Hippocampal pathology in progressive supranuclear palsy (PSP): a quantitative study of 8 cases.

OBJECTIVE: To quantify the neuronal and glial cell pathology in the hippocampus and the parahippocampal gyrus (PHG) of 8 cases of progressive supranuclear palsy (PSP). MATERIAL: tau-immunolabeled sections of the temporal lobe of 8 diagnosed cases of PSP. METHOD: The densities of lesions were measured in the PHG, CA sectors of the hippocampus and the dentate gyrus (DG) and studied using spatial pattern analysis. RESULTS: Neurofibrillary tangles (NFT) and abnormally enlarged neurons (EN) were most frequent in the PHG and in sector CA1 of the hippocampus, oligodendroglial inclusions ("coiled bodies") (GI) in the PHG, subiculum, sectors CA1 and CA2, and neuritic plaques (NP) in sectors CA2 and CA4. The DG was the least affected region. Vacuolation and GI were observed in the alveus. No tufted astrocytes (TA) were observed. Pathological changes exhibited clustering, the lesions often exhibiting a regular distribution of the clusters parallel to the tissue boundary. There was a positive correlation between the degree of vacuolation in the alveus and the densities of NFT in CA1 and GI in CA1 and CA2. CONCLUSION: The pathology most significantly affected the output pathways of the hippocampus, lesions were topographically distributed, and hippocampal pathology may be one factor contributing to cognitive decline in PSP.

A quantitative study of the pathological changes in the cerebellum in 15 cases of variant Creutzfeldt-Jakob disease (vCJD).

AIMS: To determine in the cerebellum in variant Creutzfeldt-Jakob disease (vCJD): (i) whether the pathology affected all laminae; (ii) the spatial topography of the pathology along the folia; (iii) spatial correlations between the pathological changes; and (iv) whether the pathology was similar to that of the common methionine/methionine Type 1 subtype of sporadic CJD. METHODS: Sequential cerebellar sections of 15 cases of vCJD were stained with haematoxylin and eosin, or immunolabelled with monoclonal antibody 12F10 against prion protein (PrP) and studied using spatial pattern analysis. RESULTS: Loss of Purkinje cells was evident compared with control cases. Densities of the vacuolation and the protease-resistant form of prion protein (PrP(Sc)) (diffuse and florid plaques) were greater in the granule cell layer (GL) than the molecular layer (ML). In the ML, vacuoles and PrP(Sc) plaques occurred in clusters regularly distributed along the folia with larger clusters of vacuoles and diffuse plaques in the GL. There was a negative spatial correlation between the vacuoles and the surviving Purkinje cells in the ML. There was a positive spatial correlation between the vacuoles and diffuse PrP(Sc) plaques in the ML and GL. CONCLUSIONS: (i) all laminae were affected by the pathology, the GL more severely than the ML; (ii) the pathology was topographically distributed along the folia especially in the Purkinje cell layer and ML; (iii) pathological spread may occur in relation to the loop of anatomical connections involving the cerebellum, thalamus, cerebral cortex and pons; and (iv) there were pathological differences compared with methionine/methionine Type 1 sporadic CJD.

Progressive supranuclear palsy (PSP): a quantitative study of the pathological changes in cortical and subcortical regions of eight cases.

In eight cases of progressive supranuclear palsy (PSP), neurofibrillary tangles (NFT) were numerous in the substantia nigra (SN), red nucleus (RN), locus caeruleus (LC), pontine nuclei (PN), and inferior olivary nucleus (ION) and abnormally enlarged neurons (EN) in the ION, LC and PN. Loss of Purkinje cells was evident in the cerebellum. Tufted astrocytes (TA) were abundant in the striatum, SN and RN and glial inclusions ('coiled bodies') (GI) in the midbrain (SN, RN) and pons (LC). Neuritic plaques were frequent in one case. NFT, GI, and TA densities were uncorrelated in most areas. NFT and EN densities were positively correlated in the midbrain and surviving neurons and disease duration in several areas. These results suggest: 1) predominantly subcortical pathology in PSP with widespread NFT while TA and GI have a more localized distribution, 2) little correlation between neuronal and glial pathologies, and 3) shorter duration cases may be more likely to develop cortical pathology.

Familial prion disease in a Hungarian family with a novel 144-base pair insertion in the prion protein gene.

About 15% of human prion diseases are inherited, and are associated with point or insertional mutations of the prion protein gene (PRNP). Four families with six octapeptide repeat insertions (OPRI) in the PRNP gene have been described in the literature so far. Here we report two cases in a Hungarian family with a new six OPRI (R1R2R2R3R2R3gR3R2R2R3R4) in the PRNP gene. The clinical features (progressive ataxia, dementia and anosmia), the age of onset and the duration of disease were almost identical. In addition to the cerebellar and parahippocampal pathological changes already described, we also found deposits of pathological prion protein in the olfactory system.

Multiple system atrophy (MSA): topographic distribution of the alpha-synuclein-associated pathological changes.

To study the topographic distribution of the pathology in multiple system atrophy (MSA). Pattern analysis was carried out using alpha-synuclein immunohistochemistry in 10 MSA cases. The glial cytoplasmic inclusions (GCI) were distributed randomly or in large clusters. The neuronal inclusions (NI) and abnormal neurons were distributed in regular clusters. Clusters of the NI and abnormal neurons were spatially correlated whereas the GCI were not spatially correlated with either the NI or the abnormal neurons. The data suggest that the GCI represent the primary change in MSA and the neuronal pathology develops secondary to the glial pathology.

Multiple system atrophy: laminar distribution of the pathological changes in frontal and temporal neocortex--a study in ten patients.

OBJECTIVE: To determine the distribution of the pathological changes in the neocortex in multiple-system atrophy (MSA). METHOD: The vertical distribution of the abnormal neurons (neurons with enlarged or atrophic perikarya), surviving neurons, glial cytoplasmic inclusions (GCI) and neuronal cytoplasmic inclusions (NI) were studied in alpha-synuclein-stained material of frontal and temporal cortex in ten cases of MSA. RESULTS: Abnormal neurons exhibited two common patterns of distribution, viz., density was either maximal in the upper cortex or a bimodal distribution was present with a density peak in the upper and lower cortex. The NI were either located in the lower cortex or were more uniformly distributed down the cortical profile. The distribution of the GCI varied considerably between gyri and cases. The density of the glial cell nuclei was maximal in the lower cortex in the majority of gyri. In a number of gyri, there was a positive correlation between the vertical densities of the abnormal neurons, the total number of surviving neurons, and the glial cell nuclei. The vertical densities of the GCI were not correlated with those of the surviving neurons or glial cells but the GCI and NI were positively correlated in a small number of gyri. CONCLUSION: The data suggest that there is significant degeneration of the frontal and temporal lobes in MSA, the lower laminae being affected more significantly than the upper laminae. Cortical degeneration in MSA is likely to be secondary to pathological changes occurring within subcortical areas.

Quantitative analysis of tau isoform transcripts in sporadic tauopathies.

A number of neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by intraneuronal accumulation of the tau protein. Some forms of FTDP-17 are caused by mutations in the tau gene affecting exon 10 splicing. Therefore, dysregulation of tau pre-mRNA splicing may be a contributing factor to sporadic tauopathies. To address this question, we devised a real-time RT-PCR strategy based on the use of a single fluorogenic probe to evaluate the ratio between tau isoforms containing or lacking exon 10 (4R/3R ratio) in post-mortem brain samples. We found a two- to six-fold increase in the 4R/3R ratio in cases of FTDP-17 linked to a splice site mutation, hence confirming the validity of the strategy. The difference in the 4R/3R ratio in the superior temporal and superior frontal gyri between AD and control brains was not statistically significant. Similarly, there was no significant difference in the 4R/3R ratio between Pick's disease cases and controls, indicating that the predominance of tau3R protein in PiD reflects post-translational modifications of specific isoforms. This study indicates that post-translational events are likely to be the main factors controlling tau isoform composition in sporadic tauopathies and highlights the benefit of quantitative RT-PCR in the assessment of splicing abnormalities in tauopathies.

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 beta-amyloid (A beta) 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.

A quantitative study of the pathological changes in ten patients with multiple system atrophy (MSA).

The densities of the glial cytoplasmic inclusions (GCI), neuronal inclusions (NI), and abnormal neurons were studied in the frontal cortex, hippocampus, cerebellum, basal ganglia and areas of the pons and medulla in 10 cases of multiple system atrophy (MSA). GCI density was greater in the substantia nigra and globus pallidus compared with the frontal cortex and hippocampus. Abnormal neurons were most abundant in the frontal cortex, substantia nigra, and inferior olivary nucleus. NI and abnormal neuron densities were positively correlated in the globus pallidus but negatively correlated in the hippocampus. The NI and GCI were only positively correlated in the pons. GCI in the pons and inferior olivary nucleus, NI in the substantia nigra, and abnormal neurons in the frontal cortex varied significantly between cases. The MSA cases did not cluster according to disease subtype. The data suggest that: 1) the greatest densities of pathological changes occur in the substantia nigra and globus pallidus, 2) density of the GCI is unrelated to that of the NI, and 3) there is overlapping pathology between the various subtypes of MSA.

Spatial correlation between the vacuolation, prion protein, deposition and surviving neurons in patients with 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 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 florid and diffuse deposits were either negatively correlated or uncorrelated. These data suggest: 10 that clusters of vacuoles in the cerebral cortex are associated with the presence of surviving neuronal cell bodies, 2) that 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.

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.

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.

Neuronal loss in familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions.

The neuronal density in the frontal, temporal, and parietal lobes was determined in nine cases of familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions (FTDU). The mean age at onset was 56.9 +/- 2.2 years and the duration of disease was 6.7 +/- 0.5 years. The mean age at death was 63.6 +/- 2.2 years. There was substantial loss (34%) of brain weight (877 +/- 73 g) in the familial cases in comparison with 10 normal aged controls (1326 +/- 50 g, P < 0.001). All of the familial FTDU cases showed atrophy of the frontal, temporal, and parietal lobes; neuronal loss; vacuolation in superficial laminae; reactive astrocytosis; and ubiquitin-positive, tau-negative intracytoplasmic and intranuclear inclusions and dystrophic neurites in varying sites and numbers. Neuronal loss was estimated in nine cases of familial FTDU and in 10 aged controls using a stereological probe, the optical "disector," and a computerized stereology system (CAST-Grid, Olympus, Denmark). There was a significant reduction in neuronal density in the frontal lobe (22.3 +/- 3.8 x 10(3)/mm(3)) of familial FTDU in comparison to aged controls (33.1 +/- 1.7 x 10(3) per mm(3), P < 0.05). An estimate of the relative numbers of neurons was calculated by multiplying the numerical density by the cortical thickness, which showed a striking loss of neurons of 56% in the frontal lobe, 52% loss in the temporal lobe, and a 49% loss in the parietal lobe of familial FTDU when compared to controls. This study shows that familial FTDU has profound focal neuronal loss in multiple association areas that relate to the clinical symptoms characteristic of the disease.

Spatial patterns of the vacuolation in subcortical white matter in sporadic Creutzfeldt-Jakob disease (sCJD).

OBJECTIVE: To study the spatial patterns of the vacuolation ("spongiform change") in the subcortical white matter in the "classical" form of sporadic Creutzfeldt-Jakob disease (sCJD). MATERIAL: Frontal, parietal, occipital and temporal lobes of 11 cases of sCJD. METHOD: Spatial patterns were studied across the white matter at the base of the gyri using spatial pattern analysis. RESULTS: In the white matter of all gyri studied, vacuoles were aggregated into clusters, 50 to > 800 microm in diameter and in 22/37 (59%) of gyri, the clusters of vacuoles exhibited a regular distribution across the base of the gyri. In the remaining gyri, the vacuoles were aggregated into large clusters, at least 400 microm or 800 microm in diameter, but without evidence of a regular distribution. In a significant proportion of gyri, the spatial patterns of the vacuolation were similar to those reported previously for spongiform change and prion protein (PrP) deposits in the corresponding grey matter. CONCLUSIONS: Degeneration of the white matter and the formation of clusters of vacuoles may occur before the degeneration of the grey matter or could be a consequence of pathology affecting the cortico-cortical pathways.

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 than 1,600 micro m 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.

Office of Rare Diseases neuropathologic criteria for corticobasal degeneration.

A working group supported by the Office of Rare Diseases of the National Institutes of Health formulated neuropathologic criteria for corticobasal degeneration (CBD) that were subsequently validated by an independent group of neuropathologists. The criteria do not require a specific clinical phenotype, since CBD can have diverse clinical presentations, such as progressive asymmetrical rigidity and apraxia, progressive aphasia, or frontal lobe dementia. Cortical atrophy, ballooned neurons, and degeneration of the substantia nigra have been emphasized in previous descriptions and are present in CBD, but the present criteria emphasize tau-immunoreactive lesions in neurons, glia, and cell processes in the neuropathologic diagnosis of CBD. The minimal pathologic features for CBD are cortical and striatal tau-positive neuronal and glial lesions, especially astrocytic plaques and thread-like lesions in both white matter and gray matter, along with neuronal loss in focal cortical regions and in the substantia nigra. The methods required to make this diagnosis include histologic stains to assess neuronal loss, spongiosis and ballooned neurons, and a method to detect tau-positive neuronal and glial lesions. Use of either the Gallyas silver staining method or immunostains with sensitive tau antibodies is acceptable. In cases where ballooned neurons are sparse or difficult to detect, immunostaining for phospho-neurofilament or alpha-B-crystallin may prove helpful. Methods to assess Alzheimer-type pathology and Lewy body pathology are necessary to rule out other causes of dementia and Parkinsonism. Using these criteria provides good differentiation of CBD from other tauopathies, except frontotemporal dementia and Parkinsonism linked to chromosome 17, where additional clinical or molecular genetic information is required to make an accurate diagnosis.

Analysis of tau haplotypes in Pick's disease.

Pick's disease (PiD) is characterized by the deposition of tau protein as three-repeat tau Pick bodies, whereas progressive supranuclear palsy (PSP) involves the deposition of four-repeat tau neurofibrillary tangles. PSP is associated with the tau H1 haplotype. The authors investigated a possible association between PiD and the tau H1 or H2 haplotype. There was no difference between the tau H2 haplotype or H2H2 genotype frequency in PiD cases and control subjects. No tau mutations were identified in pathologically typical cases of PiD, with antibody 12-E8-negative Pick bodies.

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.