaged neurons may lose resistance to the toxic effects of the afferent excitatory neurotransmitter glutamate (afferents from the cortex, pedunculopontine nucleus, and subthalamic nucleus), whose toxicity is mediated by excessive Ca⁺⁺ flux and nitric oxide synthesis (Figure 15-3). In the most severe case, these reactions can lead to apoptosis and cell death.

FIGURE 15-2 Dopamine metabolism and the oxidative challenge to the substantia nigra pars compacta. Metabolism of dopamine can generate hydrogen peroxide (H₂O₂) at steps A and B. In the presence of Fe⁺⁺ (pathologically elevated in the substantia nigra of patients with Parkinson’s disease), increased generation of reactive hydroxy ions (OH⁻), superoxide species (O₂⁻), and free radicals occurs (steps C, D, and E). Finally, additional reactions may occur between these active oxygen species and nitric oxide to generate toxic peroxynitrite free radicals (OONO⁻) (step F). Dysregulation of these reactions may lead to oxidative damage in dopaminergic nerves. COMT, Catechol-O-methyltransferase; HVA, homovanillic acid; MAO-B, monoamine oxidase B.

FIGURE 15-3 Ca⁺⁺-mediated oxidative stress in nerves with glutamate (or glutamatergic) receptors. Activation of N-methyl-d-aspartate (NMDA) receptors (NMDA-R), one type of glutamate receptor permits Ca⁺⁺ currents to enter the cell. Intracellular Ca⁺⁺ is normally reduced by sequestration in mitochondria and endoplasmic reticulum (not shown). Excess Ca⁺⁺ stimulates nitric oxide synthase (NOS), which catalyzes the synthesis of nitric oxide (NO). Excessive Ca⁺⁺ currents are thought to compromise the function of mitochondria and permit the generation of free radicals and superoxide (O₂⁻), which can react with NO to produce the toxic peroxynitrite radical (OONO⁻), which can damage the mitochondria and cell membranes. Damaged membranes can be metabolized further by phospholipase A₂ (PLA₂), producing arachidonic acid (AA), a substrate for cyclooxygenase (COX). Additional reactive oxygen species (ROS) are generated in the synthesis of prostaglandins (PGs) from AA. These reactions may contribute to the sensitivity of the substantia nigra pars compacta neurons to premature cell death.

The brain is usually protected from damage caused by free radicals because it contains protective substances (e.g., glutathione, ascorbic acid, melatonin, vitamin E) and enzymes (e.g., glutathione peroxidase, superoxide dismutase) that prevent free radical buildup. The SNc of patients with Parkinson’s disease has reduced concentrations of glutathione and glutathione peroxidase. This decrease occurs early in the disorder and can by itself decrease mitochondrial complex 1 function.

Free radical scavenger drugs such as vitamin E have been administered experimentally, albeit so far without much success. The monoamine oxidase (MAO) B inhibitor selegiline offers a potential, but as yet unproved, neuroprotective action by inhibiting the breakdown of dopamine. The pituitary hormone melatonin has antioxidant and proglutathione actions and has been found to be protective in the MPP+ model. Other vitamins may influence neuroprotective processes. Vitamin A and D receptors (RXR and VDR) are concentrated in the substantia nigra, and deficiencies may contribute to Parkinson symptoms. The NURR1 genetic defect affects the RXR receptor. Inadequate levels of vitamins A and D may potentiate the degree of Parkinson symptoms in addition to increasing the risks of bone fractures associated with falls.^49,63

Late-stage Parkinson’s disease is quite resistant to treatment; drugs become ineffective, and tissue grafts and implants lose efficacy. Examples of irreversible neural degenerative cascades⁴⁵ may provide a framework for understanding why Parkinson’s disease continues to progress (pathologic remodeling, gliosis, or vascular problems) despite attempts to replace dopamine. Earlier interventions that could prevent such irreversible changes are needed.

Tomographic Imaging in Parkinson’s Patients

Tomographic imaging techniques are useful for investigations into causes, disturbed brain processing, and diagnostic information about Parkinson’s disease.⁴¹ Systems used to image brain changes in patients with Parkinson’s disease include positron emission tomography; single photon emission computed tomography, which can assess ligand binding within the brain; and functional magnetic resonance imaging (fMRI) and the related blood oxygen level–dependent (BOLD) fMRI. These all are indirect measures of brain tissue function.¹⁶ Transcranial ultrasound has been useful for finding changes in substantia nigra iron levels. Table 15-2 summarizes several imaging ligands and how they are used to assess the function of the basal ganglia and other related brain regions. In particular, β-CIT has been used to visualize dopamine uptake transporters in the basal ganglia. These images distinctly outline the caudate-putamen region of the brain and show that in Parkinson’s disease the labeling in the basal ganglia is reduced either unilaterally or bilaterally.

TABLE 15-2 Imaging Techniques Used to Evaluate Parkinson’s Disease

NAME	USES
18Fluoro-DOPA	Labels levodopa-to-dopamine conversion and presynaptic dopamine
Beta-CIT, (2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane)	Selectively labels DAT
SCH 39166 and NNC 756	Selective D1 receptor binding
Raclopride	Selectively binds to dopamine D2 receptors
d-Methylphenidate	Sensitive to dopamine system loss in basal ganglia
WAY100635	Labeling 5-HT1A, shown to be inversely related to Parkinson’s tremor
Fluorodeoxyglucose	Labels glucose (energy) use for differential diagnosis between Parkinson’s disease and MSA
15Oxygen	PET oxygen use technique for assessment of Parkinson’s disease and MSA
PK11195	PET marker of PBBS, which are selectively expressed by activated microglia associated with brain inflammation
fMRI and BOLD fMRI	Indirect activity measure based on blood desaturation in brain active regions. Used to assess relative activity in different brain regions. May be useful to assess MSA
Transcranial ultrasound	Used to identify iron accumulation in substantia nigra in pre–Parkinson’s disease or early Parkinson’s disease

Positron emitters include ¹²³I, ¹⁸F, or ¹¹C.

5-HT_1A, 5-Hydroxytryptamine type 1A; BOLD, blood oxygen leveldependent; DAT, dopamine transporter; fMRI, functional magnetic resonance imaging; MSA, multiple system atrophy; PBBS, peripheral benzodiazepine sites; PET, positron emission tomography.

Data from references 16, 18, 26, and 29.

Unified Parkinson’s Disease Rating Scale

Parkinson’s disease signs and symptoms can be semiquantitatively estimated with the Unified Parkinson’s Disease Rating Scale (UPDRS). This scale evaluates four separate dimensions of the disorder: I, Mentation, Behavior, and Mood (4 items); II, Activities of Daily Living (13 items); III, Motor Examination (14 items); and IV, Complications of Therapy (A, Dyskinesias; B, Clinical Fluctuations [“on” or “off”; see below], and C, Other). This scale, or parts of it, has been used to estimate the impact of treatments on patients with Parkinson’s disease.

Using only Part III, Motor Examination, an individual without Parkinson’s disease would score 0 or a low value. For a Parkinson’s patient whose symptoms have been reduced with treatments and who feels “on” (i.e., able to move freely), the score is less than 8. Patients feel “off” when the score is greater than 20.¹³ One sample of Parkinson’s patients⁶⁵ averaged around 41 in the untreated state and around 22 in the group with levodopa treatment. Some of these patients also received subthalamic nucleus deep brain stimulation, and their scores also decreased about 20 points on deep brain stimulation alone. There is considerable variation in responding, such that one patient may improve from 56 to less than 8, whereas another patient may show no improvement or worsening. Some patients respond to placebo with improvement of motor function.³² Over time without treatment, a typical patient’s score increases about 6 points per year as the disease progresses.²³ Published UPDRS scores for several Parkinson’s disease treatments are summarized in Table 15-3.

TABLE 15-3 Selected Anti-Parkinson Drugs and Their Approximate Effect on Unified Parkinson’s Disease Rating Scale (UPDRS) Motor Examination Scores

AGENT	REDUCTION OF UPDRS III
Levodopa	22
Deep brain stimulation	20
Apomorphine*	10
Bromocriptine	5
Pergolide	5
Pramipexole	4
Ropinirole	5
Rotigotine	5
Amantadine	6
Selegiline	2
Rasagiline	5
Tocopherol (vitamin E)	0
Melatonin	0
Placebo	0-5

* Intraperitoneal.

DOPAMINE REPLACEMENT AS A BASIS FOR THERAPY

In the 1960s, investigators discovered high concentrations of dopamine in two areas of the extrapyramidal system: the striatum and the SNc. Patients with Parkinson’s disease were found to have low concentrations of dopamine in these areas, which can now be shown in living patients using appropriate tomographic imaging. The drug reserpine was known to reduce catecholamines and produce characteristic Parkinson’s disease–like effects (extrapyramidal signs). Levodopa (l-3,4-dihydroxyphenylalanine, the precursor of dopamine) was shown to reverse reserpine-induced bradykinesia, and a link between dopamine and extrapyramidal motor function was established.

The clinical effectiveness of intravenously administered levodopa on Parkinson’s disease was soon discovered, but its oral effectiveness was limited. Much of the drug (97% to 99%) is metabolized to dopamine before gaining access to the CNS, which led to adverse side effects such as nausea, vomiting, and cardiovascular problems.

Carbidopa, a dopa-decarboxylase inhibitor, prevents much of the peripheral metabolism of levodopa (Figure 15-4). Carbidopa does not cross the blood-brain barrier, so it does not inhibit the CNS synthesis of dopamine from levodopa. Systemically administered levodopa is transported into the brain through the blood-brain barrier by a saturable amino acid transporter. Combining levodopa with carbidopa permits the use of lower doses of levodopa with greater effectiveness in parkinsonism compared with levodopa alone. It has been found that catechol-O-methyltransferase (COMT) may become upregulated in patients taking carbidopa. This discovery prompted the development of COMT inhibitors to inhibit further the peripheral metabolism of levodopa. Another enzyme important in catecholamine metabolism is MAO. MAO-B inhibitors may also help reduce the amount of levodopa required to reduce Parkinson’s symptoms.

FIGURE 15-4 Levodopa (l-dopa) metabolism alone and with a dopa-decarboxylase inhibitor. l-Dopa can be eliminated by several mechanisms before it reaches the brain. Substantial elimination occurs in the gastrointestinal (GI) tract and peripheral tissues. Carbidopa reduces l-dopa metabolism outside the brain. A higher percentage (10% versus 1% to 3%) of the dose of l-dopa gets to the brain when administered with carbidopa. To reduce metabolism of dopamine further, catechol-O-methyltransferase (COMT) inhibitors may be added; these drugs also reduce 3-O-methyldopa competition for levodopa transport into the brain. MAO, Monoamine oxidase.

The classic dopaminergic/cholinergic imbalance concept of Parkinson’s disease explains various clinical and pharmacologic responses, but clinical parkinsonism is more complicated than an imbalance between two neurotransmitters. There are many other neurotransmitters in the basal ganglia, including norepinephrine, 5-hydroxytryptamine (5-HT), GABA, adenosine, and glutamate. Peptides such as enkephalins (indirect pathway) and substance P (direct pathway) coexist with GABA in some striatal efferent neurons. Although the role of these substances in Parkinson’s disease is unknown, they offer possible pharmacologic approaches for therapy. There are occasional reports of parkinsonism being exacerbated or improved by agents acting on these other receptor systems.

Dopamine is a neurotransmitter in numerous areas of the brain, and the side effects of its supplementation can be understood in the context of it actions. Dopamine can act to amplify the effects of stimulation and can modulate functions of numerous cortical and subcortical structures. Dopamine in the basal ganglia is crucial for regulating motor tone, and its loss is associated with motor stiffness. Dopamine modulates learning and memory. The mesolimbic dopamine and basal ganglia seem to be associated with drive, salience, and reward. Drugs that increase the actions of dopamine can cause dependence.

Increased dopamine release in the basal ganglia is produced by such behaviors as eating food, listening to music,⁴⁶ and sexual activity. In fear-mediating brain regions (e.g., amygdala), dopamine may act to make fearful stimuli more salient.² Dopamine cells fire more during waking than sleep, suggesting a role in sleep-wake cycles. This relationship is complicated by the multiple dopamine receptors, some of which seem to promote sleepiness.⁴⁸ Dopamine may modulate appetite, but again the relationship is not simple. Dopamine neurons inhibit the release of prolactin by an action on the hypothalamus. Dopamine is associated with the chemoreceptor trigger zone where it produces an emetic action. Dopamine neurons are also found in the eye and olfactory tract. Dopamine is also a precursor for the neurotransmitter norepinephrine and so may alter blood pressure or cardiovascular function. Dopamine has a vasodilatory action in the kidney. Similar to many neurotransmitters, dopamine has many and varied actions.

There are several types of dopamine receptors, D_1-5 with two important variants: a D₂ short version associated with a presynaptic autoreceptor that decreases dopamine release, and a D₂ long version that acts as a postsynaptic receptor. D₅ is thought to be similar to D₁ in function, and D₃ and D₄ are similar to D₂. Dopamine D₂ type receptors are thought to be more important than D₁ and D₅ receptors for anti-Parkinson effectiveness, but stimulation of both groups of receptors seems to be involved in the therapeutic efficacy of levodopa.

DRUG THERAPY FOR PARKINSON’S DISEASE

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