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Box 17.2 Inhibition of MAO-B and COMT in the manipulation of brain dopamine levels
• Inhibition of both MAO-B and COMT will prolong
the life of dopamine formed in the brain by
inhibiting its metabolism. e form of MAO found
in the nerve terminals of the striatum is unclear
the synapse, and therefore to the dopamine receptors in
the striatum and elsewhere. Amantadine is the only drug
available for the treatment of Parkinson’s disease which
may act in this manner, although its mechanism of action
is by no means clear; it is also a weak agonist at
dopamine receptors. It is useful in controlling
dyskinesias which result from prolonged levodopa
treatment. Its side eects include confusion and
peripheral oedema.
17.3.3 Dopaminergic drugs and psychotic
illness
We will establish in the next chapter that excessive
stimulation of dopamine receptors in the brain is
associated with schizophrenia, and that the major drug
therapies for this condition reduce the inuence of this
neurotransmitter. Schizophrenia is thought to be the
result of dopamine’s actions in the cortico-limbic areas
of the brain, and not the striatum. However, when
dopamine receptor-stimulating drugs are given in
Parkinson’s disease their eect is widespread in the
brain, and include an enhancement of dopamine
stimulation in cortico-limbic areas as well as in the
striatum. It is not surprising, therefore, that some
Parkinson’s disease patients on levodopa and associated
therapies develop psychotic symptoms. (is issue is
explored further in Workbook 14 when Andreas
develops psychotic symptoms as a consequence of the
drugs used to treat Parkinson’s disease.) e converse is
also true—as discussed in Chapter 18, movement
disorders are common side eects of antipsychotic
medication (dopamine receptor antagonists). ere is
an obvious need for the development of drugs which
specically target the appropriate brain regions aected
in schizophrenia and Parkinson’s disease, in order to
produce improved drugs hampered by fewer side
eects.
(see Chapter 19, Box 19.2); it is possible that the
main eect of MAO-B inhibition is in the
astrocytes.
17.3.4 Strategy in the drug treatment of
Parkinson’s disease
e severity of initial presenting symptoms and the age
and general health of the patient, as well as progression of
the disease with time, all mean that there is no single
strategy that can be applied to the management of
Parkinson’s disease. As indicated at the beginning of this
chapter, a drug that is eective at rst can be expected to
become less satisfactory with time, with respect to both
controlling symptoms and unwanted eects. However, as
a guide to an initial approach to drug therapy we might
consider the following generalizations based on the
presenting symptoms.
• Modest movement disorder, no cognitive problems:
MAO-B inhibitor.
• Mid-range movement disorders, no cognitive
problems: direct-acting dopamine agonist.
• Severe movement disorder with cognitive problems,
and older (>70 years): levodopa with peripheral
decarboxylase inhibitor (e.g. carbidopa).
An idea of the evolving pattern of drug use that may be
expected can be gained from Workbook 14.
17.3.5 New approaches to treatment of
Parkinson’s disease
Because drugs often lose their benecial eects with
time, other non-drug treatment strategies have been
explored. Excess output from a region of the brain called
the subthalamic nucleus has been shown to play a
critical role in the symptoms of Parkinson’s disease. With
this background knowledge, a recent method of deep
brain stimulation has been used successfully in the
treatment of Parkinson’s disease. e basis for this new
treatment involves the implantation of an electrode,
17.4 Symptoms and diagnosis of Alzheimer’s disease: a brief comment 443
which at an appropriate stimulation frequency
inactivates the subthalamic nucleus, resulting in relief
from symptoms, at least temporarily. Neural
transplantation is another non-pharmacological method
that has been attempted. It involves transplantation of
fetal dopaminergic neurons into the striatum of
Parkinsonian patients. Alternatively, stem cells
programmed to dierentiate into dopaminergic neurons
may be transplanted.
Most recent research eorts into novel treatments for
Parkinson’s disease have focused on the delivery of
various types of neurotrophic factors to the striatum or
substantia nigra. Brain-derived neurotrophic factor
(BDNF), discussed in Chapter 19 in relation to
antidepressant drugs, and glial cell line derived
neurotrophic factor (GDNF) have received the most
attention, given their ability to promote the survival of
dopamine neurons in animal models.
17.4 Symptoms and diagnosis of Alzheimer’s disease:
a brief comment
Alzheimer’s disease is a slowly progressing physical and
selective degeneration of brain tissue, resulting in a
variety of mental symptoms that accumulate and get
worse over a number of years. It is mainly a condition of
the elderly, aecting about 5% of the population over 65
years old, and increasing sharply to about 30% in those
over 80. is explains its increasing prevalence in the
ageing populations of the developed world. Alarmingly, it
has been estimated by the World Health Organization
(WHO) that by the year 2040, 80 million people
worldwide will have Alzheimer’s disease. ere is
therefore a great need to develop new treatments to slow
down or halt the progress of this form of dementia.
However, it has always been recognized that there are
cases of early-onset Alzheimer’s disease, and it is now
understood that the neuropathological changes seen in
these cases have the same pattern as in older patients (see
below); the disease process is considered to be the same.
ere is a clear contribution from inheritance in some
cases (familial), particularly with early-onset Alzheimer’s
disease, whilst this is not evident in other cases
(sporadic).
Early symptoms are characteristically reduced memory
for recent events and variable diculties in
concentration, together with some disorientation,
depression, aggression, self-neglect, and inability to
interact with those closest to them. ere is progressive
impairment of cognitive and functional capacities with
loss of:
• global memory
• recognition of relatives and everyday objects
• purposeful movements and ability to plan activities
• judgement.
Overall, Alzheimer’s disease leads to a gross loss of
ordered mental activity, with increasing incapacity and
disintegration of the suerer’s personality.
ese symptoms result from the neuropathological
changes which can be observed in post-mortem
examinations of brains of Alzheimer’s disease suerers,
and which characteristically include tissue shrinkage,
with larger gyri (surface spaces between the tissue of the
cortex) and enlarged ventricles (the uid-lled spaces
deep within the brain). In particular there is a marked
reduction in size of the frontal and temporal lobes. e
hippocampus, a region associated with memory recall,
may also show signs of degeneration. Some of these gross
changes are illustrated in Figure 17.4.
Plaques and tangles are protein aggregates seen as
histological markers at post mortem in brains of
Alzheimer’s disease patients. Plaques accumulate in the
cortex as part of the normal ageing process, but to a much
greater extent in the brains of Alzheimer’s disease
patients (Figure 17.5).
e relationship of plaques and tangles to neuronal loss
and reduced brain function has been the subject of an
enormous amount of recent research. It is beyond the
remit of this text to consider this in detail; for further
information see the key references and suggested reading
listed at the end of this chapter. However, it is worth
noting that both plaques and tangles are thought to be
involved in destroying brain function. e degree of
plaque and tangle pathology is highly correlated with
neuronal loss in brains from Alzheimer’s disease patients,
and with the severity of memory loss. In particular, plaque
proteins, the amyloids (also referred to as amyloid--
peptides; A) and the mechanisms behind their
progressive increase are the focus of novel strategies to
444 Chapter 17 Neurodegenerative diseases
Cerebral cortex
Ventricles
Hippocampus Extreme shrinkage of
Figure 17.4 Cross-sectionofanormalhumanbrain(left)comparedwiththatfromapatientwithAlzheimer’s
disease (right).
develop drugs capable of slowing or halting the
progression of the disease. Tangles (intracellular protein
aggregates) are also implicated in the disease process. e
primary component of these tangles is a highly
phosphorylated form of the normal neuronal protein, tau.
In Alzheimer’s disease, with a build-up of tangles these
highly phosphorylated tau proteins spread throughout
Extreme shrinkage
of cerebral cortex
hippocampus
the brain, and together with A have a toxic action on
neurons. is means that Alzheimer’s disease could
theoretically originate at a single location in the brain and
then spread by virtue of these modied tau proteins,
invading adjacent brain regions and eventually causing
widespread damage and loss of brain function. is
picture of a progressive disease is important because it
Severely enlarged
ventricles
Tangle
Plaque
Figure 17.5 A histological section of the hippocampus from a patient
withAlzheimer’sdisease(magnication×251).
The accumulation of plaques and tangles is indicated by the arrows.
From Janssen JC, et al. Alzheimer’s disease due to an intronic presenilin-1 (PSEN1 intron 4)
mutation. Brain 2000; 123(5): 894–907. By permission of Oxford University Press.
17.5 Drug treatment of Alzheimer’s disease 445
may reveal opportunities for future drugs to interfere with
its spread, thereby reducing brain damage.
As in Parkinson’s disease, there is also evidence of gross
cell loss from ascending neuronal systems in Alzheimer’s
disease. ese include pathways with 5-HT- and
noradrenaline-containing neurons. But of particular
importance for us here is the loss of neurons which
release acetylcholine and form the ascending cholinergic
system with its origins in the nucleus basalis, a collection
of cell bodies located in the basal forebrain. ese
cholinergic neurons innervate the cortex and the
hippocampus (a brain region sitting just below the
neocortex that is involved in memory functions).
Cholinergic loss here can be over 50%; notably, the extent
of this loss correlates with the severity of symptoms in
Alzheimer’s disease.
17.5 Drug treatment of Alzheimer’s disease
As noted at the start of this chapter, drug treatments for
Alzheimer’s disease are limited, mainly being restricted to
restoring a degree of cholinergic function to the brain. A
separate approach targets the glutamatergic excitatory
system in the brain with an NMDA antagonist, because a
dysfunctional glutamate system has also been implicated
in Alzheimer’s disease. (e glutamate–NMDA system in
the brain is discussed in Chapter 18, Box 18.2.)
Drug treatment for Alzheimer’s disease should be
initiated by an experienced specialist within an
appropriate monitoring framework, with the option of
continuing care by a GP.
17.5.1 Acetylcholinesterase inhibitors in
the treatment of Alzheimer’s disease
Acetylcholine released from neurons in the brain and
elsewhere is rapidly removed by acetylcholinesterases,
widespread and extremely ecient enzymes which break
down acetylcholine into two inactive fragments.
Inhibition of acetylcholinesterase activity will therefore
increase the availability of acetylcholine at its receptors in
the brain. e main drugs available are donepezil,
galantamine, and rivastigmine. ese drugs have been
shown to produce a small improvement in cognitive
function in patients with mild to moderately severe
Alzheimer’s disease. eir use is hampered by
predictable cholinergic side eects including nausea,
abdominal cramps, agitation, fatigue, and sleep
disturbances.
selective agents is a hope for the future therapy of
Alzheimer’s disease.
17.5.2 NMDA antagonism in the treatment
of Alzheimer’s disease
Glutamate is the principal excitatory neurotransmitter
within the brain (see Chapter 16, Box 16.1). Activation of
NMDA glutamate receptors promotes Ca
excessive stimulation can lead to cytotoxic Ca
cell death.
Memantine is a competitive NMDA antagonist that will
reduce this route of Ca
management of moderate to severe Alzheimer’s disease,
where it produces a small improvement in cognitive
function although it does not appear to have
neuroprotective properties. Its benecial action in
treating the symptoms of Alzheimer’s disease is, however,
not fully clear. e confusion arises, in part, from the
observation that NMDA receptor activation promotes
neurophysiological animal models of learning and
memory, and may therefore be expected to enhance
cognition. It follows that an NMDA antagonist, such as
memantine, may be expected to decrease it. It is therefore
possible that memantine’s therapeutic eect of reducing
cognitive impairment is in fact mediated via entirely
dierent mechanisms, yet to be identied.
17.5.3 Future hopes for treating
Alzheimer’s disease
2+
inux, and
2+
levels and
2+
entry into cells. It is used for the
An alternative approach to increasing the cholinergic
inuence in the brain of an Alzheimer’s disease patient
would be through the use of muscarinic agonists.
Currently there are very few clinically useful drugs of this
type because of a lack of selectivity of agents for specic
muscarinic receptor subtypes. e development of more
From the above it is clear that all currently available drugs
for Alzheimer’s disease focus on symptomatic treatment
only. Since this disease is so disabling, and at the same
time so common, intense research in both academia and
the pharmaceutical industry has been devoted to
developing new drugs which could prevent or retard the
446 Chapter 17 Neurodegenerative diseases
disease. is has led to several strategies directed at the
disease process itself, including eorts to discover new
molecules that regulate or target proteins associated with
Key references and suggested reading
Andersen OM, Willnow TE. Lipoprotein receptors in
Alzheimer’s disease. Trends Neurosci 2006; 29(12): 687–94.
Brown D. Antipsychotics in dementia: use only if the risks are
justied. Prescriber 2009; 20(8): 7–9.
Giord J, Jones R. Assessment and treatment of cognitive
decits in dementia. Prescriber 2009; 20(6): 45–9.
Lindvall O, Koaia Z. Prospects of stem cell therapy for replacing
dopamine neurons in Parkinson’s disease. Trends Pharmacol
Sci 2009; 30(5): 260–7.
plaques and tangles (i.e. amyloid--peptides and highly
phosphorylated tau).
Metta V, Davidson C, Iqbal N. Treatment options for the
management of parkinsonism. Prescriber 2009; 20(12):
32–45.
Revell MA. Deep brain stimulation for movement disorders.
Nurs Clin North Am 2015; 50(4): 691–701.
Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT.
Neuropathological alterations in Alzheimer disease. Cold
Spring Harb Perspect Med 2011; 1(1): a006189. doi: 10.1101/
cshperspect.a006189.
SUMMARY OF COMMON DRUGS USED FOR PARKINSON’S DISEASE AND ALZHEIMER’S DISEASE
17.5 Drug treatment of Alzheimer’s disease 447
Therapeutic class Drugs Mechanism of action Common clinical
uses
Anticholinergics Benzhexol
Dopamine receptor
agonists
Drugs containing
levodopa
Selective monoamine
oxidase-B inhibitors
Catechol-Omethyltransferase
inhibitors
(trihexyphenidyl)
Orphenadrine
Procyclidine
Apomorphine
Pramipexole
Rotigotine
Ergot-derived dopamine
receptor agonists:
Bromocriptine
Cabergoline
Pergolide
Levodopa with
benserazide
(co-beneldopa)
Levodopa with
carbidopa
(co-careldopa)
Rasagiline
Selegiline
Entacapone
Tolcapone
Block muscarinic acetylcholine
receptors
Stimulate dopamine receptors Parkinson’s disease
Dopamine precursor converted in
the brain and periphery to
dopamine
Given with a peripheral dopa
decarboxylase inhibitor
(benserazide or carbidopa) to
reduce peripheral dopamine
production
Reduces breakdown of dopamine
by irreversibly inhibiting MAO B
Prevent breakdown of levodopa
in the periphery by inhibiting
catechol-O-methyl transferase
Drug-induced
parkinsonism
Parkinson’s disease
Restless legs
syndrome (moderate
to severe)
Parkinson’s disease
Chronic endocrine
disorders
Parkinson’s disease Co-administering levodopa with peripheral
Parkinson’s disease Often used in conjunction with levodopa
Parkinson’s disease Adjunct therapy to levodopa
Comments Common adverse drug
reactions
Rarely used except to treat movement
dysfunction induced by antipsychotic
medication (Chapter 18)
Often used for initial treatment of
Parkinson’s disease
Fewer motor complications (i.e. dyskinesia)
but more psychiatric side effects (e.g.
impulse control disorders) than levodopa
Apomorphine used in advanced stages of
Parkinson’s disease
Co-treatment with domperidone (peripheral
D2-receptor antagonist) prevents nausea
Cardiac and pulmonary function should be
monitored during treatment
decarboxylator inhibitor ensures:
1) more levodopa enters brain
2) peripherally mediated side effects are
reduced (e.g. nausea, vomiting, and
cardiovascular effects)
Produces good initial improvement, but
effectiveness declines with time
Selegiline is metabolized to amphetamine
and can cause CNS excitation
Less risk of drug and food interactions
compared with non-selective MAO inhibitors
used in depression (Chapter 19)
Tolcapone can cause liver toxicity, so
prescribed only under specialist supervision
and with monitoring of liver function
Constipation
Dry mouth
Impaired vision
Urinary retention
Sudden onset of sleep and
drowsiness
Hypotension
Nausea and vomiting
(marked with high doses of
apomorphine)
Psychiatric side effects
See side effects of
non-ergots above
Also serious fibrosis involving
lungs, heart, and abdomen
Nausea and vomiting
Dry mouth
Postural hypotension
Delusions
Hallucinations
Drowsiness
Dyskinesia (involuntary
writhing movements)
Sudden ‘on–off’ transitions in
mobility
Dry mouth
GI disturbance
Sleep disturbance
Excitation
Headache
Anxiety
Depression
GI disturbance
Dry mouth
Confusion
Dizziness
Sleep disturbance
448 Chapter 17 Neurodegenerative diseases
Therapeutic class Drugs Mechanism of action Common clinical
uses
Other drugs for
Parkinson’s disease
Acetylcholinesterase
inhibitors
NMDA antagonism Memantine Blocks NMDA glutamate
Amantadine Mechanism unclear; may increase
Donepezil
Galantamine
Rivastigmine
dopamine release
Inhibit breakdown of acetylcholine Alzheimer’s disease Rivastigmine often administered via
receptors
Parkinson’s disease Improves bradykinesia, tremor, and rigidity GI disturbance
Alzheimer’s disease Memantine reduces cognitive symptoms in
Comments Common adverse drug
reactions
Anorexia
Confusion
Peripheral oedema
Hallucinations
Insomnia
transdermal patch
some Alzheimer patients
GI disturbance
Sleep disturbance
Agitation
Confusion
Fatigue
Weight loss
Urinary incontinence
Bradycardia
Constipation
Hypertension
Dyspnoea
Headache
Dizziness
WORKBOOK 14
Parkinson’s disease
Andreas, a case of early-onset Parkinson’s disease: benefits
Andreas, a simplified case history
Andreas, the hypertensive patient from Workbook 2, has recently started experiencing some
strange symptoms, including difficulties getting out of a chair. His GP diagnosed this as
stiffness caused by a sports injury.
Then his daughter remarked that his hand was shaking when it was resting on the table. After
several more visits to his GP with various mild and diverse symptoms, such as tightness in his
arms and legs, trembling of his hand, inability to relax his grip on his cutlery after eating, and
memory loss, he has been referred to a neurology clinic.
A table of clinical clerking abbreviations is given on page xviii.
CLINICAL CLERKING FOR ANDREAS AS OUT-PATIENT AT
NEUROLOGY CLINIC
Age: 45 years
The average age of onset of Parkinson’s disease is 55 years, and the incidence rises significantly
with age. However, about 5–10% of cases are early onset, beginning before the age of 50.
PC: Inability to relax grip of cutlery after eating, memory loss, trembling of hand, and slight limp.
HPC: Referred to neurologist by GP following several visits with the above symptoms, which have
developed over the past 18 months. Diagnosed with depression by GP during one consultation.
PMH: Hypertension, with a hypertensive crisis 8 years earlier, depression, and recently gastroenteritis.
Also diabetes and ischaemic heart disease.
DH:
1) Fluoxetine for depression
Psychiatric disturbances like depression are very common (30%) in Parkinson’s disease.
2) Amlodipine for hypertension
3) Losartan for hypertension
4) Simvastatin, lipid lowering for ischaemic heart disease
450 Chapter 17 Neurodegenerative diseases
5) Aspirin, antiplatelet for ischaemic heart disease
6) Metformin for diabetes
7) Metoclopramide for nausea associated with recent bout of gastroenteritis
SH: Lives with wife and two daughters.
O/E:
1) Blood pressure = 138/85 mmHg (reference: <140/90 mmHg)
2) Pulse = 60/min (normal)
Blood pressure and pulse are both normal.
O/O:
Well-nourished and strong-looking man with following signs:
• Slight tremor of left hand at rest
• Reduced blink rate
• Monotonous voice
• Slight difficulty initiating walking
• Muscle rigidity
• Sweating.
Andreas’s symptoms are very slight and barely detectable to the untrained eye.
They will get worse if he has Parkinson’s disease.
Tremor, rigidity, bradykinesia, and postural disturbances are the four classic features of Parkinson’s
disease.
• TremorassociatedwithParkinson’sdiseasehasacharacteristicappearance.Typicallyittakesthe
form of a rhythmic back-and-forth motion, at a rate of 4–6 beats/sec. It may involve the thumb
and forefinger, and appear as a ‘pill-rolling’ tremor. It often begins in a hand, although a foot or
the jaw can be affected first. It is unilateral on presentation. It is most obvious when the hand is
at rest or when a person is under stress, so the shaking may become more pronounced a few
seconds after the hands are rested on a table. Tremor usually disappears during sleep and
improves with intentional movement. The voice is not affected.
• RigidityofmusclesorresistancetomovementaffectsmostpeoplewithParkinson’sdisease.
Normal movement of the body is achieved by the opposing action of skeletal muscle pairs. In
Parkinson’s disease this balance is disturbed. The muscles remain constantly tensed and
contracted, so that the person aches, or feels stiff or weak. Rigidity is obvious when another
person tries to move the patient’s arm, which will move only in ratchet-like short jerky
movements, a condition known as ‘cogwheel’ rigidity.
• Bradykinesia,ortheslowingdownandlossofspontaneousandautomaticmovement,isseenin
all cases of Parkinson’s disease. It is particularly frustrating as simple routine tasks become
difficult or impossible. Patients find it hard to start walking; the gait becomes shuffling with
short steps, and the arms are held flexed to the waist. Activities once performed quickly and
easily—suchaswashingordressing—maytakeseveralhours.
WORKBOOK 14 Parkinson’s disease 451
• Posturalinstability,orimpairedbalance,causespatientstofalleasily.Thisisalatefeatureof
Parkinson’s disease. Affected people may also develop a stooped posture in which the head is
bowed, and the shoulders droop.
A number of other symptoms can accompany Parkinson’s disease. Those related to Andreas are as
follows.
• Facialexpressionandblinkrate:thefacebecomesmask-like,withmouthopenanddiminished
blinking.
• Voice:reducedvolume(hypophonic)andcharacteristicmonotonousspeechleadtodifcultiesin
communication.
• Sweating:thisisasignofautonomicnervoussystemdysfunction.
• Depression:thisisacommonprobleminParkinson’sdiseaseandmayappearearlyinthecourse
of the disease before other symptoms are noticed.
FH: Grandfather suffered from Parkinson’s disease.
Early-onset forms of Parkinson’s disease are often inherited, and some have been linked to specific
gene mutations. People with one or more close relatives who have Parkinson’s disease have an
increased risk of developing the disease themselves.
Differential diagnosis:
• Parkinson’s disease
• Drug-induced parkinsonism
• Toxin-induced parkinsonism (rare)
• Arteriosclerotic parkinsonism
• Lewy body dementia
The neurologist thinks that Andreas has Parkinson’s disease because of his symptoms, age,
and family history, but he considers other possibilities:
• Drug-induced parkinsonism A reversible form of parkinsonism, occasionally resulting from
useofcertaindrugs,suchaschlorpromazineandhaloperidol,prescribedforpatientswith
psychiatric disorders. Some drugs used for gastrointestinal disorders (metoclopramide) and
epilepsy (sodium valproate) may also produce parkinsonian symptoms. Andreas was recently
prescribed metoclopramide for nausea after contracting a stomach virus.
• Toxin-induced parkinsonism Some chemicals and toxins can cause parkinsonism. Investigators
discoveredthiswhenaheroinaddictmistakenlytooktheneurotoxin,1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP), and developed severe parkinsonism. Andreas has worked in the
pharmaceutical industry and could have been exposed to such chemicals (though it is unlikely).
• Arteriosclerotic parkinsonism (also known as atherosclerotic, vascular, or pseudo-
parkinsonism) involves damage to the brain due to multiple small strokes. Andreas suffers
from hypertension; non-compliance with his medication could have resulted in
cerebrovascular episodes.
Investigations: Positron emission tomography (PET) scan
Establishing the diagnosis of Parkinson’s disease is normally based on clinical symptoms. But
because of Andreas’s age, a PET scan was used to confirm diagnosis.