Elizabeth Head

The canine as an animal model of human aging and dementia

The aged canine displays many features that make it an excellent model for studying the progression of pathology in brain aging and linking these findings to learning, memory and other cognitive functions. Canines develop extensive beta-amyloid deposition within neurons and their synaptic fields, which appears to give rise to senile plaques. These plaques are primarily of the early diffuse subtype. Aged canines also exhibit accumulations of lipofuscin, cerebral vascular changes, dilation of the ventricles, and cytoskeletal changes. Neurofibrillary tangles (NFTs) are not present in the aged canine. Thus, the aged canine brain provides a suitable model for studying early degeneration normally considered to be pre-Alzheimers. This supposition is also supported by behavioral data. We have found that the extent of beta-amyloid deposition correlates with a decline in select measures of cognitive function. These data provide the first evidence of a correlation between beta-amyloid accumulation and cognitive decline in the absence of NFTs. We summarize four lines of evidence that support using the aged canine as a model of human aging: (a) Aged canines develop aspects of neuropathology similar to that observed in aged humans; (b) Veterinarians have observed that many canines exhibit a clinical syndrome of age-related cognitive dysfunction; (c) Aged canines are deficient on a variety of neuropsychological tests of cognitive function; (d) The level of beta-amyloid accumulation correlates with cognitive dysfunction in the canine. These data indicate that the aged canine is a particularly useful model for studying age-related cognitive dysfunction (ARCD), early neuronal changes associated with aging, and the initial stages of senile plaque formation.

Cognitive functions and aging in the dog: acquisition of nonspatial visual tasks.

Old, middle-aged, and young dogs were compared on discrimination and reversal learning and on acquisition of a delayed-nonmatching-to-sample (DNMS) test of recognition memory. DNMS acquisition was acquired more rapidly by young dogs. Reversal deficits were found between aged mixed-breed dogs and young beagles, but not between old and young beagles. Aged beagles also showed unexpected deficits in reward approach and object approach learning. Aged mixed-breed dogs did not show deficits in reward approach and object approach learning, but they learned the discrimination task more slowly than the age-matched beagles. A detailed analysis of response patterns indicated that once present, the development of side preferences contributed to deficits of old dogs in discrimination learning. In the discrimination reversal, old dogs were more persistent in responding to the previously rewarded stimulus object. Findings suggest that the dog, like other species, shows age-dependent deterioration in cognitive function, the extent of deterioration is a function of both task and previous experience, and at least part of the deterioration is a result of increased behavioral rigidity. Results also indicate that it is important to control for breed differences and previous experience.

Spatial learning and memory as a function of age in the dog.

Spatial learning and memory were studied in dogs of varying ages and sources. Compared to young dogs, a significantly higher proportion of aged dogs could not acquire a spatial delayed nonmatching-to-sample task. A regression analysis revealed a significant age effect during acquisition. Spatial memory was studied by comparing performance at delay interval of 20, 70, and 110 s. At short delays aged and young dogs were similar; at longer delays, errors increased to a greater extent in old than in young dogs; however this was not statistically significant. It was possible to identify 2 groups of aged animals, age-impaired and age-unimpaired. Several of the dogs were also tested on an object recognition memory task, which was more difficult to learn than the spatial task. The possibility that these findings are confounded by breed differences is considered. Overall, the present results provide further evidence of the value of a canine model of aging.

Diffuse plaques contain C-terminal Aβ42 and not Aβ40: Evidence from cats and dogs ☆

Abstract Recent reports have suggested that β-amyloid (Aβ) species of variable length C-termini are differentially deposited within early and late-stage plaques and the cerebrovasculature. Specifically, longer C-terminal length A β 42 3 fragments (i.e., Aβ forms extending to residues 42 and/or 43) are thought to be predominant within diffuse plaques while both A β 42 3 and Aβ40 (Aβ forms terminating at residue 40) are present within a subset of neuritic plaques and cerebrovascular deposits. We sought to clarify the issue of differential Aβ deposition using aged canines, a partial animal model of Alzheimers disease that exhibits extensive diffuse plaques and frequent vascular amyloid, but does not contain neuritic plaques or neurofibrillary tangles. We examined the brains of 20 aged canines, 3 aged felines, and 17 humans for the presence of Aβ immunoreactive plaques, using antibodies to Aβ1–17, Aβ17–24, Aβ1–28, Aβ40, and Aβ42. We report that plaques within the canine and feline brain are immunopositive for Aβ42 but not Aβ40. This is the first observation of nascent AD pathology in the aged feline brain. Canine plaques also contained epitopes within Aβ1–17, Aβ17–24, and Aβ1–28. In all species examined, vascular deposits were immunopositive for both Aβ40 and Aβ42. In the human brain, diffuse plaques were preferentially Aβ42 immunopositive, while neuritic plaques and vascular deposits were both Aβ40 and Aβ42 immunopositive. However, not all neuritic plaques contain Aβ40 epitopes.

Chapter 22 Canine cognitive dysfunction as a model for human age-related cognitive decline, dementia and Alzheimer's disease: clinical presentation, cognitive testing, pathology and response to 1-deprenyl therapy

Publisher Summary This chapter explores the potential of the canine as a model of human age-related cognitive decline (ARCD), dementia, and Alzheimers disease (AD). It also discuss a number of studies that indicate that some people with dementia and dogs with cognitive dysfunction respond to therapy with the monoamine oxidase inhibitor, 1-deprenyl (selegiline HCl). Results indicate that elderly pet dogs exhibit multiple behavioral or cognitive problems indicative of cognitive dysfunction, which in some canine patients are sufficiently severe to disrupt the dogs function as an adequate pet. In some affected pet dogs, the change in behavior was found to be due to the presence of systemic, non-neurological disease; however, in numerous cases, no such general medical condition was identified, suggesting that the behavioral or cognitive dysfunction may be due to brain pathology. Studies indicate that some cognitive deficits, but not others, are correlated with age and with amyloid accumulation. Screening tests might be developed to predict amyloid accumulation and/or response to therapy in pet dogs. If so, this information might be extrapolated to cognitively impaired people. The dogs in the study presented in the chapter responded quite favorably to once-daily therapy with 0.5 mg/kg 1-deprenyl. Similarly, human patients with dementia of the Alzheimers type have responded to 1-deprenyl therapy.

The Progression of β-amyloid Deposition in the Frontal Cortex of the Aged Canine

Abstract Brains from 41 aged canines (≥10 years of age) were examined immunohistochemically to characterize the laminar distribution and age-related progression of β-amyloid (Aβ) in frontal cortex. We classified the Aβ patterns into four distinct types. Type I was characterized by small, faint deposits of Aβ in deep cortical layers. Type II consisted of diffuse deposits of Aβ mainly in layers V and VI. Type III had both dense plaques in superficial layers, and diffuse deposits in deep layers. Finally, Type IV had solely dense plaques throughout all layers of cortex. We compared the Aβ distribution pattern between the Old canines (10–15 years, n=22) and the Very Old canines (>15 years, n=19). The Old group primarily had negative staining, or Type I and Type II patterns of amyloid deposition (73%). Conversely, the Very Old group had predominantly Types II, III and IV deposits (89.5%), a difference that was significant (P

The effect of L-deprenyl on behavior, cognitive function, and biogenic amines in the dog

Behavioral and pharmacological effects of oral administration ofl-deprenyl in the dog are described. Spontaneous behavior is unaffected at doses below 3 mg/kg while at higher doses there was stereotypical responding. There was evidence of improved cognitive function in animals chronically treated with a 1 mg/kg dose but the effectiveness varied considerably between subjects. Chronic administration produced a dose dependent inhibition in brain, kidney and liver monoamine oxidase B, and had no effect on monoamine oxidase A. There were also dose dependent increases in brain phenylethylamine and in plasma levels of amphetamine. Dog platelets did not have significant levels of MAO-B. Brain dopamine and serotonin metabolism were unaffected byl-deprenyl at doses up to 1 mg/kg. It appears that for the dog, deamination of catecholamines is controlled by MAO-A. Nevertheless, it is suggested thatl-deprenyl serves as a dopaminergic agonist, and there is also evidence that it affects adrenergic transmission. These catecholaminergic actions may account for the effects ofl-deprenyl on behavior and cognitive function.

Open Field Activity and Human Interaction as a Function of Age and Breed in Dogs

Open field (OF) activity was studied in kennel reared purebred beagles from two separate colonies (2-13 years in age) and pound source mixed breed dogs (9 months to 10 years in age). Dogs were observed for 10 min sessions and records were taken of: locomotion, urination, sniffing, grooming, rearing, vocalizing, jumping frequencies and inactivity (16). Since dogs are uniquely social towards people, we also measured human interaction (HI), which recorded the same behaviors as during OF when a person was present in the room. Measures of exploratory behavior decreased as a function of age in pound source dogs in the OF test, but not in beagles from either colony. No breed differences were found between the young dogs. In the HI test, age effects were found in beagles but not pound source dogs. OF activity correlated with tests of cognitive function, but differences were found between the three groups. These findings indicate that OF activity is age-sensitive in dogs, but that breed and test conditions are also essential factors.

Development of spontaneous seizures over extended electrical kindling. II Persistence of dentate inhibitory suppression

The effect of an extended program of perforant path or amygdala kindling on paired-pulse suppression in the dentate gyrus was studied in male hooded rats. Repeated kindling stimulations were delivered twice or three times daily until either 300 stimuli had been delivered or generalized convulsions had been observed to occur spontaneously. Paired-pulse suppression was monitored prior to and over the course of kindling using a standard variable interval paradigm. We also used a variable intensity paradigm in which the intensity of the conditioning pulse was varied while the test pulse intensity was fixed at 600 microA and the interpulse interval was fixed at 30 ms. Both procedures revealed progressive increases in paired-pulse suppression which persisted over the course of kindling. This increased inhibition also persisted in animals which developed spontaneous seizures. The variable intensity paired-pulse procedure also allowed us to monitor facilitation effects which were relatively uncontaminated by recurrent inhibition (when the conditioning pulse intensity was low). Kindling was found to increase paired-pulse facilitation. With the standard variable interval paradigm, these increases in facilitation masked the increases in suppression.

Neurobiological Models of Aging in the Dog and Other Vertebrate Species

The rodent and nonhuman primate are not the only species to develop neuropathologic lesions similar to those seen in the aged human brain. Dogs and cats develop diffuse senile plaques with age, but do not show neurofibrillary tangle formation. The goat, sheep, bear, and wolverine, by contrast, are reported to develop neurofibrillary-like lesions but, in the first two cases, not senile plaques. The only one of these six species that has been extensively studied, however, is the dog, and the neurobiology of aging in canines is therefore the main focus of this chapter. Dogs exhibit extensive individual variability in the aging process on measures of learning and memory and in extent of β-amyloid (Aβ) deposition in the brain. Dogs, like humans, also show variability in cognitive aging. Some dogs develop severe cognitive impairment; these same dogs develop extensive Aβ deposition. Other dogs remain cognitively intact, and also show little or only moderate Aβ deposition. These findings suggest that dogs can be used to model the earliest phases of cognitive and neuroanatomical changes associated with pathological aging in humans. In addition, the existence of aged dogs that can learn and remember as well as younger dogs may also offer us insight into promoting successful aging in humans.