Mohammed T. Abou-Saleh

Principles and Practice of Geriatric Psychiatry.Editors: Professor John R. M. Copeland, Dr Mohammed T. Abou-Saleh and Professor Dan G. BlazerCopyright & 2002 John Wiley & Sons LtdPrint ISBN 0-471-98197-4 Online ISBN 0-470-84641-043Neurotransmitter Changes in Alzheimer’s Disease:Relationships to Symptoms and NeuropathologyPaul T Francis 1 and Elaine K. Perry 21Centre for Neuroscience Research, King’s College London, UK,and 2 MRC Building, Newcastle upon Tyne General Hospital, UKCell death and histopathological changes affecting a number ofneuronal systems are considered to result in the development ofthe typical symptomology of Alzheimer’s disease (AD), characterizedby gross and progressive impairments of cognitivefunction, which are often accompanied by behavioural disturbancessuch as aggression, depression, psychosis, apathy andwandering. Such non-cognitive behavioural symptoms are alsoconsidered to relate to structural and functional alterations inneurotransmission. Carers find behavioural disturbances difficultto cope with and the presence of such behaviours in AD patientsoften leads to the need for institutionalization 1 . The challenge hasbeen to identify changes in specific neurotransmitter systems thatunderlie cognitive impairment and particular behavioural problemsand to develop rational therapeutic strategies.NEUROCHEMICAL ANDHISTOPATHOLOGICAL CHANGES IN ADThe majority of biochemical studies of AD have relied oninformation derived from post mortem brain which typicallyrepresents the late stage of the disease (8–10 years after onset ofsymptoms). In these studies there is considerable evidence of grossbrain atrophy, histopathological features and multiple neurotransmitterabnormalities affecting many brain regions. However,investigations of biopsy tissue taken from AD patients 3–5 years(on average) after the onset of symptoms indicate that a selectiveneurotransmitter pathology occurs early in the course of thedisease 2 .AcetylcholineChanges affecting many aspects of the cholinergic system inpatients with AD have been reported since the initial discovery ofdeficits in choline acetyltransferase activity in post mortembrains 3–5 . In biopsy samples from AD patients, presynapticmarkers of the cholinergic system were also uniformly reduced 2 .Thus, choline acetyltransferase activity, choline uptake andacetylcholine synthesis are all reduced to 30–60% of controlvalues. The clinical correlate of this cholinergic deficit in AD was,until recently, considered to be cognitive dysfunction. Such aconclusion was supported by clinicopathological studies in ADand parallel experiments in non-human primates or rodents,which demonstrated disruptive effects of basal forebraincholinergic lesions on cognitive functions. Such studies led tothe ‘‘cholinergic hypothesis of geriatric memory dysfunction’’ 6 .Furthermore, cholinergic deficits in AD occur to the greatestextent in cortical areas primarily concerned with memory andcognition—the hippocampus, adjacent temporal lobe regions andselect frontal areas. In a recent study 7 regional variations in theloss of cholinergic fibres in AD were assessed on the basis ofacetylcholinesterase (AChE) histochemistry. Greatest fibre loss(>75%) was apparent in temporal association areas, with variousfrontal areas, including granular orbitofrontal, dysgranularorbitofrontal, prefrontal association, frontal operculum, prefrontalassociation and frontal pole, demonstrating fibre lossesin the range 45–75%. In other cortical areas, including primarymotor, premotor association, anterior and posterior cingulate,fibre loss was less than 45%.Neuropathologically, loss of neurons from the nucleus ofMeynert (Ch4 cholinergic nucleus) is well documented in AD,although the extent of the loss reported varies from moderate tosevere, and it has been suggested that in AD cholinergicdysfunction exceeds degeneration 8 . Detailed analysis of subpopulationsof cholinergic perikarya in the nucleus basalis have beenreported by Mesulam and Geula 9 , who identified selective cell lossin Ch4p (the posterior section projecting to temporal cortex). Inthe intermediate sector, Ch4id, which includes projections to thefrontal cortex, neuron loss is not as extensive, consistent with themoderate loss of cholinergic enzyme activity.On the basis of the above evidence, neocortical cholinergicinnervation appears to be lost at an early stage of the disease andthis is supported by a recent study 10 in which the cholinergicdeficit (reduced ChAT activity) has been related to Braakstageing. Braak stages I and II are considered to represent theearliest presentation of AD, with neurofibrillary tangles in theentorhinal cortex, and a 20–30% loss of ChAT activity wasreported in brains from patients at these stages of AD 11 . However,another study using the Clinical Dementia Rating Scale (CDR)suggests that the greatest reduction in markers of the cholinergicsystem occurs between moderate (CDR 2.0) and severe (CDR 5.0)disease, with little change between non-demented and the mildstage (CDR 0–2) 12 .There has been a recent shift of emphasis regarding the clinicalsignificance of cholinergic deficits. Non-cognitive or neuropsychiatric,in addition to cognitive, symptoms also appear tohave a cholinergic component 13 . For example, visual hallucinationsrelate to neocortical cholinergic deficits 14 , such deficits (e.g.loss of ChAT) being greater in Lewy body dementia (DLB), wherePrinciples and Practice of Geriatric Psychiatry, 2nd edn. Edited by J. R. M. Copeland, M. T. Abou-Saleh and D. G. Blazer&2002 John Wiley & Sons, Ltd