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 0-470-84641-042The Neuropathology of Alzheimer’s DiseaseDavid M. A. MannUniversity of Manchester, Manchester UKAlzheimer’s disease (AD) is the most common cause of dementiaat any time of life and, although the brains of patients with thisdisorder show remarkable pathological changes, the nosologicalstatus of these and their relevance to the underlying neurodegenerativeprocess has been the subject of vigorous debate. In thischapter the gross and microscopical changes of AD will bedescribed.HISTOPATHOLOGICAL CHANGESThe histopathology of AD displays several abnormalities and,although these changes can also be found in the brains of mostnormal elderly individuals, it is their greater extent and severityand regional pattern of distribution that is characteristic of AD.IMAGING STUDIESStructural imaging, by CT or MRI, fails to reveal changes in thebrain specific to AD. Usually there is evidence of widespreadcortical atrophy and ventricular enlargement, although not in away that obviously discriminates AD from other neurodegenerativedementing disorders. A more severe medial temporal atrophyhas been claimed to distinguish AD from normal ageing 1 ,although this does not differentiate between AD and otherdisorders, such as frontotemporal dementia, where a similardegree of hippocampal atrophy is seen 2,3 . Functional imaging,using PET or SPECT, reveals a conspicuous biparietal deficit inmany patients with AD, although not all individuals show thisand this pattern can also be seen in patients with Lewy bodydementia 4 . Hence, definitive diagnosis still remains the province ofhistopathology, although this is usually made retrospectivelyfollowing the death of the affected person.THE AUTOPSY APPEARANCE OF THE BRAINAlthough the pattern of atrophy in AD may be quite distinct fromthat of the normal elderly 2,5 and of other dementing disorders ofdiverse aetiology 3,6 the diagnosis cannot be made at autopsy fromvisual inspection alone. Nonetheless, brain weight is usuallyreduced due to cortical atrophy (shrinkage of the gyri andwidening of the sulci), which can be widespread but most often issevere in the medial temporal regions, particularly the parahippocampalgyrus, while the occipital lobe and the motor cortexare generally spared 2 .The cortical grey matter is reduced in thickness and the whitematter, while macroscopically normal in appearance, is lostproportionately to that of the grey matter 2 . The ventricularsystem is dilated, most markedly in the temporal horns of thelateral ventricles. The substantia nigra usually shows normalpigmentation but frequently there is loss of pigment from thelocus caeruleus. Cerebrovascular changes are often coincidentallypresent, but do not necessarily indicate a multi-infarctdementia.Amyloid PlaquesThese are aggregates (plaques) of an amyloid protein—amyloid bprotein (Ab)—typically 50–200 mm in diameter, within thecerebral cortex and other grey matter regions of the brain. TheAb may be surrounded by abnormal presynaptic nerve cellprocesses called dystrophic neurites. The same protein is oftenpresent within the walls of leptomeningeal and intracortical bloodvessels, causing an amyloid angiopathy. Four plaque types havebeen identified 7 :1. Diffuse plaques have even Ab deposition with ill-definedborders, not forming discrete rounded masses. They are themost common plaque type in AD and can only be defined byimmunohistochemical staining with antibodies to Ab; theyhave no dystrophic neurites.2. Primitive plaques are discrete rounded Ab deposits without adense core but having some dystrophic neurites. They can bestained using conventional amyloid stains.3. Classical plaques have a dense star-shaped Ab core surroundedby a corona of radiating wisps of Ab and manydystrophic neurites.4. Compact or burnt-out plaques have dense Ab cores without asurrounding corona, or neurites.Primitive and classical plaques with dystrophic neuritescontaining PHF are termed ‘‘neuritic plaques’’, synonymouswith what used to be known as ‘‘senile plaques’’. Synapse lossoccurs from primitive and classical plaques, but not diffuseplaques 62 .Neuritic, but not diffuse, plaques contain reactive astrocytesand activated microglial cells 8,9 ; the latter may play a role in the‘‘processing’’ of Ab during plaque evolution. Although unproved,the prevailing view is that amyloid plaques undergo, during theirprolonged life history, a series of evolutionary changes fromdiffuse to cored plaques. This involves not only compositionalchanges in Ab, but also changes in associated glial cells. Thisevolutionary process has largely been deduced from studies ofpersons with trisomy 21 (Down’s syndrome) dying at differentages 9,10 , who inevitably develop the histopathology of AD if theylive past 50 years of age.Principles 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