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You are here: Home / Publications / Bibliographies and Resource Guides / Canine Models in Biomedical Research, 1990-2009  / Aging Models  Printer Friendly Page
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Canine Models in Biomedical Research,  1990-2009
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Aging Models

Araujo, J.A., A.D.F. Chan, L.L. Winka, P.A. Seymour, and N.W. Milgram (2004). Dose-specific effects of scopolamine on canine cognition: impairment of visuospatial memory, but not visuospatial discrimination. Psychopharmacology 175(1): 92-98. ISSN: 0033-3158.
Abstract: Rationale. The cholinergic system is linked extensively to memory, but its exact role remains controversial. In particular, scopolamine-induced impairment in rodents is not task specific, which may be due to difficulty in developing rodent protocols to assess deficits in recent memory, in which the remembered event is brief and distinct, and/or to non-specific behavioral impairment. Objectives. The present study sought to determine whether scopolamine-induced deficits in recent memory, using a working memory task, could be dose-specifically dissociated from deficits in associative memory in dogs. Methods. A Latin-square design was used to determine the effect of scopolamine (5, 10 and 15 mug/kg; SC) on a variable delayed-non-matching-to-position (DNMP) task, which assesses visuospatial working memory. Subsequently, the minimal effective dose (15 mug/kg; SC) was administered prior to testing on a landmark discrimination task, which provides a measure of allocentric spatial ability, a black-white discrimination task, an oddity discrimination task and tests of exploratory behavior. We also investigated the effects of a 30 mug/kg dose (SC) on tests of oddity discrimination and behavioral activity. Results. A 15 mug/kg dose produced significant impairment on the DNMP task, but did not affect performance of any discrimination task and did not alter behavior on tests of open field or curiosity. A 30 mug/kg dose caused disruption on discrimination performance and on open field measures. Conclusions. Working memory performance is most sensitive to scopolamine-induced impairment and can be dissociated from scopolamine-induced deficits in discrimination performance and non-cognitive behaviors. The present results indicate that scopolamine-induced impairments of working memory in the dog can serve as a model of age-related cholinergic dysfunction.
Descriptors: aging, behavior, nervous system, neural coordination, pharmacology, age related cholinergic dysfunction, visuospatial discrimination, visuospatial memory, impairment.

Colle, M.A., C. Duyckaerts, T. Uchihara, F. Dessi, F. Crespeau, D. Seilhan, and J.J. Hauw (1997). Behavioral alterations and beta-amyloid accumulation in aged canine brain. Society for Neuroscience Abstracts 23(1-2): 1639 ISSN: 0190-5295.
NAL Call Number: QP351.S6
Descriptors: aging, behavior, metabolism, nervous system, neural coordination, aged, aged canine brain accumulation, animal model, behavior, behavioral alterations, beta amyloid.

Colle, M.A., J.J. Hauw, F. Crespeau, T. Uchihara, H. Akiyama, F. Checler, P. Pageat, and C. Duykaerts (2000). Vascular and parenchymal abeta deposition in the aging dog: correlation with behavior. Neurobiology of Aging 21(5): 695-704. ISSN: 0197-4580.
Abstract: The behavior of 25 dogs was indirectly assessed by a formal questionnaire (evaluation of Age-Related Cognitive and Affective Disorders-ARCAD), filled out by the owner. The density of diffuse and vascular deposits was evaluated using four anti-Abeta peptide antibodies, in four temporal areas. Parenchymal, diffuse deposits of Abeta42 peptide were found in all aged animals but one. They were Congo red negative and were not immunostained by the anti-Abeta40 antibody, contrary to the vascular deposits. The densities of vascular and parenchymal deposits were not correlated. The ARCAD score was correlated with age, density of Abeta parenchymal and vascular deposits, and with the number of areas containing deposits (extension index). Multivariate analysis showed that the age and the extension index explained most of the variance. Congo red positivity (indicating that the Abeta peptide has the characteristics of an amyloid substance) is limited in the dog to the vascular wall and is associated, as in man, with the deposition of the Abeta 1-40 isoform. Parenchymal Abeta deposition seems to be a common correlate of behavioral problems in aging dogs.
Descriptors: aging, behavior, biochemistry and molecular biophysics, neural coordination, Alzheimer's disease, behavioral and mental disorders, nervous system disease, canine model, senile plaques, animal model, age related cognitive and affective disorders questionnaire, arcad questionnaire, analytical method, cognitive disturbances, cognitive evaluation.

Cooley, D.M., D.L. Schlittler, L.T. Glickman, M. Hayek, and D.J. Waters (2003). Exceptional longevity in pet dogs is accompanied by cancer resistance and delayed onset of major diseases. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 58(12): B1078-84. ISSN: 1079-5006.
Abstract: To characterize extreme aged pet dogs as a first step in developing an animal model of exceptional longevity, we constructed lifetime medical histories for 345 Rottweiler dogs using information collected from owners and veterinarians. Extreme aged dogs (alive at the 95th percentile age at death for the study population, > or =13.3 years) were compared with a usual longevity group (9-10 years). Exceptional longevity in Rottweiler dogs was accompanied by a significant delay in the onset of major life-threatening diseases; 76% of extreme aged dogs remained free of all major diseases during the first 9 years of life. Only 19% of extreme aged dogs died of cancer versus 82% of dogs with usual longevity (p <.0001). The reduction in cancer mortality in oldest-old pet dogs mimics that seen in human centenarians and provides strong rationale for using this animal model to study comparative mechanisms of cancer resistance in the extreme aged.
Descriptors: animal model, longevity, aging, medical history, cancer resistance.

Head, E., J. Liu, B.N. Ames, B.A. Muggenburg, N.W. Milgram, and C.W. Cotman (2000). Oxidative stress, beta-amyloid and cognitive function in the aged canine brain. Society for Neuroscience Abstracts 26(1 2): Abstract No. 873.2 ISSN: 0190-5295.
NAL Call Number: QP351.S6
Abstract: Several studies report evidence of oxidative stress in aged human brain. We examined the extent of lipid peroxidation in the aged canine, which we have suggested as a model of human brain aging. Eighteen beagle dogs ranging in age from 2-15 years were tested for size discrimination learning and subsequently the extent of beta-amyloid-42 (Abeta) deposition was measured in the prefrontal cortex using immunostained 4% paraformaldehyde-fixed sections. Oxidative damage to lipids was measured in serum and in frozen blocks from the contralateral prefrontal cortex using a biochemical assay for malondialdehyde (MDA) and GC-MS methodology. MDA levels were significantly elevated with age (F(1,17)=12.144 p<.003). In addition, MDA levels were a significant predictor of Abeta deposition in the prefrontal cortex (r=.70 p<.001, n=13) even when the effects of age were partialled out (r=.5041, p<.039 n=13). Further, MDA levels were significantly correlated with cognitive function; higher error scores were associated with increased levels of MDA (r=.534 p<.04). Finally, serum levels of MDA predicted brain levels of MDA (r=.494 p<.037) and thus serum assays may serve as a measure of brain oxidative stress. These results suggest that like the human, dogs show evidence of oxidative stress in the brain that is associated with age, the extent of Abeta deposition and with cognitive function.
Descriptors: aging, nervous system, neural coordination, gc ms, gas chromatography mass spectrometry, analytical method, biochemical assay, analytical method, cognitive function, oxidative stress, meeting abstract.

Milgram, N.W. (2003). Cognitive experience and its effect on age dependent cognitive decline in beagle dogs. Neurochemical Research 28(11): 1677-1682. ISSN: 0364-3190.
NAL Call Number: QP356.3 .N457
Abstract: Test-sophisticated beagle dogs show marked age sensitivity in a size discrimination learning task, with old and senior dogs performing significantly more poorly than young dogs. By contrast, age differences in learning were not seen in dogs naive with respect to neuropsychological test experience. These results indicate that old animals benefit less from prior cognitive experience than young animals, which is an example of an age-dependent loss in plasticity. This finding also suggests that behaviorally experienced animals are a more useful model of human cognitive aging than behaviorally naive animals. We also looked at the effect of a program of behavioral enrichment in aged dogs. One year of enrichment did not lead to significant differences, but after 2 years the behaviorally enriched group performed significantly better than the control group. The effect after 2 years indicates that a prolonged program of cognitive enrichment can serve as an effective intervention in aged dogs. These findings demonstrate that cognitive abilities in aged animals can be modified by providing behavioral experience, indicating that cognitive abilities remain moderately plastic, even in very old animals.
Descriptors: beagle, breed, age effects, cognition, neuropsychological tests, age-dependent loss in plasticity, behavioral enrichment, length of enrichment program.

Milgram, N.W., E. Head, S.C. Zicker, C.J. Ikeda Douglas, H. Murphey, B. Muggenburg, C. Siwak, D. Tapp, and C.W. Cotman (2005). Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study. Neurobiology of Aging 26(1): 77-90. ISSN: 0197-4580.
Abstract: The effectiveness of two interventions, dietary fortification with antioxidants and a program of behavioral enrichment, was assessed in a longitudinal study of cognitive aging in beagle dogs. A baseline protocol of cognitive testing was used to select four cognitively equivalent groups: control food-control experience (C-C), control food-enriched experience (C-E), antioxidant fortified food-control experience (A-C), and antioxidant fortified food-enriched experience(A-E). We also included two groups of young behaviorally enriched dogs, one receiving the control food and the other the fortified food. Discrimination learning and reversal was assessed after one year of treatment with a size discrimination task, and again after two years with a black/white discrimination task. The four aged groups were comparable at baseline. At one and two years, the aged combined treatment group showed more accurate learning than the other aged groups. Discrimination learning was significantly improved by behavioral enrichment. Reversal learning was improved by both behavioral enrichment and dietary fortification. By contrast, the fortified food had no effect on the young dogs. These results suggest that behavioral enrichment or dietary fortification with antioxidants over a long-duration can slow age-dependent cognitive decline, and that the two treatments together are more effective than either alone in older dogs.
Descriptors: dietary fortification, antioxidants, longitudinal study, cognitive aging, behavioral enrichment, age-dependent cognitive decline.

Pomeroy, M.J. and J.L. Robertson (2004). The relationship of age, sex, and glomerular location to the development of spontaneous lesions in the canine kidney: analysis of a life-span study. Toxicologic Pathology 32(2): 237-242. ISSN: 0192-6233.
Abstract: It is well documented that the presence of spontaneous renal disease and renal dysfunction increases with age in many species of mammals. Such alterations in renal structure and function may significantly affect the interpretation of long-term toxicology studies. The purpose of the present study was to assess the temporal evolution of selected renal lesions (cysts, interstitial inflammation, interstitial fibrosis, and glomerulosclerosis) in laboratory Beagle dogs, an important animal model in chronic toxicology studies. We examined representative sections of the kidneys from 159 purpose-bred and laboratory housed Beagle dogs and analyzed the extent and distribution of spontaneous lesions using the World Health Organization classification system for renal lesions. All dogs examined had renal lesions of varying severities. In the youngest dogs (up to 2 years of age), the density and severity of lesions were minimal, but were more severe by middle age (defined as 3-7 years). The density and severity of interstitial fibrosis and inflammation progressed with advancing age (p<0.0001 for both) in both sexes. The density of tubular cysts increased linearly with advancing age in females (p=0.0006), but not in males (p=0.49). The cortical distribution of glomeruli and advancing age of dogs were significantly related to the development of glomerulosclerosis. As age increased, the presence of glomerulosclerosis increased (p=0.0008). These data indicate that the development of renal lesions is progressive over the lifetime of a genetically similar population of laboratory Beagle dogs maintained under optimal standard environmental conditions. This information may be useful in the interpretation of compound effects during chronic toxicology studies in the dog.
Descriptors: breed, Beagle, age differences, aging, cysts pathological, fibrosis, glomerulus, inflammation, kidney diseases, lifespan, sex differences.

Siwak, C.T., P. Gruet, F. Woehrle, B.A. Muggenburg, H.L. Murphey, and N.W. Milgram (2000). Comparison of the effects of adrafinil, propentofylline, and nicergoline on behavior in aged dogs. American Journal of Veterinary Research 61(11): 1410-1414. ISSN: 0002-9645.
NAL Call Number: 41.8 Am3A
Descriptors: dogs, age differences, animal behavior, efficacy, mental disorders, drug therapy, quality of life, movement, dosage, pharmacodynamics.

Siwak, C.T., P.D. Tapp, H.J. Lee, and N.W. Milgram (2000). Age-associated changes in noncognitive behaviors in a canine model of aging. Society for Neuroscience Abstracts 26(1-2): Abstract No. 873.3. ISSN: 0190-5295.
NAL Call Number: QP351.S6
Abstract: Locomotor activity and exploration, which depend on the brain's motor system, are typically viewed independently from cognition. While this may be justified in the case of locomotion, exploration involves sensory processing, investigation, responding to novel stimuli, and information gathering - all of which depend on cognitive processes. To better understand cognitive changes associated with aging, we have developed a number of spontaneous behavior tests, including tests of exploration. Our curiosity test consists of placing a number of novel objects in the test arena and allowing the dog to explore the objects. In this test young dogs show significantly more exploration and contact with novel objects than old dogs. In the model dog test, dogs are placed in an arena with a life-size plastic dog. Young dogs again show significantly more investigative sniffing than old dogs. Young dogs spend significantly more time in contact with a human sitting in the middle of the arena than old dogs. These tests can also distinguish cognitively impaired aged dogs from successful agers. Compared to successful agers, age-impaired dogs spend less time interacting with novel objects, less time interacting with humans, and more time reacting to their reflection in a mirror. These results indicate that aging can affect curiosity, exploration and responses to novelty rather than locomotor activity per se.
Descriptors: aging, nervous system, neural coordination, arena, laboratory equipment, behavior test, analytical method, life size plastic dog, equipment, model dog test, analytical method, age associated changes noncognitive behavior changes, investigative sniffing, mirror, meeting abstract.

Siwak, C.T., P.D. Tapp, and N.W. Milgram (2001). Effect of age and level of cognitive function on spontaneous and exploratory behaviors in the beagle dog. Learning and Memory 8(6) ISSN: 1072-0502.
Abstract: Cognitively characterized young and aged beagle dogs were administered six different spontaneous behavior tests, which provided measures of locomotion, exploration, and social interaction. Consistent with our previous findings, we obtained no overall effect of age on locomotion. We did find, however, that for the aged dogs locomotion correlated with level of cognitive function, being lowest in age-unimpaired dogs and highest in impaired dogs. Exploratory behavior, as measured by response to novelty, varied with age, with young dogs scoring the highest. Young dogs spent more time with novel toys and a person, responded more to a silhouette of a dog, and interacted more with a model dog compared to aged dogs. Among the aged dogs, age-unimpaired dogs spent the greatest amount of time sitting or standing beside a person whereas age-impaired dogs spent the most time reacting to a reflection in a mirror. The age-impaired dogs show undirected, stereotypical types of behavioral patterns. These differences in activity patterns may be linked to underlying age-associated neuropathology.
Descriptors: age differences, animal behavior, Beagle, cognitive development, dog breeds, exploration, locomotion, social interaction, dogs.

Siwak, C.T., P.D. Tapp, and N.W. Milgram (2002). Behavioural correlates of age-associated cognitive changes in dogs. Symposium on brain aging and related behavioral changes in dogs, Orlando, Florida, USA, 11 January 2002,20-22 p.
Descriptors: abnormal behavior, age, aging, analytical methods, animal behavior, mental ability, dogs.

Siwak, C.T., P.D. Tapp, and N.W. Milgram (2001). Effect of age and level of cognitive function on spontaneous and exploratory behaviors in the beagle dog. Learning and Memory 8(6): 317-325. ISSN: 1072-0502.
Abstract: Cognitively characterized young and aged beagle dogs were administered six different spontaneous behavior tests, which provided measures of locomotion, exploration, and social interaction. Consistent with our previous findings, we obtained no overall effect of age on locomotion. We did find, however, that for the aged dogs locomotion correlated with level of cognitive function, being lowest in age-unimpaired dogs and highest in impaired dogs. Exploratory behavior, as measured by response to novelty, varied with age, with young dogs scoring the highest. Young dogs spent more time with novel toys and a person, responded more to a silhouette of a dog, and interacted more with a model dog compared to aged dogs. Among the aged dogs, age-unimpaired dogs spent the greatest amount of time sitting or standing beside a person whereas age-impaired dogs spent the most time reacting to a reflection in a mirror. The age-impaired dogs show undirected, stereotypical types of behavioral patterns. These differences in activity patterns may be linked to underlying age-associated neuropathology.
Descriptors: aging, behavior, nervous system, neural coordination, spontaneous behavior test, assessment method, experimental method, age effects, age associated neuropathology, cognitive function, level, exploration, exploratory behavior, locomotion, social interaction, spontaneous behavior.

Skoumalova, A., J. Rofina, Z. Schwippelova, E. Gruys, and J. Wilhelm (2003). The role of free radicals in canine counterpart of senile dementia of the alzheimer type. Experimental Gerontology 38(6): 711-719. ISSN: 0531-5565.
NAL Call Number: QP86.E85
Abstract: The pathogenesis of Alzheimer's disease is still unknown. In recent time oxidative stress has been discussed as an important contributor. In the present study we investigated the role of free radicals in the spontaneous canine model of Alzheimer's disease. We analysed end-products of lipid peroxidation: lipofuscin-like pigments (LFP), protein carbonyls, and vitamin E to obtain data on oxidative damage in brain of demented dogs. When the generation of free radicals is intensive the toxic products of lipid peroxidation can diffuse from the site of the primary formation and merge with erythrocytes. Therefore we also determined the level of lipid peroxidation in red blood cells. In brain of demented animals the level of LFP increased (to 247%, P < 0.05) as well as of protein carbonyls (to 438%, P < 0.01) while the vitamin E concentration was lowered (to 34%, P < 0.01) when compared to age-matched non-demented controls. The end-products of lipid peroxidation have been found increased also in erythrocytes of demented dogs (250%, P < 0.05). These results indicate intensive production of free radicals in brain of animals with dementia which induces damage to erythrocytes. Detection of the specific products of free radical damage in blood samples could be used for diagnostic purposes.
Descriptors: aging, behavior, metabolism, nervous system, neural coordination, Alzheimer's disease, behavioral and mental disorders, nervous system disease, etiology, senile dementia, lipid peroxidation end products.

Torp, R., E. Head, N.W. Milgram, F. Hahn, O.P. Ottersen, and C.W. Cotman (2000). Ultrastructural evidence of fibrillar beta-amyloid associated with neuronal membranes in behaviorally characterized aged dog brains. Neuroscience 96(3): 495-506. ISSN: 0306-4522.
Abstract: The aged dog brain accumulates beta-amyloid in the form of diffuse senile plaques, which provides a potentially useful in vivo model system for studying the events surrounding the deposition of beta-amyloid. We used postembedding immunocytochemistry at the electron microscopic level to determine the subcellular distribution of beta-amyloid 1-40 and beta-amyloid 1-42 peptides in the prefrontal and parietal cortex of behaviorally characterized dogs ranging in age from one to 17 years. Immunogold particles signaling beta-amyloid 1-42 occurred over intracellular and extracellular fibrils that were approximately 8 nm in width. Intracellular beta-amyloid 1-42 fibrils were found in close proximity to glial fibrillary acidic protein fibers within astrocytes, but only in cells with signs of plasma membrane disruption. Neuronal labeling of beta-amyloid 1-42 appears to be associated with the plasma membrane. Membrane-bound beta-amyloid 1-42 occurs in the form of fine fibrils that are embedded in the dendritic membrane and appear to project into the extracellular space as determined by quantitative analysis of the immunogold particle distribution. Bundles of beta-amyloid 1-42 were also closely associated and/or integrated with degenerating myelin sheaths of axons. In one dog that was impaired on several cognitive tasks, extensive beta-amyloid 1-42 deposition was associated with microvacuolar changes and vascular pathology. The present findings suggest that beta-amyloid 1-42 may be generated at the dendritic plasma membrane as well as in intracellular compartments. The close association between beta-amyloid 1-42 destroyed myelin suggests one possible new mechanism by which beta-amyloid 1-42 induces neurodegeneration.
Descriptors: nervous system, neural coordination, neurodegeneration, nervous system disease.

Zaucha, J.M., C. Yu, G. Mathioudakis, K. Seidel, G. Georges, G. Sale, M.T. Little, B. Torok Storb, and R. Storb (2001). Hematopoietic responses to stress conditions in young dogs compared with elderly dogs. Blood 98(2): 322-327. ISSN: 0006-4971.
NAL Call Number: RB145.A1B57
Abstract: Clinical observations show that older patients do not tolerate high-dose chemoradiotherapy as well as younger patients. It is unclear whether this is due to age-related differences in their responses to hematopoietic injury or to differential toxicities to other organs. In the present study, 6 young (0.5 years) and 6 elderly (8 years) dogs were challenged with 7 repeated nonlethal doses of 50 or 100 cGy total body irradiation (TBI) each (total 550 cGy), and 21 days of recombinant canine granulocyte-colony stimulating factor (rcG-CSF) after the last TBI dose. Recoveries of absolute neutrophil, platelet, and lymphocyte counts after each TBI dose, responses to rcG-CSF treatment, and telomere lengths in neutrophils were compared before and after the study. No differences were found in recoveries of neutrophils, platelets, or in responses to rcG-CSF among young and old dogs. In contrast, recoveries were suggestively worse in younger dogs. After rcG-CSF, platelet recoveries were poor in both groups compared with previous platelet recoveries (P<.01). Consequently, 2 old and 3 young dogs were euthanized because of persistent thrombocytopenia and bleeding. At the study's completion, marrow cellularities and peripheral blood counts of the remaining young and elderly dogs were equivalent. The telomere lengths in both groups were significantly reduced after the study versus beforehand (P=.03), but the median attritions of telomeres were not different. It was concluded that aging does not appear to affect hematopoietic cell recoveries after repeated low-dose TBI, suggesting that poor tolerance of radiochemotherapy regimens in older patients may be due to nonhematopoietic organ toxicities rather than age-related changes in hematopoietic stem cells reserves.
Descriptors: aging, pharmacology, radiation biology, blood and lymphatics, transport and circulation, thrombocytopenia, blood and lymphatic disease, radiochemotherapy, radiologic method, therapeutic method, bleeding, hematopoietic responses, stress conditions, total body irradiation.

Zicker, S.C. (2005). Cognitive and behavioral assessment in dogs and pet food market applications. Progress in Neuro Psychopharmacology and Biological Psychiatry 29(3): 455-459.
Abstract: A multi-disciplinary program was developed to assess the efficacy of antioxidant inclusion in a canine pet food on cognitive decline in aged beagles. A systematic approach to development of the food was used prior to beginning the cognitive studies. Comprehensive evaluation of antioxidant ingredients included assessments of commodities with naturally occurring antioxidants and synthetic antioxidants not commonly utilized, or at different concentrations than what was commonly utilized, in commercial pet foods. Studies were conducted to insure stability through processing, absorption from the gastrointestinal tract, safety, and tests for potential antioxidant biological benefit by ex vivo tests. Testing of the antioxidant-fortified food in aged beagles slowed the rate of cognitive decline in aged dogs. In addition, environmental enrichment also slowed the rate of cognitive decline. Importantly, the combination of dietary antioxidants and environmental enrichment was synergistic and resulted in the least amount of cognitive decline over the 30-month study period. Finally, a clinical study showed that antioxidant fortified food improved age-related behavioral changes in older pet dogs at in-home situations.

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