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 0-470-84641-044Antemortem MarkersSusan J. Van Rensburg, Felix C. V. Potocnik and Dan J. SteinTygerberg Hospital and University of Stellenbosch Medical School, South AfricaINTRODUCTIONIt has become increasingly clear that the disease process ofAlzheimer’s disease (AD) is multifaceted. It is thus difficult tosingle out any particular factor as the root cause of the disease,since AD appears to be a complex disorder involving several genesinteracting with environmental factors. Apart from the familialforms of the disease, in which the gene mutations have beenelucidated, many proteins, enzymes and other factors are involvedin the process of neurodegeneration, in the formation of plaquesand tangles and in the development of an inflammatory state ofthe brain. In all, more than 100 proteins and other factors havebeen found to be altered in AD patients compared with controls.For all that, very few markers suitable for antemortemdiagnostic purposes have emerged, since many of the abovementionedalterations are not specific for AD, while others pertainonly to subsets of AD 1 . While it has been argued that the mostpowerful antemortem marker in AD is a clinical diagnosis basedon an adequate range of observations 2 , such diagnosis is atpresent to some degree still one of exclusion. An ideal biologicalmarker would allow for greater specificity and sensitivity thanclinical diagnosis, and be readily obtainable. While neuropathologicalbiopsy diagnosis of AD allows specificity and sensitivity, itis rarely clinically warranted or available. The neurobiologicalalterations present in AD may be reflected in changes incerebrospinal fluid (CSF) neurotransmitters or neurochemicals,or in a change in systemic tissues, including blood constituents. Itshould be borne in mind, however, that CSF measurements areinfluenced by a variety of factors, including CSF gradients, ageand sex, diurnal and seasonal variation, state of the blood–brainbarrier, blood contamination, contributions from the spinal cord,phase of illness, psychomotor activity, stress and diet. Measurementof blood constituents may also reflect concentrationdifferences due to diurnal rhythms and other factors.In this chapter on antemortem markers, we will briefly reviewneurotransmitters and neurochemistry, systemic pathology andbrain imaging.NEUROTRANSMITTERS AND NEUROCHEMISTRYThe Cholinergic SystemThe most effective drugs so far for the treatment of AD are theacetylcholinesterase (AChE) inhibitors. The introduction of theseagents followed the discovery that cholinergic neurons weredepleted and that cholinergic function was significantly decreasedin the basal forebrain of AD patients 3 . CSF markers ofcholinergic function have been studied, but have not yieldedconsistent results. For example, measurements of AChE andpseudocholinesterase (PChE) have led to the conclusion thatcholinergic basal forebrain neurons are not a major source ofcholinesterases in the CSF and do not provide evidence for usingCSF cholinesterases as a diagnostic marker of basal forebraincholinergic cell loss 4 .The Noradrenergic SystemAutopsy studies of AD brains demonstrate loss of cells in the locuscoeruleus, the major nucleus of origin of noradrenergic fibres.Reduced noradrenaline (norepinephrine NE) in autopsy samplesof AD brains has been a fairly consistent finding. In contrast, CSFand plasma NE and 3-methoxy-4-hydroxyphenylethylene glycol(MHPG) appear significantly higher in patients with advancedAD than in patients with moderate AD or controls 5,6 . Patientswith advanced AD have not only biochemical indices ofnoradrenergic hyperactivity but also physiological pointers tothis, including higher heart rate and blood pressure. AD patientswith the most severe dementia have the greatest rise in CSFMHPG levels following administration of probenecid. There isalso evidence for blunted growth hormone response to clonidinein AD patients, suggestive of altered a-2-adrenergic receptorsensitivity 7 . It may be hypothesized that increased activity andturnover of the noradrenergic system may compensate for cell lossand that a limited number of NE cells remain highly active in ADpatients. Severe neuronal loss in advanced AD may lead to acompensatory increase in locus coeruleus firing rate, contributingto symptoms such as pacing, agitation, insomnia and weight loss.The Serotonergic SystemNumerous autopsy studies of AD brains have suggested aserotonergic deficit. Although there have been reports that themajor serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA),is unchanged in the CSF of AD patients, most studies indicate areduction in CSF 5-HIAA. In one study that demonstratedsignificantly lower mean 5-HIAA levels in AD, the wide variabilityin values suggested that the changes were non-specific, secondaryto the cerebral degeneration in AD 8 . There is also evidence ofincreased behavioural sensitivity to m-chlorophenylpiperazine inAD patients, consistent with damage to serotonin pathways 9 .Melatonin, the pineal hormone biosynthesized from serotonin,has been demonstrated to be significantly decreased in the CSF ofelderly patients, and more so in AD patients. In elderly (>80 yearsPrinciples 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