Joseph A. Araujo

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.

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 Alzheimers 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.

Dietary supplementation with medium-chain TAG has long-lasting cognition-enhancing effects in aged dogs

The present study focused on the hypothesis that dietary supplementation with medium-chain TAG (MCT) will improve cognitive function in aged dogs by providing the brain with energy in the form of ketones. Aged Beagle dogs were subjected to a baseline battery of cognitive tests, which were used to establish cognitively equivalent control or treatment groups. The dogs in the treatment group were maintained on a diet supplemented with 5.5 % MCT. After an initial wash-in period, all the dogs were tested with a battery of cognitive test protocols, which assessed sequentially landmark discrimination learning ability, egocentric visuospatial function and attention. The groups were maintained on the diets for 8 months. The MCT-supplemented group showed significantly better performance in most of the test protocols than the control group. The group differences also varied as a function of task difficulty, with the more difficult task showing greater supplementation effects than the easier tasks. The group given the MCT supplement showed significantly elevated levels of beta-hydroxybutyrate, a ketone body. These results indicate, first, that long-term supplementation with MCT can have cognition-improving effects, and second, that MCT supplementation increases circulating levels of ketones. The results support the hypothesis that brain function of aged dogs can be improved by MCT supplementation, which provides the brain with an alternative energy source.

Cognitive Dysfunction Syndrome A Disease of Canine and Feline Brain Aging

Brain aging is a degenerative process manifest by impairment of cognitive function; although not all pets are affected at the same level, once cognitive decline begins it is generally a progressive disorder. Diagnosis of cognitive dysfunction syndrome (CDS) is based on recognition of behavioral signs and exclusion of other medical causes that might mimic CDS or complicate its diagnosis. Drugs, diets, and supplements are now available that might slow CDS progression by various mechanisms including reducing oxidative stress and inflammation or improving mitochondrial and neuronal function. Moreover, available therapeutics may provide some level of improvement in cognitive and clinical signs of CDS.

The canine model of human cognitive aging and dementia: Pharmacological validity of the model for assessment of human cognitive-enhancing drugs

For the past 15 years we have investigated the aged beagle dog as a model for human aging and dementia. We have shown that dogs develop cognitive deficits and neuropathology seen in human aging and dementia. These similarities increase the likelihood that the model will be able to accurately predict the efficacy of Alzheimers disease (AD) treatments as well as detect therapeutics with limited or no efficacy. Better predictive validity of cognitive-enhancing therapeutics (CETs) could lead to enormous cost savings by reducing the number of failed human clinical trials and also may reduce the likelihood of negative outcomes such as those recently observed in the AN-1792 clinical trials. The current review assesses the pharmacological validity of the canine model of human aging and dementia. We tested the efficacy of (1) CP-118,954 and phenserine, two acetylcholinesterase inhibitors, (2) an ampakine, (3) selegiline hydrochloride, two drugs that have failed human AD trials, and (4) adrafinil, a putative CET. Our research demonstrates that dogs not only develop isomorphic changes in human cognition and brain pathology, but also accurately predict the efficacy of known AD treatments and the absence or limited efficacy of treatments that failed clinical trials. These findings collectively support the utilization of the dog model as a preclinical screen for identifying novel CETs for both age-associated memory disorder and dementia.

Cognitive Dysfunction in Cats: A Syndrome we Used to Dismiss as ‘Old Age’:

Practical relevance Cognitive dysfunction syndrome (CDS) is a widely accepted diagnosis in dogs, with established treatment options. In cats, however, our understanding of cognitive dysfunction is still being shaped by ongoing research in the field, and limited treatment options are available. Recent clinical studies indicate that old age in the cat is accompanied by increased behavioural signs such as wandering, vocalization and night-time activity that are not attributable to identifiable medical problems. It is essential, therefore, that veterinarians include behavioural well-being in the routine care of senior cats. Patient group While the exact age of onset is not established, studies suggest that age-related behavioural changes consistent with cognitive dysfunction are prevalent in cats as early as 10 years of age and that prevalence increases significantly in older cats. Clinical challenges The diagnosis of cognitive dysfunction requires the identification of geriatric behavioural changes that are not caused by other medical problems, although the two may not be mutually exclusive. Therefore, the practitioner must rely heavily on owner reports and history to ensure prompt diagnosis and treatment. The absence of any approved dietary or pharmaceutical interventions for cognitive dysfunction adds a further challenge, although several possibilities exist. Evidence base This article draws on recent research that has produced neuropathological, cognitive and behavioural evidence for cognitive dysfunction in aging cats. As an impetus to further our understanding of this disease and potential treatment options, the authors propose a behavioural checklist that might aid in the clinical diagnosis of feline CDS and discuss treatment options that have proven successful in the canine counterpart of this disease.

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.

Clinical Signs and Management of Anxiety, Sleeplessness, and Cognitive Dysfunction in the Senior Pet

Physical signs of old age may be obvious, but mental and cognitive changes require more careful observation. Changes in behavior may represent the earliest indications of medical problems, or disorders of the central nervous system, and these may be bidirectional. Cognitive dysfunction syndrome is underdiagnosed and affects a substantial portion of aged companion animals. This article describes potential treatment regimens to address age-related behavioral problems, as well as a framework for investigating differential diagnoses. Early identification of changes in behavior is essential for the adequate treatment and management of medical and behavioral problems, and for monitoring outcomes.

Assessment of nutritional interventions for modification of age-associated cognitive decline using a canine model of human aging

The present review focuses on the utility of a canine model in evaluating nutritional interventions for age-related cognitive dysfunction. Aged dogs demonstrate progressive cognitive decline with concurrent amyloid-beta pathology that parallels the pathology observed in aging humans. Dogs, therefore, provide a natural model of human pathological aging. We have and are in the process of evaluating several nutritional-based interventions aimed at preventing cognitive decline and brain aging. In a three-year longitudinal study, we examined the effects of a diet enriched with antioxidants and mitochondrial cofactors on several measures of cognition and brain aging. Compared to controls, aged dogs on the enriched diet demonstrated both short- and long-term cognitive benefits, as well decreased deposition of amyloid-beta protein. The diet also reduced behavioral signs associated with canine Cognitive Dysfunction Syndrome when assessed in veterinary clinical trials. We also have preliminary evidence suggesting a beneficial effect of a proprietary blend of docosahexaenoic acid and phospholipids on both cognitive and physiological measures. Collectively, our data indicate (1) that the dog, either in the laboratory or in the clinic, provides an important tool for assessing nutritional interventions and (2) that combination interventions aimed at several mechanisms of pathological aging may prove more effective than single nutritive components in human trials.

Aged dogs demonstrate both increased sensitivity to scopolamine impairment and decreased muscarinic receptor density

Memory deficits associated with aging and Alzheimers disease have been linked to cholinergic dysfunction. The present study investigated this hypothesis by comparing the effects of the muscarinic cholinergic receptor antagonist scopolamine on recent memory performance and by examining muscarinic receptor density in aged and young dogs. Scopolamine (15 μg/kg; SC) was administered prior to testing young (M=2.8 years) and aged (M=13.0 years) dogs on a delayed-non-matching-to-position task (DNMP). Scopolamine significantly impaired performance of aged, but not young dogs. Muscarinic receptor density was assessed autoradiographically using the non-selective radioligand [(3)H]quinuclidinylbenzilate. Aged dogs (M=14.1 years) showed significantly decreased density of muscarinic receptors in all brain regions examined except the cerebellum compared to young dogs (M=3.7 years). The results are consistent with those seen in aged humans and Alzheimers patients and support the hypothesis of age-dependent cholinergic dysfunction in the dog, although this was not directly determined in the current study. These findings demonstrate that markers of cholinergic hypofunction, in addition to the natural cognitive decline and amyloid pathology previously noted, are seen in canine aging. Collectively, this supports the use of the aged dog as a model for examining early pathological events in the development of Alzheimers disease.