The distribution of senile plaques, neurofibrillary tangles and beta/A4 deposits in the hippocampus in Alzheimer's disease

The density of senile plaques (SP) and neurofibrillary tangles (NFT) was studied in Glees and Marsland stained sections of the hippocampus and parahippocampal gyrus (PHG) in 20 pateints with Alzheimer's disease. In addition, in six of the patients, the density of beta/A4 protein deposits, as revealed by immunohistochemistry and neurofibrillary changes demonstrated with the Gallyas stain, were studied in adjacent sections. The density of Glees SP and beta/A4 deposits was significantly greater in area CA1 of the hippocampus and in the subiculum than in the PHG. Hence, neurofibrillary degeneration appears to be a more important lesion than beta/A4 deposition in the hippocampus compared with the PHG. In addition, the detailed distribution of the lesions in the hippocampus could be explained if beta/A4/SP and NFT occur on the axon terminals and in the cell bodies respectively of the same neurons.

Spatial distribution of diffuse, primitive, and classic amyloid-beta deposits and blood vessels in the upper laminae of the frontal cortex in Alzheimer disease

The spatial distribution of the diffuse, primitive, and classic amyloid-beta deposits was studied in the upper laminae of the superior frontal gyrus in cases of sporadic Alzheimer disease (AD). Amyloid-beta-stained tissue was counterstained with collagen IV to determine whether the spatial distribution of the amyloid-beta deposits along the cortex was related to blood vessels. In all patients, amyloid-beta deposits and blood vessels were aggregated into distinct clusters and in many patients, the clusters were distributed with a regular periodicity along the cortex. The clusters of diffuse and primitive deposits did not coincide with the clusters of blood vessels in most patients. However, the clusters of classic amyloid-beta deposits coincided with those of the large diameter (>10 microm) blood vessels in all patients and with clusters of small-diameter (< 10 microm) blood vessels in four patients. The data suggest that, of the amyloid-beta subtypes, the clusters of classic amyloid-beta deposits appear to be the most closely related to blood vessels and especially to the larger-diameter, vertically penetrating arterioles in the upper cortical laminae.

Laminar distribution of amyloid-beta (Abeta) deposits in dementia with Lewy bodies: comparison with Alzheimer's disease

Significant amyloid-beta (Abeta) deposition in cases of dementia with Lewy bodies (DLB) may represent concurrent Alzheimer's disease (AD). To test this hypothesis, the laminar distribution of the diffuse, primitive, and classic Abeta deposits was studied in the frontal and temporal cortex in cases of DLB and were compared with AD. In DLB, the diffuse and primitive deposits exhibited two common patterns of distribution; either maximum density occurred in the upper cortical laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. In addition, a bimodal distribution of the classic deposits was observed in approximately half of the cortical areas analysed. A number of differences in the laminar distributions of Abeta deposits were observed in DLB and AD. First, the proportion of the primitive relative to the diffuse and classic deposits present was lower in DLB compared with AD. Second, the primitive deposits were more frequently bimodally distributed in DLB. Third, the density of the diffuse deposits reached a maximum lower in the cortical profile in AD. These data suggest differences in the pattern of cortical degeneration in the two disorders and therefore, DLB cases with significant Abeta pathology may not represent the coexistence of DLB and AD.

Size frequency distribution of beta-amyloid (Abeta) deposits in dementia with Lewy bodies

In Alzheimer's disease (AD) and Down's syndrome (DS), the size frequency distribution of the beta-amyloid (Abeta) deposits can be described by a log-normal model and may indictae the growth of the deposits. This study determined the size frequency distribution of the Abeta deposits in the temporal lobe in 8 casaes of dementia with Lewy bodies (DLB) with associated AD pathology (DLB/AD. The size distributions of Abeta deposits were unimodal and positively skewed; the mean size of deposi and the degree of skew varying with deposit type and brain region. Size distributions of the primitive deposits had lower means and were less skewed compared with the diffuse and classic deposits. In addition, size distributions in the hippocampus and parahippocampal gyrus (PHG) had larger means and a greater degree of skew compared with other cortical gyri. All size distributions deviated significantly from a log-normal model. There were more Abeta deposits than expected in the smaller size classes and fewer than expected near the mean and in the larger size classes. The data suggest thatthe pattern of growth of the Abeta deposits in DLB/AD depends both on deposit morphology and brain area. In addition, Abeta deposits in DLB appear to grow to within a more restricted size range than predicted and hence, to have less potential for growth compared with cases of 'pure' AD and DS.

Beta-amyloid (Abeta) deposits and blood vessels: laminar distribution in the frontal cortex of patients with Alzheimer’s disease

The laminar distribution of diffuse, primitive and classic beta-amyloid (Abeta) deposits and blood vessels was studied in the frontal cortex of patients with Alzheimer’s disease (AD). In most patients, the density of the diffuse and primitive Abeta deposits was greatest in the upper cortical layers and the classic deposits in the deeper cortical layers. The distribution of the larger blood vessels (>10 micron in diameter) was often bimodal with peaks in the upper and deeper cortical layers. The incidence of capillaries (<10 micron) was significantly higher in the deeper cortical layers in most patients. Multiple regression analysis selected vertical distance below the pia mater as the most significant factor correlated with the Abeta deposit density. With the exception of the classic deposits in two patients, there was no evidence that these vertical distributions were related to laminar variations in the incidence of large or small blood vessels.

The spatial patterns of beta-amyloid (Abeta) deposits and neurofibrillary tangles (NFT) in late-onset sporadic Alzheimer's disease

The spatial patterns of beta-amyloid (Abeta) deposits and neurofibrillary tangles (NFT) were studied in areas of the cerebral cortex in 16 patients with the late-onset, sporadic form of Alzheimer’s disease (AD). Diffuse, primitive, and classic Abeta deposits and NFT were aggregated into clusters; the clusters being regularly distributed parallel to the pia mater in many areas. In a significant proportion of regions, the sizes of the regularly distributed clusters approximated to those of the cells of origin of the cortico-cortical projections. The diffuse and primitive Abeta deposits exhibited a similar range of spatial patterns but the classic Abeta deposits occurred less frequently in large clusters >6400microm. In addition, the NFT often occurred in larger regularly distributed clusters than the Abeta deposits. The location, size, and distribution of the clusters of Abeta deposits and NFT supports the hypothesis that AD is a 'disconnection syndrome' in which degeneration of specific cortico-cortical and cortico-hippocampal pathways results in synaptic disconnection and the formation of clusters of NFT and Abeta deposits.

Size frequency distribution of the β-amyloid (aβ) deposits in dementia with Lewy bodies with associated Alzheimer’s disease pathology

The objective is to study beta-amyloid (Abeta) deposition in dementia with Lewy bodies (DLB) with Alzheimer's disease (AD) pathology (DLB/AD). The size frequency distributions of the Abeta deposits were studied and fitted by log-normal and power-law models. Patients were ten clinically and pathologically diagnosed DLB/AD cases. Size distributions had a single peak and were positively skewed and similar to those described in AD and Down's syndrome. Size distributions had smaller means in DLB/AD than in AD. Log-normal and power-law models were fitted to the size distributions of the classic and diffuse deposits, respectively. Size distributions of Abeta deposits were similar in DLB/AD and AD. Size distributions of the diffuse deposits were fitted by a power-law model suggesting that aggregation/disaggregation of Abeta was the predominant factor, whereas the classic deposits were fitted by a log-normal distribution suggesting that surface diffusion was important in the pathogenesis of the classic deposits.

Beta-amyloid deposition in the temporal lobe of patients with dementia with Lewy bodies:Comparison with non-demented cases and Alzheimer's disease

β-Amyloid (Aβ) deposition in regions of the temporal lobe in patients with dementia with Lewy bodies (DLB) was compared with elderly, non-demented (ND) cases and with Alzheimer's disease (AD). The distribution, density and clustering patterns of diffuse, primitive and classic Aβ deposits were similar in 'pure' DLB and ND cases. The distribution of Aβ deposits and the densities of the diffuse and primitive deposits were similar in 'mixed' DLB/AD cases compared with AD. However, the density of the classic deposits was significantly lower in DLB/AD compared with AD. In addition, the primitive Aβ deposits occurred more often in small, regularly spaced clusters in the tissue and less often in a single large cluster in DLB/AD compared with 'pure' AD. These results suggest that pure DLB and AD are distinct disorders which can coexist in some patients. However, the Aβ pathology of DLB/AD cases is not identical to that observed in patients with AD alone. (C) 2000 S. Karger AG, Basel.

Classic beta-amyloid deposits cluster around large diameter blood vessels rather than capillaries in sporadic Alzheimer's disease

Various hypotheses could explain the relationship between beta-amyloid (Abeta) deposition and the vasculature in Alzheimer's disease (AD). Amyloid deposition may reduce capillary density, affect endothelial cells of blood vessels, result in diffusion from blood vessels, or interfere with the perivascular clearance mechanism. Hence, the spatial pattern of the classic ('cored') type of Abeta deposit was studied in the upper laminae (I,II/III) of the superior frontal gyrus in nine cases of sporadic AD (SAD). Sections were immunostained with antibodies against Abeta and with collagen IV to study the relationships between the spatial distribution of the classic deposits and the blood vessel profiles. Both the classic deposits and blood vessel profiles were distributed in clusters. In all cases, there was a positive spatial correlation between the clusters of the classic deposits and the larger diameter (>10 microm) blood vessel profiles and especially the vertically penetrating arterioles. In only 1 case, was there a significant spatial correlation between the clusters of the classic deposits and the smaller diameter (<10 microm) capillaries. There were no negative correlations between the density of Abeta deposits and the smaller diameter capillaries. In 9/11 cases, the clusters of the classic deposits were significantly larger than those of the clusters of the larger blood vessel profiles. In addition, the density of the classic deposits declined as a negative exponential function with distance from a vertically penetrating arteriole. These results suggest that the classic Abeta deposits cluster around the larger blood vessels in the upper laminae of the frontal cortex. This aggregation could result from diffusion of proteins from blood vessels or from overloading the system of perivascular clearance from the brain.

The spatial patterns of beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex in Alzheimer's disease

In Alzheimer's disease (AD) brain, beta-amyloid (Abeta) deposits and neurofibrillary tangles (NFT) are not randomly distributed but exhibit a spatial pattern, i.e., a departure from randomness towards regularity or clustering. Studies of the spatial pattern of a lesion may contribute to an understanding of its pathogenesis and therefore, of AD itself. This article describes the statistical methods most commonly used to detect the spatial patterns of brain lesions and the types of spatial patterns exhibited by ß-amyloid deposits and NFT in the cerebral cortex in AD. These studies suggest that within the cerebral cortex, Abeta deposits and NFT exhibit a similar spatial pattern, i.e., an aggregation of individual lesions into clusters which are regularly distributed parallel to the pia mater. The location, size and distribution of these clusters supports the hypothesis that AD is a 'disconnection syndrome' in which degeneration of specific cortical pathways results in the formation of clusters of NFT and Abeta deposits. In addition, a model to explain the development of the pathology within the cerebral cortex is proposed.

The spatial pattern of discrete beta-amyloid deposits in Alzheimer's disease reflects synaptic disconnection

The spatial pattern of discrete beta-amyloid (A beta) deposits was studied in the superficial laminae of cortical fields of different types and in the hippocampus in 6 cases of Alzheimer's disease (AD). In 41/42 tissues examined, discrete A beta deposits were aggregated into clusters and in 34/41 tissues (25/34 of the cortical tissues), there was evidence for a regular periodicity of the A beta deposit clusters parallel to the tissue boundary. The dimensions of the clusters varied from 400 to > 12,800 microns in different tissues. Although the A beta deposit clusters were larger than predicted, the regular periodicity suggests that they develop in relation to groups of cells associated with specific projections. This would be consistent with the hypothesis that the distribution of discrete A beta deposits in AD could reflect progressive synaptic disconnection along interconnected neuronal pathways. This implies that amyloid deposition could be a response to, rather than a cause of, synaptic disconnection in AD.

Beta-amyloid deposition in the medial temporal lobe in elderly non-demented brains and in Alzheimer's disease

The density of diffuse, primitive, classic and compact β-amyloid (β/A4) deposits was estimated in the medial temporal lobe in elderly non-demented brains and in Alzheimer's disease (AD). In the non-demented cases, β/A4 deposits were absent in the hippocampus but in 8/14 cases they were present in the adjacent cortical regions. Variation in β/A4 deposition in the non-demented cases was large and overlapped with that of the AD cases. The ratio of mature to diffuse β/A4 deposits was greater in the non-demented than in the AD cases. In both the non-demented cases and AD, the β/A4 deposits were clustered with, in many tissues, a regular distribution of clusters along the cortex parallel to the pia. However, the mean cluster size of the deposits in the cortex was greater in AD than in the non-demented cases. These results suggest that the spread of β/A4 pathology between the modular units of the cortex and into the hippocampus could be important factors in the development of AD.

Dispersion of classic beta-amyloid deposits around blood vessels in Alzheimer’s disease

The spatial pattern of the classic (‘cored’) type of beta-amyloid (Abeta) deposit was studied in the upper laminae of the superior temporal gyrus in 9 cases of sporadic Alzheimer’s disease (SAD). Abeta stained tissue was counterstained with collagen IV to study the relationships between the spatial distribution of the classic deposits and the blood vessel profiles. Both the classic deposits and blood vessel profiles were distributed in clusters. In all cases, there was a spatial correlation between the clusters of the classic deposits and the larger diameter (>10 micron) blood vessel profiles and especially the vertically penetrating arterioles. In only 1 case, was there a significant spatial correlation between the clusters of the classic deposits and the smaller diameter (<10 micron) capillaries. In 9/11 cases, the clusters of the classic deposits were significantly larger than those of the clusters of the larger blood vessels. In addition, the density of the classic deposits declined as a negative exponential function with distance from the vertically penetrating arterioles. These results suggest that the classic Abeta deposits cluster around the larger blood vessels in the frontal cortex and that diffusion of proteins from these blood vessels could be involved in the pathogenesis of the classic deposits in SAD.

Changes in the clustering patterns of beta-amyloid (Abeta) with age in Down's syndrome

The spatial distribution patterns of the diffuse, primitive, and classic beta-amyloid (Abeta) deposits were studied in areas of the medial temporal lobe in 12 cases of Down's Syndrome (DS) 35 to 67 years of age. Large clusters of diffuse deposits were present in the youngest patients; cluster size then declined with patient age but increased again in the oldest patients. By contrast, the cluster sizes of the primitive and classic deposits increased with age to a maximum in patients 45 to 55 and 60 years of age respectively and declined in size in the oldest patients. In the parahippocampal gyrus (PHG), the clusters of the primitive deposits were most highly clustered in cases of intermediate age. The data suggest a developmental sequence in DS in which Abeta is deposited initially in the form of large clusters of diffuse deposits that are then gradually replaced by clusters of primitive and classic deposits. The oldest patients were an exception to this sequence in that the pattern of clustering resembled that of the youngest patients.

Distribution of A4 protein and neurofibrillary change in the hippocampus in Alzheimer's disease

The principal components of classical senile plaques (SP) in Alzheimer's disease (AD) appear to be A4/beta protein and paired helical filaments (PHF). A4 deposits may evolve into classical SP in brain regions vulnerable to the formation of PHF. We have investigated the diatribution of A4 deposits using an immunostain and the neurofibrillary change using the Gallyas stain in various regions of the hippocampus. This region is particularly affected in AD and also has relatively restricted inputs and outputs. In 6 patients we found a significant preponderance of A4 deposits in the adjacent parahippocampal gyrus (PHG) compared with all regions of the hippocampus. However, plaque-like clusters of PHF (Gallyas plaques) were more abundant in the subiculum while neurofibrillary tangles (NFT) were more abundant in the subiculum and region CA1 compared with the PHG and other hippocampal regions. Hence, A4 deposits appear to be concentrated in the region providing a major input into the hippocampus while the neurofibrillary changes are characteristic of the major output areas (subiculum and CA1). Hence, the data suggest that A4 formation and the neurofibrillary changes may occur in regions of the hippocampus that are connected anatomically.