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

Measuring the spatial arrangement patterns of pathological lesions in histological sections of brain tissue

The development of abnormal protein aggregates in the form of extracellular plaques and intracellular inclusions is a characteristic feature of many neurodegenerative diseases such as Alzheimer's disease (AD), Creutzfeldt-Jakob disease (CJD) and the fronto-temporal dementias (FTD). An important aspect of a pathological protein aggregate is its spatial topography in the tissue. Lesions may not be randomly distributed within a histological section but exhibit spatial pattern, a departure from randomness either towards regularity or clustering. Information on the spatial pattern of a lesion may be useful in elucidating its pathogenesis and in studying the relationships between different lesions. This article reviews the methods that have been used to study the spatial topography of lesions. These include simple tests of whether the distribution of a lesion departs significantly from random using randomized points or sample fields, and more complex methods that employ grids or transects of contiguous fields and which can detect the intensity of aggregation and the sizes, distribution and spacing of the clusters. The usefulness of these methods in elucidating the pathogenesis of protein aggregates in neurodegenerative disease is discussed

A spatial pattern analysis of beta-amyloid (Abeta) deposition in the temporal lobe in Alzheimer's disease

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

Quantitative methods in neuropathology

The last decade has seen a considerable increase in the application of quantitative methods in the study of histological sections of brain tissue and especially in the study of neurodegenerative disease. These disorders are characterised by the deposition and aggregation of abnormal or misfolded proteins in the form of extracellular protein deposits such as senile plaques (SP) and intracellular inclusions such as neurofibrillary tangles (NFT). Quantification of brain lesions and studying the relationships between lesions and normal anatomical features of the brain, including neurons, glial cells, and blood vessels, has become an important method of elucidating disease pathogenesis. This review describes methods for quantifying the abundance of a histological feature such as density, frequency, and 'load' and the sampling methods by which quantitative measures can be obtained including plot/quadrat sampling, transect sampling, and the point-quarter method. In addition, methods for determining the spatial pattern of a histological feature, i.e., whether the feature is distributed at random, regularly, or is aggregated into clusters, are described. These methods include the use of the Poisson and binomial distributions, pattern analysis by regression, Fourier analysis, and methods based on mapped point patterns. Finally, the statistical methods available for studying the degree of spatial correlation between pathological lesions and neurons, glial cells, and blood vessels are described

β-amyloid (Aβ) deposition in cognitively normal brain, dementia with Lewy bodies, and Alzheimer's disease:a study using principal components analysis

The densities of diffuse, primitive, and classic ß-amyloid (Aß) deposits were studied in the temporal lobe in cognitively normal brain, dementia with Lewy bodies (DLB), familial Alzheimer’s disease (FAD), and sporadic AD (SAD). Principal components analysis (PCA) was used to determine whether there were distinct differences between groups or whether Aß pathology was more continuously distributed from group to group. Three principal components (PC) were extracted from the data accounting for 56% of the total variance. Plots of cases in relation to the PC did not result in distinct groups but suggested overlap in Aß deposition between the groups. In addition, there were linear correlations between the densities of Aß deposits and the distribution of the cases along the PC in specific brain regions suggesting continuous variation from group to group. PC1 was associated with the degree of maturation of Aß deposits, PC2 with differences between FAD and SAD, and PC3 with the degree of spread of Aß pathology into the hippocampus. Apolipoprotein E (APOE) genotype was not associated with variation in Aß deposition between cases. PCA may be a useful method of studying the pathological interface between closely related neurodegenerative disorders

Clustering and periodicity of neurofibrillary tangles in the upper and lower cortical laminae in Alzheimer's disease

In Alzheimer's disease (AD), neurofibrillary tangles (NFT) occur within neurons in both the upper and lower cortical laminae. Using a statistical method that estimates the size and spacing of NFT clusters along the cortex parallel to the pia mater, two hypotheses were tested: 1) that the cluster size and distribution of the NFT in gyri of the temporal lobe reflect degeneration of the feedforward (FF) and feedback (FB) cortico-cortical pathways, and 2) that there is a spatial relationship between the clusters of NFT in the upper and lower laminae. In 16 temporal lobe gyri from 10 cases of sporadic AD, NFT were present in both the upper and lower laminae in 11/16 (69%) gyri and in either the upper or lower laminae in 5/16 (31%) gyri. Clustering of the NFT was observed in all gyri. A significant peak-to-peak distance was observed in the upper laminae in 13/15 (87%) gyri and in the lower laminae in 8/ 12 (67%) gyri, suggesting a regularly repeating pattern of NFT clusters along the cortex. The regularly distributed clusters of NFT were between 500 and 800 μm in size, the estimated size of the cells of origin of the FF and FB cortico-cortical projections, in the upper laminae of 6/13 (46%) gyri and in the lower laminae of 2/8 (25%) gyri. Clusters of NFT in the upper laminae were spatially correlated (in phase) with those in the lower laminae in 5/16 (31%) gyri. The clustering patterns of the NFT are consistent with their formation in relation to the FF and FB cortico-cortical pathways. In most gyri, NFT clusters appeared to develop independently in the upper and lower laminae

Spatial relationships between diffuse prion protein deposits and neuronal perikarya in variant Creutzfeldt-Jakob disease

Two morphological types of prion protein (PrPsc) deposit occur in the cerebral cortex of cases of variant Creutzfeldt-Jakob disease (vCJD), viz., diffuse and florid deposits. The objective of this study was to determine whether diffuse-type PrPsc deposits in areas of the cerebral cortex in six cases of the variant form of CJD (vCJD) were spatially correlated with neurons and whether diffuse deposit size was related to the number of adjacent neurons contributing PrPsc. In cortical gyri, density of surviving neurons was 5.38-12.15 per 50 × 200 µm sample field, neurons being distributed randomly, regularly or were clustered relative to the pia mater. Density of neurons embedded within diffuse deposits, however, was three to eight times their overall density in the section. In addition, diffuse deposit area was positively correlated with the number of embedded neurons. The frequency distribution of diffuse deposits with 0, 1, 2, 3, …, n, embedded neurons did not deviate from a Poisson distribution. These results suggest: (1) diffuse deposits in vCJD develop in situ as a result of the formation of PrPsc in relation to clusters of neurons, (2) size of a diffuse deposit is determined by the number of adjacent neurons which develop PrPsc, and (3) the probability that PrPsc is formed in relation to one neuron is independent of that of its neighbour

A comparison of the spatial patterns of β-amyloid (Aβ) deposits in five neurodegenerative disorders

Alzheimer’s disease neuropathologic change (ADNC) in the form of β-amyloid (Aβ) deposits is important not only in the pathogenesis of Alzheimer’s disease (AD) and Down’s syndrome (DS) but also as a ‘co-pathology’ in disorders such as dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and chronic traumatic encephalopathy (CTE). To compare cortical and hippocampal degeneration in different disorders, the spatial patterns of the diffuse, primitive, and classic Aβ deposits were studied in regions of frontal and temporal cortex in five neurodegenerative disorders, viz. AD, DS, DLB, CBD, and CTE using spatial pattern analysis. In all disorders, the Aβ deposits were clustered and in a proportion of brain regions, the clusters were regularly distributed parallel to the tissue boundary. Cluster dimensions in the cortex, measured parallel to the pia mater, were frequently in the range 400-800 µm suggesting a spatial association with the cortico-cortical pathways. Differences were also observed among disorders, the diffuse Aβ deposits being more frequently distributed in regular clusters in AD while cluster sizes of the diffuse and primitive deposits were significantly smaller in CTE. The data suggest considerable similarities in the spatial patterns of Aβ deposits in different disorders, regardless of the clinical or pathological setting, which suggests that the spread of Aβ via neuro-anatomical pathways may be common to several disorders

What causes alzheimer's disease?

Since the earliest descriptions of Alzheimer's disease (AD), many theories have been advanced as to its cause. These include: (1) exacerbation of aging, (2) degeneration of anatomical pathways, including the cholinergic and cortico-cortical pathways, (3) an environmental factor such as exposure to aluminium, head injury, or malnutrition, (4) genetic factors including mutations of amyloid precursor protein (APP) and presenilin (PSEN) genes and allelic variation in apolipoprotein E (Apo E), (5) mitochondrial dysfunction, (6) a compromised blood brain barrier, (7) immune system dysfunction, and (8) infectious agents. This review discusses the evidence for and against each of these theories and concludes that AD is a multifactorial disorder in which genetic and environmental risk factors interact to increase the rate of normal aging ('allostatic load'). The consequent degeneration of neurons and blood vessels results in the formation of abnormally aggregated 'reactive' proteins such as ß-amyloid (Aß) and tau. Gene mutations influence the outcome of age-related neuronal degeneration to cause early onset familial AD (EO-FAD). Where gene mutations are absent and a combination of risk factors present, Aß and tau only slowly accumulate not overwhelming cellular protection systems until later in life causing late-onset sporadic AD (LO-SAD). Aß and tau spread through the brain via cell to cell transfer along anatomical pathways, variation in the pathways of spread leading to the disease heterogeneity characteristic of AD

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