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 Alzheimer's 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.

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 Alzheimer's 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.

The visual complications of Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder affecting middle-aged and elderly people. The disorder is of particular interest to Optometrists because it is associated with a range of visual problems including defects in eye movement and pupillary function. This article reviews the visual complications of PD and the pathological changes in the eye and brain which may explain these symptoms.

Clustering patterns of neurofibrillary tangles in Alzheimer’s disease

Clustering of cellular neurofibrillary tangles (NFT) was studied in the cerebral cortex and hippocampus in cases of Alzheimer’s disease (AD) using a regression method. The objective of the study was to test the hypothesis that clustering of NFTs reflects the degeneration of the cortico-cortical pathways. In 25/38 (66%) of analyses of individual brain areas, a significant peak to trough and peak to peak distance was obtained suggesting that the clusters of NFTs were regularly distributed in bands parallel to the tissue boundary. In analyses of cortical tissues with regularly distributed clusters, peak to peak distance was between 1000 and 1600 microns in 13/24 (54%) of analyses, >1600 microns in 10/24 (42%) and <1000 microns in 1/24 (4%) of analyses. A regular distribution of NFT clusters was less evident in the CA sectors of the hippocampus than in the cortex. Hence, in a significant proportion of brain areas, the spacing of NFT clusters along the cerebral cortex was consistent with the predicted distribution of the cells of origin of specific cortico-cortical projections. However, in many brain regions, the sizes of the NFT clusters were larger than predicted which may be attributable to the spread of NFTs to adjacent groups of cells as the disease progresses.

The spatial patterns of Pick bodies, Pick cells and Alzheimer’s disease pathology in Pick’s disease

The spatial patterns of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) were studied in the frontal and temporal lobe in nine cases of Pick’s disease (PD). Pick bodies exhibited clustering in 41/44 (93%) of analyses and clusters of PB were regularly distributed parallel to the tissue boundary in 24/41 (58%) of analyses. Pick cells exhibited clustering with regular periodicity of clusters in 14/16 (88%) analyses, SP in three out of four (75%) analyses and NFT in 21/27 (78%) analyses. The largest clusters of PB were observed in the dentate gyrus and PC in the frontal cortex. In 10/17 (59%) brain areas studied, a positive or negative correlation was observed between the densities of PB and PC. The densities of PB and NFT were not significantly correlated in the majority of brain areas but a negative correlation was observed in 7/29 (24%) brain areas. The data suggest that PB and PC in patients with PD exhibit essentially the same spatial patterns as SP and NFT in Alzheimer’s disease (AD) and Lewy bodies (LB) in dementia with Lewy bodies (DLB). In addition, there was a spatial correlation between the clusters of PB and PC, suggesting a pathogenic relationship between the two lesions. However, in the majority of tissues examined there was no spatial correlation between the clusters of PB and NFT, suggesting that the two lesions develop in association with different populations of neurons.

Are neuritic plaques in Alzheimer’s disease related to neurofibrillary tangles?

The density and spatial patterns of neuritic plaques (NP) and cellular neurofibrillary tangles (cNFT) were studied in various brain regions in cases of Alzheimer’s disease. The objective was to test the hypothesis that NP develop from cNFT. cNFT were most abundant in the cornu Ammonis (CA) region of the hippocampus while NP were most abundant in gyri adjacent to the hippocampus. The density of NP in a brain region was positively correlated with the density of cNFT. In 83% of brain regions examined, NP occurred in clusters and in 51% the clusters exhibited a regular periodicity parallel to the tissue boundary. cNFT were clustered in 97% of brain regions, 61% exhibiting a regular periodicity. Mean cluster size of NP in a brain region was not significantly correlated with the cluster size of the cNFT. In most cortical regions, clusters of NP and cNFT were spatially unrelated to each other. However, coincident clusters of NP and cNFT were observed in the CA region of the hippocampus in 4/5 patients. It was concluded that the spatial patterns of the NP and cNFT clusters were not consistent with the hypothesis that the majority of NP evolved from cNFT.

The levels of neopterin, biopterin and the neopterin/biopterin ratio in urine from control subjects and patients with Alzheimer’s disease and Down’s syndrome

The levels of neopterin, biopterin and the neopterin/biopterin ratio (N/B) were measured in urine samples taken from normal young and elderly control subjects, exceptionally healthy elderly control subjects classified according to the ‘Senieur’ protocol and patients with Down’s syndrome (DS) or Alzheimer’s disease (AD). The N/B ratio was approximately unity in control groups with the exception of the normal elderly controls. The levels of neopterin and biopterin declined with age in the exceptionally healthy ‘Senieur’ control group. The N/B ratio was elevated in young and old DS patients as a result of the significant increase in neopterin. Neopterin levels were significantly elevated in AD patients compared with the healthy elderly controls, but this did not result in a significant increase in the N/B ratio in these patients. The N/B ratio increased with age in AD patients as a result of a decline in biopterin. These results suggested that there is a cellular immune reponse in DS and AD patients which in DS, may precede the formation of beta-amyloid deposits in the brain. In addition, there may be a deficiency in tetrahydrobiopterin biosynthesis in AD which becomes more marked with age.

A comparison of βamyloid (aβ deposition in the medial temporal lobe in late-onset sporadic Alzheimer's disease, and down's syndrome

The density of diffuse, primitive, classic and compact βamyloid (Aβ deposits was estimated in regions of the medial temporal lobe (MTL) in 15 cases of late-onset sporadic Alzheimer's disease (AD) and 12 cases of Down's syndrome (DS). A similar pattern of Aβ deposition was observed in the MTL in the AD and DS cases with a reduced density of deposits in the hippocampus compared with the adjacent cortical regions. Total Aβ deposit density was greater in DS than in AD in all brain regions examined. This could be attributable to overexpression of the amyloid precursor protein gene. The ratio of the primitive to the diffuse Aβ deposits was greater in DS than in AD which suggests that the formation of mature amyloid deposits is enhanced in DS. The diffuse deposits exhibited a parabolic and the primitive deposits an inverted parabolic response with age in the DS cases. This suggests either that the diffuse and primitive deposits are sequentially related or that there are alternate pathways of Aβ deposition. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Elevated urinary neopterin suggests immune activation in Alzheimer’s disease and Down’s syndrome

Neopterin, an unconjugated pteridine, is secreted in large quantities by activated macrophages and can be used as a clinical marker of activated cellular immunity in a patient. Hence, neopterin levels were measured in urine samples taken from patients with Down’s syndrome (DS), non-hospitalized and hospitalized Alzheimer’s disease (AD) and age and sex matched controls. All subjects and patients were free from infectious and malignant disease. A significant effect of age on urinary neopterin levels was found in control subjects, levels being greater in younger and older subjects. No significant trends with age were found in AD and DS patients. The mean level of neopterin was significantly increased in DS and AD compared with age matched controls suggesting immune activation in these patients. In DS, elevated neopterin levels were present in individuals at least 17yrs old suggesting that immune activation could be associated with the initial deposition of beta/A4 in the brain.

The usefulness of spatial pattern analysis in understanding the pathogenesis of neurodegenerative disorders, with particular reference to plaque formation in Alzheimer's disease

Discrete, microscopic lesions are developed in the brain in a number of neurodegenerative diseases. These lesions may not be randomly distributed in the tissue but exhibit a spatial pattern, i.e., a departure from randomness towards regularlity or clustering. The spatial pattern of a lesion may reflect its development in relation to other brain lesions or to neuroanatomical structures. Hence, a study of spatial pattern may help to elucidate the pathogenesis of a lesion. A number of statistical methods can be used to study the spatial patterns of brain lesions. They range from simple tests of whether the distribution of a lesion departs from random to more complex methods which can detect clustering and the size, distribution and spacing of clusters. This paper reviews the uses and limitations of these methods as applied to neurodegenerative disorders, and in particular to senile plaque formation in Alzheimer's disease.

The spatial patterns of beta/A4 deposit subtypes and blood vessels in Alzheimer's disease cases with pronounced congophilic angiopathy

The spatial patterns of diffuse, primitive and classic beta/A4 deposits was studied in relation to blood vessels in 24 cortical tissues from five elderly cases of Alzheimer's disease with pronounced congophilic angiopathy (CA). Beta/A4 deposit subtypes and beta/A4 stained blood vessels were clustered in the tissue. In many instances, the clusters of beta/A4 deposits and blood vessels were regularly spaced along the cortical strip. Total beta/A4 deposits were positively correlated with blood vessels in five tissues only. Similarly, clusters of diffuse and primitive beta/A4 subtypes were each positively correlated with blood vessels in two brain regions. By contrast, clusters of classic beta/A4 deposits were positively correlated with blood vessels in 62% of the cortical tissues examined. These results suggest that in patients with significant CA, initial deposition of beta/A4 protein was unrelated to blood vessels. However, clusters of classic beta/A4 deposits appeared to be in phase with clusters of blood vessels along the cortex.

Alzheimer's disease: Are cellular neurofibrillary tangles linked to beta/A4 formation at the projection sites?

The density of senile plaques (SP) and cellular neurofibrillary tabgles (NFT) revealed by the Glees and Gallyas stains; and beta/A4 deposits revealed by immunocytochemical staining, was estimated in the hippocampus and adjacent gyri in Alzheimer's disease (AD). Stepwise multiple regression was used to detemine whether the density of cellular NFT was related to the density of SP or beta/A4 deposits totalled over the projection sites. Cellular NFT density was only weakly correlated with the density of Glees SP and beta/A4 deposits at some of the projection sites. However, beta/A4 deposit density in a tissue was strongly correlated with the density of beta/A4 deposits at the projection sites suggesting that the lesions could spread through the brain. Hence, although there is a strong correlation between the density of beta/A4 deposits in different parts of the hippocampal formation there is little association between SP or beta/A4 and cellular NFT. These results do not provide strong evidence that beta/A4 protein is the cause of the neuritc changes in AD.

The relationship between senile plaques, neurofibrillary tangles and amyloid (A4) deposits in Alzheimer’s disease: A Principal Components Analysis

A Principal Components Analysis (PCA) was carried out on the density of lesions revealed by different stains in a total of 47 brain regions from six elderly patients with Alzheimer’s disease (AD). The aim was to determine the relationships between the density of senile plaques (SP) revealed by the Glees and Gallyas stains and A4 deposits and between the plaques and neurofibrillary tangles (NFT) in the same brain region. The analysis indicated that the populations of plaques revealed by the Glees and Gallyas stains were closely related to the A4 protein deposits but none of the lesions were related to NFT. The data suggest: 1) that neocortical regions differ from the hippocampus in the relative development of A4 and NFT; the former having more A4 deposits and the latter more NFT and 2) that the processes that lead to the formation of SP and NFT occur independently of each other in the same brain region.

The relationship between the spatial pattern of senile plaques and neurofibrillary tangles in Alzheimer's disease

The topographic pattern of senile plaques (SP) and neurofibrillary tangles (NFT) was studied in silver stained coronal sections of neocortex and hippocampus in ten cases of Alzheimer's disease (AD). Both lesions showed evidence of clustering in the tissue with many of the clusters being regularly spaced. The patterns of SP and NFT were compared 1) in the same cortical zone, 2) between upper and lower zones of the cortex and 3) in regions connected by either association fibres or the perforant path. Correlations between the lesions in the same cortical zone were found in 20% of the layers examined while correlations between upper and lower zones occurred in 64% of cortical regions examined. There was evidence that NFT in upper and lower cortex may be in register in some tissues. In addition, positive correlations were found between upper NFT and lower SP and negative correlations between upper SP and lower NFT in some tissues. Regular clustering of lesions was also observed in brain regions connected to one another suggesting that they develop on functinally related sets of neurons.

Neuropathological changes in the visual cortex in Alzheimer's disease

A survey of 106 cases of Alzheimer's disease (AD) indicated that senile plaques (SP) and neurofibrillary tangles (NFT) were recorded as frequent or abundant in the visual cortex in 72% and 27% of cases respectively. Comparable estimates for other brain regions were 89% for both lesions in temporal cortex and 94% and 95% respectively in the hippocampus. In 18 cases studied in detail, the density of SP and NFT was greater in B19/18 than in B17 in cases with early onset and short duration. The density of SP and NFT in B17, B18/19 and parietal cortex was negatively correlated with age at death of the patient but not with duration of the disease. In about 50% of tissue sections examined SP and NFT were clustered at a particular depth in the cortex. Clustering was more frequent in the upper layers of the cortex and in early onset cases. It was concluded that visual stimuli that evoke activity in different areas of visual cortex might be developed as a diagnostic test for early onset AD.