Brain, Vol. 124, No. 5, 1054-1055,
May 2001
© 2001 Oxford University Press
Book reviews |
CEREBRAL AMYLOID ANGIOPATHY IN ALZHEIMER'S DISEASE AND RELATED DISORDERS.
By Marcel M. Verbeel, Robert M. W. de Waal and Harry V. Vinters. 2000. Dordrecht: Kluwer Academic Publishers. Price £90. Pp. 384. ISBN 0-79-236366-3.
Pathology Directorate, University Hospital of Wales, Cardiff, UK
Cerebral amyloid angiopathy (CAA) is the accumulation of leptomeningeal and cortical vessel amyloid in the ageing brain. It exists in familial and sporadic forms, is associated with a variety of stroke subtypes, in particular recurrent lobar haemorrhages, and is a pathological feature in over 80% of Alzheimer disease brains. This multi-author text aims to weave together the threads of what is known about this common age-related vasculopathy at clinical, pathological, molecular and genetic levels.
The 20 chapters are divided into four sections and each chapter broken down into manageable, bite-sized portions. Section 1 (Clinical aspects of CAA and CAA-related haemorrhage) begins with a useful overview of clinical features and diagnostic criteria of sporadic CAA-related haemorrhage. It is my impression that such bleeds are still much underdiagnosed clinically. This is followed by an interesting discussion of neuroimaging of CAA, which reminds us of the gulf between scientific knowledge and clinical application in this field. Chapter 3 outlines vascular risk factors for Alzheimer's disease, hinting that cerebrovascular and Alzheimer's diseases may be more closely linked than hitherto assumed. Many of the data presented, however, appear to be conflicting, emphasizing perhaps how inadequate many such risk-factor studies continue to be. Section 1 concludes with an attempt to compare cerebral macro- and microvascular diseases, but is hampered on the one hand by oversimplification of the complexities of atherosclerosis, and on the other by terminological confusion regarding the different varieties of cerebral small vessel disease. Confused terminology, between and within medical specialities, can be an obstacle to progress in understanding.
Section 2 (Genetics of CAA) opens with an excellent review of the observed associations between ApoE genotypes and vascular amyloid deposition, CAA-related haemorrhage and putative haemorrhage-inducing vessel lesions such as fibrinoid necrosis. The conclusions about possible underlying mechanisms are balanced and thought-provoking. The following chapters on hereditary Dutch-type and cystatin C CAA variants illustrate how important such diseases may prove to be as in vivo models of the more common, sporadic type.
Section 3 (Cellular and molecular pathology of CAA) begins with a helpful overview of the neuropathology of CAA, both sporadic and Alzheimer-related, and ends with descriptions of the neuropathology of Dutch-, British-type and prion protein-related CAAs. Neuropathologists have contributed greatly to our present understanding of CAA and in this area, as in many others, the effects of the relentless decline in autopsy rates and the heated debate on organ retention, will be keenly felt. Sandwiched between are contributions on the chemistry and immunochemistry of amyloid ß-protein in CAA. It is here the contentious issue as to the cellular origin of vascular amyloid is raised—vascular smooth muscle cells, cerebrospinal fluid, blood or even brain cells? There is also a chapter devoted to the topical subject of a possible role for microvascular factors in the morphological and clinical phenotype of Alzheimer's disease. It is concluded that microvascular disease and blood–brain barrier breakdown are important in the pathogenesis of late-onset Alzheimer's, although the evidence presented is not yet compelling. This particular field appears ripe for further study.
The final section of the book (In vitro and animal models of CAA) begins by considering the ageing canine brain as a potentially useful model of sporadic human CAA, particularly as the morphological appearances and ß-amyloid amino acid sequences are identical in the two species. We are not told, however, whether such elderly dogs suffer, for example, from CAA-related haemorrhages (dogs, it is taught in vet school, have a peculiarly low incidence of strokes). There follow chapters describing the differential toxic effects of various amyloid moieties on cells in the vessel wall and in the brain, and the in vitro effects of ß-amyloid peptides on cerebrovascular vasoreactivity. The section concludes with a review of the different transgenic mouse models of Alzheimer's and CAA, a topic with a colourful history, which nonetheless represents an important bridge between in vitro models and the human reality.
Given the potential importance of CAA, this is a timely distillation of what has become an impressive collection of data, both clinical and scientific. Less impressive perhaps is our ignorance concerning some of the more fundamental issues about CAA and its effects on the brain, some of which the authors choose not to address. Does CAA actually cause intracerebral haemorrhage? In other words, does vascular amyloid deposition cause, directly or indirectly, vessel rupture? It is, for example, notable that a significant number of smaller, lobar CAA-associated haematomas appear to be confined to subcortical white matter, presumably due therefore to rupture of vessel segments devoid of amyloid. Does CAA contribute significantly to the cognitive decline in Alzheimer's disease? What, exactly, is the cell (or cells) of origin of vascular amyloid? These are certainly awkward questions, but they appear sometimes to be forgotten in the reductionist rush to accumulate, and fund, molecular genetic data. Therefore, much of the section devoted to clinical aspects of CAA centres upon diagnosis and speculative treatment, assuming that CAA is a `disease' which requires treatment. When CAA can eventually be prevented or reversed, its effects on the brain will perhaps become more transparent, and it may well prove to have been a major cause of ageing brain damage. Meanwhile, the case against CAA remains to a large degree unproven.
I did therefore feel that each section of this book would benefit from an overview or summary, as I found it difficult to reconcile the sometimes conflicting views put forward by different authors. In a relatively young and rapidly advancing field, where much is known but relatively little understood, the broad overview is invaluable. The illustrations too are of disappointing quality and the references less than comprehensive in some areas. That having been said, I am indebted to the editors and I am sure many others will be, for bringing together so many expert opinions, for their wide-ranging discussion and for the provocative hypotheses and speculations they offer. The potential clinical importance of CAA is, as discussed, considerable. Research from clinic and laboratory now appears to be gaining momentum and it is hoped that insight into some of the fundamental clinical questions will be gained in the near future. Meantime, this book offers good value for money for those clinicians and scientists interested in the current state of play.
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