Mohammed T. Abou-Saleh

230 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYhallucinations are common, than in AD where they are lesscommon 15 . Reductions in cortical ChAT activity in patients withdementia, in addition to correlating with cognitive decline, arealso related to overactivity and aggressive behaviour 16 .It has also been suggested that acetylcholine is centrallyinvolved in the process of conscious awareness 17 , and that thevariety of clinical symptoms associated with cholinergic dysfunctionin AD and related disorders reflects disturbances in theconscious processing of information. There is evidence thatimplicit memory, for example (which does not involve consciousawareness), is relatively intact in AD 18,19 .GlutamateLoss of synapses and pyramidal cell perikarya (both considered tobe markers of glutamatergic neurones) from the neocortex of ADpatients correlate with measures of cognitive decline 2 . Althoughneurochemical studies of glutamate neurotransmission have failedto demonstrate extensive alterations, this may be related to thedifficulty in distinguishing the transmitter pool of glutamate fromthe metabolic pool. Nevertheless, glutamate concentration wasreduced by 14% in temporal lobe biopsy samples and by 86% inthe terminal zone of the perforant pathway at autopsy of ADpatients 20 . Uptake of D-aspartate, a putative marker of glutamatergicnerve endings, is also reduced in many cortical areas in ADbrain 2 . Thus, additional factors other than impaired cholinergicfunction are likely to contribute to cognitive impairment in AD.However, it is important to remember that glutamatergicneurones of the neocortex and hippocampus are influenced byacetylcholine through nicotinic and muscarinic receptors 2 . Thus,treatment of patients with cholinomimetics is likely to increaseglutamatergic function.Other neurotransmittersUsing biopsy samples from AD patients, serotonergic and somenoradrenergic markers are affected, whereas markers for dopamine,g-aminobutyric acid (GABA) or somatostatin are notaltered. When post mortem studies of AD brain are considered,many neurotransmitter systems, including GABA and somatostatin,are involved or are affected to a greater extent 2 . Based onpost mortem studies, however, changes in serotonergic neurotransmissionmay be linked to the behavioural disturbances ofAD, such as depression, rather than cognitive dysfunction. Forexample, patients with AD who were also depressed had lowernumbers of serotonin reuptake sites in the neocortex than didpatients without this symptom 21 . Furthermore, both reducedserotonergic 22,23 and increased noradrenergic activities andsensitivity 24,25 have been linked to aggressive behaviour.Neurotransmitter receptorsMany neurotransmitter receptors appear to be unaltered in AD;however, studies have demonstrated a reduction in the number ofnicotinic and muscarinic (M2) ACh receptors, most of which areconsidered to be located on presynaptic cholinergic terminals.Despite continuing, often unconfirmed, reports of changes in oneor more of the muscarinic receptor subtypes (M–M 5 ), it isgenerally agreed, on the basis of autopsy studies, that the M1subtype is unchanged until later in the disease when it maydecline, probably in relation to cholinoceptive (postsynaptic)neurodegeneration. The status of the other subtypes is not clearlyestablished, primarily due to the lack of specific pharmacologicallabels. Results using antibodies against the different receptorsubtypes, while specific, are complicated by discrepancies betweenthe distribution and density of immunoreactive proteins andlocalized functional receptors. With respect to muscarinic receptorcoupling to G-proteins, most studies using a variety of investigativeprocedures have identified some degree of uncoupling,especially with respect to the M1 receptor 26 .A highly consistent receptor abnormality in AD is the loss ofthe nicotinic receptor 27,28 , which appears to primarily reflect lossof the a4-containing subtype (generally associated with b2) asopposed to a3 ora7 subtypes 29 . Immunohistochemically, loss ofa4 and b2 reactive fibres has been observed in temporal cortex,associated with reactive neuropil threads, tangles and plaques 30 .NEUROIMAGINGWith respect to the cholinergic deficit, whilst measurements ofCSF acetylcholine, choline and acetylcholinesterase have beenreported in AD, such reports are either unconfirmed orinconsistent. More promising and potentially diagnostic findingshave been obtained using in vivo functional imaging. The vesicularacetylcholine transporter and acetylcholinesterase, imaged usingPET and iodobenzovesamicol and N-methylpiperidin-4-yl propionate,respectively, are both reduced in AD patients, andfurthermore relate to reductions in MMSE 31,32 . Using SPECT,muscarinic QNB binding is reduced in advanced but not earlycases 33 , and iododexetamide, with preference for M2, is alsoreduced in mild/early cases 34 . Reductions in nicotine binding havealso been detected using PET 35 . In vivo observations relating tonon-cholinergic systems (principally noradrenaline, 5-HT anddopamine) have been equally inconsistent regarding CSF parametersand, with respect to neuroimaging markers, onlydopaminergic markers have so far been investigated and thereis, as expected, no consistent abnormality of the transporter or D2receptor.LINKS BETWEEN NEUROTRANSMISSIONAND NEUROPATHOLOGYMismetabolism of amyloid precursor protein (APP) leading toincreased production of b-amyloid has been proposed as thecritical event in both familial and sporadic AD causing otherchanges (tangles, neurone loss, synapse loss and neurotransmissiondysfunction). Cholinergic neurotransmission may be aspecific target for b-amyloid, since it has been shown to reduceboth choline uptake and acetylcholine release in vitro 36 . Furthermore,b-amyloid is reported to bind with high affinity to the a7subtype of the nicotinic receptor, suggesting that cholinergicfunction through this receptor may be compromised because ofhigh levels of (soluble) peptide in AD brains 37 .There is increasing evidence that various neurotransmittersystems are capable of influencing the metabolism of APP,favouring the non-amyloidogenic processing 38 . In particular,stimulation of muscarinic M1 receptors increases APP secretion,while decreasing b-amyloid production 39 . Furthermore, nicotinicreceptor stimulation is associated with reduced plaque densities inhuman brain 40 . These results suggest that compounds beingdeveloped for symptomatic treatment may have a serendipitouseffect on the continuing emergence of pathology by reducing theproduction of b-amyloid.CHOLINERGIC APPROACHES TO TREATMENTBiochemical studies of postmortem brains from AD patientsshowing evidence of a substantial presynaptic cholinergic deficit,