ALZHEIMER’SDISEASE 131Cholinergic crisis
Treatment of myasthenia with anticholinesterases can be use-
fully monitored clinically by observation of the pupil (a diam-
eter of 2 mm or less in normal lighting suggests overdose).
Overdosage produces a cholinergic crisis, and further drug
should be withheld.
ALZHEIMER’S DISEASE
Alzheimer’s disease (AD) is the most common cause of demen-
tia. Its incidence increases with age. It is estimated that approxi-
mately 500 000 people in the USA are affected. The symptoms
of Alzheimer’s disease are progressive memory impairment
associated with a decline in language, visuospatial function,
calculation and judgement. Ultimately, this leads to major
behavioural and functional disability. Acetylcholinesterase
inhibiting drugs, e.g. donepezil, can slow down the progres-
sion of mild and moderate Alzheimer’s disease, but the benefit
is pitifully small and only temporary. Clinical trials of other
drug therapy, such as oestrogens, non-steroidal anti-inflamma-
tory drugs (NSAIDs), statins, metal chelation and vitamin E,
have failed to show conclusive benefit. Depression is com-
monly associated with Alzheimer’s disease and can be treated
with a selective serotonin reuptake inhibitor (SSRI), e.g. sertra-
line. Antipsychotic drugs and benzodiazepines are sometimes
indicated in demented patients for symptoms of psychosis
or agitation but their use is associated with an increased risk
of stroke.
PATHOPHYSIOLOGY
Specific pathological changes in the brains of patients with AD
can be demonstrated, for example by positron emission tomog-
raphy (PET) scanning (Figure 21.4). Forty per cent of AD
patients have a positive family history. Histopathology features
of AD are the presence of amyloid plaques, neurofibrillary tan-
gles and neuronal loss in the cerebrum. Degeneration of cholin-
ergic neurones has been implicated in the pathogenesis of
Alzheimer’s disease. Neurochemically, low levels of acetyl-
choline are related to damage in the ascending cholinergic
tracts of the nucleus basalis of Meynert to the cerebal cortex.
Other neurotransmitter systems have also been implicated. The
brains of patients with Alzheimer’s disease show a reduction in
acetylcholinesterase, the enzyme in the brain that is primarily
responsible for the hydrolysis of acetylcholine. This loss is
mainly due to the depletion of cholinesterase-positive neurones
within the cerebral cortex and basal forebrain.
These findings led to pharmacological attempts to augment
the cholinergic system by means of cholinesterase inhibitors.
Donepezil, galantamine and rivastigmine are acetyl-
cholinesterase inhibitors that are licensed for the treatment of
mild to moderate AD. Memantineis an NMDA receptor
antagonist and inhibits glutamate transmission. It is licensed
for moderate to severe dementia in AD.DONEPEZIL, GALANTAMINE AND RIVASTIGMINE
Use
Donepezil, galantamine and rivastigmine have been licensed for
the treatment of mild to moderate dementia in AD. Only special-
ists in management of AD should initiate treatment. Regular
review through Mini-Mental State Examination with assessment
of global, functional and behavioural condition of the patient is
necessary to justify continued treatment (Table 21.2).Mechanism of action
These drugs are centrally acting, reversible inhibitors of
acetylcholinesterase. Galantamine is also a nicotinic receptor
agonist.FDG(^11) C-PIB
60
50
40
30
20
10
0
3
2
1
0
Figure 21.4:PET images of the brain of a
67-year-old healthy control subject (left) and a
79-year-old Alzheimer’s disease patient (right).
The top images show^18 FDG uptake, and the
bottom images show Pittsburgh Compound-B
(PIB) retention. The left column shows lack of
PIB retention in the entire grey matter of the
healthy subject (bottom left) and normal^18 FDG
uptake (top left). Nonspecific PIB retention is
seen in the white matter (bottom left). The
right column shows high PIB retention most
marked in the frontal and temporoparietal
cortices of the Alzheimer patient (bottom right)
and generalized^18 FDG hypometabolism (top
right) (adapted from Klunk WE et al. Annals of
Neurology2004; 55 : 306–19).