Neuropathological changes in striate and extrastriate visual cortex in variant Creutzfeldt-Jakob disease (vCJD)

Pathological changes in striate (B17, V1) and extrastriate (B18, V2) visual cortex were studied in variant Creutzfeldt-Jakob disease (vCJD). No differences in densities of vacuoles or surviving neurons were observed in B17 and B18 but densities of glial cell nuclei and deposits of prion protein (PrP) were greater in B18. PrP deposit densities in B17 and B18 were positively correlated. Diffuse deposit density in B17 was negatively correlated with the density of surviving neurons in B18. The vacuoles either exhibited a density peak in laminae II/III and V/VI or were more uniformly distributed across the laminae. Diffuse deposits were most frequent in laminae II/III and florid 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 than in B17. Hence, both striate and extrastriate visual cortex is affected by the pathology of vCJD, the pathological changes being most severe in B18. Neuronal degeneration in B18 appears to be associated with diffuse PrP deposit formation 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.

Creutzfeldt-Jakob disease and vision

This review describes a group of diseases known as the transmissible spongiform encephalopathies (TSEs), which affect animals and humans. Examination of affected brain tissue suggests that these diseases are caused by the acquisition and deposition of prion protein (PrP). Creutzfeldt-Jakob disease (CJD) is the most important form of TSE in humans with at least four different varieties of the disease. Variant CJD (vCJD), a new form of the disease found in the UK, has several features that differ from the classical forms including early age of onset, longer duration of disease, psychiatric presentation (for example, depression) and extensive florid plaque development in the brain. About 10 per cent of patients with CJD exhibit visual symptoms at disease presentation and approximately 50 per cent during the course of the disease. The most commonly reported visual symptoms include diplopia, supranuclear palsies, complex visual disturbances, homonymous visual field defects, hallucinations and cortical blindness. Saccadic and smooth pursuit movements appear to be more rarely affected. The agent causing vCJD accumulates in lymphoid tissue such as the spleen and tonsils. The cornea has lymphoid tissue in the form of corneal dendritic cells that are important in the regulation of the immune response in the anterior segment of the eye. The presence of these cells in the cornea has raised the possibility of transmission between patients via optical devices that contact the eye. Although such transmission is theoretically possible it remains highly improbable.

Quantification of the pathological changes with laminar depth in the cortex in sporadic Creutzfeldt-Jakob disease

The laminar distribution of the vacuolation ('spongiform change'), surviving neurons, glial cell nuclei, and prion protein (PrP) deposits was studied in the frontal, parietal and temporal cortex in 11 cases of sporadic Creutzfeldt-Jakob disease (CJD). The distribution of the vacuolation was mainly bimodal with peaks of density in the upper and lower cortical laminae. The density of surviving neurons was greatest in the upper cortex while glial cell nuclei were distributed largely in the lower cortex. PrP deposits exhibited either a bimodal distribution or reached a maximum density in the lower cortex. The vertical density of the vacuoles was positively correlated with the surviving neurons in 12/44 of cortical areas studied, with glial cell nuclei in 16/44 areas and with PrP deposition in 15/28 areas. PrP deposits were positively correlated with glial cell nuclei in 12/31 areas. These results suggest that in sporadic CJD: (1) the lower cortical laminae are the most affected by the pathological changes; (2) the development of the vacuolation may precede that of the extracellular PrP deposits and the glial cell reaction; and (3) the pathological changes may develop initially in the lower cortical laminae and spread to affect the upper cortical laminae. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

Spatial correlations between the vacuolation, prion protein deposits, and surviving neurons in the cerebral cortex in sporadic Creutzfeldt-Jakob disease

In the cerebral cortex of cases of sporadic Creutzfeldt-Jakob disease (sCJD), the vacuolation (spongiform change) and PrP deposits are aggregated into clusters which are regularly distributed parallel to the pia mater. The objective of the present study was to determine the spatial relationships between the clusters of the vacuoles and PrP deposits and between the pathological changes and variations in the density of surviving neurons. In areas with low densities of pathological change, clusters of vacuoles were spatially correlated with the surviving neurons and not with the PrP deposits. By contrast, in more significantly affected areas, clusters of vacuoles were spatially correlated with those of the PrP deposits and not with the surviving neurons. In addition, areas with a high density of vacuoles and a low density of PrP deposits exhibited no spatial correlations between the variables. These data suggest that the spatial relationships between the vacuolation, PrP deposits and surviving neurons in sCJD depend on the density of lesions present. Differences in the pattern of correlation may reflect the developmental stage of the pathology in particular cortical areas.

Size frequency distributions of abnormal protein deposits in Alzheimer’s disease and variant Creutzfeldt-Jakob disease

TThe size frequency distributions of ß-amyloid (Aß) and prion protein (PrPsc) deposits were studied in Alzheimer’s disease (AD) and the variant form of Creutzfeldt-Jakob disease (vCJD) respectively. All size distributions were unimodal and positively skewed. Aß deposits reached a greater maximum size and their distributions were significantly less skewed than the PrPsc deposits. All distributions were approximately log-normal in shape but only the diffuse PrPsc deposits did not deviate significantly from a log-normal model. There were fewer larger classic Aß deposits than predicted and the florid PrPsc deposits occupied a more restricted size range than predicted by a log-normal model. Hence, Aß deposits exhibit greater growth than the corresponding PrPsc deposits. Surface diffusion may be particularly important in determining the growth of the diffuse PrPsc deposits. In addition, there are factors limiting the maximum size of the Aß and florid PrPsc deposits.

Size frequency distributions of the florid prion protein aggregates in variant Creutzfeldt-Jakob disease follow a power-law function

The objective was to test the hypothesis that the size frequency distributions of the prion protein (PrP) plaques in cases of variant Creutzfeldt-Jakob disease (vCJD) follow a power-law function. The design was a retrospective neuropathological study. The patients were 11 cases of clinically and neuropathologically verified vCJD. Size distributions of the diffuse and florid-type plaques were measured in several areas of the cerebral cortex and hippocampus from each case and a power-law function fitted to each distribution. The size distributions of the florid and diffuse plaques were fitted successfully by a powerlaw function in 100% and 42% of brain areas investigated respectively. Processes of aggregation/disaggregation may be more important than surface diffusion in the pathogenesis of the florid plaques. By contrast, surface diffusion may be a more significant factor in the development of the diffuse plaques. © Springer-Verlag Italia 2006.

Spatial correlations between the vacuolation, prion protein deposition and surviving neurons in variant Creutzfeldt-Jakob Disease (vCJD)

The histological features of cases of variant Creutzfeldt-Jakob disease (vCJD) are often distributed in the brain in clusters. This study investigated the spatial associations between the clusters of the vacuoles, surviving neurons, and prion protein (PrP) deposits in various brain areas in 11 cases of vCJD. Clusters of vacuoles and surviving neurons were positively correlated in the cerebral cortex but negatively correlated in the dentate gyrus. Clusters of the florid and diffuse type of PrP deposit were not positively correlated with those of either the vacuoles or the surviving neurons although a negative correlation was observed between the florid plaques and surviving neurons in some cortical areas. Clusters of the florid and diffuse deposits were either negatively correlated or uncorrelated. These data suggest: 1) that clusters of vacuoles in the cerebral cortex are associated with the presence of surviving neuronal cell bodies, 2) that the clusters of vacuoles are not spatially related to those of the PrP deposits, and 3) different factors are involved in the pathogenesis of the florid and diffuse PrP deposits.

Size frequency distribution of prion protein (PrP) aggregates in variant Creutzfeldt-Jakob disease (vCJD)

The frequency distribution of aggregate size of the diffuse and florid-type prion protein (PrP) plaques was studied in various brain regions in cases of variant Creutzfeldt-Jakob disease (vCJD). The size distributions were unimodal and positively skewed and resembled those of β-amyloid (Aβ) deposits in Alzheimer's disease (AD) and Down's syndrome (DS). The frequency distributions of the PrP aggregates were log-normal in shape, but there were deviations from the expected number of plaques in specific size classes. More diffuse plaques were observed in the modal size class and fewer in the larger size classes than expected and more florid plaques were present in the larger size classes compared with the log-normal model. It was concluded that the growth of the PrP aggregates in vCJD does not strictly follow a log-normal model, diffuse plaques growing to within a more restricted size range and florid plaques to larger sizes than predicted. © Springer-Verlag 2005.

Spatial patterns of the pathological changes in the cerebellar cortex in sporadic Creutzfeldt-Jakob disease (sCJD)

The spatial patterns of the vacuolation ("spongiform change"), surviving cells, and prion protein (PrP) deposition were studied in the various cell laminae of the cerebellar cortex in 11 cases of sporadic Creutzfeldt-Jakob disease (sCJD). Clustering of the histological features, with the clusters regularly distributed along the folia, was evident in all cell laminae. In the molecular layer, clusters of vacuoles coincided with the surviving Purkinje cells. In the granule cell layer, however, the spatial relationship between the vacuoles and surviving cells was more complex and varied between cases. PrP deposition was not spatially correlated with either the vacuoles or the surviving cells in any of the cerebellar laminae in the majority of cases. In some cases, there were spatial relationships between th histological features in the molecular and granule cell layers. The data suggest that degeneration of the cerebellar cortex in sCJD may occur in a topographic pattern consistent with the spread of prion pathology along anatomical pathways. The development of the vacuolation may be an early stage of the pathology in the cerebellum preceding the appearance of the PrP deposits. In addition, there is evidence that the pathological changes may spread across the different laminae of the cerebellar cortex.

Differences in the density and spatial distribution of florid and diffuse plaques in variant Creutzfeldt-Jakob disease (vCJD)

Objective: To determine whether in cases of variant Creutzfeldt-Jakob disease (vCJD), the florid-type plaques are derived from the diffuse plaques or whether the 2 plaque types develop independently. Material: Blocks of frontal, parietal, occipital and temporal neocortex and cerebellar cortex from 11 cases of vCJD. Method: The density, distribution and spatial pattern of the florid and diffuse plaques were determined in each brain region using spatial pattern analysis. Results: The density of the diffuse plaques was significantly greater than that of the florid plaques in most areas. The ratio of the diffuse to florid plaques varied between brain regions and was maximal in the molecular layer of the cerebellum. The densities of the florid and diffuse plaques were positively correlated in the parietal cortex, occipital cortex, the inferior temporal gyrus and the dentate gyrus. Plaque densities were not related to disease duration. In the cerebral cortex, the diffuse plaques were more commonly evenly distributed or occurred in large clusters along the cortex parallel to the pia mater compared with the florid plaques which occurred more frequently in regularly distributed clusters. Conclusion: The florid plaques may not be derived from the diffuse plaques, the 2 plaque types appearing to develop independently with unique factors involved in their pathogenesis.

A quantitative study of the pathological changes in cortical neurons in sporadic Creutzfeldt-Jakob disease

The frequency of morphological abnormalities in neuronal perikarya was studied in the cerebral cortex in cases of sporadic CJD (sCJD) and in elderly control patients. Three hypotheses were tested, namely that the proportion of neurons exhibiting abnormal morphology was increased: (i) in sCJD compared with control patients; (ii) in sCJD, in areas with significant prion protein (PrP) deposition compared with regions with little or no PrP deposition; and (iii) when neurons were spatially associated with a PrP deposit compared with neurons between PrP deposits. Changes in cell shape (swollen or atrophic cell bodies), nuclei (displaced, indistinct, shrunken or absent nuclei; absence of nucleolus), and cytoplasm (dense or pale cytoplasm, PrP positive cytoplasm, vacuolation) were commonly observed in all of the cortical areas studied in the sCJD cases. The proportion of neurons exhibiting each type of morphological change was significantly increased in sCJD compared with age-matched control cases. In sCJD, neuronal abnormalities were present in areas with little PrP deposition, but at significantly lower frequencies compared with areas with significant densities of PrP deposits. Abnormalities of cell shape, nucleus and the presence of cytoplasmic vacuolation were increased when the neurons were associated with a PrP deposit, but fewer of these neurons were PrP-positive compared with neurons between deposits. The data suggest significant neuronal degeneration in the cerebral cortex in sCJD in areas without significant PrP deposition and a further phase of neuronal degeneration associated with the appearance of PrP deposits.

Does the neuropathology of human patients with variant Creutzfeldt-Jakob disease reflect haematogenous spread of the disease?

To test the hypothesis that the distribution of the pathology in variant Creutzfeldt-Jakob disease (vCJD) represents haematogenous spread of the disease, we studied the spatial correlation between the vacuolation, prion protein (PrP) deposits, and the blood vessel profiles in the cerebral cortex, hippocampus, dentate gyrus, and cerebellum of 11 cases of the disease. In the majority of areas, there were no significant spatial correlations between either the vacuolation or the diffuse type of PrP deposit and the blood vessels. By contrast, a consistent pattern of spatial correlation was observed between the florid PrP deposits and blood vessels mainly in the cerebral cortex. The frequency of positive spatial correlations was similar in different anatomical areas of the cerebral cortex and in the upper compared with the lower laminae. Hence, with the exception of the florid deposits, the data do not demonstrate a spatial relationship between the pathological features of vCJD and blood vessels. The spatial correlation of the florid deposits and blood vessels may be attributable to factors associated with the blood vessels that promote the aggregation of PrP to form a condensed core rather than reflecting the haematogenous spread of the disease. © 2003 Elsevier Ireland Ltd. All rights reserved.

Pathological changes in the primary visual cortex (area V1) in sporadic Creutzfeldt-Jakob disease

Purpose. To determine the degree of pathological change in the primary visual cortex (area V1) in patients with Creutzfeldt-Jakob disease. Method. The vacuolation, surviving neurons, glial cells, and deposits of prion protein were quantified in area V1 obtained postmortem in nine cases of the sporadic type of Creutzfeldt-Jakob disease. Results. Variations in the density of glial cells and in prion protein deposition were particularly evident between patients. In the upper and lower cortical laminae, vacuoles and prion protein deposits were regularly distributed in clusters with a mean dimensions of 450 to 1000 µm. Vacuolation in area V1 was most severe in lamina III and the glial cell reaction in lamina V or VI. Surviving neurons were most abundant in lamina II or III, whereas prion protein deposition either affected all laminae equally or was maximal in lamina II or III. Conclusion. The data suggest that pathological changes in area V1 in sporadic type of Creutzfeldt-Jakob disease may affect the transmission of visual information from area V1 to V2 and to subcortical visual areas. In addition, the data suggest an association between the developing pathology and the functional domains of area V1.

Florid prion protein (PrP) plaques in patients with variant Creutzfeldt-Jakob disease (vCJD) are spatially related to blood vessels

This study tested the hypothesis that variations in the density of the florid prion protein (PrP) plaques in the brain of patients with variant Creutzfeldt-Jakob disease (vCJD) were spatially related to blood vessels. In 81% of areas of the cerebral cortex sampled and in 37% of the remaining areas, which included the hippocampus, dentate gyrus, and cerebellum, there was a positive spatial correlation between the density of the florid plaques and the larger blood vessel profiles. The frequency of the positive spatial correlations was similar in different anatomical areas of the cerebral cortex and in the upper compared with the lower cortical laminae. The data support the hypothesis that the florid plaques cluster around the larger blood vessels in vCJD, the density of associated plaques increasing with vessel size. The development of florid plaques close to blood vessels may be due to factors associated with the blood vessels that enhance the aggregation of PrP to form the dense cores of florid plaques and is unlikely to reflect the haematogenous spread of PrP into the brain.

Laminar distribution of the pathological changes in the cerebral cortex in variant Creutzfeldt-Jakob disease (vCJD)

To determine the pattern of cortical degeneration in cases of variant Creutzfeldt-Jakob disease (vCJD), the laminar distribution of the vacuolation ("spongiform change"), surviving neurones, glial cell nuclei, and prion protein (PrP) deposits was studied in the frontal, parietal and temporal lobes. The vacuolation exhibited two common patterns of distribution: either the vacuoles were present throughout the cortex or a bimodal distribution was present with peaks of density in the upper and lower cortical laminae. The distribution of the surviving neurones was highly variable in different regions; the commonest pattern being a uniform distribution with cortical depth. Glial cell nuclei were distributed largely in the lower cortical laminae. The non-florid PrP deposits exhibited either a bimodal distribution or exhibited a peak of density in the upper cortex while the florid deposits were either uniformly distributed down the cortex or were present in the upper cortical laminae. In a significant proportion of areas, the density of the vacuoles was positively correlated with either the surviving neurones or with the glial cell nuclei. These results suggest similarities and differences in the laminar distributions of the pathogenic changes in vCJD compared with cases of sporadic CJD (sCJD). The laminar distribution of vacuoles was more extensive in vCJD than in sCJD whereas the distribution of the glial cell nuclei was similar in the two disorders. In addition, PrP deposits in sCJD were localised mainly in the lower cortical laminae while in vCJD, PrP deposits were either present in all laminae or restricted to the upper cortical laminae. These patterns of laminar distribution suggest that the process of cortical degeneration may be distinctly different in vCJD compared with sCJD.