Biomedical subjects

Elizabeth Head

Publications and source records attributed to Elizabeth Head.

At least 37 records · Page 2Linked to original sources

PubMed2005

Effects of scopolamine challenge on regional cerebral blood volume. A pharmacological model to validate the use of contrast enhanced magnetic resonance imaging to assess cerebral blood volume in a canine model of aging.

Cognitive impairment resulting from disruption of cholinergic function may occur through modulation of cerebrovascular volume (CBV). In the present study, dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) was used to examine cerebrovascular volume in young and old dogs during baseline and after administration of a cholinergic antagonist (scopolamine). In the first study, 24 animals (2-15 years of age) were given a baseline scan followed by a second scan after scopolamine administration (30 microg/kg). Gray matter rCBV was significantly higher than white matter rCBV during baseline and scopolamine administration. In the second study a subset of 7 dogs (4 young and 3 old) received scopolamine before anesthesia was induced for a second DSC-MRI scan. Consistent with the first study, gray matter rCBV was significantly higher than white matter rCBV. Scopolamine administered before anesthesia however, resulted in higher rCBV values compared to baseline in cerebral gray matter. Additionally, rCBVs were higher in young dogs at baseline in gray and white matter and marginally higher in gray matter when scopolamine was administered before anesthesia. These results indicate that in the dog, rCBV varies with brain compartment, decreases with age, and that DSC-MRI provides a measure of cerebrovascular function which may be related to age-dependent changes in cognition, brain structure, and neuropathology.

Aging↗

PubMed2005

Learning and memory as a function of age in Down syndrome: a study using animal-based tasks.

Individuals with Down syndrome (DS) are at a high risk for developing Alzheimer disease (AD) after the age 40; however, low levels of intellectual functioning, coupled with impaired language ability, confound the detection of AD. Comparative neuropsychological tests developed in animal models of aging and cognition do not require intact language function and can be useful for detecting changes in cognition. Experimental paradigms used to detect age-dependent cognitive deficits in animal models were applied in the present study to measure cognitive function in a group of 20 adults with DS ranging in age from 22 to 58 years. Object discrimination, reversal learning, and spatial and object memory were administered using a modified Wisconsin General Testing Apparatus and reinforcement (penny rewards). When considering age as the only clinical variable to parallel the animal studies, age was significantly correlated with performance on object memory and marginally related to performance on reversal learning and spatial memory. However, when evaluating multiple clinical variables including age, a measure of intellectual ability (FSIQ), scores on the Dementia Questionnaire for Persons with Mental Retardation (DMR), and gender using regression analysis, scores on the DMR were the best predictors of errors of reversal learning, whereas FSIQ was the best predictor of performance on object memory. These results suggest that while age may be related to performance on learning and memory tasks, other clinical variables may be stronger predictors of performance in adults with DS. These changes may reflect prefrontal and medial temporal lobe dysfunction that is associated with the development of AD pathology in DS.

Adult↗

PubMed2005

Chronic antioxidant and mitochondrial cofactor administration improves discrimination learning in aged but not young dogs.

The present experiment was part of a 3-year longitudinal study examining the effects of age and antioxidant treatment on cognitive decline in beagles. Two size-concept tasks were administered following pretraining on a series of two-choice (six subtests) and three-choice size discrimination tasks. Thirty-nine young and aged dogs were matched for age and cognitive ability then divided into four treatment groups. A combined antioxidant-mitochondrial cofactor treatment led to significantly improved performance in aged dogs on the first subtest of the two-choice size discrimination series. Treated aged dogs did not significantly differ from the young. Aged dogs on the antioxidant diet continued to perform better than aged controls on the second and third subtests, but these effects did not achieve significance. Young dogs performed significantly better than the aged dogs on the second and third subtests. The remaining two-choice tasks of the discrimination series were comparatively easy, leading to a floor effect. The antioxidant animals performed better on the three-choice size discrimination, but not on the two size-concept tasks. Antioxidants improved the performance of aged dogs on the initial learning tests, suggesting a selective improvement of factors related to the aging process and specific cognitive processes rather than general cognitive enhancement.

Age Factors↗

PubMed2005

Reduced neuronal expression of synaptic transmission modulator HNK-1/neural cell adhesion molecule as a potential consequence of amyloid beta-mediated oxidative stress: a proteomic approach.

Abstract Oxidative stress imparted by reactive oxygen species (ROS) is implicated in the pathogenesis of Alzheimer's disease (AD). Given that amyloid beta (Abeta) itself generates ROS that can directly damage proteins, elucidating the functional consequences of protein oxidation can enhance our understanding of the process of Abeta-mediated neurodegeneration. In this study, we employed a biocytin hydrazide/streptavidin affinity purification methodology followed by two-dimensional liquid chromatography tandem mass spectrometry coupled with SEQUEST bioinformatics technology, to identify the targets of Abeta-induced oxidative stress in cultured primary cortical mouse neurons. The Golgi-resident enzyme glucuronyltransferase (GlcAT-P) was a carbonylated target that we investigated further owing to its involvement in the biosynthesis of HNK-1, a carbohydrate epitope expressed on cell adhesion molecules and implicated in modulating the effectiveness of synaptic transmission in the brain. We found that increasing amounts of Abeta, added exogenously to the culture media of primary cortical neurons, significantly decreased HNK-1 expression. Moreover, in vivo, HNK-1 immunoreactivity was decreased in brain tissue of a transgenic mouse model of AD. We conclude that a potential consequence of Abeta-mediated oxidation of GlcAT-P is impairment of its enzymatic function, thereby disrupting HNK-1 biosynthesis and possibly adversely affecting synaptic plasticity. Considering that AD is partly characterized by progressive memory impairment and disordered cognitive function, the data from our in vitro studies can be reconciled with results from in vivo studies that have demonstrated that HNK-1 modulates synaptic plasticity and is critically involved in memory consolidation.

Amino Acid Sequence↗

PubMed2004

Frontal lobe volume, function, and beta-amyloid pathology in a canine model of aging.

Application of magnetic resonance imaging (MRI) techniques reveals that human brain aging varies across cortical regions. One area particularly sensitive to normal aging is the frontal lobes. In vitro neuropathological studies and behavioral measures in a canine model of aging previously suggested that the frontal lobes of the dog might be sensitive to aging. In the present study, MRI scans were acquired to compare age-related changes in frontal lobe volume with changes in executive functions and beta-amyloid pathology in the frontal cortex of beagle dogs aged 3 months to 15 years. Decreases in total brain volume appeared only in senior dogs (aged 12 years and older), whereas frontal lobe atrophy developed earlier, appearing in the old dogs (aged 8-11 years). Hippocampal volume also declined with age, but not occipital lobe volume past maturity. Reduced frontal lobe volume correlated with impaired performance on measures of executive function, including inhibitory control and complex working memory, and with increased beta-amyloid accumulation in the frontal cortex. Age-related hippocampal atrophy also correlated with complex working memory but not inhibitory control, whereas occipital lobe volume did not correlate with any cognitive measure. These findings are consistent with the frontal lobe theory of aging in humans, which suggests that the frontal lobes and functions subserved by this region are compromised early in aging.

Aging↗

PubMed2004

Concept abstraction in the aging dog: development of a protocol using successive discrimination and size concept tasks.

The present study examined the effects of age on concept learning in beagle dogs. In experiment one, subjects were tested on a series of 2-choice size discrimination (2CSD) tasks, in which the correct response was to always approach the larger or smaller of the two blocks. Compared to old and senior dogs, young and middle-aged dogs solved the initial training subtest faster and were more successful at transferring this learning to subsequent tests. The second experiment extended the task by using three rather than two objects and introducing novel objects to test concept acquisition. Young and middle-aged dogs made fewer errors than old or senior dogs on a 3-choice size discrimination (3CSD) task. Transfer performance was above chance for all four groups on the 3CSD and first 3-choice size concept (CSC) task and for the young dogs on the second 3CSC but did not differ from the original learning criterion in any group. Age impairments in concept learning may account for differences in transfer performance on both 3CSC tests.

Age Factors↗

PubMed2004

Nutraceuticals, aging, and cognitive dysfunction.

Decline in cognitive function that accompanies aging in dogs might have a biological basis, and many of the disorders associated with aging in canines might be preventable through dietary modifications that incorporate specific nutraceuticals. Based on previous research and the results of laboratory and clinical studies, antioxidants might be one class of nutraceutical that benefits aged dogs. Brains of aged dogs accumulate oxidative damage to proteins and lipids, which can lead to dysfunction of neuronal cells. The production of free radicals and lack of increase in compensatory antioxidant enzymes might lead to detrimental modifications to important macromolecules within neurons. Reducing oxidative damage through food ingredients rich in a broad spectrum of antioxidants significantly improves, or slows the decline of, learning and memory in aged dogs; however, determining which compounds, combinations, dosage ranges, when to initiate intervention, and long-term effects constitute critical gaps in knowledge about this subject.

Aging↗

PubMed2004

Long-term treatment with antioxidants and a program of behavioral enrichment reduces age-dependent impairment in discrimination and reversal learning in beagle dogs.

The effects of long-term treatment with both antioxidants and a program of behavioral enrichment were studied as part of a longitudinal investigation of cognitive aging in beagle dogs. Baseline performance on a battery of cognitive tests was used to assign 48 aged dogs (9-12 years) into four cognitively equivalent groups, of 12 animals per group: Group CC (control food-control environment), group CE (control food-enriched environment); Group AC (antioxidant fortified food-control environment); Group AE (fortified food-enriched environment). We also tested a group of young dogs fed the control food and a second group fed the fortified food. Both groups of young dogs received a program of behavioral enrichment. To evaluate the effects of the interventions on cognition after 1 year, the dogs were tested on a size discrimination learning task and subsequently on a size discrimination reversal learning task. Both tasks showed age-sensitivity, with old dogs performing more poorly than young dogs. Both tasks were also improved by both the fortified food and the behavioral enrichment. However, in both instances the treatment effects largely reflected improved performance in the combined treatment group. These results suggest that the effectiveness of antioxidants in attenuating age-dependent cognitive decline is dependent on behavioral and environmental experience.

Aging↗

PubMed2004

Down syndrome and beta-amyloid deposition.

PURPOSE OF REVIEW: Exciting new therapeutic approaches to the treatment or prevention of Alzheimer's disease involve preventing, slowing or reversing beta-amyloid accumulation. These interventions may also apply to the treatment of Alzheimer's disease in Down syndrome. The purpose of the current review is therefore to summarize developments and advances in our understanding of beta-amyloid pathogenesis in Down syndrome over the past year. RECENT FINDINGS: A shift in research to a focus on early events in beta-amyloid pathogenesis in Down syndrome has led to several novel observations. Several authors have reported the accumulation of both soluble and intracellular beta-amyloid before extracellular beta-amyloid (senile plaques) in Down syndrome. Increases in beta-amyloid levels in Down syndrome may reflect the increased expression and protein levels of beta-site amyloid precursor protein cleavage enzyme 2 on chromosome 21. The impact of the accumulation of beta-amyloid may have differential effects on development and aging in Down syndrome. SUMMARY: The past year has seen significant advances in our understanding of beta-amyloid pathogenesis and the functional consequences of beta-amyloid accumulation in Down syndrome. However, there are still large gaps in our knowledge of the pathways involved in beta-amyloid degradation and clearance. It will be critical to conduct clinical trials to test therapeutic strategies that may reduce beta-amyloid in Down syndrome directly to determine the optimal age and dose for specific interventions. Given the differences in the mechanism of beta-amyloid accumulation in Down syndrome, careful consideration needs to be given to potential clinical trials to treat this disorder.

Adult↗

PubMed2004

Isolated executive impairment and associated frontal neuropathology.

Cognitive impairment in the absence of dementia is common in elderly individuals and is most often studied in the context of an isolated impairment in memory. In the current study, we report the neuropsychological and neuropathological features of a nondemented elderly individual with isolated impairment on a test of executive function (i.e., Trail Making Test) and preserved memory, language, and visuospatial function. Postmortem studies indicated that cortical neurofibrillary tangles (NFT) varied considerably, and some regions contained large numbers of neuritic senile plaques. Semiquantitative immunohistochemistry showed higher NFT and amyloid-beta (Abeta) loads in the frontal cortex relative to the temporal, entorhinal, occipital, and parietal cortices. A survey of the entire cingulate gyrus showed a wide dispersion of Abeta42 with the highest concentration in the perigenual part of the anterior cingulate cortex; Abeta appeared to be linked with neuron loss and did not overlap with the heaviest neuritic degeneration. The current case may represent a nonmemory presentation of mild cognitive impairment (executive mild cognitive impairment) that is associated with frontal and anterior cingulate pathology and may be an early stage of the frontal variant of Alzheimer disease.

Aged↗

PubMed2004

Comparison of the effects of L-carnitine and acetyl-L-carnitine on carnitine levels, ambulatory activity, and oxidative stress biomarkers in the brain of old rats.

L-carnitine and acetyl-L-carnitine (ALC) are both used to improve mitochondrial function. Although it has been argued that ALC is better than l-carnitine in absorption and activity, there has been no experiment to compare the two compounds at the same dose. In the present experiment, the effects of ALC and L-carnitine on the levels of free, acyl, and total L-carnitine in plasma and brain, rat ambulatory activity, and biomarkers of oxidative stress are investigated. Aged rats (23 months old) were given ALC or L-carnitine at 0.15% in drinking water for 4 weeks. L-carnitine and ALC were similar in elevating carnitine levels in plasma and brain. Both increased ambulatory activity similarly. However, ALC decreased the lipid peroxidation (malondialdehyde, MDA) in the old rat brain, while L-carnitine did not. ALC decreased the extent of oxidized nucleotides (oxo8dG/oxo8G) immunostaining in the hippocampal CA1 and cortex, while L-carnitine did not. ALC decreased nitrotyrosine immunostaining in the hippocampal CA1 and white matter, while L-carnitine did not. In conclusion, ALC and L-carnitine were similar in increasing ambulatory activity in old rats and elevating carnitine levels in blood and brain. However, ALC was effective, unlike L-carnitine, in decreasing oxidative damage, including MDA, oxo8dG/oxo8G, and nitrotyrosine, in old rat brain. These data suggest that ALC may be a better dietary supplement than L-carnitine.

Acetylcarnitine↗

PubMed2003

Spatial patterns of mammalian brain aging: distribution of cathepsin D-immunoreactive cell bodies and dystrophic dendrites in aging dogs resembles that in Alzheimer's disease.

Elevated levels of the lysosomal enzyme cathepsin D are found in the early stages of Alzheimer's disease (AD) and co-occur with intraneuronal tangles. The present study tested whether increases in cathepsin D would emerge during aging in another mammalian species. Regional brain patterns of cathepsin D immunostaining were compared in dogs ages 0.35 to 16 years. Accumulations of immunopositive material were evident in neuronal cell bodies in many forebrain sites in middle-age to old dogs (>/=6 years). Three types could be distinguished: (1) dense aggregates with no particular position within the cell body; (2) crescent-shaped "caps" that occupied one pole of the cell body; and (3) very dense "spikes" that extended from the cell body for variable distances into the apical dendrite; these spikes were found in only a few areas, most notably the subiculum and layer V of neocortex. The spikes appeared between ages 2 and 5 years and increased steadily with age thereafter. Spikes were found in the subiculum in the aged human brain but only infrequently; they were, however, present in large numbers in AD brains. These results established that brain aging in dogs is (1) well advanced by middle age, (2) varies markedly across regions, and (3) in at least some of its aspects (dystrophic dendrites) is prominent in areas known to exhibit pathology early in the course of AD. Combined with previous results for rats, these findings indicated that changes in cathepsin D observed in AD, in particular in the temporal lobe, reflect a generalized mammalian pattern of brain aging.

Aged↗

PubMed2003

Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.

Aged↗

PubMed2003

Generation and characterization of the humoral immune response to DNA immunization with a chimeric beta-amyloid-interleukin-4 minigene.

Active immunization with fibrillar beta-amyloid peptide (Abeta(42)) as well as passive transfer of anti-Abeta antibodies significantly reduces Abeta plaque deposition, neuritic dystrophy, and astrogliosis in the brain of mutant amyloid precursor protein (APP)-transgenic mice. Although the mechanism(s) of clearance of Abeta from the brain following active or passive immunization remains to be determined, it is clear that anti-Abeta antibodies are critical for clearance. DNA immunization provides an attractive alternative to direct peptide and adjuvant approaches for inducing a humoral response to Abeta. We constructed a DNA minigene with Abeta fused to mouse interleukin-4 (pAbeta(42)-IL-4) as a molecular adjuvant to generate anti-Abeta antibodies and enhance the Th2-type of immune responses. Gene gun immunizations induced primarily IgG1 and IgG2b anti-Abeta antibodies. Fine epitope analysis with overlapping peptides of the Abeta(42) sequence identified the 1-15 region as a dominant B cell epitope. The DNA minigene-induced anti-Abeta antibodies bound to Abeta plaques in brain tissue from an Alzheimer's disease patient demonstrating functional activity of the antibodies and the potential for therapeutic efficacy.

Amyloid beta-Peptides↗

PubMed2003

Accumulation of caspase cleaved amyloid precursor protein represents an early neurodegenerative event in aging and in Alzheimer's disease.

The activation of caspase-3 and possibly other caspases during apoptosis may lead to the cleavage of the amyloid precursor protein (APP) and subsequent accumulation of APP cleavage products (cAPP). We examined the association between activated caspase-3 and cAPP in human brain by qualitative and quantitative analysis of in situ immunohistochemistry and Western blots. Frontal cortex and hippocampal tissue from age-matched control and Alzheimer's brains (AD) was used. Both activated caspase-3 and cAPP are increased in AD [Braak and Braak (BB) stage IV-VI] compared to aged control (BB stage 0-1) and transitional (BB stage II-III) cases in the hippocampal and frontal cortex. Caspase-3 activation and the accumulation of APP cleavage fragments appear to either parallel or precede neurofibrillary tangle formation. These findings raise the possibility that the activation of caspase-3 and cleavage of APP may be involved with neuronal degeneration and that pathways characteristic of apoptosis are activated in AD.

Aged↗

PubMed2003

Locomotor activity rhythms in dogs vary with age and cognitive status.

Beagle dogs exhibited diurnal patterns of locomotor activity that varied as a function of age, cognitive status, and housing environment. Aged dogs housed in an indoor facility showed a delayed onset of activity following lights on and displayed shorter bouts of activity, with more rest periods during the day, compared with young dogs. Cognitively impaired aged dogs were more active and showed a delayed peak of activity compared with unimpaired aged dogs. Housing in continuous light did not disrupt activity rhythms. The effect of age was less prominent in dogs housed in an indoor/outdoor facility. This suggests that bright sunlight and natural light-dark transitions are better able to consolidate and synchronize the activity rhythms of the dogs.

Aging↗

PubMed2003

Response latency in Canis familiaris: mental ability or mental strategy?

Animal studies of cognitive aging typically use measures of response accuracy (RA) to evaluate cognitive function, which declines with age. Human aging studies, by contrast, frequently measure response latency (RL), with faster responses being indicative of superior performance. To examine the influence of age on RL in an animal model, the authors assessed RA with RL in young and aged beagle dogs (Canis familiaris) tested on a 3-component delayed nonmatching-to-position task, which comprised 3 subtests. Young dogs displayed significantly slower RLs and higher RAs and showed RL slowing with greater complexity, compared with aged dogs. In addition, the slower responding young dogs made fewer errors. Thus, RL appears to reflect the learning strategy applied, rather than the level of mental ability.

Aging↗

PubMed2002

Beta-amyloid deposition and neurofibrillary tangle association with caspase activation in Down syndrome.

Individuals with Down syndrome (DS) and Alzheimer's disease (AD) develop senile plaques, neurofibrillary tangles (NFT), and neuron loss. Recent studies demonstrate the activation of apoptotic pathways in AD; less data is available in DS. The DS brain was examined using immunocytochemistry and antibodies against the active fragment of caspase-8 (AC, 8) and to caspase-3 cleavage products of fodrin (CCP), a neuronal cytoskeleton protein. The hippocampus demonstrated widespread accumulation of fodrin CCP and AC8 in NFTs and dystrophic neurites. Individual neurons contained intracellular beta-amyloid (Abeta) and fodrin CCP providing evidence that caspase activation can occur with both NFT and Abeta. Abeta within or around neurons in addition to contributing to NFT formation may also trigger apoptotic pathways. Caspase activation may lead to the cleavage of critical cellular proteins and neuronal cell death associated with DS.

Adult↗