1. Discuss the epidemiology and etiology of idiopathic Parkinson’s disease (PD).

Epidemiology

Up to 1 million individuals in the United States have PD. The approximate annual
incidence of PD (ie, number of persons diagnosed with PD per year) is age-dependent
and ranges from 10 per 100,000 persons in the sixth decade of life (ie, 50-59 years) to
120 per 100,000 persons in the ninth decade of life (ie, 80-89 years).2 Likewise, the
prevalence of PD also increases with age, affecting less than 0.5% of people in their 60s
and 2.5% of those older than 80 years.3The usual age at time of diagnosis ranges
between 55 and 65 years. Overall, a higher preponderance of PD is reported among
males
Etiology

PD occurs sporadically and the true etiology is unknown. At the cellular level, degeneration of
dopaminergic neurons (axons and soma) projecting from the substantia nigra pars compacta (SNc) to the
striatum (caudate nucleus and putamen) are a hallmark of PD.4 Additionally, neurons in autonomic
ganglia, enteric nervous system, limbic system, olfactory bulb, spinal cord, and neocortex are affected.
The underlying mechanisms are interconnected and multifaceted with involvement of toxic biochemical
reactions (excitotoxicity, nitric oxide toxicity, oxidative stress), abnormal cellular and cell death signaling
pathways (apoptosis, inflammation), dysfunctional organelles (lysosomes, mitochondria), and
dysfunctional protein degradation systems (autophagy, ubiquitin proteasomal system) resulting in
cytoplasmic protein (α-synuclein) accumulation.5 Several of these mechanisms result in excessive
production of free radicals which exert stress on cells by damaging membranes and organelles. The SNc
and the striatum are regions characterized by high levels of oxidative stress due to dopamine degradation
and the Fenton reaction (Fig. 59-1). Normally, intrinsic antioxidants (eg, glutathione) buffer against
oxidant stress, but in PD, this buffer might be impaired or overwhelmed. Pathologic findings reveal a
correlation between the extent of nigrostriatal dopamine loss and the severity of certain PD motor
features (eg, bradykinesia). At the time of PD onset, the estimate losses of SNc neurons and striatal
dopamine content are 30% and 50%, respectively.6 The loss of striatal dopamine exceeds the loss of SNc
cell bodies because cellular degeneration begins in the distal presynaptic axon terminals and proceeds
over time toward the cell body/soma (ie, “dying back” axonopathy). 6

Aging, genetic constitution, and environmental factors likely increase an individual’s risk for
PD.7,8 Epidemiologic research links environmental factors (eg, chronic exposure to pesticides), with an
elevated risk. Interestingly, cigarette smoking and caffeine consumption are consistently associated with
a lower risk.9,10 Genetic polymorphisms and epigenetics also modify an individual’s risk for PD. It is known
that pesticide exposure and genetic forms of parkinsonism (eg, leucine-rich repeat kinase
2 [LRRK2], parkin, PTEN-induced putative kinase 1 [PINK1]) are associated with mitochondrial
dysfunction and oxidative stress.

FIGURE 59-1

Dopamine metabolism results in hydrogen peroxide (H2O2) formation. In the Fenton reaction, H2O2accepts
an electron from ferrous iron (Fe2+) to produce ferric iron (Fe3+) and the hydroxyl radical (HO*). Fe3+ is
reduced back to Fe2+ by another molecule of H2O2, forming a hydroperoxyl radical (HOO*). The radicals
damage cell membranes and organelles (eg, mitochondria) and also induce apoptotic signaling. (COMT,
catechol-O-methyl transferase; DOPAC, 3,4-dihydroxyphenylacetic acid; GSH, glutathione; GSSG,
glutathione disulfide; H+, proton; H2O, water; HVA, homovanillic acid; l-AAD, l-aromatic amino acid
decarboxylase; OH–, the hydroxide ion; MAO-B, monoamine oxidase B.)

2. Explain the basic pathophysiologic mechanisms responsible for the motor features of PD.

A function of the basal ganglia (composed of subcortical structures including the

substantia nigra, striatum, globus pallidus, and subthalamic nucleus) is to
regulate voluntary movement. These subcortical structures exist in duplicate, with
one structure on each side of the midline. The substantia nigra consists of two
parts: the SNc and pars reticulata (SNr). Neuronal projections from the SNc to
the striatum are referred to as the nigrostriatal pathway. The striatum conveys
signals to the SNr, via the dopamine1 (D1) direct and the dopamine2 (D2) indirect
pathways (Fig. 59-2a). The SNr (which is closely linked to the globus pallidus
interna [GPi]) receives signals from the striatum and conveys final processed
signals to the thalamus, which serves as the “gateway” to the motor cortex.
When examining the basal ganglia circuitry, it is important to note that striatal
D1 receptors are coupled to adenylate cyclase and mediate postsynaptic
depolarization, thus D1 receptor activation results in stimulation of the striatal
GABAergic neurons.11 In contrast, striatal D2 receptors are coupled to a
guanosine triphosphate-binding protein and mediate postsynaptic
hyperpolarization, thus D2 receptor activation results in inhibition of striatal
GABAergic neurons.11 In PD, reduced dopaminergic activation of D1 and
D2 receptors and the sequential downstream effect on signaling pathways results
in a net inhibitory tone on the thalamus (Fig. 59-2b). Dopaminergic therapies
help restore functional activity within the D1 and D2 pathways with the latter
primarily responsible for mediating clinical improvements.
Within the SNc, histopathologic features of PD are (1) depigmentation of
dopamine-producing neurons (ie, loss of SNc neurons) and (2) presence of Lewy
bodies (cytoplasmic filamentous aggregates composed of the protein α-
synuclein) in the remaining neurons.4 Lewy bodies appear in association with
adjacent gliosis (ie, a response of glial cells to injury) and the formation and
spread of Lewy pathology is proposed to occur in stages. In the premotor stage
of PD, Lewy bodies are found in the medulla oblongata, locus coeruleus, raphe
nuclei, enteric nervous system, and olfactory bulb. This provides anatomic
correlates to observations that mood (eg, anxiety, depression) and peripheral
symptoms (eg, constipation, impaired olfaction) are present in premotor stages of
PD. Evidence suggests that Lewy pathology develops peripherally in the enteric
nervous system and olfactory system and may spread anterogradely or
retrogradely to the brain.12 With the development of Lewy pathology in the
midbrain (particularly the SNc), motor features begin to emerge. In advanced
stages, Lewy pathology spreads to the cortex, and this may correlate with
cognitive and additional behavior changes. Lewy pathology has also been shown
to spread into adjacent healthy neurons in a prion-like manner.
FIGURE 59-2
A. Dopaminergic pathways of the basal ganglia–thalamocortical circuit. Activation
of D1 and D2 receptors results in depolarization and hyperpolarization,
respectively, of postsynaptic neurons. (Red dots and lines represent excitatory
 input; black dots and lines represent inhibitory input) B. In Parkinson disease,
degeneration of presynaptic nigrostriatal neurons results in inhibition of the
thalamocortical circuit and reduced signaling to the motor cortex. (Dashed
lines represent reduction of neurotransmitter activity; GPe, globus pallidus
externa; GPi, globus pallidus interna; SNc, substantia nigra pars compacta; SNr,
substantia nigra pars reticulata; STN, subthalamic nucleus.)

The synaptic organization of the basal ganglia also

involves a variety of other neurotransmitters and neuromodulators, including acetylcholine, adenosine, enkephalins,

γ-aminobutyric acid (GABA), glutamate, serotonin, and substance P. The potential role for drug modulation of these
other neurotransmitters and receptor types is an active area of research and novel drug discovery.13

Atypical parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy are

characterized by damage to postsynaptic striatal neurons and dopamine receptors. Therefore, dopaminergic
therapies are less efficacious in atypical parkinsonism.
3. List drugs that can exacerbate PD.

D2 blockers (such as metoclopramide and typical antipsychotics) can worsen motor

features and should be avoided. If the patient reports memory problems, medications
with anticholinergic properties should be avoided.
4. Describe the cardinal motor features and clinical presentation of PD.

5. Describe the pharmacology, clinical effects, and safety of anticholinergic drugs for the
management of PD.

6. Describe the pharmacology, clinical effects, and safety of amantadine for the management of
PD.

7. Describe the pharmacology, clinical effects, and safety of levodopa and peripheral
decarboxylase inhibitors for the management of PD.

8. Describe the pharmacology, clinical effects, and safety of dopamine agonists for the
management of PD.

9. Describe the pharmacology, clinical effects, and safety of catechol-O-methyltransferase (COMT)

inhibitors for the management of PD.

10. Describe the pharmacology, clinical effects, and safety of monoamine oxidase (MAO-B)
inhibitors for the management of PD.