D. Myers

The spatial patterns of beta/A4 deposit subtypes in Alzheimer's disease.

SummaryThe spatial patterns of diffuse, primitive, classic (cored) and compact (burnt-out) subtypes of β/A4 deposits were studied in coronal sections of the frontal lobe and hippocampus, including the adjacent gyri, in nine cases of Alzheimers disease (AD). If the more mature deposits were derived from the diffuse deposits then there should be a close association between their spatial patterns in a brain region. In the majority of tissues examined, all deposit subtypes occurred in clusters which varied in dimension from 200 to 6400 μm. In many tissues, the clusters appeared to be regularly spaced parallel to the pia or alveus. The mean dimension of the primitive deposit clusters was greater than those of the diffuse, classic and compact types. In about 60% of cortical tissues examined, the clusters of primitive and diffuse deposits were not in phase, i.e. they alternated along the cortical strip. Clusters of classic deposits appeared to be distributed independently of the diffuse deposit clusters. Cluster size of the primitive deposits was positively correlated with the density of the primitive deposits in a tissue but no such relationship could be detected for the diffuse deposits. This study suggested that there was a complex relationship between the clusters of the different subtypes of β/A4 deposits. If the diffuse deposits do give rise to the primitive and classic varieties then factors unrelated to the initial deposition of β/A4 in the form of diffuse plaques were important in the formation of the mature deposits.

Alzheimer's disease: the relationship between the density of senile plaques, neurofibrillary tangles and A4 protein in human patients

The numerical density of senile plaques (SP) and neurofibrillary tangles (NFT) as revealed by the Glees silver method was compared with SP and NFT revealed by the Gallyas method and with amyloid (A4) deposits in immunostained sections in 6 elderly cases of Alzheimers disease. The density of NFT was generally greater and A4 lower in tissue from hippocampus compared with the neocortex suggesting that A4 deposition was less important than the degree of paired helical filament (PHF) related damage in the hippocampus. The density of Glees SP was positively correlated Gallyas SP weakly correlated with A4 deposit number. A stepwise multiple regression analysis which included A4 deposit and Gallyas SP density and accounted for 54% of the variation in Glees SP density. Hence, different populations of SP were revealed by the different staining methods. The results suggested that the Glees method may stain a population of SP in a region of cortex where both amyloid deposition and neurofibrillary changes have occurred.

Alzheimer's disease: size class frequency distribution of senile plaques: do they indicate when a brain tissue was affected?

The size class frequency distribution of a sample of senile plaques (SP) was determined in a total of 20 brain regions from 5 elderly cases of Alzheimers disease (AD). The purpose of the study was to determine whether a comparison of the frequency distributions could be used to determine the chronology of SP development in the AD brain. SP from 10 microns to a maximum diameter of 160 microns were present in the tissue and the size class frequency distributions were positively skewed. The frequency distributions varied between brain regions in: (1) the size class containing the mode, (2) the degree of positive skew, and (3) the ratio of large to small SP. In most patients the ratio of large to small SP was higher in the hippocampus or adjacent gyrus compared with temporal, parietal and frontal neocortex. If the diameter of a SP reflects its age in the tissue than the data suggest that SP formed earlier either in the hippocampus or adjacent gyrus compared with the other neocortical tissues. However, this conclusion rests on a number of assumptions including: (1) that SP diameter is directly related to age, (2) that SP development occurs at similar rates in different brain regions and (3) that, once formed, SP are not removed from the tissue by astrocytes.

The Use of Multivariate Methods in the Identification of Subtypes of Alzheimer's Disease: A Comparison of Principal Components and Cluster Analysis

Two contrasting multivariate statistical methods, viz., principal components analysis (PCA) and cluster analysis were applied to the study of neuropathological variations between cases of Alzheimers disease (AD). To compare the two methods, 78 cases of AD were analyzed, each characterised by measurements of 47 neuropathological variables. Both methods of analysis revealed significant variations between AD cases. These variations were related primarily to differences in the distribution and abundance of senile plaques (SP) and neurofibrillary tangles (NFT) in the brain. Cluster analysis classified the majority of AD cases into five groups which could represent subtypes of AD. However, PCA suggested that variation between cases was more continuous with no distinct subtypes. Hence, PCA may be a more appropriate method than cluster analysis in the study of neuropathological variations between AD cases.

The Ratio of Diffuse to Mature Beta/ A4 Deposits in Alzheimer's Disease Varies in Cases with and without Pronounced Congophilic Angiopathy

The density of diffuse, primitive, classic and compact beta/A4 deposits was estimated in the cortex and hippocampus in Alzheimers disease (AD) cases with and without pronounced congophilic angiopathy (CA). The total density of beta/A4 deposits in a given brain region was similar in cases with and without CA. Significantly fewer diffuse deposits and more primitive/classic deposits were found in the cases with CA. The densities of the primitive, classic and compact deposits were positively correlated in the cases without CA. However, no correlations were observed between the density of the mature subtypes and the diffuse deposits in these cases. In the cases with CA, the density of the primitive deposits was positively correlated with the diffuse but not with the classic deposits. The data suggest that the mature beta/A4 deposits are derived from the diffuse deposits and that the presence of pronounced CA enhances their formation.

What determines the size frequency distribution of β-amyloid (Aβ) deposits in Alzheimer's disease patients ?

The factors determining the size of individual β-amyloid (A,8) deposits and their size frequency distribution in tissue from Alzheimers disease (AD) patients have not been established. In 23/25 cortical tissues from 10 AD patients, the frequency of Aβ deposits declined exponentially with increasing size. In a random sample of 400 Aβ deposits, 88% were closely associated with one or more neuronal cell bodies. The frequency distribution of (Aβ) deposits which were associated with 0,1,2,...,n neuronal cell bodies deviated significantly from a Poisson distribution, suggesting a degree of clustering of the neuronal cell bodies. In addition, the frequency of Aβ deposits declined exponentially as the number of associated neuronal cell bodies increased. Aβ deposit area was positively correlated with the frequency of associated neuronal cell bodies, the degree of correlation being greater for pyramidal cells than smaller neurons. These data suggested: (1) the number of closely adjacent neuronal cell bodies which simultaneously secrete Aβ was an important factor determining the size of an Aβ deposit and (2) the exponential decline in larger Aβ deposits reflects the low probability that larger numbers of adjacent neurons will secrete Aβ simultaneously to form a deposit.

Factors Determining the Size Frequency Distribution of β-Amyloid (Aβ) Deposits in Alzheimer's Disease

The size frequency distributions of discrete β-amyloid (Aβ) deposits were studied in single sections of the temporal lobe from patients with Alzheimers disease. The size distributions were unimodal and positively skewed. In 18/25 (72%) tissues examined, a log normal distribution was a good fit to the data. This suggests that the abundances of deposit sizes are distributed randomly on a log scale about a mean value. Three hypotheses were proposed to account for the data: (1) sectioning in a single plane, (2) growth and disappearance of Aβ deposits, and (3) the origin of Aβ deposits from clusters of neuronal cell bodies. Size distributions obtained by serial reconstruction through the tissue were similar to those observed in single sections, which would not support the first hypothesis. The log normal distribution of Aβ deposit size suggests a model in which the rate of growth of a deposit is proportional to its volume. However, mean deposit size and the ratio of large to small deposits were not positively correlated with patient age or disease duration. The frequency distribution of Aβ deposits which were closely associated with 0, 1, 2, 3, or more neuronal cell bodies deviated significantly from a log normal distribution, which would not support the neuronal origin hypothesis. On the basis of the present data, growth and resolution of Aβ deposits would appear to be the most likely explanation for the log normal size distributions.

Beta/A4 deposits and their relationship to senile plaques in Alzheimer's disease

The density and spatial pattern of immunostained beta/A4 deposits and mature senile plaques (SP) stained by the Glees method were compared in Alzheimers diseased brain. Thirty-seven percent of the variance in Glees SP density in a tissue could be explained by beta/A4. Both lesions were clustered with the beta/A4 clusters often larger than the Glees SP clusters. Beta/A4 and Glees SP cluster size were not correlated in a tissue. The size of Glees SP clusters was positively correlated with SP density but no correlation could be detected for beta/A4. Hence, the density and spatial pattern of beta/A4 deposits in most tissues did not predict the development of Glees SP.