A quantitative study of the pathological changes in the cortical white matter in variant Creutzfeldt-Jakob disease (vCJD)

The objective of this study was to determine the degree of white matter pathology in the cerebral cortex in cases of variant Creutzfeldt-Jakob disease (vCJD) and to study the relationships between the white matter and grey matter pathologies. Hence, the pathological changes in cortical white matter were studied in individual gyri of the frontal, parietal, occipital, and temporal cortex in eleven cases of vCJD. Vacuolation (‘spongiform change’), deposition of the disease form of prion protein (PrPsc) in the form of discrete PrP deposits, and gliosis were observed in the white matter of virtually all cortical regions studied. Mean density of the vacuoles in the white matter was greater in the parietal lobe compared with the frontal, occipital, and temporal lobes but there were fewer glial cells in the occipital lobe compared with the other cortical regions. In the white matter of the frontal cortex, vacuole density was negatively correlated with the density of both glial cell nuclei and the PrP deposits. In addition, the densities of glial cells and PrP deposits were positively correlated in the frontal and parietal cortex. In the white matter of the frontal cortex and inferior temporal gyrus, there was a negative correlation between the densities of the vacuoles and the number of surviving neurons in laminae V/VI of the adjacent grey matter. In addition, in the frontal cortex, vacuole density in the white matter was negatively correlated with the density of the diffuse PrP deposits in laminae II/III and V/VI of the adjacent grey matter. The densities of PrP deposits in the white matter of the frontal cortex were positively correlated with the density of the diffuse PrP deposits in laminae II/III and V/V1 and with the number of surviving neurons in laminae V/V1. The data suggest that in the white matter in vCJD, gliosis is associated with the development of PrP deposits while the appearance of the vacuolation is a later development. In addition, neuronal loss and PrP deposition in the lower cortical laminae of the grey matter may be a consequence of axonal degeneration within the white matter.

Studies on the behaviour of Reticulitermes santonensis (Feytaud) in laboratory colonies and its implications for some methods of termite control

An investigation of behavioural patterns that form a basis for termite control in the Australasian region was undertaken using laboratory colonies of the subterranean termite Reticulitermes santonensis (Feytaud). The study attempted to build a picture of the behavioural elements of individuals in a colony and based on this, trophallaxis, aggression and cannibalism were investigated in detail. Preliminary study of food transmission showed that 'workers' played a major role in the distribution of food. It was found, that among factors responsible for release of trophallactic behaviour the presence of 'right odour' between participants was important. It also appeared that the role taken by individuals depended on whether they were hungry or fully fed. Antennal palpation was shown by donors and acceptors alike and this seemed to be excitatory in function. Introduction of aliens into nests elicited aggression and these aliens were often killed. Factors eliciting aggression were investigated and colony odour was found to be important. Further investigations revealed that development of colony odour was governed by genetical and environmental mechanisms. Termite response to injury and death was also governed by odour. In the case of injury either the fresh haemolymph from the wound or some component of the haemolymph evoked cannibalism. Necrophagic behaviour was found to be released by fatty acids found in the corpses. Finally, the response of colonies to nestmates carrying arsenic trioxide was investigated. It was found that living and freshly dead arsenic-carrying nestmates were treated like normal nestmates, resulting in high initial mortality. However, poisoned cadavers soon became repellant and were buried thus preventing further spread of the poison to the rest of the colony. This suggested that complete control of subterranean termites by arsenic trioxide is unlikely to be fully effective, especially in those species which are capable of developing secondary reproductives from survivors and thus rebuilding the community.

A morphometric study of the spatial patterns of TDP-43 immunoreactive neuronal inclusions in frontotemporal lobar degeneration (FTLD) with progranulin (GRN) mutation

Mutations of the progranulin (GRN) gene are a major cause of familial frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). We studied the spatial patterns of TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCI) and neuronal intranuclear inclusions (NII) in histological sections of the frontal and temporal lobe in eight cases of FTLD-TDP with GRN mutation using morphometric methods and spatial pattern analysis. In neocortical regions, the NCI were clustered and the clusters were regularly distributed parallel to the pia mater; 58% of regions analysed exhibiting this pattern. The NII were present in regularly distributed clusters in 35% of regions but also randomly distributed in many areas. In neocortical regions, the sizes of the regular clusters of NCI and NII were 400-800 µm, approximating to the size of the modular columns of the cortico-cortical projections, in 31% and 36% of regions respectively. The NCI and NII also exhibited regularly spaced clustering in sectors CA1/2 of the hippocampus and in the dentate gyrus. The clusters of NCI and NII were not spatially correlated. The data suggest degeneration of the cortico-cortical and cortico-hippocampal pathways in FTLD-TDP with GRN mutation, the NCI and NII affecting different clusters of neurons.

Investigations of attentional processing in parietal and occipital human cortical regions with magnetoencephalography

Attention defines our mental ability to select and respond to stimuli, internal or external, on the basis of behavioural goals in the presence of competing, behaviourally irrelevant, stimuli. The frontal and parietal cortices are generally agreed to be involved with attentional processing, in what is termed the 'fronto-parietal' network. The left parietal cortex has been seen as the site for temporal attentional processing, whereas the right parietal cortex has been seen as the site for spatial attentional processing. There is much debate about when the modulation of the primary visual cortex occurs, whether it is modulated in the feedforward sweep of processing or modulated by feedback projections from extrastriate and higher cortical areas. MEG and psychophysical measurements were used to look at spatially selective covert attention. Dual-task and cue-based paradigms were used. It was found that the posterior parietal cortex (PPC), in particular the SPL and IPL, was the main site of activation during these experiments, and that the left parietal lobe was activated more strongly than the right parietal lobe throughout. The levels of activation in both parietal and occipital areas were modulated in accordance with attentional demands. It is likely that spatially selective covert attention is dominated by the left parietal lobe, and that this takes the form of the proposed sensory-perceptual lateralization within the parietal lobes. Another form of lateralization is proposed, termed the motor-processing lateralization, the side of dominance being determined by handedness, being reversed in left- relative to right-handers. In terms of the modulation of the primary visual cortex, it was found that it is unlikely that V1 is modulated initially; rather the modulation takes the form of feedback from higher extrastriate and parietal areas. This fits with the idea of preattentive visual processing, a commonly accepted idea which, in itself, prevents the concept of initial modulation of V1.

The visually evoked magnetic response (VEMR) to a pattern onset/offset stimulus

This study characterizes the visually evoked magnetic response (VEMR) to pattern onset/offset stimuli, using a single channel BTi magnetometer. The influence of stimulus parameters and recording protocols on the VEMR is studied with inferences drawn about the nature of cortical processing, its origins and optimal recording strategies. Fundamental characteristics are examined, such as the behaviour of successive averaged and unaveraged responses; the effects of environmental shielding; averaging; inter- and intrasubject variability and equipment specificity. The effects of varying check size, field size, contrast and refractive error on latency, amplitude and topographic distribution are also presented. Latency and amplitude trends are consistent with previous VEP findings and known anatomical properties of the visual system. Topographic results are consistent with the activity of sources organised according to the cruciform model of striate cortex. A striate origin for the VEMR is also suggested by the results to quarter, octant and annulus field stimuli. Similarities in the behaviour and origins of the sources contributing to the CIIm and CIIIm onset peaks are presented for a number of stimulus conditions. This would be consistent with differing processing event in the same, or similar neuronal populations. Focal field stimuli produce less predictable responses than full or half fields, attributable to a reduced signal to noise ratio and an increased sensitivity to variations in cortical morphology. Problems with waveform peak identification are encountered for full field stimuli that can only be resolved by the careful choice of stimulus parameters, comparisons with half field responses or with reference to the topographic distribution of each waveform peak. An anatomical study of occipital lobe morphology revealed large inter- and intrasubject variation in calcarine fissure shape and striate cortex distribution. An appreciation of such variability is important for VEMR interpretation, due to the technique's sensitivity to source depth and orientation, and it is used to explain the experimental results obtained.

Topographic studies of scalp potentials evoked by pattern presentation

The waveform and scalp distribution of the visual evoked potentials elicited by stimuli in the foveal and parafoveal regions have been investigated in a group of normal humans using a 16-channel `brain mapping' system. The waveform and topography of the responses to pattern onset and pattern reversal stimulation were investigated, using 4 x 4o full field and 4 x 2o lateral and altitudinal half-field stimuli. The responses were composed of several successive peaks which are in some respects consistent with those demonstrated by other workers using larger field sizes. The differences in the behaviour of these components with respect to the position of the stimulus in the visual field were suggestive of origins in different areas of the visual cortex and/or different visual mechanism. Of particular interest were the major early positive components `P90' and `P95' of the responses to pattern onset and pattern reversal stimulation respectively. More detailed exploration of the behaviour of these major early positive components was carried out using `M-scaled' stimuli selected to activate one square centimetre patches of striate cortex and associated extrastriate re-projections, positioned at different points in the foveal and parafoveal area of the visual field. The inter- and intra-subject variability in amplitude and localisation of the signals elicited by these targets was considered to be a reflection of the individual variations in relationship of visual field projections with the pattern of gyri and fissures on the proximal surface of the occipital lobe. The behaviour of component P90 of the onset response is consistent with a lateral origin in extrastriate visual cortex; that of P95 of the pattern reversal response is consistent in some respects with a striate cortical origin, but in others with a partial origin in extrastriate cortex.

Growth of foliose lichens: a review

This review considers various aspects of the growth of foliose lichens including early growth and development, variation in radial growth rate (RaGR) of different species, growth to maturity, lobe growth variation, senescence and fragmentation, growth models, the influence of environmental variables, and the maintenance of thallus symmetry. The data suggest that a foliose lichen thallus is essentially a ‘colony’ in which the individual lobes exhibit a considerable degree of autonomy in their growth processes. During development, recognisable juvenile thalli are usually formed by 15 months to 4 years while most mature thalli exhibit RaGR between 1 and 5 mm yr-1. RaGR within a species is highly variable. The growth rate-size curve of a foliose lichen thallus may result from growth processes that take place at the tips of individual lobes together with size-related changes in the intensity of competition for space between the marginal lobes. Radial growth and growth in mass is influenced by climatic and microclimatic factors and also by substratum factors such as rock and bark texture, chemistry, and nutrient enrichment. Possible future research topics include: (1) measuring fast growing foliose species through life, (2) the three dimensional changes that occur during lobe growth, (3) the cellular changes that occur during regeneration, growth, and division of lobes, and (4) the distribution and allocation of the major lichen carbohydrates within lobes.

The neuropathology of the occipital cortex and its significance in the visual problems of patients with variant Creutzfeldt-Jakob disease (vCJD)

The occipital lobe is one of the cortical areas most affected by the pathology of variant Creutzfeldt-Jakob disease (vCJD). To understand the visual problems of vCJD patients, neuropathological changes were studied in striate (B17, V1) and extrastriate (B18, V2) regions of the occipital cortex in eleven cases of vCJD. No differences in the density of vacuoles or surviving neurons were observed in B17 and B18 but densities of glial cell nuclei and deposits of the protease resistant form of prion protein (PrPsc) were greater in B18. The density of PrPsc deposits in B17 was positively correlated with their density in B18. The density of the diffuse PrPsc deposits in B17 was negatively correlated with the density of the surviving neurons in B18. In B17 and B18, the vacuoles either exhibited density peaks in laminae II/III and V/VI or were more uniformly distributed across the laminae. Diffuse PrPsc deposits were most frequent in laminae II/III and florid PrPsc 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 compared with B17. Hence, both striate and extrastriate areas of the occipital cortex are affected by the pathology of vCJD, the pathological changes being most severe in B18. Neuronal degeneration in B18 may be associated with the development of diffuse PrPsc deposits 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. Pathological changes in striate and extrastriate regions of the occipital cortex may contribute to several of the visual problems identified in patients with vCJD including oculomotor and visuo-spatial function.

Brain ictal state characterisation through multimodal information integration

This Thesis addresses the problem of automated false-positive free detection of epileptic events by the fusion of information extracted from simultaneously recorded electro-encephalographic (EEG) and the electrocardiographic (ECG) time-series. The approach relies on a biomedical case for the coupling of the Brain and Heart systems through the central autonomic network during temporal lobe epileptic events: neurovegetative manifestations associated with temporal lobe epileptic events consist of alterations to the cardiac rhythm. From a neurophysiological perspective, epileptic episodes are characterised by a loss of complexity of the state of the brain. The description of arrhythmias, from a probabilistic perspective, observed during temporal lobe epileptic events and the description of the complexity of the state of the brain, from an information theory perspective, are integrated in a fusion-of-information framework towards temporal lobe epileptic seizure detection. The main contributions of the Thesis include the introduction of a biomedical case for the coupling of the Brain and Heart systems during temporal lobe epileptic seizures, partially reported in the clinical literature; the investigation of measures for the characterisation of ictal events from the EEG time series towards their integration in a fusion-of-knowledge framework; the probabilistic description of arrhythmias observed during temporal lobe epileptic events towards their integration in a fusion-of-knowledge framework; and the investigation of the different levels of the fusion-of-information architecture at which to perform the combination of information extracted from the EEG and ECG time-series. The performance of the method designed in the Thesis for the false-positive free automated detection of epileptic events achieved a false-positives rate of zero on the dataset of long-term recordings used in the Thesis.

Modulation of network oscillatory activity and GABAergic synaptic transmission by CB1 cannabinoid receptors in the rat medial entorhinal cortex

Cannabinoids modulate inhibitory GABAergic neurotransmission in many brain regions. Within the temporal lobe, cannabinoid receptors are highly expressed, and are located presynaptically at inhibitory terminals. Here, we have explored the role of type-1 cannabinoid receptors (CB1Rs) at the level of inhibitory synaptic currents and field-recorded network oscillations. We report that arachidonylcyclopropylamide, an agonist at CB1R, inhibits GABAergic synaptic transmission onto both superficial and deep medial entorhinal (mEC) neurones, but this has little effect on network oscillations in beta/gamma frequency bands. By contrast, the CB1R antagonist/inverse agonist LY320135 (500?nM), increased GABAergic synaptic activity and beta/gamma oscillatory activity in superficial mEC, was suppressed, whilst that in deep mEC was enhanced. These data indicate that cannabinoid-mediated effects on inhibitory synaptic activity may be constitutively active in vitro, and that modulation of CB1R activation using inverse agonists unmasks complex effects of CBR function on network activity.

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.

Factors determining the size frequency distribution of β-amyloid (Aβ) deposits in Alzheimer's disease

The size frequency distributions of discrete β-amyloid (Aβ) deposits were studied in single sections of the temporal lobe from patients with Alzheimer's disease. The size distributions were unimodal and positively skewed. In 18/25 (72%) tissues examined, a log normal distribution was a good fit to the data. This suggests that the abundances of deposit sizes are distributed randomly on a log scale about a mean value. Three hypotheses were proposed to account for the data: (1) sectioning in a single plane, (2) growth and disappearance of Aβ deposits, and (3) the origin of Aβ deposits from clusters of neuronal cell bodies. Size distributions obtained by serial reconstruction through the tissue were similar to those observed in single sections, which would not support the first hypothesis. The log normal distribution of Aβ deposit size suggests a model in which the rate of growth of a deposit is proportional to its volume. However, mean deposit size and the ratio of large to small deposits were not positively correlated with patient age or disease duration. The frequency distribution of Aβ deposits which were closely associated with 0, 1, 2, 3, or more neuronal cell bodies deviated significantly from a log normal distribution, which would not support the neuronal origin hypothesis. On the basis of the present data, growth and resolution of Aβ deposits would appear to be the most likely explanation for the log normal size distributions.

The spatial patterns of beta/A4 deposit subtypes in Alzheimer's disease

The spatial patterns of diffuse, primitive, classic (cored) and compact (burnt-out) subtypes of beta/A4 deposits were studied in coronal sections of the frontal lobe and hippocampus, including the adjacent gyri, in nine cases of Alzheimer's disease (AD). If the more mature deposits were derived from the diffuse deposits then there should be a close association between their spatial patterns in a brain region. In the majority of tissues examined, all deposit subtypes occurred in clusters which varied in dimension from 200 to 6400 microns. In many tissues, the clusters appeared to be regularly spaced parallel to the pia or alveus. The mean dimension of the primitive deposit clusters was greater than those of the diffuse, classic and compact types. In about 60% of cortical tissues examined, the clusters of primitive and diffuse deposits were not in phase, i.e. they alternated along the cortical strip. Clusters of classic deposits appeared to be distributed independently of the diffuse deposit clusters. Cluster size of the primitive deposits was positively correlated with the density of the primitive deposits in a tissue but no such relationship could be detected for the diffuse deposits. This study suggested that there was a complex relationship between the clusters of the different subtypes of beta/A4 deposits. If the diffuse deposits do give rise to the primitive and classic varieties then factors unrelated to the initial deposition of beta/A4 in the form of diffuse plaques were important in the formation of the mature deposits.

The neuropathology of the occipital cortex and its significance in the visual problems of patients with variant Creutzfeldt-Jakob Disease (vCJD)

The occipital lobe is one of the cortical areas most affected by the pathology of variant Creutzfeldt-Jakob disease (vCJD). To understand the visual problems of vCJD patients, neuropathological changes were studied in striate (B17, V1) and extrastriate (B18, V2) regions of the occipital cortex in eleven cases of vCJD. No differences in the density of vacuoles or surviving neurons were observed in B17 and B18 but densities of glial cell nuclei and deposits of the protease resistant form of prion protein (PrPsc) were greater in B18. The density of PrPsc deposits in B17 was positively correlated with their density in B18. The density of the diffuse PrPsc deposits in B17 was negatively correlated with the density of the surviving neurons in B18. In B17 and B18, the vacuoles either exhibited density peaks in laminae II/III and V/VI or were more uniformly distributed across the laminae. Diffuse PrPsc deposits were most frequent in laminae II/III and florid PrPsc 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 compared with B17. Hence, both striate and extrastriate areas of the occipital cortex are affected by the pathology of vCJD, the pathological changes being most severe in B18. Neuronal degeneration in B18 may be associated with the development of diffuse PrPsc deposits 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. Pathological changes in striate and extrastriate regions of the occipital cortex may contribute to several of the visual problems identified in patients with vCJD including oculomotor and visuo-spatial function. © 2012 Nova Science Publishers, Inc. All rights reserved.

Laminar distribution of the pathological changes in sporadic frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy:a quantitative study using polynomial curve fitting

Aims: Previous data suggest heterogeneity in laminar distribution of the pathology in the molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP). To study this heterogeneity, we quantified the changes in density across the cortical laminae of neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe. Methods: Changes in density of histological features across cortical gyri were studied in 10 sporadic cases of FTLD-TDP using quantitative methods and polynomial curve fitting. Results: Our data suggest that laminar neuropathology in sporadic FTLD-TDP is highly variable. Most commonly, neuronal cytoplasmic inclusions, dystrophic neurites and vacuolation were abundant in the upper laminae and glial inclusions, neuronal intranuclear inclusions, abnormally enlarged neurones, and glial cell nuclei in the lower laminae. TDP-43-immunoreactive inclusions affected more of the cortical profile in longer duration cases; their distribution varied with disease subtype, but was unrelated to Braak tangle score. Different TDP-43-immunoreactive inclusions were not spatially correlated. Conclusions: Laminar distribution of pathological features in 10 sporadic cases of FTLD-TDP is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feedforward and feedback cortico-cortical connections may be compromised in FTLD-TDP. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.