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.

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.

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.

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.

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.

HIV-associated brain pathology in the United Kingdom: an epidemiological study.

OBJECTIVES: To examine the epidemiology of HIV-associated neuropathology in the United Kingdom and to investigate whether the prevalence of different forms of HIV-associated brain pathology varies with exposure category. DESIGN: The study was a cross-sectional survey; data was analysed from the Medical Research Council National AIDS Neuropathology database. SETTING: Information was gathered from throughout England, Scotland and Wales. SUBJECTS: Individuals who died from AIDS in the United Kingdom and had a postmortem examination. The database comprised 7% of all AIDS deaths in the United Kingdom between 1982 and 1993. MAIN OUTCOME: Neuropathological diagnoses based on internationally accepted neuropathological terminology of AIDS-related brain lesions. RESULTS: HIV encephalitis was the most prevalent pathological diagnosis, occurring in 25.3% [95% confidence interval (CI), 21.0-29.6] of the study sample. Statistically significant independent associations for the occurrence of HIV encephalitis were found for injecting drug use (odds ratio, 6.86; 95% CI, 2.91-16.17), and age less than 30 years at death (odds ratio, 3.58; 95% CI, 1.99-6.44). Vascular lesions were significantly higher among blood product recipients, 95% of whom were haemophiliacs. CONCLUSIONS: This was the first epidemiological investigation of HIV-associated brain pathology in the United Kingdom. HIV encephalitis appeared to occur more frequently in injecting drug users and those who died younger. Whereas the findings must be interpreted cautiously, one hypothesis was that differences in the route of transmission may have affected the manifestation of HIV-associated brain damage.

Decrease and structural modifications of phosphatidylethanolamine plasmalogen in the brain with Alzheimer disease.

Several lipid modifications, some of which were attributed to oxidative stress, have been reported in the brains of patients with Alzheimer disease (AD). To evaluate this possibility, all phospholipids and their ether subclasses from the frontal cortex, hippocampus, and the white matter of AD brain were analyzed by high performance liquid chromatography and gas chromatography. The total phospholipid in the frontal cortex and hippocampus decreased on a DNA basis by about 20% and this change was essentially explained by a selective decrease in phosphatidylethanolamine and phosphatidylcholine. The lower content of phosphatidylethanolamine was due to a specific decrease in the plasmalogen subclass. Phosphatidylethanolamine plasmalogen was also the only lipid exhibiting major structural modifications: a significant decrease in polyunsaturated fatty acids and oleic acid as well as a shift of the aldehyde pattern from 18:1 to 18:0. The only modification observed in the other phospholipids was a decrease in oleic acid in diacyl-phosphatidylethanolamine and diacyl-phosphatidylcholine. None of these changes were observed in the white matter. Both the vinyl ether bond of phosphatidylethanolamine plasmalogen and polyunsaturated fatty acids are major targets in oxidative stress; thus, these specific lipid modifications strongly support the involvement of free radicals in the pathogenesis of AD.

Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders.

We investigated the validity and reliability of diagnoses made by eight neuropathologists who used the preliminary NINDS neuropathologic diagnostic criteria for progressive supranuclear palsy (PSP) and related disorders. The specific disorders were typical, atypical, and combined PSP, postencephalitic parkinsonism, corticobasal ganglionic degeneration, and Pick's disease. These disorders were chosen because of the difficulties in their neuropathologic differentiation. We assessed validity by measuring sensitivity and positive predictive value. Reliability was evaluated by measuring pairwise and group agreement. From a total of 62 histologic cases, each neuropathologist independently classified 16 to 19 cases for the pairwise analysis and 5 to 6 cases for the group analysis. The neuropathologists were unaware of the study design, unfamiliar with the assigned cases, and initially had no clinical information about the cases. Our results showed that with routine sampling and staining methods, neuropathologic examination alone was not fully adequate for differentiating the disorders. The main difficulties were discriminating the subtypes of PSP and separating postencephalitic parkinsonism from PSP. Corticobasal ganglionic degeneration and Pick's disease were less difficult to distinguish from PSP. The addition of minimal clinical information contributed to the accuracy of the diagnosis. On the basis of results obtained, we propose clinicopathologic diagnostic criteria to improve on the NINDS criteria.

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.

Hyperosmolar opening of the blood-brain barrier in the energy-depleted rat brain. Part 1. Permeability studies.

A simple saline perfusion system was used to investigate the effects of hyperosmolar solutions of arabinose and mannitol upon the permeability of the blood-brain barrier. The small, polar molecule [14C]mannitol and the larger, visual marker Evans blue were used as indicators of barrier integrity in the perfused energy-depleted brain. One-minute perfusion of hyperosmolar solutions consistently opened the barrier suggesting that the mechanism of osmotic barrier opening is independent of energy-producing metabolism. The accumulation of radiolabel in the brain was expressed as the ratio of tissue to perfusate radioactivity (Rt/Rp) and, for cerebrum, this increased from a control value of 0.0022 +/- 0.0007 (mean +/- SEM; n = 4) to a value of 0.0124 +/- 0.0008 (n = 4) following 0.9 M arabinose and to 0.0495 +/- 0.0072 (n = 4) following 1.8 M arabinose. There was a significant reduction of water content of hyperosmolar perfused brains. These findings support the hypothesis that osmotic barrier opening is the result of the passive shrinkage of endothelial cells and the surrounding tissue.

Distinguishable effects of presenilin-1 and APP717 mutations on amyloid plaque deposition.

Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral Abeta deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Abeta40 and Abeta42. Abeta isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Abeta42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm(2)) and area (%) of Abeta42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Abeta40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Abeta burden in a different fashion from APP717 mutations in their familial AD brains.

Dementia with Lewy bodies studied with positron emission tomography.

OBJECTIVE: To report a case initially fulfilling the clinical criteria for probable Alzheimer disease, although later clinical features suggested dementia with Lewy bodies. Oxygen 15-labeled positron emission tomograms revealed a pattern of hypometabolism characteristic of Alzheimer disease. At post mortem, there was no evidence of the pathological features of Alzheimer disease, but diffuse cortical Lewy bodies were seen in the pigmented brainstem nuclei and cerebral cortex. DESIGN: A case report. SETTING: Tertiary referral center. PATIENT: A 65-year-old white man presented with a 3-year history of memory loss and language difficulties. RESULTS: Oxygen 15-labeled positron emission tomograms revealed hypometabolism in the frontal, temporal, and parietal lobes, more severe on the left than right. Metabolism in the left caudate was just outside the 95% reference range. Occipital metabolism was normal. CONCLUSIONS: Positron emission tomographic studies have been reported to show occipital hypometabolism in dementia with Lewy bodies, in addition to the characteristic posterior bitemporal biparietal pattern of Alzheimer disease. We suggest that although this finding may favor a diagnosis of dementia with Lewy bodies, it is not necessary for diagnosis.

Autopsy-confirmed familial early-onset Alzheimer disease caused by the l153V presenilin 1 mutation.

BACKGROUND: Three affected individuals are described from a small English kindred with early-onset autosomal dominant familial Alzheimer disease (FAD) caused by a leucine-to-valine change at codon 153 (L153V) of the presenilin 1 (PSEN1) gene. METHODS: Clinical information on the pedigree was collected directly from family members and from hospital records. Samples of DNA were screened by means of direct sequencing of all coding exons of PSEN1. One patient underwent neuropathological examination. RESULTS: Mean age at onset of symptoms was 35.3 years (95% confidence interval [CI], 34.6-36.0 years); at death, 44.0 years (95% CI, 39.1-48.9 years). Mean duration of illness was 8.3 years (95% CI, 4.7-11.9 years). Myoclonus was a late feature in 1 patient; seizures were not reported in any subjects. Spastic paraparesis and extrapyramidal signs were absent. The neuropsychometric profile of 1 patient showed relatively preserved naming skills in the setting of global cognitive deficits. Results of neuropathological examination demonstrated the signature lesions of Alzheimer disease and the presence of occasional cortical Lewy bodies. CONCLUSIONS: The PSEN1 L153V mutation lies in the main mutation cluster of PSEN1 in the second transmembrane domain. It causes early-onset FAD with clinical features similar to those of other reported FAD pedigrees.

Ultrastructural changes in the frontal cortex and hippocampus in the ageing marmoset.

The ultrastructure of the cells and capillaries of the frontal cortex and hippocampus was studied in marmosets to assess age-related changes. The appearances in the brains of four marmosets, more than 12 years of age, were compared with those of two young marmosets aged 26 and 21 months. There was widespread accumulation of lipofuscin in neurons, glial cells, perivascular macrophages and pericytes, but not in endothelial cells. Many of the nerve cell nuclei showed marked membrane infolding, alteration of nuclear morphology and occasional inclusions. A few degenerated and dystrophic axons containing abnormal organelles were seen. The capillaries displayed irregularly thickened and split basal laminae. No neurofibrillary tangles, neuritic plaques, amyloid deposits or granulovacuoles were present. These changes are compared to those occurring in other animal species and in man during ageing.

Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy).

We present the preliminary neuropathologic criteria for progressive supranuclear palsy (PSP) as proposed at a workshop held at the National Institutes of Health, Bethesda, MD, April 24 and 25, 1993. The criteria distinguish typical, atypical, and combined PSP. A semiquantitative distribution of neurofibrillary tangles is the basis for the diagnosis of PSP. A high density of neurofibrillary tangles and neuropil threads in the basal ganglia and brain-stem is crucial for the diagnosis of typical PSP. Tau-positive astrocytes or their processes in areas of involvement help to confirm the diagnosis. Atypical cases of PSP are variants in which the severity or distribution of abnormalities deviates from the typical pattern. Criteria excluding the diagnosis of typical and atypical PSP are large or numerous infarcts, marked diffuse or focal atrophy, Lewy bodies, changes diagnostic of Alzheimer's disease, oligodendroglial argyrophilic inclusions, Pick bodies, diffuse spongiosis, and prion protein-positive amyloid plaques. The diagnosis of combined PSP is proposed when other neurologic disorders exist concomitantly with PSP.

Neuropathologic variation in frontotemporal dementia due to the intronic tau 10(+16) mutation.

BACKGROUND: An increasing number of recently described tau mutations show considerable clinical heterogeneity. The assessment of this phenotypic variation is of vital importance in the differential diagnosis of neurodegenerative diseases. OBJECTIVE: To assess the neuropathologic heterogeneity in a comprehensive study of 12 brains with a tau mutation at exon 10(+16) (C-to-T) splice site from 9 families. METHODS: A comprehensive neuropathologic examination has been carried out, using a wide range of tau antibodies. RESULTS: All brains showed frontotemporal atrophy of varying severity and pallor of the pigmented nuclei of the brainstem. The histologic changes were more extensive to include other cortical areas, the deep gray matter, and the white matter. The hallmark histologic lesions were the tau-positive neuronal and glial inclusions. In neurons, these ranged from typical neurofibrillary tangles through well-circumscribed inclusions to diffuse cytoplasmic staining. This tau pathology was complemented by the presence of large, abnormal achromatic neurons, neuronal loss, astrocytosis, and superficial status spongiosus. CONCLUSION: The distribution, type, and severity of these histologic abnormalities varied not only from case to case but also within the same brain. These brains with a common tau mutation raise important differential diagnostic problems: cases in the past might have been misdiagnosed as corticobasal degeneration or even atypical Pick disease, disorders with similar, if not identical, phenotypic manifestations.

Multiple system atrophy/progressive supranuclear palsy: alpha-Synuclein, synphilin, tau, and APOE.

Article abstract-Alpha synuclein, tau, synphilin, and APOE genotypes were analyzed in patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and controls. The predisposing effect of the tau insertion polymorphism to the development of PSP is confirmed. However, no effect of alpha-synuclein, synphilin, or APOE variability on the development of PSP, or of tau, alpha-synuclein, APOE, or synphilin gene variability on the development of MSA, are demonstrated.

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.

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.

OBJECTIVE: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). BACKGROUND: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. METHODS: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. RESULTS: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). CONCLUSIONS: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.