Mohammed T. Abou-Saleh

318 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYrates approximately double every 5 years (65–90), such that about20–25% of those over 80 are affected. UK demographic studiespredict that old people who are cognitively impaired will increaseby 11% during 2001–2011. The prevalence of AD seems likely todouble by 2050. All AD sufferers are currently regarded aspotentially eligible for dementia treatment.What Are the Benefits of Current Dementia Treatment?Anti-dementia therapy benefits are now recognized to be widerthan just the slowing or improvement of cognitive decline.Additional improvements include reduced disability, time toinstitutionalization and fewer acute medical or surgical emergencies.Disabilities place considerable burdens on health and socialservices and the incidence of disability increases with age. Theseburdens include needs for social support, especially in best use ofavailable health services, problems of co-morbidity and institutionalization.In London, the Gospel Oak studies reporteddisability in 38% of community residents aged 65–74, 77% aged75–84 and 96% aged 85+ 13 and the overall prevalence ofdementia was 9.8%. Predictions based on the MRC CognitiveFunction and Ageing Study (MRC CFAS) suggest that peopleaged 65+ with severe disability will make up 2.2% and 3.9% ofthe population in 2011 and 2051, respectively 14 . In general terms,disability from whatever cause forecasts both mortality andprolongation of length of stay after admission to hospital.The MRC CFAS provides further valuable information on theburden of health care linked to cognitive impairment. Cognitiveimpairment was detected in 38% of disabled people aged 65 yearsand in 46% of people in institutional care. Cognitive impairmentalso generates other health service demands, some not immediatelyobvious. For example, a reduction of dementia prevalence of1–2% would reduce the number of hip fractures in the UK by20 000/year 15,16 .The Anti-dementia DrugsCurrently available drugs are based on the established cholinergicdeficits in AD and early recognition that these may besufficient to explain ‘‘core’’ symptoms. There are no claims thatcurrent drugs do any more than provide symptomatic relief.Large-scale randomized placebo-controlled trial results areavailable for three anticholinesterase drugs: donepezil 17,18 ,rivastigmine 19,20 and galantamine 21,22 . These show that, ingeneral, these drugs: (a) improve global outcome; (b) slow orarrest cognitive decline; and (c) improve activities of daily living.Carers also report that some troublesome behaviours, such asapathy and apparent responses to hallucinations or delusions, arehelped by drugs of this type but as yet no satisfactory clinicaltrial data are available. There is a consensus to support arelatively enduring good cognitive response equivalent to anarrest of disease progression of about 9 months. This is notsustained, however, and is followed by a fairly rapid decline thatreverses any earlier benefit. Primarily for this reason, mostcommentators agree that anticholinesterase drugs do not modifyany underlying disease process.The generality can obscure some quite remarkable andsustained improvements in a subset of patients. Almost half ofAD patients show evidence of improvement and sustain thatimprovement for up to about 18 months. Within this group thereis a small proportion (roughly around 1 in 12) who show veryextensive improvements, sometimes sufficient to permit resumptionof mentally effortful recreational pursuits. Unfortunately,there is no evidence that this group of high responders obtainlong-term benefits. Such patients are highly encouraging inroutine clinical practice and certainly help motivate and improvemorale in dementia care teams.This class of drugs is usually well tolerated. Common unwantedeffects include cholinergic actions on the GI tract (nausea,vomiting and diarrhoea). Few data are available on the effectsof these drugs on disability and institutionalization rates. Tacrinewas one of the early antidementia drugs and is now discontinued.Patients receiving tacrine and remaining on doses greater than80 mg/day may be less likely to enter a nursing home than thoseon lower doses or who have stopped the drug 23,24 .Cost ConcernsAlthough the licensing of cholinesterase inhibitors has introducedwidely available drug treatment for AD for the first time, the costsof these drugs prohibits extensive use in less developed countries,where the greatest increase in numbers of people with AD isexpected. Even within the UK there is considerable geographicalvariation in the availability of antidementia drugs. In part thisremains attributable to poorly informed pessimism aboutdementia treatment, but the fact that much-needed pharmacoeconomicdata were not collected in trials sponsored by thepharmaceutical industry must share part of the responsibility.Largely at the direction of regulatory authorities, the sponsorsinclude clinically meaningful measures of competencies in dailyliving, and these have become the cornerstone of currentrecommendations to administer these drugs as widely as possible.At present, there is an impression that these drugs are ‘‘costbeneficial’’and reduce overall spending on services for dementia.If delay to institutional care is accepted as a valid proxy ineconomic analyses, the eventual conclusion seems likely tosupport their use 25 . Data from Canada indicate that the largestproportion of costs is attributable to institutionalization. Use ofdonepezil for mild-to-moderate AD was associated with lower 5year costs and less time spent with severe AD when comparedwith the alternative of usual care 26 . In a retrospective cost analysisin Dutch patients with Alzheimer’s disease who were being caredfor at home at the start of the study period, treatment withdonepezil did not increase overall direct medical costs 27 .To obtain an improvement of four points on the ADAS-COG,it is estimated that between four and six patients taking donepezil10 mg once daily for 6 months would need to be treated. Clinicalexperience in the UK suggests the NNT to achieve clinicallysignificant activities of daily living score improvement is likely tobe about twice that for the cognitive end point of ADAS-COGimprovement of four points.BRAIN AGEING: NEUROPROTECTION ANDPREVENTION OF DEMENTIANeurochemical studies support an association between brainoxidative stress and AD 28,29 . Current studies are examiningwhether this association is a cause or a consequence of AD,perhaps an artifact of the AD process. Therapeutic agents arecurrently available (and more potent compounds are underinvestigation) that reduce oxidative stress. These agents mayprove to be potent neuroprotective agents relevant to AD.Evidence of oxidative stress in AD is detectable throughout thebrain, irrespective of the site or extent of AD neuropathology.This evidence includes increased concentrations of advancedglycation end products 30 , nitration 31 , increased products of lipidperoxidation 32 and carbonyl modified proteins 33,34 . The sources ofoxidative stress in AD extend beyond the generation of reactiveoxygen species (ROS) during aerobic metabolism. Contributionsare made by activated microglia near senile plaques 35 and by