Changes in the clustering patterns of beta-amyloid (Abeta) with age in Down's syndrome

The spatial distribution patterns of the diffuse, primitive, and classic beta-amyloid (Abeta) deposits were studied in areas of the medial temporal lobe in 12 cases of Down's Syndrome (DS) 35 to 67 years of age. Large clusters of diffuse deposits were present in the youngest patients; cluster size then declined with patient age but increased again in the oldest patients. By contrast, the cluster sizes of the primitive and classic deposits increased with age to a maximum in patients 45 to 55 and 60 years of age respectively and declined in size in the oldest patients. In the parahippocampal gyrus (PHG), the clusters of the primitive deposits were most highly clustered in cases of intermediate age. The data suggest a developmental sequence in DS in which Abeta is deposited initially in the form of large clusters of diffuse deposits that are then gradually replaced by clusters of primitive and classic deposits. The oldest patients were an exception to this sequence in that the pattern of clustering resembled that of the youngest patients.

The spatial pattern of beta-amyloid (Abeta) deposits in Alzheimer’s disease patients is related to apolipoprotein genotype

The spatial patterns of the diffuse, primitive, and classic beta-amyloid (Abeta) deposits was studied in the frontal and temporal cortex in cases of Alzheimer’s disease (AD) expressing different apolipoprotein (Apo E) genotypes. No significant differences in the density of the three Abeta deposit subtypes were observed in individuals expressing genotypes e2/3 and e3/3 compared with those expressing e3/4 and e4/4. In all patients, Abeta deposit subtypes occurred in the tissue in clusters. Chi-square contingency analyses of the data suggested that the cluster size of the diffuse and classic Abeta deposits was unrelated to Apo E genotype. However, the primitive (‘neuritic’) type Abeta deposits occurred more frequently in smaller, denser clusters in individuals expressing genotypes e3/4 and e4/4 compared with those expressing e2/3 and e3/3. Hence, the presence of the e4 allele may be associated with a more specific pattern of neuronal degeneration in the frontal and temporal cortex in AD.

The spatial patterns of beta-amyloid (Abeta) deposits in elderly non-demented patients and patients with Alzheimer’s disease

The spatial patterns of diffuse, primitive, classic and compact beta-amyloid (Abeta) deposits were studied in the medial temporal lobe in 14 elderly, non-demented patients (ND) and in nine patients with Alzheimer’s disease (AD). In both patient groups, Abeta deposits were clustered and in a number of tissues, a regular periodicity of Abeta deposit clusters was observed parallel to the tissue boundary. The primitive deposit clusters were significantly larger in the AD cases but there were no differences in the sizes of the diffuse and classic deposit clusters between patient groups. In AD, the relationship between Abeta deposit cluster size and density in the tissue was non-linear. This suggested that cluster size increased with increasing Abeta deposit density in some tissues while in others, Abeta deposit density was high but contained within smaller clusters. It was concluded that the formation of large clusters of primitive deposits could be a factor in the development of AD.

The spatial patterns of beta/A4 deposit subtypes and blood vessels in Alzheimer's disease cases with pronounced congophilic angiopathy

The spatial patterns of diffuse, primitive and classic beta/A4 deposits was studied in relation to blood vessels in 24 cortical tissues from five elderly cases of Alzheimer's disease with pronounced congophilic angiopathy (CA). Beta/A4 deposit subtypes and beta/A4 stained blood vessels were clustered in the tissue. In many instances, the clusters of beta/A4 deposits and blood vessels were regularly spaced along the cortical strip. Total beta/A4 deposits were positively correlated with blood vessels in five tissues only. Similarly, clusters of diffuse and primitive beta/A4 subtypes were each positively correlated with blood vessels in two brain regions. By contrast, clusters of classic beta/A4 deposits were positively correlated with blood vessels in 62% of the cortical tissues examined. These results suggest that in patients with significant CA, initial deposition of beta/A4 protein was unrelated to blood vessels. However, clusters of classic beta/A4 deposits appeared to be in phase with clusters of blood vessels along the cortex.

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.

The effect of beta-adrenergic receptor antagonists on the temporal accommodative response

In this thesis a modified Canon IR optometer was used to record static and continuous responses of accommodation during sustained visual tasks. The instrument was assessed with regard to the ocular exit pupil used, its frequency response and noise levels. Experimental work concerned essentially the temporal characteristics and neurological basis of the accommodative mechanism. In the absence of visual stimuli, the accommodative system assumes a resting or tonic accommodative (TA) position, which may be modified by periods of sustained fixation. The rate of regression from a near task to TA in darkness has exhibited differences between regression rates for enunetropes (EMMs) compared with late-onset myopes (WMs). The rate of accommodative regression from a task set at 3D above TA was examined for a group of 10 EMMs and 10 LOMs for 3 conditions: saline, timolol and betaxolol. Timolol retarded the regression to TA for a sub-group of EMMs. The patterns of regression for the remaining emmetropes mirrored that for the LOMs, the drugs showing no difference in rate of regression compared with the saline condition. This provides support for the conjecture that LOMs and certain EMMs appear to be deficient in a sympathetic inhibitory component to the ciliary muscle which may attenuate adaptational changes in tonus and which leave them susceptible to the development of LOM. It is well established that the steady-state accommodative response is characterised by temporal changes in lens power having 2 dominant frequency components: a low frequency component (LFC: < 0.6Hz) and a high frequency component (HFC: 1.0-2.2Hz). This thesis investigates various aspects of these microfluctuations of accommodation.The HFC of accommodative fluctuations was shown to be present in central and peripheral lens zones, although the magnitude of the rms of accommodative microfluctuations was found to be reduced in the lens periphery. These findings concur with the proposal that the lens capsule acts as a force distributor, transmitting the tension from the zonules evenly over the whole of the lens surface.An investigation into the correlation between arterial pulse and the HFC of accommodative fluctuations showed that the peak frequency of the HFC was governed by the arterial pulse frequency. It was proposed that the microflucutations comprised a combination of neurological control (LFC) and physiological variations (HFC).The effect of timolol maleate on the steady-state accommodative response for a group of 10 emmetropes showed that timolol reduced significantly the rms of accommodative microfluctuations in treated but not untreated eyes. Consequently, the effect was considered to be locally, rather than systemically induced.The influence of the sympathetic system on within-task measurements of accommodation was examined by recording the accommodative response of 3 subjects to a sinusoidally moving target at 6 temporal frequencies from 0.05Hz to 0.5Hz for 3 drug conditions: saline, timolol and betaxolol. Timolol caused a reduced gain for frequencies below 0.3 whereas betaxolol reduced accommodative gain for all frequencies. It was proposed that the results for timolol were consistent with temporal response characteristics of sympathetic innervation of the ciliary muscle whereas the betaxolol results were thought to be a manifestation of fatigue resulting from the CNS depressant effect of the drug.

Regulation of beta-cell viability and gene expression by distinct agonist fragments of adiponectin

Obesity is an established risk factor for type 2 diabetes. Activation of the adiponectin receptors has a clear role in improving insulin resistance although conflicting evidence exists for its effects on pancreatic beta-cells. Previous reports have identified both adiponectin receptors (ADR-1 and ADR-2) in the beta-cell. Recent evidence has suggested that two distinct regions of the adiponectin molecule, the globular domain and a small N-terminal region, have agonist properties. This study investigates the effects of two agonist regions of adiponectin on insulin secretion, gene expression, cell viability and cell signalling in the rat beta-cell line BRIN-BD11, as well as investigating the expression levels of adiponectin receptors (ADRs) in these cells. Cells were treated with globular adiponectin and adiponectin (15-36) +/-leptin to investigate cell viability, expression of key beta-cell genes and ERK1/2 activation. Both globular adiponectin and adiponectin (15-36) caused significant ERK1/2 dependent increases in cell viability. Leptin co-incubation attenuated adiponectin (15-36) but not globular adiponectin induced cell viability. Globular adiponectin, but not adiponectin (15-36), caused a significant 450% increase in PDX-1 expression and a 45% decrease in LPL expression. ADR-1 was expressed at a higher level than ADR-2, and ADR mRNA levels were differentially regulated by non-esterified fatty acids and peroxisome-proliferator-activated receptor agonists. These data provide evidence of roles for two distinct adiponectin agonist domains in the beta-cell and confirm the potentially important role of adiponectin receptor agonism in maintaining beta-cell mass.

The size frequency distributions of beta-amyloid deposit subtypes in Alzheimer's disease

The size frequency distributions of diffuse, primitive and classic beta/A4 deposits was studied in single sections in the hippocampus, parahippocampal gyrus (PHG) and lateral occipitotemporal gyrus (LOT) in five cases of Alzheimer's disease. In most brain regions, the size distribution of the diffuse deposits was significantly different from that of the primitive and classic deposits. The data suggested that larger diffuse deposits appeared to be converted less often into primitive and classic deposits. Significant differences in the size distribution of primitive deposits were commonly observed between brain regions in which there was no difference in the size distribution of the diffuse deposits. Hence, local brain factors may influence the size of diffuse deposit which can be converted into mature amyloid deposit.

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.

A comparison of beta-amyloid deposition in the medial temporal lobe in sporadic Alzheimer's disease, Down's syndrome and normal elderly brains

The density of beta-amyloid (A beta) deposits was studied in the medial temporal lobe in non-demented individuals and in sporadic Alzheimer's disease (SAD) and Down's syndrome (DS). No A beta deposits were recorded in six of the non-demented cases, while in a further eight cases, these were confined to either the lateral occipitotemporal or parahippocampal gyrus. The mean density of A beta deposits in the cortex was greater in SAD and DS than in non-demented cases but with overlap between patient groups. The mean density of A beta deposits was greater in DS than SAD consistent with a gene dosage effect. The ratio of primitive to diffuse A beta deposits was greater in DS and in non-demented cases than in SAD and the ratio of classic to diffuse deposits was lowest in DS. In all groups, A beta deposits occurred in clusters which were often regularly distributed. In the cortex, the dimension of the A beta clusters was greater in SAD than in the non-demented cases and DS. The data suggest that the development of A beta pathology in the hippocampus could be a factor in the development of DS and SAD. Furthermore, the high density of A beta deposits, and in particular the high proportion of primitive type deposits, may be important in DS while the development of large clusters of A beta deposits may be a factor in SAD.