55 resultados para spatial patterns


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The transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) is an RNA binding protein encoded by the TARDPB gene. Abnormal aggregations of TDP-43 in neurons in the form of neuronal cytoplasmic inclusions (NCI) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of TDP-43 in FTLD-TDP, the spatial patterns of the NCI were studied in frontal and temporal cortex of FTLD-TDP cases using a phosphorylation dependent anti-TDP-43 antibody (pTDP-43). In many regions, the NCI formed clusters and the clusters were distributed regularly parallel to the tissue boundary. In about 35% of cortical regions, cluster size of the NCI was within the size range of the modular columns of the cortex. The spatial patterns of the pTDP-immunoreactive inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody and also similar to inclusions characterized by other molecular pathologies such as tau, ?-synuclein and ‘fused in sarcoma’ (FUS). In conclusion, the data suggest degeneration of cortical and hippocampal anatomical pathways associated with accumulation of cellular pTDP-43 is characteristic of FTLD-TDP. In addition, the data are consistent with the hypothesis of cell to cell transfer of pTDP-43 within the brain.

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Abnormal protein aggregates of transactive response (TAR) DNA-binding protein (TDP-43) in the form of neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal internuclear inclusions (NII), and dystrophic neurites (DN) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of phosphorylated TDP-43 (pTDP-43) in neurodegeneration in FTLD-TDP, the spatial patterns of the pTDP-43-immunoreactive NCI, GI, NII, and DN were studied in frontal and temporal cortex in three groups of cases: (1) familial FTLD-TDP caused by progranulin (GRN) mutation, (2) a miscellaneous group of familial cases containing cases caused by valosin-containing protein (VCP) mutation, ubiquitin associated protein 1 (UBAP1) mutation, and cases not associated with currently known genes, and (3) sporadic FTLD-TDP. In a significant number of brain regions, the pTDP-43-immunoreactive inclusions developed in clusters and the clusters were distributed regularly parallel to the tissue boundary. The spatial patterns of the inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody. The spatial patterns and cluster sizes of the pTDP-43-immunoreactive inclusions were similar in GRN mutation cases, remaining familial cases, and in sporadic FTLD-TDP. Hence, pathological changes initiated by different genetic factors in familial cases and by unknown causes in sporadic FTLD-TDP appear to follow a parallel course resulting in very similar patterns of degeneration of frontal and temporal lobes.

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The spatial patterns of β-amyloid (Aβ) 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 Aβ 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 Aβ deposits exhibited a similar range of spatial patterns but the classic Aβ deposits occurred less frequently in large clusters >6400m. In addition, the NFT often occurred in larger regularly distributed clusters than the Aβ deposits. The location, size, and distribution of the clusters of Aβ 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 Aβ deposits. © 2011 Nova Science Publishers, Inc.

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The tauopathies are a major molecular group of neurodegenerative disorders characterised by the deposition of abnormal cellular aggregates of the microtubule associated protein (MAP) tau in the form of neuronal cytoplasmic inclusions (NCI). Recent research suggests that cell to cell propagation of pathogenic tau may be involved in the neurodegeneration of these disorders. If pathogenic tau spreads along anatomical pathways it may give rise to specific spatial patterns of the NCI in brain tissue. To test this hypothesis, the spatial patterns of NCI in cerebral cortical regions were compared in tissue sections taken from five major tauopathies: (1) argyrophilic grain disease (AGD), (2) Alzheimer's disease (AD), (3) corticobasal degeneration (CBD), (4) Pick's disease (PiD), and (5) progressive supranuclear palsy (PSP). In the cerebral cortex of these disorders, NCI were frequently aggregated into clusters and the clusters were regularly distributed parallel to the pia mater. In a significant proportion of regions, the mean size of the regularly distributed clusters of NCI was in the range 400 – 800 m, measured parallel to the pia mater, approximating to the dimension of cell columns associated with the cortico-cortical anatomical pathways. Hence, the data suggest that cortical NCI in the tauopathies exhibit a spatial pattern in the cortex which could result from the spread of pathogenic tau along anatomical pathways. Treatments designed to protect the cortex from tau propagation may therefore be applicable across several different disorders within this molecular group.

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The spatial pattern of the vacuolation ('spongiform change') was studied in areas of the cerebral cortex in 11 cases of variant Creutzfeldt-Jakob disease (vCJD). The vacuoles were evenly distributed along the cortex in 40/106 (38%) areas studied and randomly distributed in 6/106 (5.6%) areas. In 22/106 (21%) areas, the vacuoles were aggregated into clusters, 50 - 1600 μm in diameter and which were distributed in a regular pattern parallel to the pia mater. In 38/106 (36%) areas, large clusters of vacuoles, at least 1600 μm in diameter, were present. No significant differences in spatial patterns were observed between the different cortical regions or between the upper and lower laminae. In addition, age at onset and duration of the disease had no significant affect on spatial patterns. The spatial distribution of the vacuolation contrasts with that reported in sporadic CJD (sCJD) suggesting a different pattern of cortical degeneration in vCJD.

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The spatial patterns of senile plaques (SP) and neurofibrillary tangles (NFT) as visualised using the Gallyas stain and of discrete A4 protein deposits were determined in coronal serial sections from a variety of brain regions in six elderly patients with Alzheimer's disease (AD). These lesions showed clustering in virtually all tissues examined with many of the clusters being regularly spaced. These spatial patterns were compared with the clustering observed for SP and NFT stained by the Glees and Marsland method in the same tissues. The data suggest that on average, while the regular clusters of A4 deposits and NFT were of approximately the same mean diameter (3600 microns), clusters of both Glees and Gallyas SP were approximately half this diameter (1800 - 2000 microns). If SP develop in local areas of the brain where both A4 deposition and neurofibrillary changes have occurred, the data suggest that the SP clusters would represent the region of overlap of the A4 deposits and neurofibrillary changes. Various hypothese are advocated to explain the regular clsuetring of the A4 deposits.

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The spatial patterns of discrete beta-amyloid (Abeta) deposits in brain tissue from patients with Alzheimer disease (AD) were studied using a statistical method based on linear regression, the results being compared with the more conventional variance/mean (V/M) method. Both methods suggested that Abeta deposits occurred in clusters (400 to <12,800 mu m in diameter) in all but 1 of the 42 tissues examined. In many tissues, a regular periodicity of the Abeta deposit clusters parallel to the tissue boundary was observed. In 23 of 42 (55%) tissues, the two methods revealed essentially the same spatial patterns of Abeta deposits; in 15 of 42 (36%), the regression method indicated the presence of clusters at a scale not revealed by the V/M method; and in 4 of 42 (9%), there was no agreement between the two methods. Perceived advantages of the regression method are that there is a greater probability of detecting clustering at multiple scales, the dimension of larger Abeta clusters can be estimated more accurately, and the spacing between the clusters may be estimated. However, both methods may be useful, with the regression method providing greater resolution and the V/M method providing greater simplicity and ease of interpretation. Estimates of the distance between regularly spaced Abeta clusters were in the range 2,200-11,800 mu m, depending on tissue and cluster size. The regular periodicity of Abeta deposit clusters in many tissues would be consistent with their development in relation to clusters of neurons that give rise to specific neuronal projections.

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The spatial patterns of the diffuse, primitive, and classic beta-amyloid (Abeta) deposits was studied in the frontal and temporal cortex in cases of Alzheimer’s disease (AD) expressing different apolipoprotein (Apo E) genotypes. No significant differences in the density of the three Abeta deposit subtypes were observed in individuals expressing genotypes e2/3 and e3/3 compared with those expressing e3/4 and e4/4. In all patients, Abeta deposit subtypes occurred in the tissue in clusters. Chi-square contingency analyses of the data suggested that the cluster size of the diffuse and classic Abeta deposits was unrelated to Apo E genotype. However, the primitive (‘neuritic’) type Abeta deposits occurred more frequently in smaller, denser clusters in individuals expressing genotypes e3/4 and e4/4 compared with those expressing e2/3 and e3/3. Hence, the presence of the e4 allele may be associated with a more specific pattern of neuronal degeneration in the frontal and temporal cortex in AD.

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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.

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To determine the factors influencing the distribution of -amyloid (Abeta) deposits in Alzheimer's disease (AD), the spatial patterns of the diffuse, primitive, and classic A deposits were studied from the superior temporal gyrus (STG) to sector CA4 of the hippocampus in six sporadic cases of the disease. In cortical gyri and in the CA sectors of the hippocampus, the Abeta deposits were distributed either in clusters 200-6400 microm in diameter that were regularly distributed parallel to the tissue boundary or in larger clusters greater than 6400 microm in diameter. In some regions, smaller clusters of Abeta deposits were aggregated into larger 'superclusters'. In many cortical gyri, the density of Abeta deposits was positively correlated with distance below the gyral crest. In the majority of regions, clusters of the diffuse, primitive, and classic deposits were not spatially correlated with each other. In two cases, double immunolabelled to reveal the Abeta deposits and blood vessels, the classic Abeta deposits were clustered around the larger diameter vessels. These results suggest a complex pattern of Abeta deposition in the temporal lobe in sporadic AD. A regular distribution of Abeta deposit clusters may reflect the degeneration of specific cortico-cortical and cortico-hippocampal pathways and the influence of the cerebral blood vessels. Large-scale clustering may reflect the aggregation of deposits in the depths of the sulci and the coalescence of smaller clusters.

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Corticobasal degeneration (CBD) is a rare, progressive movement disorder characterized neuropathologically by widespread neuronal and glial pathology including tau-immunoreactive neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), and astrocytic plaques (AP). However, ß -amyloid (A ß) deposits have been observed in the cerebral cortex and/or hippocampus in some cases of CBD. To clarify the role of Aß deposition in CBD, the densities and spatial patterns of the Aß deposits were studied in three cases. In two cases, expressing apolipoprotein E (APOE) genotypes 2/3 or 3/3, the densities of the Aß deposits were similar to those in normal elderly brain. In the remaining case, expressing APOE genotype 3/4, Aß deposition was observed throughout the cerebral cortex, sectors CA1 and CA2 of the hippocampus, and the molecular layer of the dentate gyrus. The densities of the Aß deposits in this case were typical of those observed in Alzheimer's disease (AD). In the three cases, clustering of Aß deposits, with clusters ranging in size from 200 to >6400 µm in diameter, was evident in 25/27 (93%) of analyses. In addition, the clusters of Aß deposits were regularly distributed parallel to the tissue boundary in 52% of analyses, a spatial pattern similar to that observed in AD. These results suggest: (1) in some CBD cases, Aß pathology is age-related, (2) more extensive Aß deposition is observed in some cases, the density and spatial patterns of the Aß deposits being similar to AD, and (3) extensive deposition of Aß in CBD may be associated with APOE allele e4.

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To determine the factors influencing the distribution of β-amyloid (Aβ) deposits in Alzheimer's disease (AD), the spatial patterns of the diffuse, primitive, and classic Aβ deposits were studied from the superior temporal gyrus (STG) to sector CA4 of the hippocampus in six sporadic cases of the disease. In cortical gyri and in the CA sectors of the hippocampus, the Aβ deposits were distributed either in clusters 200-6400 μm in diameter that were regularly distributed parallel to the tissue boundary or in larger clusters greater than 6400 μm in diameter. In some regions, smaller clusters of Aβ deposits were aggregated into larger 'superclusters'. In many cortical gyri, the density of Aβ deposits was positively correlated with distance below the gyral crest. In the majority of regions, clusters of the diffuse, primitive, and classic deposits were not spatially correlated with each other. In two cases, double immunolabelled to reveal the Aβ deposits and blood vessels, the classic Aβ deposits were clustered around the larger diameter vessels. These results suggest a complex pattern of Aβ deposition in the temporal lobe in sporadic AD. A regular distribution of Aβ deposit clusters may reflect the degeneration of specific cortico-cortical and cortico-hippocampal pathways and the influence of the cerebral blood vessels. Large-scale clustering may reflect the aggregation of deposits in the depths of the sulci and the coalescence of smaller clusters.

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In patients with Pick's disease (PD), high densities of tau positive Pick bodies (PB) have been observed within the granule cell layer of the dentate gyrus. This study investigated the spatial patterns of PB along the granule cell layer in coronal sections of the hippocampus in eight patients with PD. In all patients, there was evidence of clustering of PB within the granule cell layer; however, there was considerable variation in the pattern of clustering. In five patients, the clusters of PB were regularly distributed along the dentate gyms, and in two of these patients, the smaller clusters were aggregated into larger superclusters. In three patients, a single large cluster of PB, more than 1200 μm in diameter, was present. Clustering of PB may reflect a primary degenerative process within the granule cells or the degeneration of pathways that project to the dentate gyrus.

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Dementia with neurofilament inclusions (DNI) is a new disorder characterized clinically by early-onset dementia and histologically by the presence of intraneural inclusions immunopositive for neurofilament antigens but lacking tau and α-synuclein reactivity. We studied the clustering patterns of the neurofilament inclusions (NI) in regions of the temporal lobe in three cases of DNI to determine whether they have the same spatial patterns as inclusions in the tauopathies and α-synucleinopathies. The NI exhibited a clustered distribution (mean size of clusters 400 μm, range 50-800 μm, SD 687.8) in 24/28 of the areas studied. In 22 of these areas, the clusters exhibited a regular distribution along the tissue parallel to the pia mater or alveus. In 3 cortical areas, there was evidence of a more complex pattern in which the NI clusters were aggregated into larger superclusters. In 6 cortical areas, the size of the clusters approximated to those of the cells of origin of the cortico-cortical pathways but in the remaining areas cluster size was smaller than 400 μm. Despite the unique molecular profile of the NI, their spatial patterns are similar to those shown by filamentous neuronal inclusions in the tauopathies and α-synucleinopathies.

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Clustering of Pick bodies (PB) was studied in the frontal and temporal lobe in 10 cases of Pick's disease (PD). Pick bodies exhibited clustering in 47/50 (94%) brain areas analysed. In 20/50 (40%) brain areas, PB were present in a single large cluster ≤ 6400 μm in diameter, in 27/50 (54%) PB occurred in smaller clusters (200-3200 μm in diameter) which exhibited a regular periodicity relative to the tissue boundary, in 1/50 (2%) there was a regular distribution of individual PB and in 2/50 (4%), PB were randomly distributed. Mean cluster size of the PB was greater in the dentate gyrus compared with the inferior temporal gyrus and lateral occipitotemporal gyrus. Mean cluster size of PB in a brain region was positively correlated with the mean density of PB. Hence, PB exhibit essentially the same spatial patterns as senile plaques and neurofibrillary tangles in Alzheimer's disease (AD) and Lewy bodies in Dementia with Lewy bodies (DLB).