Is the clustering of β-amyloid (Aβ) deposits in the frontal cortex of Alzheimer patients determined by blood vessels?

The clustering pattern of diffuse, primitive and classic β-amyloid (Aβ) deposits was studied in the upper laminae of the frontal cortex of 9 patients with sporadic Alzheimer's disease (AD). Aβ stained tissue was counterstained with collagen type IV antiserum to determine whether the clusters of Aβ deposits were related to blood vessels. In all patients, Aβ deposits and blood vessels were clustered, with in many patients, a regular periodicity of clusters along the cortex parallel to the pia. The classic Aβ deposit clusters coincided with those of the larger blood vessels in all patients and with clusters of smaller blood vessels in 4 patients. Diffuse deposit clusters were related to blood vessels in 3 patients. Primitive deposit clusters were either unrelated to or negatively correlated with the blood vessels in six patients. Hence, Aβ deposit subtypes differ in their relationship to blood vessels. The data suggest a direct and specific role for the larger blood vessels in the formation of amyloid cores in AD. © 1995.

Plasma antioxidant status, immunoglobulin G oxidation and lipid peroxidation in demented patients:Relevance to Alzheimer disease and vascular dementia

A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD, but there is a substantial lack of data regarding the simultaneous behavior of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobulin G (IgG) levels of protein carbonyls and dityrosine] in patients and controls. With the exception of β-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, AD patients showed a significantly higher IgG dityrosine content as compared to controls. AD and VaD patients showed similar plasma levels of plasma antioxidants and MDA as well as a similar IgG content of protein carbonyls and dityrosine. We conclude that, independent of its nature - vascular or degenerative - dementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development. Copyright © 2004 S. Karger AG, Basel.

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.

Do β-amyloid (Aβ) deposits in patients with Alzheimer's disease and Down's syndrome grow according to the log-normal model?

The size frequency distributions of diffuse, primitive and classic β- amyloid (Aβ) deposits were studied in single sections of cortical tissue from patients with Alzheimer's disease (AD) and Down's syndrome (DS) and compared with those predicted by the log-normal model. In a sample of brain regions, these size distributions were compared with those obtained by serial reconstruction through the tissue and the data used to adjust the size distributions obtained in single sections. The adjusted size distributions of the diffuse, primitive and classic deposits deviated significantly from a log-normal model in AD and DS, the greatest deviations from the model being observed in AD. More Aβ deposits were observed close to the mean and fewer in the larger size classes than predicted by the model. Hence, the growth of Aβ deposits in AD and DS does not strictly follow the log-normal model, deposits growing to within a more restricted size range than predicted. However, Aβ deposits grow to a larger size in DS compared with AD which may reflect differences in the mechanism of Aβ formation.

Visual field defects in Alzheimer's disease patients may reflect differential pathology in the primary visual cortex

The aim of this study was to test the hypothesis that differences in density of senile plaques (SP) and neurofibrillary tangles (NFT) in the cuneal and lingual gyri of area V1 of the visual cortex could explain the predominantly inferior visual field defects seen in patients with Alzheimer's disease (AD). The density of SP and NFT was measured in the cuneal and lingual gyri of 18 AD patients. In 7/18 (39%) patients, the density of SP and/or NFT was significantly greater in the cuneal compared with the lingual gyri. In 3/18 (17%) patients, densities were greater in the lingual than the cuneal gyri and in 8/18 (44%) patients there were no significant differences among gyri. The data suggest that pathological differences between cuneal and lingual gyri could contribute to the reported visual field defects in some AD patients.

Relationships between beta-amyloid (A beta) deposits and blood vessels in patients with sporadic and familial Alzheimer's disease

The density of diffuse, primitive and classic beta-amyloid (A beta) deposits was studied in relation to the incidence of blood vessels in the superior frontal gyrus of nine cases of sporadic Alzheimer's disease (SAD), two cases of familial Alzheimer's disease (FAD) with amyloid precursor protein (APP) mutations (APP717, Val --> Ile), and eight cases of FAD not linked to chromosomes 21, 14 or 1. Stepwise multiple regression was used to determine for each patient whether variations in the density of A beta deposits along the cortex were significantly correlated with the incidence of blood vessels. In the majority of FAD and SAD cases, the density of the diffuse and primitive type A beta deposits was not related to blood vessels. However, the incidence of the larger diameter (> 10 microns) blood vessels was positively correlated with the density of the classic A beta deposits in eight (89%) SAD and two (20%) FAD cases. The data suggest that the densities of vessels and deposits were not significantly correlated between cases but only within cases, suggesting a strictly local effect. In addition, the spatial association between classic A beta deposits and blood vessels may be more apparent in SAD compared with FAD cases.

β-Amyloid (Aβ) deposition in elderly non-demented patients and patients with Alzheimer's disease

β-amyloid (Aβ) deposition in the medial temporal lobe (MTL) was studied in elderly non-demented (ND) cases and in patients with Alzheimer's disease (AD). In AD, Aβ deposits were present throughout the MTL although density was less in the hippocampus than the adjacent cortical regions. In the ND cases, no Aβ deposits were recorded in 6 cases and in the remaining 8 cases, Aβ deposits were confined to the cortical regions adjacent to the hippocampus. The mean density of Aβ deposits in the cortical regions examined was greater in AD than in the ND cases but there was a significant overlap between the two groups. The ratio of mature to diffuse Aβ deposits was greater in the ND than the AD cases. In both patient groups, Aβ deposits formed clusters in the cortex and many tissues exhibited a regular distribution of clusters along the cortex parallel to the pia. The mean dimension of the Aβ clusters was greater in AD than in the ND cases. Hence, few aspects of Aβ deposition appeared to consistently separate AD from ND cases. However, the spread of Aβ pathology between modular units of the cortex and into regions of the hippocampus could be factors in the development of AD. © 1994.

Differences in β-amyloid ( β A4) deposition in human patients with Down's syndrome and sporadic Alzheimer's disease

The density of diffuse, primitive, classic and compact β-amyloid ( β A4) deposits was estimated in the hippocampus and adjacent gyri in human patients with Down's syndrome (DS) and sporadic Alzheimer's disease (AD). The objective of the study was to determine whether there were differences in β A4 deposition in DS and sporadic AD and whether these differences could be attributed to overexpression of the amyloid precursor gene (APP) in DS. Total β A4 deposit density was greater in DS than AD in all brain regions studied but the DS/AD density ratios varied between brain regions. In the majority of brain regions, the ratio of primitive to diffuse β A4 deposits was greater in DS but the ratio of classic to diffuse deposits was greater in AD. The data were consistent with the hypothesis that overexpression of the APP gene in DS may lead to increased β A4 deposition. However, local brain factors also appear to be important in β A4 deposition in DS. Overexpression of the APP gene may also be responsible for increased production of paired helical filaments (PHF) and result in enhanced formation of primitive β A4 deposits in DS. In addition, increased formation of classic deposits in AD suggests that factors necessary for the production of a compact amyloid core are enhanced in AD compared with DS. © 1994.

Is the clustering of neurofibrillary tangles in Alzheimer's patients related to the cells of origin of specific cortico-cortical projections?

The spatial pattern of cellular neurofibrillary tangles (NFT) was studied in the supra- and infragranular layers of various cortical regions in cases of Alzheimer's disease (AD). The objective was to test the hypothesis that NFT formation was associated with the cells of origin of specific cortico-cortical projections. The novel feature of the study was that pattern analysis enabled the dimension and spacing of NFT clusters along the cortical ribbon to be estimated. In the majority of brain regions studied, NFT occurred in clusters of neurons which were regularly spaced along the cortical strip. This pattern is consistent with the predicted distribution of the cells of origin of specific cortico-cortico projections. Mean NFT cluster size varied from 250 to > 12800 microns in different cortical tissues suggesting either variation in the size of the cell clusters or a dynamic process in the development of NFT in relation to these cell clusters. The formation of NFT in cell clusters which may give rise to the feed-forward and feed-back cortico-cortical projections suggests a possible route of spread of NFT pathology in AD between cortical regions and from the cortex to subcortical areas.

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 Alzheimer's 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.

Size frequency distribution of senile plaques in post-mortem brains of five patients with senile dementia of the Alzheimer type (SDAT)

Numerous senile plaques are one of the most characteristic histological findings in SDAT brains. Large classical plaques may develop from smaller uncored forms. There is no strong evidence that, once formed, plaques disappear from the tissue. We have examined cresyl-violet stained sections of the parahippocampal gyrus (PHG), hippocampus, frontal lobe and temporal lobe of five SDAT patients. The frequency of various sizes of plaques were determined in each of these brain regions. Statistical analysis showed that the ratio of large plaques to small plaques was greater in the hippocampal formation (especially the PHG) than in the neocortex. One explanation of these results is that plaques grow more rapidly in the hippocampal formation than elsewhere. Alternatively, if the rate of plaque growth is much the same in different brain regions, the data suggest that plaques develop first in the hippocampal formation (especially the PHG) and only later spread to the neocortex. This interpretation is also consistent with the theory that the neuropathology of SDAT spreads from the olfactory cortex via the hippocampal formation to the neocortex. Further development of this technique may help identify the site of the primary lesion in SDAT.

Principal components analysis of Alzheimer's disease based on neuropathological data: a study of 79 patients

A principal components analysis was carried out on neuropathological data collected from 79 cases of Alzheimer's disease (AD) diagnosed in a single centre. The purpose of the study was to determine whether on neuropathological criteria there was evidence for clearly defined subtypes of the disease. Two principal components (PC1 and PC2) were extracted from the data. PC1 was considerable more important than PC2 accounting for 72% of the total variance. When plotted in relation to the first two principal components the majority of cases (65/79) were distributed in a single cluster within which subgroupings were not clearly evident. In addition, there were a number of individual, mainly early-onset cases, which were neither related to each other nor to the main cluster. The distribution of each neuropathological feature was examined in relation to PC1 and 2, Disease onset, rhe degree of gross brain atrophy, neuronal loss and the devlopment of senile plaques (SP) and neurofibrillary tangles (NFT) were negatively correlated with PC1. The devlopment of SP and NFT and the degree of brain athersclerosis were positively correlated with PC2. These results suggested: 1) that there were different forms of AD but no clear division of the cases into subclasses could be made based on the neuropathological criteria used; the cases showing a more continuous distribution from one form to another, 2) that disease onset was an important variable and was associated with a greater development of pathological changes, 3) familial cases were not a distinct subclass of AD; the cases being widely distributed in relation to PC1 and PC2 and 4) that there may be two forms of late-onset AD whic grade into each other, one of which was associated with less SP and NFT development but with a greater degree of brain atherosclerosis.

The incidence of corpora amylacea (CA) in the optic nerve of patients with Alzheimer's disease

Corpora amylacea (CA) are spherical or ovoid bodies 50-50 microns in diameter. They have been described in normal elderly brain as well as in a number of neurodegenerative disorders. In this study, the incidence of CA in the optic nerves of Alzheimer's disease (AD) patients was compared with normal elderly controls. Samples of optic nerves (MRC Brain Bank, Institute of Psychiatry) were taken from 12 AD patients (age range 69-94 years) and 18 controls (43-82 years). Optic nerves were fixed in 2% buffered glutaraldehyde, post-fixed in osmium tetroxide, embedded in epoxy resin and then sectioned to a thickness of 2 microns. Sections were stained with toluidine blue. CA were present in all of the optic nerves examined. In addition, a number of similarly stained but more irregularly shaped bodies were present. Fewer CA were found in the optic nerves of AD patients compared with controls. By contrast, the number or irregularly shaped bodies was increased in AD. In AD, there may be a preferential decline in the large diameter fibres which may mediate the M-cell pathway. Hence, the decline in the incidence of CA in AD may be associated with a reduction in these fibres. It is also possible that the irregualrly shaped bodies are a degeneration product of the CA.

A quantitative analysis of optic nerve axons in elderly control subjects and patients with Alzheimer's disease

Objective: To study the density and cross-sectional area of axons in the optic nerve in elderly control subjects and in cases of Alzheimer's disease (AD) using an image analysis system. Methods: Sections of optic nerves from control and AD patients were stained with toluidine blue to reveal axon profiles. Results: The density of axons was reduced in both the center and peripheral portions of the optic nerve in AD compared with control patients. Analysis of axons with different cross-sectional areas suggested a specific loss of the smaller sized axons in AD, i.e., those with areas less that 1.99 μm2. An analysis of axons >11 μm2 in cross-sectional area suggested no specific loss of the larger axons in this group of patients. Conclusions: The data suggest that image analysis provides an accurate and reproducible method of quantifying axons in the optic nerve. In addition, the data suggest that axons are lost throughout the optic nerve with a specific loss of the smaller-sized axons. Loss of the smaller axons may explain the deficits in color vision observed in a significant proportion of patients with AD.

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 Alzheimer's 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. © 1995.