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.

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.

What risk factors are associated with Alzheimer's disease?

A large number of risk factors have been associated with Alzheimer’s disease (AD). This article discusses the validity of the major risk factors that have been identified including age, genetics, exposure to aluminium, head injury, malnutrition and diet, mitochondrial dysfunction, vascular disease, immune system dysfunction, and infection. Rare forms of early-onset familial AD (FAD) are strongly linked to the presence of specific gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factors associated with diet, the immune system, mitochondrial function, and infection may all be involved. Life-style changes that may reduce the effect of these risk factors and therefore, the risk of AD are discussed.

Variations in dentate gyrus pathology in neurodegenerative disease

The dentate gyrus (DG) is an important part of the hippocampal formation and is believed to be involved in a variety of brain functions including episodic and spatial memory and the exploration of novel environments. In several neurodegenerative disorders, significant pathology occurs in the DG which may be involved in the development of clinical dementia. Based on the abundance of pathological change, neurodegenerative disorders could be divided into three groups: (1) those in which high densities of neuronal cytoplasmic inclusions (NCI) were present in DG granule cells, e.g., Pick’s disease (PiD), frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP), and neuronal intermediate filament inclusion disease (NIFID), (2) those in which aggregated protein deposits were distributed throughout the hippocampal formation including the molecular layer of the DG, e.g., Alzheimer’s disease (AD), Down’s syndrome (DS), and variant Creutzfeldt-Jakob disease (vCJD), and (3) those in which in there was significantly less pathology in the DG, e.g., Parkinson’s disease dementia (PD-Dem), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA), and sporadic CJD (sCJD). Hence, DG pathology varied significantly among disorders which could contribute to differences in clinical dementia. Pathological differences among disorders could reflect either differential vulnerability of the DG to specific molecular pathologies or variation in the degree of spread of pathological proteins into the hippocampal formation from adjacent regions.

Pathology of the dentate gyrus in neurodegenerative disease

The dentate gyrus (DG) is an important part of the hippocampal formation and is believed to be involved in a variety of brain functions including episodic and spatial memory and the exploration of novel environments. In several neurodegenerative disorders, significant pathology occurs in the DG which may be involved in the development of clinical dementia. Based on the abundance of pathological change, neurodegenerative disorders can be divided into three groups: (1) those in which high densities of neuronal cytoplasmic inclusions (NCI) are present in DG granule cells, e.g., Pick’s disease (PiD), frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP), and neuronal intermediate filament inclusion disease (NIFID), (2) those in which aggregated protein deposits are distributed throughout the hippocampal formation including the molecular layer of the DG, e.g., Alzheimer’s disease (AD), Down’s syndrome (DS), and variant Creutzfeldt-Jakob disease (vCJD), and (3) those in which in there is significantly less pathology in the DG, e.g., Parkinson’s disease dementia (PD-Dem), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA), and sporadic CJD (sCJD). Hence, DG pathology varies significantly among disorders which could contribute to differences in clinical dementia. Pathological differences among disorders could reflect either differential vulnerability of the DG to specific molecular pathologies or variation in the degree of spread of pathological proteins into the hippocampal formation from adjacent regions.

The human hippocampus and its significance in neuropsychology and disease

This article discusses the structure, anatomical connections, and functions of the hippocampus (HC) of the human brain and its significance in neuropsychology and disease. The HC is concerned with the analysis of highly abstract data derived from all sensory systems but its specific role remains controversial. Hence, there have been three major theories concerning its function, viz., the memory theory, the spatial theory, and the behavioral inhibition system (BIS) theory. The memory theory has its origin in the surgical destruction of the HC, which results in severe anterograde and partial retrograde amnesia. The spatial theory has its origin in the observation that neurons in the HC of animals show activity related to their location within the environment. By contrast, the behavioral inhibition theory suggests that the HC acts as a ‘comparator’, i.e., it compares current sensory events with expected or predicted events. If a set of expectations continues to be verified then no alteration of behavior occurs. If, however, a ‘mismatch’ is detected then the HC intervenes by initiating appropriate action by active inhibition of current motor programs and initiation of new data gathering. Understanding the anatomical connections of the hippocampus may lead to a greater understanding of memory, spatial orientation, and states of anxiety in humans. In addition, HC damage is a feature of neurodegenerative diseases such as Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Pick’s disease (PiD), and Creutzfeldt-Jakob disease (CJD) and understanding HC function may help to explain the development of clinical dementia in these disorders.

Oligodendrocyte pathology in neurodegenerative disease

Oligodendrocytes have multiple functions in the central nervous system including mechanical support of neurons, production of myelin sheaths, and uptake and inactivation of chemical neurotransmitters released by neurons. Consequently, oligodendrocytes could be involved in the pathology of a number of neurodegenerative diseases. Although, the molecular mechanisms involved require further elucidation, it is likely that oligodendrocyte dysfunction is important in Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). In addition, abnormal protein aggregates in the form of oligodendrocyte inclusions (OI) have been observed in several other disorders, most notable in multiple system atrophy (MSA), in which the glial cytoplasmic inclusion (GCI) is the ‘signature’ pathology of the disease. OI have also been identified in argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) (Armstrong et al 2007), and various forms of frontotemporal lobar degeneration (FTLD) (Armstrong et al 2010), although their role in the pathology of these disorders is less clear. It is likely that future research will expand the range of disorders in which oligodendrocytes play a significant role in neurodegeneration.

Quantification of white matter abnormalities in neurodegenerative disease

Degeneration of white matter fibre tracts occurs in several neurodegenerative disorders and results in various histological abnormalities including loss of axons, vacuolation, gliosis, axonal varicosities and spheroids, corpora amylacea, extracellular protein deposits, and glial inclusions (GI). This chapter describes quantitative studies that have been carried out on white matter pathology in a variety of neurodegenerative disease. First, in Alzheimer’s disease (AD), axonal loss quantified in histological sections stained with toluidine blue, occurs in several white matter fibre tracts including the optic nerve, olfactory tract, and corpus callosum. Second, in Creutzfeldt-Jakob disease (CJD), sections of cerebral cortex stained with haematoxylin and eosin (H/E) or immunolabelled with antibodies against the disease form of prion protein (PrPsc), reveal extensive vacuolation, gliosis of white matter, and deposition of PrPsc deposits. Third, GI immunolabelled with antibodies against various pathological proteins including tau, -synuclein, TDP-43, and FUS, have been recorded in white matter of a number of disorders including frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and neuronal intermediate filament inclusion disease (NIFID). Axonal varicosities have also been observed in NIFID. There are two important questions regarding white matter pathology that need further investigation: (1) what is the relative importance of white and gray matter pathologies in different disorders and (2) do white matter abnormalities precede or are they the consequence of gray matter pathology?

Retinal microvascular dysfunction occurs similarly in Alzheimer's disease and primary open angle glaucoma patients

Purpose: The exact nature of the relationship between Alzheimer’s disease (AD) and primary open angle glaucoma (POAG) is still the subject of debate. One factor attributed to the aetiology of both conditions is vascular dysfunction. This study aimed to investigate the similarities and differences in retinal microvascular function between mild AD patients, early stage POAG patients and healthy controls Methods: Retinal vessel reactivity to flickering light was assessed in 10 AD, 19 POAG and 22 healthy age matched control patients by means of dynamic retinal vessel analysis (DVA, IMEDOS, GmbH, Jena, Germany) according to an established protocol. All patients additionally underwent BP measurements and blood analysis for glucose and lipid metabolism markers Results: AD and POAG patients demonstrated comparable alterations in retinal artery reactivity, in the form of an increased arterial reaction time (RT) to flicker light on the final flicker cycle (p=0.014), which was not replicated in the healthy age and cardiovascular risk matched controls (p>0.05). Furthermore, the sequential changes in RT on progressing from flicker one to flicker three were found to differ between healthy controls and the two disease groups (p=0.001) Conclusions: AD and POAG patients demonstrate comparable signs of vascular dysfunction in their retinal arteries at the early stages of their disease process. These comparable signs may reflect similarities in the pathophysiological processes that occur in the development of both conditions

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.