Biomedical subjects

N J Cairns

Publications and source records attributed to N J Cairns.

At least 19 recordsLinked to original sources

PubMed2002

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.

Adult↗

PubMed2002

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.

Adult↗

PubMed2001

Alzheimer disease is not associated with polymorphisms in the angiotensinogen and renin genes.

Hypertension has been implicated as a risk factor for Alzheimer disease (AD) and dementia in epidemiological studies of humans. It is thus possible that there are common genetic determinants for hypertension and AD. Epidemiological, clinical, and experimental data suggest that the renin-angiotensin-aldosterone system is a critical regulator of blood pressure. The presence of an MboI site in an RFLP in the renin gene and the Thr at the Met/Thr polymorphism at codon 235 (M235T) of the angiotensinogen gene have been reported to be associated with hypertension. These variants were studied in autopsy-confirmed AD cases and matched controls from the U.K. While no association was detected with the renin polymorphism, a weak deleterious effect was observed in cases homozygous for the angiotensinogen Thr allele. However, this association was not observed in a French cohort of clinically diagnosed AD cases and controls, suggesting that the initial observation was a type I error. Thus, these polymorphisms are unlikely to be associated with AD risk.

Aged↗

PubMed2001

Olfactory centres in Alzheimer's disease: olfactory bulb is involved in early Braak's stages.

In Alzheimer's disease (AD), neurofibrillary tangles spread from the entorhinal cortex to the limbic system, then to neocortical areas, according to the Braak's stages. Olfaction is impaired in early stages of AD. The aim of this study was to describe the pathology of the cortical olfactory centres in relation to Braak's stages determining the earliest site of pathology. We examined 15 control and 15 AD cases. The primary olfactory cortices were involved in more advanced Braak's stages, while olfactory bulbs were damaged in very early (i.e. Braak's stage 0 or 1) stages. These results are supporting the fact that olfaction might be an early marker in AD and argues against the hypothesis that AD pathology is spreading through the olfactory system.

Aged↗

PubMed2001

The spatial patterns of prion protein deposits in Creutzfeldt-Jakob disease: comparison with beta-amyloid deposits in Alzheimer's disease.

Similar pathological processes may be involved in the deposition of extracellular proteins in the brains of patients with Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD). Hence, this study compared the spatial patterns of prion protein (PrP) deposits in the cerebral cortex and hippocampus in cases of sporadic CJD with those of beta-amyloid (Abeta) deposits in sporadic AD. PrP and Abeta deposits were aggregated into clusters and, in 90% of brain areas in CJD and 57% in AD, the clusters were regularly distributed parallel to the tissue boundary. In a significant proportion of cortical analyses, the mean diameter of the clusters of PrP and Abeta deposits were similar to those of the cells of origin of the cortico-cortical pathways. Abeta deposits in AD were distributed more frequently in larger-sized clusters than PrP deposits in CJD. In addition, in the hippocampus and dentate gyrus, clustering of Abeta deposits was observed in AD but PrP deposits were rare in these regions in CJD. The size, location and distribution of the extracellular protein deposits within the cortex of both disorders was consistent with the degeneration of the cortico-cortical pathways. Furthermore, spread of the pathology along these pathways may be a pathogenic feature common to CJD and AD.

Aged↗

PubMed2001

Decreased protein levels of stathmin in adult brains with Down syndrome and Alzheimer's disease.

Stathmin, distributed in neurons with high abundance, acts as an intracellular relay, integrating various transduction pathways triggered by extracellular signals and it is involved in physiological regulation of microtubule destabilization. Stathmin has been also shown to be a critical molecule in pathology of neurodegeneration such as Alzheimer's disease (AD), particularly, in neurofibrillary tangle (NFT) formation. Here we evaluated protein levels of stathmin in adult brain from patients with AD and Down syndrome (DS) showing AD-like pathology by applying proteomic technologies with two-dimensional (2-D) gel electrophoresis, matrix-assisted laser desorption ionization mass spectroscopy (MALDI-MS) identification and specific software for quantification of proteins. Significantly decreased protein levels of stathmin were observed in frontal (2.12+/-1.17, n = 6) and temporal (3.05+/-2.81, n = 10) cortices of AD compared to controls (frontal cortex: 4.41+/-1.70, n = 8; temporal cortex: 5.26+/-2.26, n = 13). Stathmin was also significantly decreased in frontal (2.47+/-1.11, n = 7) and temporal (2.02+/-1.18, n = 9) cortices of DS. We also investigated stathmin levels in fetal brain. Stathmin was not significantly changed between fetal DS brain and controls. We suggest that the decreased protein level of stathmin in brains is associated with tangle formation and microtubule instability in DS as well as AD, but stathmin is not involved in the abnormal development of fetal DS brain.

Adult↗

PubMed2001

Molecular neuropathology of transgenic mouse models of Down syndrome.

Down syndrome (DS) is a complex, clinically heterogeneous disorder which shows both impairment of neurodevelopement and the neurodegenerative changes of Alzheimer's disease (AD). The phenotype of DS is caused by triplication of chromosome 21 and transgenic mouse models have been developed, and are being created, that carry single genes and chromosomal segments to excess. For example, transgenic mice containing additional copies of the amyloid precursor protein (APP) gene, have been useful in producing the Abeta deposition characteristic of AD and DS, but not the cytoskeletal changes that are the hallmarks of these human disorders. Such models are useful in replicating aspects of pathogenesis and allow for the testing of therapeutic agents to restore impaired function. Segmental trisomic mouse models, which survive to adulthood and possess three copies of multiple genes responsible for the DS phenotype, such as Ts1Cje and Ts65Dn, have been used to explore aspects of neurodevelopment and neurodegeneration. These animal models show some but not all the pathological, biochemical, and transcriptional changes seen in DS. They also have the advantage of allowing for the testing of therapeutic agents to restore impaired function. Analysis of the transcriptome and proteome of fetal and adult DS indicates that there is a complex relationship between gene dosage, gene and protein expression, and that data from animal models will need to be compared and evaluated in the light of data obtained from DS tissue.

Animals↗

PubMed2001

Quantification of the vacuolation (spongiform change) and prion protein deposition in 11 patients with sporadic Creutzfeldt-Jakob disease.

The vacuolation (spongiform change) and prion protein (PrP) deposition were quantified in the cerebral cortex, hippocampus and cerebellum of 11 patients with sporadic Creutzfeldt-Jakob disease (CJD). The density of the vacuolation, averaged over patients, was greatest in the occipital cortex and cerebellum and least in the dentate gyrus. The degree of PrP deposition was similar in the different cortical areas and in the cerebellum but significantly lower in the hippocampus and absent in the dentate gyrus. There were no significant differences in the extent of the vacuolation and PrP deposition in the upper and lower cortical laminae. Vacuolation and PrP deposition in the upper cortex were both positively correlated with corresponding levels in the lower cortex. In addition, in the parietal cortex and parahippocampal gyrus, the density of the vacuolation was positively correlated with the level of PrP deposition but no such correlations were observed in the remaining areas studied. This quantitative study suggested that: (1) the pathological changes were most severe in the occipital cortex and cerebellum, while the hippocampus was least affected, (2) the pathological changes affect the upper and lower cortical laminae, and (3) the degree of correlation between the density of the vacuolation and PrP deposition may be dependent on brain region.

Aged↗

PubMed2001

Cases of Alzheimer's disease due to deletion of exon 9 of the presenilin-1 gene show an unusual but characteristic beta-amyloid pathology known as 'cotton wool' plaques.

The pattern of deposition of amyloid beta protein (Abeta) was investigated, using the monoclonal antibodies BA27 and BC05 detecting the C-terminal species Abeta40 and Abeta42(43), in six cases of Alzheimer's disease (AD) due to deletions in exon 9 of PS-1 gene. These cases are characterized histologically by the presence of very large rounded plaques within the frontal cortex, known as 'cotton wool' plaques, composed of both Abeta40 and Abeta42(43) that are relatively free from neuritic changes and glial cell components, and usually devoid of a compact amyloid core. In the cerebellum the plaques are almost entirely of a compact type, again composed of Abeta40 and Abeta42(43), with only few diffuse Abeta42(43) containing plaques. The area fraction of Abeta40, and the ratio between Abeta40 and Abeta42(43), in frontal cortex was significantly higher than that seen in other cases of AD due to different PS-1 mutations, or in cases of sporadic AD, all of similar APO E genotype. The area fractions of Abeta42(43), however, did not significantly differ between these three groups. The unusual nature of the Abeta deposition in these cases may reflect the uniqueness of the mutation, which results in a failure to constitutively cleave the PS-1 holoprotein into its active form, and the effect this might have on APP trafficking and catabolism.

Adult↗

PubMed2001

Spatial pattern of prion protein deposits in patients with sporadic Creutzfeldt-Jakob disease.

The spatial pattern of the prion protein (PrP) deposits was studied in the cerebral cortex and cerebellum in 10 patients with sporadic Creutzfeldt-Jakob disease (CJD). In all patients the PrP deposits were aggregated into clusters and, in 90% of cortical areas and in 50% of cerebellar sections, the clusters exhibited a regular periodicity parallel to the tissue boundary; a spatial pattern also exhibited by beta-amyloid (Abeta) deposits in Alzheimer's disease (AD). In the cerebral cortex, the incidence of regular clustering of the PrP deposits was similar in the upper and lower cortical laminae. The sizes of the PrP clusters in the upper and lower cortex were uncorrelated. No significant differences in mean cluster size of the PrP deposits were observed between brain regions. The size, location and distribution of the PrP deposit clusters suggest that PrP deposition occurs in relation to specific anatomical pathways and supports the hypothesis that prion pathology spreads through the brain via such pathways. In addition, the data suggest that there are similarities in the pathogenesis of extracellular protein deposits in prion disease and in AD.

Aged↗

PubMed2001

What does the study of the spatial patterns of pathological lesions tell us about the pathogenesis of neurodegenerative disorders?

Discrete pathological lesions, which include extracellular protein deposits, intracellular inclusions and changes in cell morphology, occur in the brain in the majority of neurodegenerative disorders. These lesions are not randomly distributed in the brain but exhibit a spatial pattern, that is, a departure from randomness towards regularity or clustering. The spatial pattern of a lesion may reflect pathological processes affecting particular neuroanatomical structures and, therefore, studies of spatial pattern may help to elucidate the pathogenesis of a lesion and of the disorders themselves. The present article reviews first, the statistical methods used to detect spatial patterns and second, the types of spatial patterns exhibited by pathological lesions in a variety of disorders which include Alzheimer's disease, Down syndrome, dementia with Lewy bodies, Creutzfeldt-Jakob disease, Pick's disease and corticobasal degeneration. These studies suggest that despite the morphological and molecular diversity of brain lesions, they often exhibit a common type of spatial pattern (i.e. aggregation into clusters that are regularly distributed in the tissue). The pathogenic implications of spatial pattern analysis are discussed with reference to the individual disorders and to studies of neurodegeneration as a whole.

Brain↗

PubMed2001

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.

Aged↗

PubMed2000

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.

Apolipoproteins E↗

PubMed2000

The spatial pattern of the vacuolation in patients with sporadic Creutzfeldt-Jakob disease.

1600 microm in diameter and, in the majority of tissue sections, the vacuole clusters were distributed with regular periodicity parallel to the tissue boundary. The size of the vacuole clusters was positively correlated with patient age in the lower laminae of the occipital cortex and the inferior temporal gyrus (ITG) and negatively correlated with age in the hippocampus. In addition, the size of the vacuole clusters was positively correlated with disease duration in the upper laminae of the ITG. The size and distribution of the vacuole clusters suggests that the vacuolation in CJD reflects the degeneration of specific brain pathways and supports the hypothesis that prion pathology may spread through the brain along well defined anatomical pathways.

Aged↗

PubMed2000

Apolipoprotein E epsilon4 allele has no effect on age at onset or duration of disease in cases of frontotemporal dementia with pick- or microvacuolar-type histology.

Frontotemporal dementia (FTD) is the second most common cause of presenile dementia. Here we have investigated the frequency of the epsilon4 allele of the Apolipoprotein (APOE) gene in FTD and in other non-Alzheimer forms of dementia related to FTD such as Motor Neurone disease dementia, semantic dementia, progressive aphasia, progressive supranuclear palsy, and corticobasal degeneration. In none of these diagnostic groups did we find a significant increase in the APOE epsilon4 allelic frequency, compared to population values. Neither did we observe any affects of the epsilon4 allele upon age at onset or duration of disease. We conclude therefore that polymorphic variations in the APOE gene do not modulate either the occurrence or progression of these non-Alzheimer forms of dementia.

Adult↗

PubMed2000

A quantitative study of the pathological lesions in the neocortex and hippocampus of twelve patients with corticobasal degeneration.

The density of ballooned neurons (BN), tau-positive neurons with inclusion bodies (tau+ neurons), and tau-positive plaques (tau+ plaques) was determined in sections of the frontal, parietal, and temporal lobe in 12 patients with corticobasal degeneration (CBD). No significant differences in the mean density of BN and tau+ neurons were observed between neocortical regions. In the hippocampus, the densities of BN were significantly lower than in the neocortex, and densities of tau+ neurons were greater in sectors CA1 and CA2, compared with CA3 and CA4. Tau+ plaques were present in one or more brain regions in six patients. Significantly more BN were recorded in the lower (laminae V/VI) compared with the upper cortex (laminae I/II/III) but tau+ neurons were equally frequent in the upper and lower cortex. No significant correlations were observed between the densities of BN and tau+ neurons, but the densities of BN in the superior temporal gyrus and tau+ plaques in the frontal cortex were positively correlated with age. A principal components analysis (PCA) suggested that differences in the density of tau+ neurons in the frontal and motor cortex were the most important sources of variation between patients. In addition, one patient with a particularly high density of tau+ neurons in the hippocampus appeared to be atypical of the patient group studied. The data support the hypothesis that, although clinically heterogeneous, CBD is a pathologically distinct disorder.

Aged↗

PubMed2000

Clustering of Pick bodies in the dentate gyrus in Pick's disease.

In patients with Pick's disease (PD), high densities of tau positive Pick bodies (PB) have been observed within the granule cell layer of the dentate gyrus. This study investigated the spatial patterns of PB along the granule cell layer in coronal sections of the hippocampus in eight patients with PD. In all patients, there was evidence of clustering of PB within the granule cell layer; however, there was considerable variation in the pattern of clustering. In five patients, the clusters of PB were regularly distributed along the dentate gyrus, and in two of these patients, the smaller clusters were aggregated into larger superclusters. In three patients, a single large cluster of PB, more than 1200 microm in diameter, was present. Clustering of PB may reflect a primary degenerative process within the granule cells or the degeneration of pathways that project to the dentate gyrus.

Adult↗

PubMed2000

Neuronal loss and neurofibrillary degeneration in the hippocampal cortex in late-onset sporadic Alzheimer's disease.

To explore more fully the relationship between neuronal death and neurofibrillary degeneration, unaffected neurons, intracellular neurofibrillary tangles (i-NFT) and extracellular NFT (e-NFT) in 22 patients with late-onset sporadic Alzheimer's disease (AD) were morphometrically evaluated in eight subdivisions of the hippocampal cortex, using the Gallyas hematoxylin-eosin stain. The subdivisions examined included CA4, CA3, CA2, CA1 (CA: cornu ammonis), prosubiculum (PRO), subiculum and presubiculum (PRE), parasubiculum (PARA) and the entorhinal cortex (ENT). The unaffected neuron density was significantly lower and both i-NFT and e-NFT densities were significantly higher in subdivisions other than CA4 and CA3 in AD patients compared with those in the aged controls. Unaffected neuron density was significantly, inversely correlated with e-NFT density and with total NFT density in all subdivisions except for PRE in AD patients. Especially in CA2, CA1, PRO and ENT, there were strong correlations between the neuron density and these NFT densities. Both unaffected neuron and e-NFT densities in CA1 and ENT were significantly correlated with the disease duration. The i/e-NFT ratio, an index of the degree and/or rate of progress of neuronal death via neurofibrillary degeneration, showed the lowest value in ENT in AD patients. The findings suggest that neuronal death via neurofibrillary degeneration starts earliest and/or most rapidly progresses in ENT. Furthermore, the i/e-NFT ratios in both ENT and CA1 were significantly correlated with the disease duration, suggesting that the neuronal death pattern in the two subdivisions parallels disease progression.

Age Factors↗