Cerebral Amyloid Angiopathy in Alzheimer’s Disease and Related Disorders

Cerebral Amyloid Angiopathy in Alzheimer's Disease and Related Disorders. Editors: Verbeek, M.M., de Waal, R.M., Vinters, Harry V. (Eds.).
Table of contents

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.

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. Beta-Amyloid- 1—42 is a major component of cerebrovascular amyloid deposits: Kokjohn TA, Roher A. Hereditary cerebral hemorrhage with amyloidosis-Dutch type.

Hereditary cerebral hemorrhage with amyloidosis.

You are here

Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases. Hereditary cerebral amyloid angiopathy: Biochem Biophys Res Comm. The role of cystatin C in cerebral amyloid angiopathy and stroke: Cell biology and animal models. Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping.

Aβ and non-Aβ CAA genetic variants

Structure Function, and Bioinformatics. Domain swapping in N-truncated cystatin C. Cell Mol Life Sci. Amyloidogenesis in Familial British Dementia is associated with a genetic defect on chromosome Molecular basis of dementia.

New York Academy of Sciences; BRI2 inhibits amyloid beta peptide precursor protein processing by interfering with the docking of secretases to the substrate. Familial presenile dementia with spastic paralysis. Systemic amyloid deposits in Familial British Dementia. A stop-codon mutation in the BRI gene associated with familial British dementia.

Cerebral Amyloid Angiopathy

Genetic alterations of the BRI2 gene: Regional distribution of fibrillar and nonfibrillar ABri deposition and its association with neurofibrillary degeneration in Familial British Dementia. J Neuropathol Exp Neurol.

Cerebral Amyloid Angiopathy

The length of amyloid-beta in hereditary cerebral hemorrhage with amyloidosis, Dutch type. DNA and protein diagnostic assays. Insoluble wild-type and protease-resistant mutant prion protein in brains of patients with inherited prion disease. Analysis of transthyretin amyloid fibrils from vitreous samples in familial amyloidotic polyneuropathy Val30Met Amyloid. Modification of transthyretin in amyloid fibrils: Cardiac amyloid in patients with familial amyloid polyneuropathy consists of abundant wild-type transthyretin.

Biochem Biophys Res Commun. Contribution of wild-type transthyretin to hereditary peripheral nerve amyloid. Opposing faces of a single coin.

CEREBRAL AMYLOID ANGIOPATHY AND ALZHEIMER’S DISEASE

Advances in clinical and basic research. John Wyley and Sons; Role of apolipoproteins in amyloidogenesis. Deamidation and isoaspartate formation in smeared tau in paired helical filaments. Unusual properties of the microtubule-binding domain of tau. Abeta species, including IsoAsp23 Abeta, in Iowa-type familial cerebral amyloid angiopathy. Acta Neuropathol Berl ; Deamination of human proteins. Lindner H, Helliger W. Age-dependent deamidation of asparagine residues in proteins. Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Wisniewski T, Frangione B.

Rostagno A, Ghiso J. Aminoff M, Daroff R, editors. Encyclopedia of neurological sciences. Familial British and Danish dementias. The beta sheet conformation and disease. A monoclonal antibody recognizing apolipoprotein E peptides in systemic amyloid deposits. Ann Clin Lab Sci. Association of apolipoprotein E with murine amyloid A protein amyloid. Nonamyloidotic monoclonal immunoglobulin deposits lack amyloid P component. Potential role of apolipoprotein-E in fibrillogenesis. Complement activation in Chromosome 13 dementias: Amyloid deposition is delayed in mice with targeted deletion of serum amyloid P component.

Isoform-specific binding of apolipoprotein E to beta-amyloid. Amyloid-associated proteins alpha 1-antichy-motrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Cerebral amyloid angiopathy has also been associated with the apolipoprotein E4 APOE4 genotype, which is in turn associated with premature coronary artery disease and atherosclerosis. Cerebral amyloid angiopathy severity was assessed using a semiquantitative scale in 4 brain regions ie, hippocampus, midfrontal cortex, inferior parietal cortex, and superior temporal cortex and an average score was computed for each case.

Logistic regression models showed that severe CAA, advanced age, atherosclerosis, and Hachinski Ischemia Scale score of 7 or more were all significantly associated with VLs, but the number of APOE4 alleles, history of hypertension, coronary artery disease, sex, and serum cholesterol levels had nonsignificant effects. The risk of infarction is particularly high in patients who have both hypertension and severe CAA. Cases included in this autopsy study met the following criteria: Most patients were followed up longitudinally at the San Diego Alzheimer Disease Research Center ambulatory clinic with the remainder evaluated in either a private practice or nursing home.

All San Diego Alzheimer's Disease Research Center subjects underwent at least one standardized evaluation that included a medical history, physical examination, structured neurological examination, cognitive screening tests, blood tests, and a neuroimaging study. Hypertension was defined as a recurrent abnormal systolic blood pressure higher than mm Hg or diastolic blood pressure higher than 90 mm Hg by history or direct measurement—taking antihypertensive medications was not required.

History of coronary artery disease was defined as either prior myocardial infarction ie, clinical diagnosis or by electrocardiogram or a history of exertional angina. Blood samples for nonfasting serum cholesterol levels were drawn in the late morning. Cases with superimposed diffuse Lewy bodies on brain autopsy were included in this analysis.

Informed consent for brain autopsy and APOE genotyping had been obtained for all cases. Three hundred six cases males and females met these criteria and had the neuropathological measures described below performed. The size and characteristics of these groups are summarized in Table 1. One hundred forty-five of the cases in this study were included in previous articles.

Apolipoprotein E genotyping was performed on either brain autopsy or blood samples using a polymerase chain reaction—amplification technique adapted from Wenham et al 21 with modifications as have been reported previously. The details of our brain autopsy procedures have been published previously. Following 10 days of formalin fixation, the left hemibrain was examined externally, serially sliced into 1-cm-thick coronal sections, and evidence of infarction noted.

Tissue blocks were taken from all gross lesions, as well as from 13 other routinely sampled brain regions.

Diagnostic Guidelines

These sections sometimes revealed cortical microinfarcts that had escaped detection at the time of brain sectioning. The cerebral vessels in these sections were examined and cases with prominent intracerebral atherosclerosis, arteriosclerosis, or. The frozen right hemibrain was examined separately and the presence of grossly detectable infarcts noted.

After partial thawing, the right hemibrain was cut in 1-cm-thick sections and any apparent infarcts noted. Entire neocortical sections were surveyed to find areas with the most lesions. The results were then averaged to provide single TP and NFT counts for each brain region from each case. These single TP and NFT counts for each of 4 brain regions ie, hippocampus, midfrontal cortex, inferior parietal cortex, and superior temporal cortex were then averaged to provide overall TP and NFT scores.

Cerebral Amyloid Angiopathy: Emerging Concepts

Separate neocortical senile plaque counts for neuritic plaques, which contained filamentous amyloid and swollen neurites, were determined in cases and an overall neuritic plaques score was calculated analogously. Total senile plaque scores included both diffuse and neuritic forms. The severity of AA was assessed semiquantitatively on thioflavin-S—stained preparations of hippocampus, midfrontal cortex, inferior parietal cortex, and superior temporal gyrus.

A score of 0 meant that there was no thioflavin-S positivity in the leptomeningeal or superficial cortical blood vessels. A score of 1 reflected trace to scattered positivity in either the leptomeningeal or the cortical blood vessels. A score of 2 indicated that at least some vessels in the leptomeninges or neocortex had circumferential brightly staining amyloid deposits. A score of 3 corresponded to widespread circumferential thioflavin-S positivity in many leptomeningeal and superficial cortical vessels.

A score of 4 meant that similarly SAA was combined with dysphoric changes, ie, thioflavin-S positivity emanating from severely amyloidotic blood vessels into surrounding neuropil. A single AA severity score for each case was calculated by averaging across brain regions.