Narcissus and Daffodil

356 D. Brown
examination of a brain biopsy, although clinical diagnoses are frequently used to
decide upon management.
It is estimated that over half a million people in the UK, 1.5 million in Japan
and 4 million in the USA have AD (Office of Population Census and Surveys,
1989). This burden is likely to increase as the average age of these populations
increases (Jorm et al., 1991). The disease already places huge demands on health
and social service budgets: for example, the UK spends in excess of £1000
million (Gray and Fenn, 1993) and the USA some 50 times this amount (Office of
Technology Assessment, 1987). It is not surprising, then, that so much effort has
been put into research to understand AD and to find effective therapies. Comprehension
of this complex disease is far from complete and, presently, realistic treatment
objectives are to minimise either the degree or rate of cognitive decline and
preserve functional ability.
ANTICHOLINESTERASES IN ALZHEIMER’S DISEASE
AD is characterizsed by depletion of a number of brain neurotransmitters, including
acetylcholine (Mucke, 1997; Davies, 1983). By the late 1960s, the role of acetylcholine
in the formation and maintenance of memory was firmly established.
Seminal experiments demonstrated that a transient AD-like syndrome could be
produced in laboratory animals and man with the centrally penetrating agent,
scopolamine (Gruber et al., 1967; Crow and Grove-White, 1973). Furthermore,
AD patients were shown to be more sensitive to cholinergic blockade than control
individuals (Sunderland et al., 1987). Davies and Maloney (1976) were the first to
report the selective loss of cholinergic neurones in AD patients and this finding
was soon corroborated (Perry et al., 1978). Workers were able to localise the cholinergic
deficit to those brain areas associated with cortical activation, notably the
nucleus basalis, an important centre for cortical enervation (Whitehouse et al.,
1981). This deficit is common to the vast majority of AD patients studied. Bartus
et al. (1982) finally advanced the cholinergic hypothesis of AD, based on accumulated
experimental and clinical evidence. In this hypothesis, the primary defect is
dysfunctional synthesis and secretion of acetylcholine from the pre-synapse, rather
than alteration in catabolism by cholinesterase in the synaptic cleft (see Figure
14.1). Consequently, intra-synaptic levels of acetylcholine are reduced, resulting in
impairment of signal transmission to cortical regions. While acknowledging the
multifactorial nature of the biochemical disorders in brain chemistry in AD
patients (levels of noradrenaline, dopamine, serotonin, gamma-amino butyric
acid, glutamate, somatostatin and substance P may also be reduced) and the likely
role of amyloid protein plaque development in its pathophysiology, the cholinergic
hypothesis remains a strong one on which to base intervention strategies to
slow the mental deterioration associated with the disease (Unni, 1998). The
abundance of experimental and clinical data, which forms this basis, means that of
all the possible mechanisms, it is the best understood. Secondary benefits which
might result from cholinergic restoration include an increase in local blood flow,
thus easing vascular dementia (Geaney et al., 1990) and promotion of normal
processing of the amyloid precursor proteins, thus reducing amyloid plaque
formation (Giacobini et al., 1996).