Neuropathological differences between areas B17 and B18: implications for visual evoked responses in Alzheimer's disease

The density of senile plaques (SP) and neurofibrillary tangles (NFT) was estimated at post-mortem in areas B17 and B18 of the visual cortex in 18 Alzheimer’s disease (AD) cases which varied in disease onset and duration. The density of SP in B17 and NFT in B17 and B18 declined significantly with age at death of the patient. The density of SP and NFT was greater in B18 than B17 but only in cases of earlier onset and shorter duration. The pathological differences between B17 and B18 could explain the visual evoked responses (VER) that have been reported in AD. However, the differences were small, and changes in the afferent pathways remain the most likely explanation for the VER in AD. © 1994 S. Karger AG, Basel.

Measuring the degree of spatial correlation between pathological lesions in Alzheimer's disease

The pathological lesions characteristic of Alzheimer's disease (AD), viz., senile plaques (SP) and neurofibrillary tangles (NFT) may not be randomly distributed with reference to each other but exhibit a degree of sptial association or correlation, information on the degree of association between SP and NFT or between the lesions and normal histological features, such as neuronal perikarya and blood vessels, may be valuable in elucidating the pathogenesis of AD. This article reviews the statistical methods available for studying the degree of spatial association in histological sections of AD tissue. These include tests of interspecific association between two or more histological features using chi-square contingency tables, measurement of 'complete' and 'absolute' association, and more complex methods that use grids of contiguous samples. In addition, analyses of association using correlation matrices and stepwise multiple regression methods are described. The advantages and limitations of each method are reviewed and possible future developments discussed.

Laminar distribution of amyloid-beta (Abeta) deposits in dementia with Lewy bodies: comparison with Alzheimer's disease

Significant amyloid-beta (Abeta) deposition in cases of dementia with Lewy bodies (DLB) may represent concurrent Alzheimer's disease (AD). To test this hypothesis, the laminar distribution of the diffuse, primitive, and classic Abeta deposits was studied in the frontal and temporal cortex in cases of DLB and were compared with AD. In DLB, the diffuse and primitive deposits exhibited two common patterns of distribution; either maximum density occurred in the upper cortical laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. In addition, a bimodal distribution of the classic deposits was observed in approximately half of the cortical areas analysed. A number of differences in the laminar distributions of Abeta deposits were observed in DLB and AD. First, the proportion of the primitive relative to the diffuse and classic deposits present was lower in DLB compared with AD. Second, the primitive deposits were more frequently bimodally distributed in DLB. Third, the density of the diffuse deposits reached a maximum lower in the cortical profile in AD. These data suggest differences in the pattern of cortical degeneration in the two disorders and therefore, DLB cases with significant Abeta pathology may not represent the coexistence of DLB and AD.

Size frequency distribution of beta-amyloid (Abeta) deposits in dementia with Lewy bodies

In Alzheimer's disease (AD) and Down's syndrome (DS), the size frequency distribution of the beta-amyloid (Abeta) deposits can be described by a log-normal model and may indictae the growth of the deposits. This study determined the size frequency distribution of the Abeta deposits in the temporal lobe in 8 casaes of dementia with Lewy bodies (DLB) with associated AD pathology (DLB/AD. The size distributions of Abeta deposits were unimodal and positively skewed; the mean size of deposi and the degree of skew varying with deposit type and brain region. Size distributions of the primitive deposits had lower means and were less skewed compared with the diffuse and classic deposits. In addition, size distributions in the hippocampus and parahippocampal gyrus (PHG) had larger means and a greater degree of skew compared with other cortical gyri. All size distributions deviated significantly from a log-normal model. There were more Abeta deposits than expected in the smaller size classes and fewer than expected near the mean and in the larger size classes. The data suggest thatthe pattern of growth of the Abeta deposits in DLB/AD depends both on deposit morphology and brain area. In addition, Abeta deposits in DLB appear to grow to within a more restricted size range than predicted and hence, to have less potential for growth compared with cases of 'pure' AD and DS.

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.

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.

Laminar distribution of cortical Lewy bodies and neurofibrillary tangles in dementia with Lewy bodies

The laminar distribution of Lewy bodies (LB) and neurofibrillary tangles (NFT) was studied in twelve cases of dementia with Lewy bodies (DLB). LB density was maximal in the lower cortex in 59% of cortical areas, in the upper cortex in 31% of areas while densities were similar in the upper and lower cortex in 9% of areas. The distribution of LB was either unimodal with a lower cortical peak, or bimodal with density peaks in the upper and lower cortex. The density of NFT was maximal in the upper cortex in all tissues. The distributions of LB and NFT were similar in temporal and frontal cortex and in cases with and without Alzheimer’s disease (AD). The vertical densities of LB and NFT were not significantly correlated. LB formation may affect the feedback cortico-cortical pathway and the efferent cortical projections whereas NFT formation may affect the feedforward cortico-cortical pathway.

Ocular and systemic vascular dysfunction in neurodegenerative disease

The important role played by vascular factors in the pathogenesis of neurodegenerative disease has been increasingly realised over recent years. The nature and impact of ocular and systemic vascular dysfunction in the pathogenesis of comparable neurodegenerative diseases such as glaucoma and Alzheimer’s disease (AD) has however never been fully explored. The aim of this thesis was therefore to investigate the presence of macro- and micro-vascular alterations in both glaucoma and AD and to explore the relationships between these two chronic, slowly progressive neurodegenerative diseases. The principle sections and findings of this work were: 1. Is the eye a window to the brain? Retinal vascular dysfunction in Alzheimer’s disease · Mild newly diagnosed AD patients demonstrated ocular vascular dysfunction, in the form of an altered retinal vascular response to flicker light, which correlated with their degree of cognitive impairment. 2. Ocular and systemic vascular abnormalities in newly diagnosed normal tension glaucoma (NTG) patients · NTG patients demonstrated an altered retinal arterial constriction response to flicker light along with an increased systemic arterial stiffness and carotid artery intima-media thickness (IMT). These findings were not replicated by healthy age matched controls. 3. Ocular vascular dysregulation in AD compares to both POAG and NTG · AD patients demonstrated altered retinal arterial reactivity to flicker light which was comparable to that of POAG patients and altered baseline venous reactivity which was comparable to that of NTG patients. Neither alteration was replicated by healthy controls. 4. POAG and NTG: two separate diseases or one continuous entity? The vascular perspective · POAG and NTG patients demonstrated comparable alterations in nocturnal systolic blood pressure (SBP) variability, ocular perfusion pressure, retinal vascular reactivity, systemic arterial stiffness and carotid IMT. · Nocturnal SBP variability was found to correlate with both retinal artery baseline diameter fluctuation and carotid IMT across the glaucoma groups.

The visual cortex in Alzheimer disease:laminar distribution of the pathological changes in visual areas V1 and V2

Alzheimer’s disease (AD) is an important neurodegenerative disorder causing visual problems in the elderly population. The pathology of AD includes the deposition in the brain of abnormal aggregates of ?-amyloid (A?) in the form of senile plaques (SP) and abnormally phosphorylated tau in the form of neurofibrillary tangles (NFT). A variety of visual problems have been reported in patients with AD including loss of visual acuity (VA), colour vision and visual fields; changes in pupillary responses to mydriatics, defects in fixation and in smooth and saccadic eye movements; changes in contrast sensitivity and in visual evoked potentials (VEP); and disturbances in complex visual tasks such as reading, visuospatial function, and in the naming and identification of objects. In addition, pathological changes have been observed to affect the eye, visual pathway, and visual cortex in AD. To better understand degeneration of the visual cortex in AD, the laminar distribution of the SP and NFT was studied in visual areas V1 and V2 in 18 cases of AD which varied in disease onset and duration. In area V1, the mean density of SP and NFT reached a maximum in lamina III and in laminae II and III respectively. In V2, mean SP density was maximal in laminae III and IV and NFT density in laminae II and III. The densities of SP in laminae I of V1 and NFT in lamina IV of V2 were negatively correlated with patient age. No significant correlations were observed in any cortical lamina between the density of NFT and disease onset or duration. However, in area V2, the densities of SP in lamina II and lamina V were negatively correlated with disease duration and disease onset respectively. In addition, there were several positive correlations between the densities of SP and NFT in V1 with those in area V2. The data suggest: (1) NFT pathology is greater in area V2 than V1, (2) laminae II/III of V1 and V2 are most affected by the pathology, (3) the formation of SP and NFT in V1 and V2 are interconnected, and (4) the pathology may spread between visual areas via the feed-forward short cortico-cortical connections.

Efficacy of memantine for agitation in Alzheimer's dementia:a randomised double-blind placebo controlled trial

Background - Agitation in Alzheimer’s disease (AD) is common and associated with poor patient life-quality and carer distress. The best evidence-based pharmacological treatments are antipsychotics which have limited benefits with increased morbidity and mortality. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD. Methods and Findings - We recruited 153 participants with AD and clinically significant agitation from care-homes or hospitals for a double-blind randomised-controlled trial and 149 people started the trial of memantine versus placebo. The primary outcome was 6 weeks mixed model autoregressive analysis of Cohen-Mansfield Agitation Inventory (CMAI). Secondary outcomes were: 12 weeks CMAI; 6 and 12 weeks Neuropsychiatric symptoms (NPI), Clinical Global Impression Change (CGI-C), Standardised Mini Mental State Examination, Severe Impairment Battery. Using a mixed effects model we found no significant differences in the primary outcome, 6 weeks CMAI, between memantine and placebo (memantine lower -3.0; -8.3 to 2.2, p = 0.26); or 12 weeks CMAI; or CGI-C or adverse events at 6 or 12 weeks. NPI mean difference favoured memantine at weeks 6 (-6.9; -12.2 to -1.6; p = 0.012) and 12 (-9.6; -15.0 to -4.3 p = 0.0005). Memantine was significantly better than placebo for cognition. The main study limitation is that it still remains to be determined whether memantine has a role in milder agitation in AD. Conclusions - Memantine did not improve significant agitation in people with in moderate-to-severe AD. Future studies are urgently needed to test other pharmacological candidates in this group and memantine for neuropsychiatric symptoms.

Impact of cholinesterase inhibitors on behavioral and psychological symptoms of Alzheimer's disease:a meta-analysis

Objective: To determine the efficacy of cholinesterase inhibitors (ChEIs) in improving the behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer’s disease (AD). Data sources: We searched MEDLINE, Cochrane Registry, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1966 to 2007. We limited our search to English Language, full text, published articles and human studies. Data extraction: We included randomized, double-blind, placebo-controlled trials evaluating the efficacy of donepezil, rivastigmine, or galantamine in managing BPSD displayed by AD patients. Using the United States Preventive Services Task Force (USPSTF) guidelines, we critically appraised all studies and included only those with an attrition rate of less than 40%, concealed measurement of the outcomes, and intention to treat analysis of the collected data. All data were imputed into pre-defined evidence based tables and were pooled using the Review Manager 4.2.1 software for data synthesis. Results: We found 12 studies that met our inclusion criteria but only nine of them provided sufficient data for the meta-analysis. Among patients with mild to severe AD and in comparison to placebo, ChEIs as a class had a beneficial effects on reducing BPSD with a standard mean difference (SMD) of -0.10 (95% confidence interval [CI]; -0.18, -0.01) and a weighted mean difference (WMD) of -1.38 neuropsychiatry inventory point (95% CI; -2.30, -0.46). In studies with mild AD patients, the WMD was -1.92 (95% CI; -3.18, -0.66); and in studies with severe AD patients, the WMD was -0.06 (95% CI; -2.12, +0.57). Conclusion: Cholinesterase inhibitors lead to a statistical significant reduction in BPSD among patients with AD, yet the clinical relevance of this effect remains unclear.

Temporal lobe pathology in neurodegenerative disease:a comparative study of eight disorders with special reference to the hippocampus

The temporal lobe is a major site of pathology in a number of neurodegenerative diseases. In this chapter, the densities of the characteristic pathological lesions in various regions of the temporal lobe were compared in eight neurodegenerative disorders, viz., Alzheimer’s disease (AD), Down’s syndrome (DS), dementia with Lewy bodies (DLB), Pick’s disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), sporadic Creutzfeldt-Jakob disease (sCJD), and neuronal intermediate filament inclusion disease (NIFID). Temporal lobe pathology was observed in all of these disorders most notably in AD, DS, PiD, sCJD, and NIFID. The regions of the temporal lobe affected by the pathology, however, varied between disorders. In AD and DS, the greatest densities of ?-amyloid (A?) deposits were recorded in cortical regions adjacent to the hippocampus (HC), DS exhibiting greater densities of A? deposits than AD. Similarly, in sCJD, greatest densities of prion protein (PrPsc) deposits were recorded in cortical areas of the temporal lobe. In AD and PiD, significant densities of neurofibrillary tangles (NFT) and Pick bodies (PB) respectively were present in sector CA1 of the HC while in CBD, the greatest densities of tau-immunoreactive neuronal cytoplasmic inclusions (NCI) were present in the parahippocampal gyrus (PHG). Particularly high densities of PB were present in the DG in PiD, whereas NFT in AD and Lewy bodies (LB) in DLB were usually absent in this region. These data confirm that the temporal lobe is an important site of pathology in the disorders studied regardless of their molecular ‘signature’. However, disorders differ in the extent to which the pathology spreads to affect the HC which may account for some of the observed differences in clinical dementia.

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.

Density and cross-sectional areas of axons in the olfactory tract in control subjects and Alzheimer's disease:an image analysis study

Objective. Using an image analysis system to determine whether there is loss of axons in the olfactory tract (OT) in Alzheimer’s disease (AD). Design. A retrospective neuropathological study. Patients Nine control patients and eight clinically and pathologically verified AD cases. Measurements and Results. There was a reduction in axon density in AD compared with control subjects in the central and peripheral regions of the tract. Axonal loss was mainly of axons with smaller (<2.99 µm2) myelinated cross-sectional areas. Conclusions. The data suggest significant degeneration of axons within the OT involving the smaller sized axons. Loss of axons in the OT is likely to be secondary to pathological changes originating within the parahippocampal gyrus rather than to a pathogen spreading into the brain via the olfactory pathways.

Aβ(1-42) induced metabolic effects in a stem cell derived neuron and astrocyte network.

Alzheimer’s Disease (AD) is the most common form of dementia currently affecting more than 35 million people worldwide. Hypometabolism is a major feature of AD and appears decades before cognitive decline and pathological lesions. This has a detrimental impact on the brain which has a high energy demand. Current models of AD fail to mimic all the features of the disease, which has an impact on the development of new therapies. Human stem cell derived models of the brain have attracted a lot of attention in recent years as a tool to study neurodegenerative diseases. In this thesis, neurons and astrocytes derived from the human embryonal carcinoma cell line (NT2/D1) were utilised to determine the metabolic coupling between neurons and astrocytes with regards to responses to hypoglycaemia, neuromodulators and increase in neuronal activity. This model was then used to investigate the effects of Aß(1-42) on the metabolism of these NT2-derived co-cultures as well as pure astrocytes. Additionally primary cortical mixed neuronal and glial cultures were utilised to compare this model to a widely accepted in vitro model used in Alzheimer’s disease research. Co-cultures were found to respond to Aß(1-42) in similar way to human and in vivo models. Hypometabolism was characterised by changes in glucose metabolism, as well as lactate, pyruvate and glycogen. This led to a significant decrease in ATP and the ratio of NAD+/NADH. These results together with an increase in calcium oscillations and a decrease in GSH/GSSG ratio, suggests Aß-induces metabolic and oxidative stress. This situation could have detrimental effects in the brain which has a high energy demand, especially in terms of memory formation and antioxidant capacity.