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Biomedical subjects

Elizabeth Head

Publications and source records attributed to Elizabeth Head.

At least 19 recordsLinked to original sources
PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Region specific neuron loss in the aged canine hippocampus is reduced by enrichment.

Neuron loss within the hippocampus and entorhinal cortex occurs as a function of age in humans. We first tested the hypothesis that neuron loss occurs in the aged dog. The total unilateral number of neurons in the canine entorhinal cortex and subdivisions of the hippocampus from the left hemisphere were estimated using the optical fractionator. The brains from 5 old (13.0-15.0 years old) and 5 young (3.4-4.5 years old) beagle dogs were analyzed. The hilus of the hippocampus showed a significant loss of neurons (approximately 30%) in the aged dog brain compared to young. Differences were not detected in the remaining hippocampal subfields and entorhinal cortex. We further tested the hypothesis that an antioxidant fortified food or behavioral enrichment would reduce the age-related loss of hilar neurons. Behaviorally enriched aged dogs had more neurons in the hilus (approximately 18%) compared to aged controls. These results suggest that the aged canine hippocampus in the left hemisphere shows selective neuron loss and that behavioral enrichment may reduce this loss.

Age Factors↗
PubMed2006

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: relevance to Alzheimer's disease.

Aging and age-related disorders such as Alzheimer's disease (AD) are usually accompanied by oxidative stress as one of the main mechanisms contributing to neurodegeneration and cognitive decline. Aging canines develop cognitive dysfunction and neuropathology similar to those seen in humans, and the use of antioxidants results in reductions in oxidative damage and in improvement in cognitive function in this canine model of human aging. In the present study, the effect of a long-term treatment with an antioxidant-fortified diet and a program of behavioral enrichment on oxidative damage was studied in aged canines. To identify the neurobiological mechanisms underlying these treatment effects, the parietal cortex from 23 beagle dogs (8.1-12.4 years) were treated for 2.8 years in one of four treatment groups: i.e., control food-control behavioral enrichment (CC); control food-behavioral enrichment (CE); antioxidant food-control behavioral enrichment (CA); enriched environment-antioxidant-fortified food (EA). We analyzed the levels of the oxidative stress biomarkers, i.e., protein carbonyls, 3-nitrotyrosine (3-NT), and the lipid peroxidation product, 4-hydroxynonenal (HNE), and observed a decrease in their levels on all treatments when compared to control, with the most significant effects found in the combined treatment, EA. Since EA treatment was most effective, we also carried out a comparative proteomics study to identify specific brain proteins that were differentially expressed and used a parallel redox proteomics approach to identify specific brain proteins that were less oxidized following EA. The specific protein carbonyl levels of glutamate dehydrogenase [NAD (P)], glyceraldehyde-3-phosphate dehydrogenase (GAPDH), alpha-enolase, neurofilament triplet L protein, glutathione-S-transferase (GST) and fascin actin bundling protein were significantly reduced in brain of EA-treated dogs compared to control. We also observed significant increases in expression of Cu/Zn superoxide dismutase, fructose-bisphosphate aldolase C, creatine kinase, glutamate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. The increased expression of these proteins and in particular Cu/Zn SOD correlated with improved cognitive function. In addition, there was a significant increase in the enzymatic activities of glutathione-S-transferase (GST) and total superoxide dismutase (SOD), and significant increase in the protein levels of heme oxygenase (HO-1) in EA treated dogs compared to control. These findings suggest that the combined treatment reduces the levels of oxidative damage and improves the antioxidant reserve systems in the aging canine brain, and may contribute to improvements in learning and memory. These observations provide insights into a possible neurobiological mechanism underlying the effects of the combined treatment. These results support the combination treatments as a possible therapeutic approach that could be translated to the aging human population who are at risk for age-related neurodegenerative disorders, including Alzheimer's disease.

Aldehydes↗
PubMed2006

Neuroprotective effects of cognitive enrichment.

Cognitive enrichment early in life, as indicated by level of education, complexity of work environment or nature of leisure activities, appears to protect against the development of age-associated cognitive decline and also dementia. These effects are more robust for measures of crystallized intelligence than for measures of fluid intelligence and depend on the ability of the brain to compensate for pathological changes associated with aging. This compensatory ability is referred to as cognitive reserve. The cognitive reserve hypothesis suggests that cognitive enrichment promotes utilization of available functions. Alternatively, late life cognitive changes in cognition may be linked to a factor, such as cholinergic dysfunction, that is also present early in life and contributes to the reduced levels of early life cognitive enrichment. Beneficial effects of environmental enrichment early in life have also been observed in rodents and primates. Research with rodents indicates that these changes have structural correlates, which likely include increased synapses in specific brain regions. Dogs also show age-dependent cognitive decline, and both longitudinal and cross-sectional studies indicate that this decline can be attenuated by cognitive enrichment. Furthermore, cognitive enrichment has differential effects, improving some functions more than others. From a neurobiological perspective, behavioral enrichment in the dog may act to promote neurogenesis later in life. This can be distinguished from nutritional interventions with antioxidants, which appear to attenuate the development of neuropathology. These results suggest that a combination of behavioral and nutritional or pharmacological interventions may be optimal for reducing the rate of age-dependent cognitive decline.

Aging↗
PubMed2006

Relapsing polychondritis with features of dementia with Lewy bodies.

We describe a 72-year old man with clinical features suggestive of dementia with Lewy bodies (DLB) who proved neuropathologically to have degeneration induced by relapsing polychondritis (RP), an autoimmune inflammatory disorder of cartilaginous tissues. There was lymphocytic infiltration of the leptomeninges, perivascular cuffing, reactive astrocytosis, and activation of microglia in multiple brain areas all consistent with an immunologically mediated process. There was widespread neuronal loss within the hippocampus, entorhinal cortex, and amygdala as well as diffuse myelin pallor of cortical pathways. Elevated levels of complement proteins and endothelial markers of inflammation were observed, which are similar to previous reports in DLB. This study demonstrates that qualitatively similar inflammation-associated neurodegeneration is present in widespread regions of the brain in a RP case presenting clinically as DLB.

Aged↗
PubMed2006

Ageing changes in cat brains demonstrated by beta-amyloid and AT8-immunoreactive phosphorylated tau deposits.

The life expectancy of domestic pet cats is increasing, along with the occurrence of geriatric-onset behavioural problems, such as cognitive dysfunction syndrome (CDS). While the cause of CDS is unclear, it has been suggested that it may result from age-related neurodegeneration. In aged and in particular senile human beings, histopathological changes may include the extracellular accumulation of plaque-like deposits of beta-amyloid (Abeta) protein and the intracellular accumulation of an abnormally hyperphosphorylated form of the microtubule-associated protein, tau. In severe cases, the latter may form into neurofibrillary tangles. Brain material was assessed from 19 cats, aged from 16 weeks to 14 years; 17 of which had clinical signs of neurological dysfunction. Immunohistochemical methods were used to detect Abeta and its intracellular precursor protein (amyloid precursor protein (APP)) and hyperphosphorylated-tau. APP was constitutively expressed, with diffuse staining of neurons and blood vessels being detected in all cats. More intense staining and diffuse extracellular Abeta staining deposits were found within the deep cortical areas of the anterior- and occasionally mid-cerebrum of seven cats, all of which were over 10 years of age. Neurons staining intensely positive for AT8-immunoreactivity were seen in two cats, aged 11 and 13 years. However, no mature neurofibrillary tangles were detected. This study demonstrated that extracellular Abeta accumulation and AT8-immunoreactivity within neurons are age-related phenomena in cats, and that they can occur concurrently. There are similarities between these changes and those observed in the brains of aged people and other old mammals.

Aging↗
PubMed2006

Visuospatial function in the beagle dog: an early marker of cognitive decline in a model of human aging and dementia.

Visuospatial learning and memory impairments are an early marker for age-related cognitive decline and Alzheimer's disease. Similar to humans, aged dogs show visuospatial learning and memory deficits (). One hundred and nine beagle dogs ranging between 0.25 and 11.99 years were tested on a visuospatial delayed non-matching to position (DNMP) task to better characterize the progression of visuospatial deficits in the dog. Age predicted 48.2% of the variability in learning the DNMP, with dogs ranging from 1 to 11.99 years generally making more errors with increasing age. By contrast, puppies (<1 year) likely were showing developmental deficits, possibly due to an immature prefrontal cortex. Mild visuospatial deficits were detected by 6 years, which precedes the typical onset of amyloid-beta (Abeta) accumulation in the dog brain by two years, and can serve as an early marker for cognitive decline in the dog. These findings suggest that (1) age-related changes in visuospatial function in the dog models that seen in humans, further validating the dog as a model for human aging and dementia; and (2) other mechanisms, such as oxidative stress, soluble Abeta oligomers or cholinergic deficits, are likely contributing to the early impairment.

Aging↗
PubMed2006

Immunization with fibrillar Abeta(1-42) in young and aged canines: Antibody generation and characteristics, and effects on CSF and brain Abeta.

We describe a study testing fibrillar beta-amyloid(1-42) (Abeta42) vaccination in dogs. Three young beagles (4.6 years) were immunized twice with Abeta42 and a Th1 adjuvant (TiterMax Gold). Animals generated primarily IgG2 and IgM antibody responses, which were specific for the Abeta(11-30) region of Abeta(1-42). Next, 3 aged beagles (8.9-13.8 years) were immunized 4 times with Abeta(42) and a Th2 adjuvant (Alum). We observed an acute increase in IgG2, a slower increase in IgG1 and Abeta antibodies of broader specificity (Abeta(1-15>) Abeta(11-30>) Abeta(6-20)). A nonsignificant increase in CSF Abeta(1-40) and decrease in Abeta(1-40/1-42) in cortex was detected. Canines may be a useful system for testing an Abeta vaccine.

Adjuvants, Immunologic↗
PubMed2006

Beta-amyloid, oxidative stress and down syndrome.

Down syndrome (DS) provides a model for studying important aspects of Alzheimer disease (AD). Chromosome 21 contains several genes that have been implicated in neurodegenerative mechanisms. These include Cu/Zn superoxide dismutase (SOD-1), Ets-2 transcription factors, Down Syndrome Critical Region 1 (DSCR1) stress-inducible factor, and the amyloid precursor protein (APP). The accumulation of Abeta plaques is progressive across the lifespan in DS. Overexpression of APP in the obligate region for DS is associated with abundant Abeta plaques and tangles consistent with Braak stage V-VI. Intraneuronal Abeta in DS appears to trigger a pathological cascade leading to oxidative stress and a neurodegeneration typical of AD. There are suggestions that an increase in subcellular processing of APP and factors related to membrane APP cleavage favor the secretion of Abeta with age in DS. A misbalance between SOD-1 and glutathione perioxidase activity in DS has been linked to free radical generation. Ets-2 and DSCR1 overexpression in DS has been linked to cell degeneration. Age-related accumulation of somatic DNA mutations in both DS and AD contribute to oxidative stress that exacerbates the imbalance in gene expression. This leads to enhanced Abeta deposition and further neuronal vulnerability. The consequence of these factors and their temporal relationships is likely to be the subject of future research. Since the pathological processes leading to AD are seen across the lifespan in DS, an opportunity is afforded for early pharmacological intervention in the disorder.

Age Factors↗
PubMed2006

Caspase-mediated cleavage of glial fibrillary acidic protein within degenerating astrocytes of the Alzheimer's disease brain.

Recent studies demonstrate roles for activation of caspases and cleavage of cellular proteins within neurons of the Alzheimer's disease (AD) brain. To determine whether a similar role for caspases also occurs within glial cells in AD, we designed a site-directed caspase-cleavage antibody specific to glial fibrillary acidic protein (GFAP), a cytoskeleton protein specifically expressed in astrocytes. In vitro characterization of this antibody using both a cell-free system and a cell model system of apoptosis demonstrated that the antibody (termed GFAP caspase-cleavage product antibody or GFAP-CCP Ab) immunolabeled the predicted caspase-cleavage fragment, but not full-length GFAP, by Western blot analysis. To determine whether caspases cleave GFAP in vivo, tissue sections from control and AD brains were examined by immunohistochemistry using the GFAP-CCP Ab. Two prominent features of staining were evident: immunolabeling of degenerating astrocytes in proximity to blood vessels and staining within plaque-rich regions of the AD brain. Furthermore, co-localization of the GFAP-CCP Ab and an antibody specific to active caspase-3 was demonstrated within damaged astrocytes of the AD brain. These data suggest that the activation of caspases and cleavage of cellular proteins such as GFAP may contribute to astrocyte injury and damage in the AD brain.

Alzheimer Disease↗
PubMed2005

Application of an automated voxel-based morphometry technique to assess regional gray and white matter brain atrophy in a canine model of aging.

In recent years, voxel-based morphometry (VBM) has emerged as a technique to examine regional brain changes associated with normal and pathological aging. Despite its popularity in studies of human aging, application of VBM to animal models of brain aging is rare. In the present study, VBM techniques were developed to validate earlier region of interest (ROI) measures of brain aging in the dog and to provide a more comprehensive analysis of local changes in a canine model of brain aging. Consistent with previous findings, frontal lobe atrophy increased with age, most notably in aged male dogs. Age-related gray matter reductions were also observed in parietal and temporal lobes, thalamus, cerebellum, and brainstem. Temporal lobe atrophy was particularly prominent in old females. A number of age-related changes in white matter not previously explored in the dog were also identified with VBM. Specifically, aged males exhibited greater decreases in the internal capsula and cranial nerve bundles compared to decreased volumes in the alveus of the hippocampus in old female dogs. Together, the present results indicate that application of VBM techniques in a canine model of aging yields more comprehensive information regarding topographical patterns of brain aging in male and female dogs than previously reported using traditional manual ROI methods.

Aging↗
PubMed2005

BioVision: an application for the automated image analysis of histological sections.

We describe a computer application, "BioVision", that can be trained to quickly and effectively classify and quantify user definable histological objects (e.g., senile plaques, neurofibrillary tangles) within single or double-labeled immunocytochemically stained sections. For a given image population, BioVision is interactively trained (in Independent User Mode) by an investigator to perform the desired classifications. This training yields a statistical model of the different types of objects occurring in the target image population. The resulting model can then be used (in Automated User Mode) to classify all objects in any image or images from the target population. BioVision simplifies the quantification of complex visual objects and improves inter-rater reliability. The program accomplishes classification in two major stages: pixel classification and blob classification. In pixel classification, each pixel is assigned to one of some number of substance classes, based on its chromatic properties and local context, reflecting basic histological distinctions of interest. In the blob classification phase, the image's pixels are first partitioned into "blobs": maximal connected sets of pixels assigned to the same substance class. Then, based on its size, shape, textural and contextual properties, each blob is assigned to a histological object class. A Bayesian classifier is used in each of the pixel and blob classification stages. We report several tests of BioVision. First, we applied BioVision to classify senile plaques and neurofibrillary tangles in several test cases of Alzheimer's brain immunostained for beta-amyloid and PHF-tau and compared the results to those produced by experienced investigators. BioVision was trained to classify Plaque-type blobs as either plaques or plaque-type nonentities, and tangle-type blobs as either tangles or tangle-type nonentities. BioVision classified the objects with an accuracy comparable to the trained investigator. Next, we applied BioVision to the task of counting all the tangles in hippocampal images from 22 Alzheimer's disease (AD) cases selected to span a broad range of dementia levels from the tissue repository of UC Irvine's Center for the study of Brain Aging and Dementia. The tangle counts produced by BioVision proved to be significantly better predictors of the cases' adjusted MMSE scores than any of tangle load, age at death, post mortem interval or the interval between the last MMSE score and death.

Alzheimer Disease↗
PubMed2005

Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and alpha-synuclein pathology.

Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or alpha-synuclein. In AD, beta-amyloid (Abeta)-associated caspase activation and cleavage of tau at Asp421 (DeltaTau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether DeltaTau accumulates in other diseases not characterized by extracellular Abeta accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied DeltaTau accumulation in DLB cases associated with intracellular alpha-synuclein. DeltaTau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of DeltaTau may represent a common pathway associated with abnormal accumulation of intracellular tau or alpha-synuclein and may be relatively less dependent on the extracellular accumulation of Abeta in non-AD dementias.

Aged↗
PubMed2005

ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons.

Down's syndrome (DS) is characterized by mental retardation and development of Alzheimer's disease (AD). Oxidative stress and mitochondrial dysfunction are both related to neurodegeneration in DS. Several genes in chromosome 21 have been linked to neuronal death, including the transcription factor ets-2. Cortical cultures derived from normal and DS fetal brains were used to study the role of ets-2 in DS neuronal degeneration. ets-2 was expressed in normal human cortical neurons (HCNs) and was markedly upregulated by oxidative stress. When overexpressed in normal HCNs, ets-2 induced a stereotyped sequence of apoptotic changes leading to neuronal death. DS HCNs exhibit intracellular oxidative stress and increased apoptosis after the first week in culture (Busciglio and Yankner, 1995). ets-2 levels were increased in DS HCNs, and, between 7 and 14 d in vitro, DS HCNs showed increased bax, cytoplasmic translocation of cytochrome c and apoptosis inducing factor, and active caspases 3 and 7, consistent with activation of an apoptotic mitochondrial death pathway. Degeneration of DS neurons was reduced by dominant-negative ets-2, suggesting that increased ets-2 expression promotes DS neuronal apoptosis. In the human brain, ets-2 expression was found in neurons and astrocytes. Strong ets-2 immunoreactivity was observed in DS/AD and sporadic AD brains associated with degenerative markers such as bax, intracellular Abeta, and hyperphosphorylated tau. Thus, in DS/AD and sporadic AD brains, converging pathological mechanisms leading to chronic oxidative stress and ets-2 upregulation in susceptible neurons may result in increased vulnerability by promoting the activation of a mitochondrial-dependent proapoptotic pathway of cell death.

Alzheimer Disease↗
PubMed2005

Alzheimer disease and Down syndrome: factors in pathogenesis.

There is evidence to suggest that certain shared features exist in the pathogenesis of vascular disease and Alzheimer disease (AD) in the general population. In Down syndrome (DS) all adults over the age of 40 years develop sufficient neuropathology for a diagnosis of AD. However, vascular disease is not as common in DS as it is in the general population, particularly with respect to the development of atheromas. We discuss biological mechanisms and risk factors that may be common to both diseases including cholesterol metabolism, inflammation, plasminogen activator inhibitor and apolipoprotein E (Apo E). The study of individuals with DS may help to identify common pathogenic links as well as a disassociation between vascular disease and AD.

Alzheimer Disease↗
PubMed2005

A comparison of egocentric and allocentric age-dependent spatial learning in the beagle dog.

Spatial discriminations can be performed using either egocentric information based on body position or allocentric information based on the position of landmarks in the environment. Beagle dogs ranging from 2 to 16 years of age were tested for their ability to learn a novel egocentric spatial discrimination task that used two identical blocks paired in three possible spatial positions (i.e. left, center and right). Dogs were rewarded for responding to an object furthest to either their left or right side. Therefore, when the center location was used, it was correct on half of the trials and incorrect on the other half. Upon successful acquisition of the task, the reward contingencies were reversed, and the dogs were rewarded for responding to the opposite side. A subset of dogs was also tested on an allocentric spatial discrimination task, landmark discrimination. Egocentric spatial reversal learning and allocentric discrimination learning both showed a significant age-dependent decline, while initial egocentric learning appeared to be age-insensitive. Intra-subject correlation analyses revealed a significant relationship between egocentric reversal learning and allocentric learning. However, the correlation only accounted for a small proportion of the variance, suggesting that although there might be some common mechanism underlying acquisition of the two tasks, additional unique neural substrates were involved depending on whether allocentric or egocentric spatial information processing was required.

Aging↗
PubMed2005

A longitudinal study of brain morphometrics using serial magnetic resonance imaging analysis in a canine model of aging.

Longitudinal changes in cortical atrophy, ventricular enlargement, and lesion development in serial MRI scans collected from 47 healthy dogs from 1999 (8-11 years old) to 2002 (11-14 years old) were studied. The first method involved manual region of interest volumetric analysis to examine changes in cerebral and ventricular volume during the three years. No change in cerebral volume was detected but ventricular volume increased significantly each year in 2000, 2001, and 2002. Increased ventricular volume parallels early studies of age-dependent ventricular enlargement in the brain of aging beagle dogs. The second method involved a visual analysis of co-registered serial MRIs for each subject. Consistent with the volumetric results, there was no visible change in cortical thickness indicating no cerebral atrophy, but a significant increase in ventricular size was noted. Visual examination also revealed a significant increase in number of dogs who developed aging lesions over the last 2 years in 2001 and 2002. Additionally, a disproportionate number of lesions were recorded in the frontal cortex and caudate nucleus compared to other brain regions. These lesion findings are consistent with other studies in the aging dog that suggest that the frontal lobes may be particularly vulnerable to age-related changes.

Aging↗