The spatial patterns of prion protein deposits in cases of variant Creutzfeldt-Jakob disease

The spatial patterns of the prion protein (PrP) deposits were studied in immunostained sections of areas of the cerebral cortex, hippocampus, dentate gyrus, and the molecular layer of the cerebellum in 11 cases of variant Creutzfeldt-Jakob disease (vCJD). Clustering of PrP deposits, with a regular distribution of the clusters parallel to the tissue boundary, was the most common spatial pattern observed. Two morphological types of PrP deposit were recognised, those consisting of a condensed core (florid deposits) and those deposits lacking a condensed core (non-florid deposits). The florid and non-florid PrP deposits exhibited a different profile of spatial patterns. First, the florid deposits exhibited a regularly distributed pattern of clusters more frequently than the non-florid deposits. Second, the florid deposits formed larger clusters (greater than1,600 µm in diameter) less frequently than the non-florid deposits. In the areas of the cerebral cortex that exhibited a regular distribution of PrP deposit clusters, the cluster size of the deposits approximated that of the groups of cells of the cortico-cortical pathway origin in only 12% of analyses. No significant differences in the frequency of the different types of spatial pattern were observed in different brain regions, or in the cerebral cortex between the upper and lower laminae. It was concluded that the spatial patterns of the PrP deposits in the cerebral cortex in vCJD are unlikely to reflect the degeneration of the cortico-cortical pathways as has been reported in sporadic CJD (sCJD). In addition, different factors could be involved in the development of the deposits with and without a condensed core.

Quantification of vacuolation ('spongiform change'), surviving neurones and prion protein deposition in eleven cases of variant Creutzfeldt-Jakob disease

Vacuolation ('spongiform change') and prion protein (PrP) deposition were quantified in the cerebral cortex, hippocampus, dentate gyrus and molecular layer of the cerebellum in 11 cases of variant Creutzfeldt-Jakob disease (vCJD). The density of vacuoles was greater in the cerebral cortex compared to the hippocampus, dentate gyrus and cerebellum. Within the cortex, vacuole density was significantly greater in the occipital compared to the temporal lobe and the density of surviving neurones was greatest in the occipital lobe. The density of the non-florid PrP plaques was greater in the cerebellum compared to the other brain areas. There were significantly more florid-type PrP plaques in the cerebral cortex compared to the hippocampus and the molecular layer of the cerebellum. No significant correlations were observed between the densities of the vacuoles and the PrP plaques. The densities of vacuoles in the parietal cortex and the non-florid plaques in the frontal cortex were positively correlated with the density of surviving neurones. The densities of the florid and the non-florid plaques were positively correlated in the parietal cortex, occipital cortex, inferior temporal gyrus and dentate gyrus. The data suggest: (i) vacuolation throughout the cerebral cortex, especially in the occipital lobe, but less evident in the hippocampus and molecular layer of the cerebellum; (ii) the non-florid plaques are more common than the florid plaques and predominate in the molecular layer of the cerebellum; and (iii) either the florid plaques develop from the non-florid plaques or both types are morphological variants resulting from the same degenerative process.

Laminar distribution of the pathological changes in sporadic and variant Creutzfeldt-Jakob disease

The laminar distributions of the pathological changes in the cerebral cortex were compared in the prion diseases sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). First, in some cortical regions the vacuolation (‘spongiform change’) was more generally distributed across the cortex in sCJD. Second, there was greater neuronal loss in the upper cortex in vCJD and in the lower cortex in sCJD. Third, the ‘diffuse’ and ‘florid’ prion protein (PrPsc) deposits were more frequently distributed in the upper cortex in vCJD and the ‘synaptic’ deposits in the lower cortex in sCJD. Fourth, there was a significant gliosis mainly affecting the lower cortex of both disorders. The data suggest that the pattern of cortical degeneration is different in sCJD and vCJD which may reflect differences in aetiology and the subsequent spread of prion pathology in the brain.

Expression of the human cachexia-associated protein (HCAP) in prostate cancer and in a prostate cancer animal model of cachexia

Prostate cancer (CaP) patients with disseminated disease often suffer from severe cachexia, which contributes to mortality in advanced cancer. Human cachexia-associated protein (HCAP) was recently identified from a breast cancer library based on the available 20-amino acid sequence of proteolysis-inducing factor (PIF), which is a highly active cachectic factor isolated from mouse colon adenocarcinoma MAC16. Herein, we investigated the expression of HCAP in CaP and its potential involvement in CaP-associated cachexia. HCAP mRNA was detected in CaP cell lines, in primary CaP tissues and in its osseous metastases. In situ hybridization showed HCAP mRNA to be localized only in the epithelial cells in CaP tissues, in the metastatic foci in bone, liver and lymph node, but not in the stromal cells or in normal prostate tissues. HCAP protein was detected in 9 of 14 CaP metastases but not in normal prostate tissues from cadaveric donors or patients with organ-confined tumors. Our Western blot analysis revealed that HCAP was present in 9 of 19 urine specimens from cachectic CaP patients but not in 19 urine samples of noncachectic patients. HCAP mRNA and protein were also detected in LuCaP 35 and PC-3M xenografts from our cachectic animal models. Our results demonstrated that human CaP cells express HCAP and the expression of HCAP is associated with the progression of CaP and the development of CaP cachexia. © 2003 Wiley-Liss, Inc.

Pathological changes in the sporadic and variant forms Of Creutzfeldt-Jakob Disease (CJD) are spatially related to blood vessels

The objective of this article was to determine whether the pathological changes of Creutzfeldt-Jacob disease (CJD) were related to the brain microcirculation. Hence, the spatial correlations between the vacuolation, prion protein (PrP) deposits, and the blood vessel profiles were studied in immunolabelled sections of the cerebral cortex, hippocampus, and cerebellum in two subtypes of CJD, viz., sporadic CJD (sCJD) and variant CJD (vCJD). In sCJD, both the vacuolation and the ‘synaptic-type’ PrP deposits were spatially correlated with the microvessels; the PrP deposits being more strongly correlated than the vacuoles. In vCJD, there were no significant spatial correlations between either the vacuolation or the diffuse-type of PrP deposit and the microvessels. By contrast, a consistent pattern of spatial correlation was observed in gyri of the cerebral cortex between the florid PrP deposits and microvessels. In both sCJD and vCJD, the frequency of positive spatial correlations was similar in the different gyri of the cerebral cortex and in the upper compared with the lower laminae. In conclusion, the microcirculation may be more significantly involved in determining the pathological changes in sCJD than in vCJD. The spatial correlations of the florid PrP deposits in vCJD and the synaptic deposits in sCJD and the blood vessels may be attributable to factors associated with the microcirculation which enhance the aggregation of PrP molecules rather than representing a possible haematogenous spread of the disease. S

Quantitative variations in the pathology of 11 cases of variant Creutzfeldt-Jakob disease (vCJD)

Quantitative variations in the density and distribution of the vacuolation ('spongiform change'), surviving neurons, and prion protein (PrP) deposits were studied in eight brain regions from 11 cases of variant Creutzfeldt-Jakob disease (vCJD). Principal components analysis (PCA) was used to study the similarities and differences between cases and to identify the neuropathological variables which could best account for these variations. Two principal components (PC) were extracted from the data accounting in total for 93.4% of the variance; the majority of the variance (90%) being associated with PC1. Some clustering of the 11 cases in relation to PC1 and PC2 was evident. The densities of the vacuolation in the occipital cortex and the molecular layer of the cerebellum were positively and negatively correlated, respectively, with PC1. No significant variation between cases was associated with PrP deposition. These data suggest that vCJD cases have a consistent neuropathological profile characterised by the presence of vacuolation, neuronal loss and PrP deposition in the form of florid and non-florid deposits. However, there are quantitative variations between cases in the development of the vacuolation especially affecting the occipital cortex and cerebellum. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Initiation and progression of ossification of the posterior longitudinal ligament of the cervical spine in the hereditary spinal hyperostotic mouse (twy/twy)

Ossification of the posterior longitudinal ligament (OPLL) is a significantly critical pathology that can eventually cause serious myelopathy. Ossification commences in the vertebral posterior longitudinal ligaments, and intensifies and spreads with the progression of the disease, resulting in osseous projections and compression of the spinal cord. However, the paucity of histological studies the underlying mechanisms of calcification and ossification processes remain obscure. The pathological process could be simulated in the ossifying process of the ligament in mutant spinal hyperostotic mouse (twy/twy). The aim of this study is to observe that enlargement of the nucleus pulposus followed by herniation, disruption and regenerative proliferation of annulus fibrosus cartilaginous tissues participated in the initiation of ossification of the posterior longitudinal ligament of twy/twy mice.

Modelling growth of prion protein aggregates in the brain in variant Creutzfeldt-Jakob disease

Deposition of insoluble prion protein (PrP) in the brain in the form of protein aggregates or deposits is characteristic of the ‘transmissible spongiform encephalopathies’ (TSEs). Understanding the growth and development of PrP aggregates is important both in attempting to elucidate the pathogenesis of prion disease and in the development of treatments designed to inhibit the spread of prion pathology within the brain. Aggregation and disaggregation of proteins and the diffusion of substances into the developing aggregates (surface diffusion) are important factors in the development of protein deposits. Mathematical models suggest that if either aggregation/disaggregation or surface diffusion is the predominant factor, then the size frequency distribution of the resulting protein aggregates will be described by either a power-law or a log-normal model respectively. This study tested this hypothesis for two different populations of PrP deposit, viz., the diffuse and florid-type PrP deposits characteristic of patients with variant Creutzfeldt-Jakob disease (vCJD). The size distributions of the florid and diffuse deposits were fitted by a power-law function in 100% and 42% of brain areas studied respectively. By contrast, the size distributions of both types of aggregate deviated significantly from a log-normal model in all areas. Hence, protein aggregation and disaggregation may be the predominant factor in the development of the florid deposits. A more complex combination of factors appears to be involved in the pathogenesis of the diffuse deposits. These results may be useful in the design of treatments to inhibit the development of PrP aggregates in vCJD.

Dispersion of prion protein deposits around blood vessels in variant Creutzfeldt-Jakob disease

In variant Creutzfeldt-Jakob disease (vCJD), a disease linked to bovine spongiform encephalopathy (BSE), florid-type prion protein (PrP(sc)) deposits are aggregated around the larger diameter (> 10 µm) cerebral microvessels. Clustering of PrP(sc) deposits around blood vessels may result from blood-borne prions or be a consequence of the cerebral vasculature influencing the development of the florid deposits. To clarify the factors involved, the dispersion of the florid PrP(sc) deposits was studied around the larger diameter microvessels in the neocortex, hippocampus, and cerebellum of ten cases of vCJD. In the majority of brain regions, florid deposits were clustered around the larger diameter vessels with a mean cluster size of between 50 µm and 628 µm. With the exception of the molecular layer of the dentate gyrus, the density of the florid deposits declined as a negative exponential function of distance from a blood vessel profile suggesting that diffusion of molecules from blood vessels is a factor in the formation of the florid deposits. Diffusion of PrP(sc) directly into the brain via the microvasculature has been demonstrated in vCJD in a small number of cases. However, the distribution of the prion deposits in vCJD is more likely to reflect molecular 'chaperones' diffusing from vessels and promoting the aggregation of pre-existing PrP(sc) in the vicinity of the vessels to form florid deposits.

A quantitative study of the pathological changes in the cortical white matter in variant Creutzfeldt-Jakob disease (vCJD).

Objective: To quantify cortical white matter pathology in variant Creutzfeldt-Jakob disease (vCJD) and to correlate white and grey matter pathologies. Methods: Pathological changes were studied in immunolabeled sections of the frontal, parietal, occipital, and temporal cortex of eleven cases of vCJD. Results: Vacuolation ("spongiform change"), deposition of the disease form of prion protein (PrPsc), and a glial cell reaction were observed in the white matter. The density of the vacuoles was greatest in the white matter of the occipital cortex and glial cell density in the inferior temporal gyrus (ITG). Florid-type PrPsc deposits were present in approximately 50% of white matter regions studied. In the white matter of the frontal cortex (FC), vacuole density was negatively correlated with the densities of both glial cell nuclei and PrPsc deposits. In addition, in the frontal and parietal cortices the densities of glial cells and PrPsc deposits were positively correlated. In the FC and ITG, there was a negative correlation between the densities of the vacuoles in the white matter and the number of surviving neurons in laminae V/VI of the adjacent grey matter. In the FC, vacuole density in the white matter was negatively correlated with the density of the diffuse PrPsc deposits in laminae II/III and V/VI of the adjacent grey matter. In addition, the densities of PrPsc deposits in the white matter of the FC were positively correlated with the density of the diffuse PrPsc deposits in laminae II/III and V/VI and with the number of surviving neurons in laminae V/VI. Conclusion: The data suggest significant degeneration of cortical white matter in vCJD; the vacuolation being related to neuronal loss in the lower cortical laminae of adjacent grey matter, PrPsc deposits the result of leakage from damaged axons, and gliosis a reaction to these changes.

Pathological changes in the sporadic and variant forms of Creutzfeldt-Jakob Disease (CJD) are spatially related to blood vessels

The objective of this article was to determine whether the pathological changes of Creutzfeldt-Jacob disease (CJD) were related to the brain microcirculation. Hence, the spatial correlations between the vacuolation, prion protein (PrP) deposits, and the blood vessel profiles were studied in immunolabelled sections of the cerebral cortex, hippocampus, and cerebellum in two subtypes of CJD, viz., sporadic CJD (sCJD) and variant CJD (vCJD). In sCJD, both the vacuolation and the ‘synaptic-type’ PrP deposits were spatially correlated with the microvessels; the PrP deposits being more strongly correlated than the vacuoles. In vCJD, there were no significant spatial correlations between either the vacuolation or the diffuse-type of PrP deposit and the microvessels. By contrast, a consistent pattern of spatial correlation was observed in gyri of the cerebral cortex between the florid PrP deposits and microvessels. In both sCJD and vCJD, the frequency of positive spatial correlations was similar in the different gyri of the cerebral cortex and in the upper compared with the lower laminae. In conclusion, the microcirculation may be more significantly involved in determining the pathological changes in sCJD than in vCJD. The spatial correlations of the florid PrP deposits in vCJD and the synaptic deposits in sCJD and the blood vessels may be attributable to factors associated with the microcirculation which enhance the aggregation of PrP molecules rather than representing a possible haematogenous spread of the disease.

The neuropathology of the occipital cortex and its significance in the visual problems of patients with variant Creutzfeldt-Jakob disease (vCJD)

The occipital lobe is one of the cortical areas most affected by the pathology of variant Creutzfeldt-Jakob disease (vCJD). To understand the visual problems of vCJD patients, neuropathological changes were studied in striate (B17, V1) and extrastriate (B18, V2) regions of the occipital cortex in eleven cases of vCJD. No differences in the density of vacuoles or surviving neurons were observed in B17 and B18 but densities of glial cell nuclei and deposits of the protease resistant form of prion protein (PrPsc) were greater in B18. The density of PrPsc deposits in B17 was positively correlated with their density in B18. The density of the diffuse PrPsc deposits in B17 was negatively correlated with the density of the surviving neurons in B18. In B17 and B18, the vacuoles either exhibited density peaks in laminae II/III and V/VI or were more uniformly distributed across the laminae. Diffuse PrPsc deposits were most frequent in laminae II/III and florid PrPsc deposits more generally distributed. In B18, the surviving neurons were more consistently bimodally distributed and the glial cell nuclei most abundant in laminae V/VI compared with B17. Hence, both striate and extrastriate areas of the occipital cortex are affected by the pathology of vCJD, the pathological changes being most severe in B18. Neuronal degeneration in B18 may be associated with the development of diffuse PrPsc deposits in B17. These data suggest that the short cortico-cortical connections between B17 and B18 and the pathways to subcortical visual areas are compromised in vCJD. Pathological changes in striate and extrastriate regions of the occipital cortex may contribute to several of the visual problems identified in patients with vCJD including oculomotor and visuo-spatial function.

Density and spatial pattern of the neuropathological changes in the cerebellum in the prion disease variant Creutzfeldt-Jakob disease (vCJD)

The objective of this chapter is to quantify the neuropathology of the cerebellar cortex in cases of the prion disease variant Creutzfeldt-Jakob disease (vCJD). Hence, sequential sections of the cerebellum of 15 cases of vCJD were stained with H/E, or immunolabelled with a monoclonal antibody 12F10 against prion protein (PrP) and studied using quantitative techniques and spatial pattern analysis. A significant loss of Purkinje cells was evident in all cases. Densities of the vacuolation and the protease resistant form of prion protein (PrPSc) in the form of diffuse and florid plaques were greater in the granule cell layer (GL) than the molecular layer (ML). In the ML, vacuoles and PrPSc plaques, occurred in clusters which were regularly distributed along the folia, larger clusters of vacuoles and diffuse plaques being present in the GL. There was a negative spatial correlation between the vacuoles and the surviving Purkinje cells in the ML and a positive spatial correlation between the clusters of vacuoles and the diffuse PrPSc plaques in the ML and GL in five and six cases respectively. A canonical variate analysis (CVA) suggested a negative correlation between the densities of the vacuolation in the GL and the diffuse PrPSc plaques in the ML. The data suggest: 1) all laminae of the cerebellar cortex were affected by the pathology of vCJD, the GL more severely than the ML, 2) the pathology was topographically distributed especially in the Purkinje cell layer and GL, 3) pathological spread may occur in relation to a loop of anatomical projections connecting the cerebellum, thalamus, cerebral cortex, and pons, and 4) there are differences in the pathology of the cerebellum in vCJD compared with the M/M1 subtype of sporadic CJD (sCJD).

The neuropathology of the occipital cortex and its significance in the visual problems of patients with variant Creutzfeldt-Jakob Disease (vCJD)

The occipital lobe is one of the cortical areas most affected by the pathology of variant Creutzfeldt-Jakob disease (vCJD). To understand the visual problems of vCJD patients, neuropathological changes were studied in striate (B17, V1) and extrastriate (B18, V2) regions of the occipital cortex in eleven cases of vCJD. No differences in the density of vacuoles or surviving neurons were observed in B17 and B18 but densities of glial cell nuclei and deposits of the protease resistant form of prion protein (PrPsc) were greater in B18. The density of PrPsc deposits in B17 was positively correlated with their density in B18. The density of the diffuse PrPsc deposits in B17 was negatively correlated with the density of the surviving neurons in B18. In B17 and B18, the vacuoles either exhibited density peaks in laminae II/III and V/VI or were more uniformly distributed across the laminae. Diffuse PrPsc deposits were most frequent in laminae II/III and florid PrPsc deposits more generally distributed. In B18, the surviving neurons were more consistently bimodally distributed and the glial cell nuclei most abundant in laminae V/VI compared with B17. Hence, both striate and extrastriate areas of the occipital cortex are affected by the pathology of vCJD, the pathological changes being most severe in B18. Neuronal degeneration in B18 may be associated with the development of diffuse PrPsc deposits in B17. These data suggest that the short cortico-cortical connections between B17 and B18 and the pathways to subcortical visual areas are compromised in vCJD. Pathological changes in striate and extrastriate regions of the occipital cortex may contribute to several of the visual problems identified in patients with vCJD including oculomotor and visuo-spatial function. © 2012 Nova Science Publishers, Inc. All rights reserved.

Associations between glia, neurons and prion protein (PrPsc) deposits in variant Creutzfeldt-Jakob disease (vCJD)

Glia may be important in the pathology of variant Creutzfeldt-Jakob disease (vCJD) in several ways: (1) glial cells could be involved in the formation of prion protein (PrPsc) deposits, (2) PrPsc deposits could stimulate the production of astrocytes and microglia, (3) PrPsc deposits could damage adjacent glial cells, and (4) glial cells could remove PrPsc from the brain. To investigate the significance of glial cells in vCJD, the relationships between PrPsc deposits and their associated glia, together with neurons and blood vessels, was studied in six cases of vCJD. Multicentric PrPsc deposits were the largest and least frequent type of deposit observed and were more commonly associated with glial cells, neuronal perikarya, and blood vessels than the more common diffuse and florid PrPsc deposits. Diffuse PrPsc deposits were more frequently associated with glial cells and neurons than the florid deposits. The ratio of astrocytes to oligodendrocytes adjacent to PrPsc deposits was similar to normal brain but the ratio of astrocytes and oligodendrocytes to microglia was less than in normal brain. The intensity of immunolabelling of multicentric PrPsc deposits was positively correlated with the presence of associated vacuoles and negatively correlated with the frequency of microglia. The patterns of correlation between deposit morphology and associated glial cells and neurons were similar for the diffuse and florid type PrPsc deposits. Deposit size was most consistently correlated with the number of associated neurons and vacuoles. The data suggest in vCJD: (1) no evidence that glia were necessary for the formation of PrPsc deposits, (2) an increase in microglia which may be an attempt to remove PrPsc from the bain, and (3) PrPsc deposits could affect adjacent astrocytes and damage the blood brain barrier (BBB).