Correlations between the clustering patterns of the pathological changes in sporadic Creutzfeldt-Jakob disease

Correlations between the clustering patterns of the vacuolation ('spongiform change'), prion protein (PrP) deposits, and surviving neurons were studied in the cerebral cortex, hippocampus, and cerebellum in 11 cases of sporadic Creutzfeldt-Jakob disease (sCJD). Differences in the sizes of the clusters of vacuoles were observed between brain regions and in the cerebral cortex, between the upper and lower laminae. With the exception of the parietal cortex, mean cluster size of the vacuoles was similar to that of the PrP deposits in each brain area. Clusters of the vacuoles were spatially correlated with the density of surviving neurons and with the clusters of PrP deposits in 47% and 53% of cortical areas analysed respectively but there were few spatial correlation between the PrP deposits and the density of surviving neurons. The data suggest that the pathology of sCJD may spread through the brain via specific anatomical pathways. Development of the clusters of vacuoles is spatially related to surviving neurons while the appearance of clusters of PrP deposits is related to the development of the vacuolation.

The spatial patterns of prion protein deposits in Creutzfeldt-Jakob disease:Comparison with β-amyloid deposits in Alzheimer's disease

Similar pathological processes may be involved in the deposition of extracellular proteins in the brains of patients with Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD). Hence, this study compared the spatial patterns of prion protein (PrP) deposits in the cerebral cortex and hippocampus in cases of sporadic CJD with those of β-amyloid (Aβ) deposits in sporadic AD. PrP and Aβ deposits were aggregated into clusters and, in 90% of brain areas in CJD and 57% in AD, the clusters were regularly distributed parallel to the tissue boundary. In a significant proportion of cortical analyses, the mean diameter of the clusters of PrP and Aβ deposits were similar to those of the cells of origin of the cortico-cortical pathways. Aβ deposits in AD were distributed more frequently in larger-sized clusters than PrP deposits in CJD. In addition, in the hippocampus and dentate gyrus, clustering of Aβ deposits was observed in AD but PrP deposits were rare in these regions in CJD. The size, location and distribution of the extracellular protein deposits within the cortex of both disorders was consistent with the degeneration of the cortico-cortical pathways. Furthermore, spread of the pathology along these pathways may be a pathogenic feature common to CJD and AD. © 2001 Elsevier Science Ireland Ltd.

Patterns of phonological errors as a function of a phonological versus an articulatory locus of impairment

WWe present the case of two aphasic patients: one with fluent speech, MM, and one with dysfluent speech, DB. Both patients make similar proportions of phonological errors in speech production and the errors have similar characteristics. A closer analysis, however, shows a number of differences. DB's phonological errors involve, for the most part, simplifications of syllabic structure; they affect consonants more than vowels; and, among vowels, they show effects of sonority/complexity. This error pattern may reflect articulatory difficulties. MM's errors, instead, show little effect of syllable structure, affect vowels at least as much as consonants and, and affect all different vowels to a similar extent. This pattern is consistent with a more central impairment involving the selection of the right phoneme among competing alternatives. We propose that, at this level, vowel selection may be more difficult than consonant selection because vowels belong to a smaller set of repeatedly activated units.

Spatial patterns of β-amyloid (Aβ) deposits in familial and sporadic Alzheimer's disease

The spatial patterns of the diffuse, primitive, and classic β-amyloid (Aβ) deposits were compared in cortical regions in early-onset familial Alzheimer's disease (EO-FAD) linked to mutations of the amyloid precursor protein APP) or presenilin 1 (PSEN1) genes, late-onset familial AD (LO-FAD), and sporadic AD (SAD). The objective was to determine whether genetic factors influenced the spatial patterns of the Aβ deposits. Aβ deposits were distributed either in clusters which were regularly distributed parallel to the pia mater or in larger, non-regularly distributed clusters. There were no significant differences in spatial pattern of the diffuse deposits between patient groups but mean cluster size of the diffuse deposits was larger in FAD compared with SAD. Primitive Aβ deposits were more frequently distributed in regular clusters and less frequently distributed in large clusters in FAD compared with SAD. Classic Aβ deposits were more frequently distributed in regularly spaced clusters and less frequently distributed in large clusters in LO-FAD compared with EO-FAD. There were no significant differences in the spatial patterns or cluster sizes of Aβ deposits in cases classified according to apolipoprotein E (APOE) genotype. These results suggest (1) greater deposition of Aβ in the form of clusters of diffuse deposits in FAD, (2) a greater proportion of diffuse deposits may be converted to primitive deposits in SAD, (3) classic deposits are more widely distributed in EO-FAD, and (4) the presence of APOE allele ε4 has little effect on the spatial patterns of Aβ deposits.

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 patterns of beta-amyloid (Abeta) deposits in dementia with Lewy bodies and Alzheimer’s disease

The spatial patterns of diffuse, primitive and classic beta-amyloid (Abeta) deposits were studied in regions of the temporal lobe in cases of ‘pure’ Dementai with Lewy bodies (DLB), cases of DLB with associated Alzheimer’s disease (AD) (DLB/AD) and cases of ‘pure’ AD. Abeta deposits occurred in clusters in all patient groups. In the majority of brain areas studied, either a single large (=6400 micron) cluster of Abeta deposits was present or Abeta deposits occurred in smaller clusters which were regularly distributed parallel to the tissue boundary. No significant differences in the spatial patterns of Abeta deposits were observed in ‘pure’ DLB compared with DLB/AD. The spatial patterns of Abeta deposits in DLB/AD cases were generally similar to those observed in AD. However, in DLB/AD the primitive deposits occurred less often in a single large cluster and more often in smaller, regularly spaced clusters than in ‘pure’ AD. The data suggest a more specific pattern of degeneration associated with Abeta deposition in DLB/AD cases compared with ‘pure’ AD.

The spatial patterns of Lewy bodies, senile plaques, and neurofibrillary tangles in dementia with Lewy bodies

The spatial patterns of Lewy bodies (LB), senile plaques (SP), and neurofibrillary tangles (NFT) were studied in ubiquitin-stained sections of the temporal lobe in cases of dementia with Lewy bodies (DLB), which varied in the degree of associated Alzheimer's disease (AD) pathology. In all patients, LB, SP, and NFT developed in clusters and in a significant proportion of brain areas, the clusters exhibited a regular periodicity parallel to the tissue boundary. In the lateral occipitotemporal gyrus (LOT) and parahippocampal gyrus (PHG), the clusters of LB were larger than those of the SP and NFT but in the hippocampus, clusters of the three lesions were of similar size. Mean cluster size of the LB, SP, and NFT was similar in cases of DLB with and without significant associated AD pathology. LB density was positively correlated with SP and NFT density in 42 and 17% of brain areas analyzed, respectively, while SP and NFT densities were positively correlated in 7% of brain areas. The data suggest that LB in DLB exhibit similar spatial patterns to SP and NFT in AD and that SP and NFT exhibit similar spatial patterns in DLB and AD. In addition, in some instances, clusters of LB appeared to be more closely related spatially to the clusters of SP than to NFT.

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.

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.

The spatial patterns of beta-amyloid (Abeta) deposits in elderly non-demented patients and patients with Alzheimer’s disease

The spatial patterns of diffuse, primitive, classic and compact beta-amyloid (Abeta) deposits were studied in the medial temporal lobe in 14 elderly, non-demented patients (ND) and in nine patients with Alzheimer’s disease (AD). In both patient groups, Abeta deposits were clustered and in a number of tissues, a regular periodicity of Abeta deposit clusters was observed parallel to the tissue boundary. The primitive deposit clusters were significantly larger in the AD cases but there were no differences in the sizes of the diffuse and classic deposit clusters between patient groups. In AD, the relationship between Abeta deposit cluster size and density in the tissue was non-linear. This suggested that cluster size increased with increasing Abeta deposit density in some tissues while in others, Abeta deposit density was high but contained within smaller clusters. It was concluded that the formation of large clusters of primitive deposits could be a factor in the development of AD.

The spatial patterns of β/A4 deposit subtypes in Down's syndrome

The spatial patterns of diffuse, primitive and classic β/A4 deposits were studied in coronal sections of the hippocampus and adjacent gyri in 11 cases of Down's syndrome (DS) varying in age from 38 to 67 years. The objectives of the study were first, to compare the spatial patterns of β/A4 deposits revealed in DS with those reported in cases of Alzheimer's disease (AD) and second, to study how the spatial patterns of β/A4 deposits may develop in the tissue. The spatial patterns revealed in DS exhibited a number of similarities with those reported in AD: (1) the range and frequency of the different types of spatial pattern revealed were similar, (2) β/A4 deposits occurred in clusters and in many cortical tissues, the clusters were distributed in a regular pattern parallel to the pia, (3) the clusters of diffuse and primitive β/A4 deposits occurred in an alternating pattern along the cortex, and (4) the clusters of classic β/A4 deposits were not correlated with the clusters of the diffuse and primitive deposits. Primitive deposits may develop from the diffuse deposits in regions of the cortex where extracellular paired helical filaments were formed. However, clusters of the classic β/A4 deposits, which are formed in older cases, appear to develop independently of the diffuse and primitive deposits. © 1994 Springer-Verlag.

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.

The spatial arrangement patterns of senile plaques in senile dementia of the Alzheimer type (SDAT)

The spatial arrangement patterns of senile plaques have been studied in 10 micron cresyl violet stained sections cut from embedded portions of 20 brain regions from SDAT brains. Two studies are reported: an initial study using the Poisson distribution and a subsequent study using pattern analysis. The initial study indicated that plaques are arranged in discrete clumps in all brain regions when examined at x100 and x400 – suggesting that both small and larger scale clumping may be present. The pattern analysis study was applied to 8 cortical regions. This technique allows a more detailed study of pattern to be made. In all regions the technique revealed that the basic pattern of plaque arrangement is the regularly spaced discrete clump – which may be present on both large and small scales.