A combination cocktail improves spatial attention in a canine model of human aging and Alzheimer's disease.

Alzheimer's disease (AD) involves multiple pathological processes in the brain, including increased inflammation and oxidative damage, as well as the accumulation of amyloid-ß (Aß) plaques. We hypothesized that a combinatorial therapeutic approach to target these multiple pathways may provide cognitive and neuropathological benefits for AD patients. To test this hypothesis, we used a canine model of human aging and AD. Aged dogs naturally develop learning and memory impairments, human-type Aß deposits, and oxidative damage in the brain. Thus, 9 aged beagles (98-115 months) were treated with a medical food cocktail containing (1) an extract of turmeric containing 95% curcuminoids; (2) an extract of green tea containing 50% epigallocatechingallate; (3) N-acetyl cysteine; (4) R-alpha lipoic acid; and (5) an extract of black pepper containing 95% piperine. Nine similarly aged dogs served as placebo-treated controls. After 3 months of treatment, 13 dogs completed a variable distance landmark task used as a measure of spatial attention. As compared to placebo-treated animals, dogs receiving the medical food cocktail had significantly lower error scores (t11 = 4.3, p = 0.001) and were more accurate across all distances (F(1,9) = 20.7, p = 0.001), suggesting an overall improvement in spatial attention. Measures of visual discrimination learning, executive function and spatial memory, and levels of brain and cerebrospinal fluid Aß were unaffected by the cocktail. Our results indicate that this medical food cocktail may be beneficial for improving spatial attention and motivation deficits associated with impaired cognition in aging and AD.

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.

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.

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.

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.

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.

Visuospatial impairments in aged canines (Canis familiaris): the role of cognitive-behavioral flexibility.

This study used a novel delayed nonmatching-to-position task to compare visuospatial learning and memory in young and aged beagle dogs (Canis familiaris). The task used 3, rather than 2, spatial locations, which markedly increased difficulty. There were striking age differences in acquisition. Most of the aged canines did not learn the task, and those that did showed impaired learning when compared with the young canines. The aged canines also showed reduced maximal working memory capacity compared with the young canines. Analysis of the response patterns of individual canines indicated that the deficits were related to the use of ineffective strategies and inflexibility in strategy modification.

Age-dependent decline in locomotor activity in dogs is environment specific.

A decrease in motor activity is an expected concomitant of normal aging and has been reported in humans and nonhuman mammals. We have previously failed to find age differences in open-field locomotor activity in beagle dogs. We now report an age-associated decline when activity measures are taken in the home cage. Locomotor activity of young and aged dogs was examined in both open-field and home-cage environments. Dogs were given six activity tests (two open field, two morning and two afternoon home-cage tests) every second day. Aged dogs were less active than young dogs in the home cage but not in the open field. Activity also varied as a function of sex and housing condition. Behavioral activity is a complex manifestation of many underlying factors.