Beta-amyloid deposition in the medial temporal lobe in elderly non-demented brains and in Alzheimer's disease

The density of diffuse, primitive, classic and compact β-amyloid (β/A4) deposits was estimated in the medial temporal lobe in elderly non-demented brains and in Alzheimer's disease (AD). In the non-demented cases, β/A4 deposits were absent in the hippocampus but in 8/14 cases they were present in the adjacent cortical regions. Variation in β/A4 deposition in the non-demented cases was large and overlapped with that of the AD cases. The ratio of mature to diffuse β/A4 deposits was greater in the non-demented than in the AD cases. In both the non-demented cases and AD, the β/A4 deposits were clustered with, in many tissues, a regular distribution of clusters along the cortex parallel to the pia. However, the mean cluster size of the deposits in the cortex was greater in AD than in the non-demented cases. These results suggest that the spread of β/A4 pathology between the modular units of the cortex and into the hippocampus could be important factors in the development of AD.

Factors associated with lobe division in the lichen Parmelia conspersa (Ehrh. ex. Ach.)Ach.

The factors associated with lobe division were studied in thalli of the lichen Parmelia conspersa (Ehrh. ex Ach.)Ach. Lobe division was studied in sequences of adjacent lobes using spatial pattern analysis. In five large thalli, lobe division within the thallus margin was randomly distributed. Correlations between the degree of lobe division, the radial growth of the lobe and lobe morphology were studied in six thalli. Lobe division was positively correlated with either lobe width or area in four thalli. Correlations were observed with radial growth or morphology of the adjacent lobes in two thalli. Dividing and non-dividing lobes were removed from large thalli and glued to pieces of slate with their tips either at the same level or in front of neighbouring lobes. Dividing lobes divided more rapidly when their tips were glued in front of their neighbours. The levels of ribitol, arabitol and mannitol were measured within a 2 mm region of the tip in dividing and non-dividing lobes on four occasions in 1994. Carbohydrate levels were significantly increased in dividing compared with non-dividing lobes. In addition, the mean size of the algal cells was greater in non-dividing compared with dividing lobes especially at the lobe base. However, the percentage of zoosporangia and aplanosporangia did not vary significantly in dividing and non-dividing lobes. These results suggest that: 1) the pattern of lobe division within the thallus margin may be random, 2) lobe division may be determined by lobe size and the location of the lobe tip relative to the neighbouring lobes and 3) there may be an increase in the productivity of lobes associated with lobe division.

Does radial growth of the lichen Parmelia conspersa depend exclusively on growth processes at the lobe tip?

The objective of this study was to test the hypothesis that the radial growth of lobes of the lichen Parmelia conspersa depends largely on growth processes which occur at the lobe tip. First, individual lobes were removed from thalli and portions of the lobe removed to within various distances from the tip. Radial growth of the lobe was unaffected until less than 2 mm of the lobe tip remained. Second, the surfaces of individual lobes were painted with acrylic paint leaving different portions of the lobe exposed. Painting lobes to within 0.5 mm and 1 mm of the tip substantially reduced radial growth. Third, the levels of ribitol, arabitol and mannitol were measured in different regions behind the lobe tip on four occasions during 1994. The concentration of the three carbohydrates was greatest at the lobe tip and the levels declined linearly with distance from the tip. Fourth, painting one vertical half of the lobe tip did not affect radial growth but artificially bisecting the lobe tip with a scalpel reduced radial growth. Although transport of carbohydrate from other regions of the lobe cannot be ruled out, the results support the hypothesis that radial growth in P. conspersa depends largely on processes within a region approximately 2 mm behind the lobe tip.

Lewy body and Alzheimer pathology in temporal lobe in dementia with Lewy bodies

The density of Lewy bodies (LB), senile plaques (SP), and neurofibrillary tangles (NFT) was studied in the temporal lobe in four patients diagnosed with ‘pure’ dementia with Lewy bodies (DLB) and eight patients diagnosed with DLB with associated Alzheimer’s disease (DLB/AD). In both patient groups, the density of LB was greatest in the lateral occipitotemporal gyrus (LOT) and least in areaas CA1 and CA4 of the hippocampus. In DLB/AD, the densities of SP and NFT were greatest in the cortical regions and in area CA1 of the hippocampus respectively. Mean LB densities in the temporal lobe were similar in ‘pure’ DLB and DLB/AD patients but mean SP and NFT densities were greater in DLB/AD. No significant correlations were observed between the densities of LB, SP and NFT in any brain region. The data suggest that in the temporal lobe LB and SP/NFT are distributed differently; SP and NFT in DLB/AD are distributed similarly to ‘pure’ AD and also that LB and AD pathologies appear to develop independently. Hence, the data support the hypothesis that some cases of DLB combine the features of DLB and AD.

A comparison of βamyloid (aβ deposition in the medial temporal lobe in late-onset sporadic Alzheimer's disease, and down's syndrome

The density of diffuse, primitive, classic and compact βamyloid (Aβ deposits was estimated in regions of the medial temporal lobe (MTL) in 15 cases of late-onset sporadic Alzheimer's disease (AD) and 12 cases of Down's syndrome (DS). A similar pattern of Aβ deposition was observed in the MTL in the AD and DS cases with a reduced density of deposits in the hippocampus compared with the adjacent cortical regions. Total Aβ deposit density was greater in DS than in AD in all brain regions examined. This could be attributable to overexpression of the amyloid precursor protein gene. The ratio of the primitive to the diffuse Aβ deposits was greater in DS than in AD which suggests that the formation of mature amyloid deposits is enhanced in DS. The diffuse deposits exhibited a parabolic and the primitive deposits an inverted parabolic response with age in the DS cases. This suggests either that the diffuse and primitive deposits are sequentially related or that there are alternate pathways of Aβ deposition. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Factors determining lobe growth in foliose lichen thalli

This study investigates the relative importance of climate, lobe morphology and lobe interactions in determining the radial growth of individual lobes in foliose lichen thalli. The radial growth of 75 lobes from thalli of Parmelia conspersa (Ehrh. Ex Ach.) Ach. and Parmelia glabratula ssp. fuliginosa (Fr. ex Duby) Laund. was measured over 22 successive months in relation to climatic factors. Individual lobes showed a fluctuating pattern of radial growth with alternating periods of fast and slow growth. In 17/75 (23%) of lobes studied, monthly radial growth was correlated with a climatic factor, usually total rainfall or the frequency of sunshine hours. In addition, the radial growth of 54 lobes of P. conspersa was measured over four months in relation to lobe morphology and the radial growth and morphology of adjacent lobes. Radial growth was correlated with lobe length and with the radial growth of adjacent lobes. In addition, the pattern of lobe branching appeared to be related to lobe width and to a lesser extent to lobe length and the width of adjacent lobes. The radial growth in one year of exceptionally long lobes which had grown beyond the thallus margin was similar to more normal lobes, but experimentally bisected lobes had significantly reduced radial growth compared with control lobes. These results suggested that the fluctuating pattern of radial growth in individual lobes may be determined by climate and the pattern of lobe branching. In addition, the pattern of lobe branching was related to lobe width and may be influenced by adjacent lobes.

Analysis of β-amyloid (Aβ) deposition in the temporal lobe in Alzheimer's disease using Fourier (spectral) analysis

To determine the spatial pattern of ß-amyloid (Aß) deposition throughout the temporal lobe in Alzheimer's disease (AD). Methods: Sections of the complete temporal lobe from six cases of sporadic AD were immunolabelled with antibody against Aß. Fourier (spectral) analysis was used to identify sinusoidal patterns in the fluctuation of Aß deposition in a direction parallel to the pia mater or alveus. Results: Significant sinusoidal fluctuations in density were evident in 81/99 (82%) analyses. In 64% of analyses, two frequency components were present with density peaks of Aß deposits repeating every 500–1000 µm and at distances greater than 1000 µm. In 25% of analyses, three or more frequency components were present. The estimated period or wavelength (number of sample units to complete one full cycle) of the first and second frequency components did not vary significantly between gyri of the temporal lobe, but there was evidence that the fluctuations of the classic deposits had longer periods than the diffuse and primitive deposits. Conclusions: (i) Aß deposits exhibit complex sinusoidal fluctuations in density in the temporal lobe in AD; (ii) fluctuations in Aß deposition may reflect the formation of Aß deposits in relation to the modular and vascular structure of the cortex; and (iii) Fourier analysis may be a useful statistical method for studying the patterns of Aß deposition both in AD and in transgenic models of disease.

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

To determine the factors influencing the distribution of -amyloid (Abeta) deposits in Alzheimer's disease (AD), the spatial patterns of the diffuse, primitive, and classic A deposits were studied from the superior temporal gyrus (STG) to sector CA4 of the hippocampus in six sporadic cases of the disease. In cortical gyri and in the CA sectors of the hippocampus, the Abeta deposits were distributed either in clusters 200-6400 microm in diameter that were regularly distributed parallel to the tissue boundary or in larger clusters greater than 6400 microm in diameter. In some regions, smaller clusters of Abeta deposits were aggregated into larger 'superclusters'. In many cortical gyri, the density of Abeta deposits was positively correlated with distance below the gyral crest. In the majority of regions, clusters of the diffuse, primitive, and classic deposits were not spatially correlated with each other. In two cases, double immunolabelled to reveal the Abeta deposits and blood vessels, the classic Abeta deposits were clustered around the larger diameter vessels. These results suggest a complex pattern of Abeta deposition in the temporal lobe in sporadic AD. A regular distribution of Abeta deposit clusters may reflect the degeneration of specific cortico-cortical and cortico-hippocampal pathways and the influence of the cerebral blood vessels. Large-scale clustering may reflect the aggregation of deposits in the depths of the sulci and the coalescence of smaller clusters.

Lobe formation and division in the foliose lichen Xanthoparmelia conspersa

New lobe development and lobe division was studied in the foliose lichen Xanthoparmelia conspersa (Ehrh. ex. Ach.) Hale. In thalli with either the centre or margin removed, the inside edge of the perimeter, the outer edge of the reproductive centre, and fragments derived from the thallus perimeter all regenerated growing points (‘lobe primordia’) within a year. Thalli possessing isidia had the greatest ability to regenerate growing points. In reproductive thalli, there was a positive correlation between the density of new growing points and thallus size. When fragments were cut from the perimeters of mature X. conspersa thalli and glued to pieces of slate, the ratio of growing points to mature lobes increased over 54 months. Lobes within a thallus exhibited different degrees of bifurcation. In some bifurcating lobes, the point of origin of the bifurcation advanced at the same rate as the lobe tips over 4 months but in most lobes, the bifurcation point either advanced less rapidly than the lobe tips or retreated from its original location. Removing adjacent lobes had no significant effect on the radial growth of a lobe over 4 months or on the location of the bifurcation point but it increased the number of growing points. These results suggest that for X. conspersa: 1) all portions of of thalli can regenerate growing points, 2) few growing points actually develop into mature lobes, 3) individual lobes within a thallus grow and divide differently, and 4) adjacent lobes inhibit the development of growing points on their neighbours.

Mechanisms of altered cortical excitability in photosensitive epilepsy

Despite the multiplicity of approaches and techniques so far applied for identifying the pathophysiological mechanisms of photosensitive epilepsy, a generally agreed explanation of the phenomenon is still lacking. The present thesis reports on three interlinked original experimental studies conducted to explore the neurophysiological correlates and the phatophysiological mechanism of photosensitive epilepsy. In the first study I assessed the role of the habituation of the Visual Evoked Response test as a possible biomarker of epileptic visual sensitivity. The two subsequent studies were designed to address specific research questions emerging from the results of the first study. The findings of the three intertwined studies performed provide experimental evidence that photosensitivity is associated with changes in a number of electrophysiological measures suggestive of altered balance between excitatory and inhibitory cortical processes. Although a strong clinical association does exist between specific epileptic syndromes and visual sensitivity, results from this research indicate that photosensitivity trait seems to be the expression of specific pathophysiological mechanisms quite distinct from the “epileptic” phenotype. The habituation of Pattern Reversal Visual Evoked Potential (PR-VEP) appears as a reliable candidate endo-phenotype of visual sensitivity. Interpreting the findings of this study in the context of the broader literature on visual habituation we can hypothesise the existence of a shared neurophysiological background between photosensitive epilepsy and migraine. Future studies to elucidate the relationship between the proposed indices of cortical excitability and specific polymorphisms of excitatroy and inhibitory neurotransmission will need to be conducted to assess their potential role as biomarkers of photosensitivity.

The effectiveness of lamotrigine in the treatment of photosensitive epilepsy

Photosensitive epilepsy and associated pattern sensitivity are more prevalent in females and are usually treated with sodium valproate. Sodium valproate has an adverse effect profile, which particularly affects females, including teratogenicity, association with the polycystic ovary syndrome and weight gain. It would be useful therefore if an alternative treatment for photosensitive epilepsy could be found. The principle aim of this study was to investigate the effectiveness of lamotrigine in the treatment of photosensitive epilepsy in adults and children. Patients were either drug-naive, commencing lamotrigine therapy or were transferring from other antiepileptic drugs to lamotrigine (primarily sodium valproate) due to lack of response, adverse effects or desired pregnancy. The photoparoxsymal response in the electroencephalograph was used as the primary measure of photo and pattern sensitivity. In addition the effects of lamotrigine on occipital spikes and normal responses in the EEG to visual stimuli were investigated. Secondary measures also included the resting EEG, seizures, body mass index, menstrual function, mood and cognitive function. The results suggest that in adult patients lamotrigine is efficacious in the treatment of photosensitive epilepsy, although it appears inferior to sodium valproate. Lamotrigine does however have a more favourable adverse effect profile than valproate. The results indicate that lamotrigine therapy is suitable for photosensitive epilepsy in women of childbearing age or in patients experiencing unacceptable adverse effects with valproate therapy. Patients are more likely to respond to lamotrigine treatment if they present with sensitivity to a limited number of frequencies. Lamotrigine does not seem to be as efficacious in the treatment of children, although against it may be considered a second line drug if the child does not respond to or will not tolerate sodium valproate.

The role of the cortical occipital spike in photosensitive epilepsy

Chapters one to three are an introduction to photosensitive epilepsy, electroencephalography (EEG) and the magnocellular and parvocellular visual pathways. Photoparoxysmal response (PPR) are strongly associated with photosensitive epilepsy. Chapters four to nine investigated whether occipital spikes were associated with PPR and hence with photosensitive epilepsy. The chapters investigated whether the response types showed similar dependence on stimulus characteristics using EEG. Chapters four and five found that occipital spikes and PPR showed different dependence on colour and luminance contrast. The differences were consistent with the magnocellular pathway mediating occipital spikes and the pavocellular pathway mediating PPR. The study in chapter eight found that monocular occlusion had a significantly greater effect on PPR than on occipital spikes, which is further evidence against an association between the two types of response. Chapters six and seven showed that occipital spikes and PPR had similar optimum spatial and temporal frequencies. Chapter nine showed that both response types could be generated via stimulation of the periphery of the retina. However, these three chapters are not strong evidence of an association, as the results do not contradict the theory that the responses are generated via different pathways. The magnocellular and pavocellular pathways have similar optimum temporal and spatial frequencies and both are present in the periphery. In chapter ten, magnetoencephalography was used to estimate the source of activity underlying the components of the VEP and occipital spike. Changes in the amplitude and latency in the components of the normal VEP are associated with epilepsy. However, the source underlying the occipital spikes was not related to that underlying the components of the VEP so this is also removed as a source of evidence for an association between occipital spikes and photosensitive epilepsy.

Ambulatory EEG monitoring in the diagnosis and treatment of epilepsy and related disorders

Ambulatory EEG recording enables patients with epilepsy and related disorders to be monitored in an unrestricted environment for prolonged periods. Attacks can therefore be recorded and EEG changes at the time can aid diagnosis. The relevant Iiterature is reviewed and a study made of' 250 clinical investigations. A study was also made of the artefacts,encountered during ambulatory recording. Three quarters of referrals were for distinguishing between epileptic and non-epileptic attacks. Over 60% of patients showed no abnormality during attacks. In comparison with the basic EEG the ambulatory EEG provided about ten times as much information. A preliminary follow-up study showed that results, of ambulatory monitoring agreed with the final diagnosis in 8 of 12 patients studied. Of 10 patients referred, for monitoring the occurrence of absence seizures, 8 showed abnormality during the baslcJ EEG .and 10 during the ambulatory EEG. Other patients. were referred: for sleep recording and to clarify the seizure type. An investigation into once daily (OD) versus twice daily administration of sodium valproate in patients with absence seizures showed that an OD regime was equally as effective as a BD regime. Circadian variations in spike and wave activity in patients on and off treatment were also examined. There was significant agreement between subjects on the time of occurrence of abnormality during sleep only, This pattern was not ,affected with treatment nor was there any difference in the daily pattern of occurrence of abnormality between the two regimes. Overall findings suggested that ambulatory monitoring was a valuable tool in the diagnosis and treatment of epilepsy which with careful planning and patient selection could be used in any EEG department and would benefit a:wide range of patients.