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 0-470-84641-0NEUROPATHOLOGY OF AD 227Oxford Project to Investigate Memory and Ageing (OPTIMA):a Longitudinal Clinicopathological Study ofDementia and Normal AgeingA. David SmithOPTIMA, Oxford, UKOPTIMA was founded in 1988 by A.D. Smith, K.A. Jobst, E.M.-F. King and M.M. Esiri, with the aim of studying in parallel acohort of patients with memory problems and age-matchedcontrols. The total number of subjects at the end of 1999 was 666,of which 361 are patients with dementia. OPTIMA is a longitudinalclinicopathological study and its main strength lies in thevery high necropsy rate (94% of the 207 who have died), whichpermits correlation of findings in life with those of neuropathology.Each year each subject has a full clinical examination, lumbarpuncture, neuropsychology (the CAMDEX, supplemented byother tests), CT scans (axial and temporal lobe-orientated) andSPECT scans (Ceretec, for cerebral blood flow). A subset of 155subjects have had annual volumetric MRI scans and moredetailed neuropsychology.The main findings so far are:. Comparison of standard clinical diagnostic procedures withhistopathological diagnosis, showing the poor accuracy ofcurrent clinical diagnostic procedures 1 .. Development of a more accurate diagnostic procedure forAlzheimer’s disease (AD) in life by a combination of structural(CT) and functional (SPECT) brain imaging 2 .. Recognition that AD is distinct from ageing and is a truedisease that follows a ‘‘catastrophic event’’ in the brain,leading to atrophy of the medial temporal lobe 3 .. Discovery of a biological ‘‘state’’ marker, the thickness of themedial temporal lobe, that can be used to follow theprogression of AD 4 .. Discovery that nerve cells in AD brain express markers of thecell division cycle 5 .. Recognition of the additive effect of minor cerebrovasculardisease and AD-type pathology in clinical dementia 6,7 .. Identification of a gene (K variant of butyrylcholinesterase)that markedly increases the risk of AD in those who also havethe ApoE4 gene 8 .. Discovery of a risk factor (elevated blood levels of homocysteine)for AD and for vascular dementia that is potentiallymodifiable by diet 9 .. Finding that raised blood homocysteine levels are associatedwith low performance on cognitive tests in the normalelderly 10 .Projects currently under way include the search for furthergenetic and non-genetic risk factors for dementia, with particularemphasis on modifiable risk factors; a pilot clinical trial of highdosefolic acid and vitamin B 12 in subjects with dementia (togetherwith Professor G. Wilcock, Bristol); development of novelmemory tests to detect pre-symptomatic AD; use of sub-voxelco-registration MRI scans to follow progression of AD over aperiod of a few months (with Professor G. Bydder, HammersmithHospital).The current Director of OPTIMA is Professor A. David Smith,the Clinical Director is Professor Robin Jacoby and theOperational Manager and Senior Nurse is Mrs Elizabeth King.Funding is from Bristol–Myers Squibb, the Medical ResearchCouncil, National Health Service R&D and several charities.REFERENCES1. Nagy Z, Esiri MM, Hindley NJ et al. Accuracy of clinical operationaldiagnostic criteria for Alzheimer’s disease in relation to differentpathological diagnostic protocols. Dement Geriat Cogn Disord 1998;9: 219–26.2. Jobst KA, Barnetson LP, Shepstone BJ. Accurate prediction ofhistologically confirmed Alzheimer’s disease and the differentialdiagnosis of dementia: the use of NINCDS–ADRDA and DSM-III-R criteria, SPECT, X-ray CT, and Apo E4 in medial temporallobe dementias. Oxford Project to Investigate Memory and Aging. IntPsychogeriatr 1998; 10: 271–302.3. Jobst KA, Smith AD, Szatmari M et al. Rapidly progressing atrophyof medial temporal lobe in Alzheimer’s disease. Lancet 1994; 343:829–30.4. Smith AD, Jobst KA. Use of structural imaging to study theprogression of Alzheimer’s disease. Br Med Bull 1996; 52: 575–86.5. Nagy Z, Esiri MM, Smith AD. The cell division cycle and thepathophysiology of Alzheimer’s disease. Neuroscience 1998; 87: 731–9.6. Esiri MM, Nagy Z, Smith MZ et al. Cerebrovascular disease andthreshold for dementia in the early stages of Alzheimer’s disease.Lancet 1999; 354: 919–20.7. Nagy Z, Esiri MM, Jobst KA et al. The effects of additionalpathology on the cognitive deficit in Alzheimer disease. J NeuropatholExp Neurol 1997; 56: 165–70.8. Lehmann DJ, Johnston C, Smith AD. Synergy between the genes forbutyrylcholinesterase K variant and apolipoprotein E4 in late-onsetconfirmed Alzheimer’s disease. Hum Mol Genet 1997; 6: 1933–6.9. Clarke R, Smith AD, Jobst KA et al. Folate, vitamin B 12 , and serumtotal homocysteine levels in confirmed Alzheimer disease. Arch Neurol1998; 55: 1449–55.10. Budge M, Johnston C, Hogervorst E et al. Plasma total homocysteineand cognitive performance in a volunteer elderly population. Ann NYAcad Sci 2000; 903: 407–10.