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Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: A two-year longitudinal study
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.
... Although single-ingredient supplements may be beneficial, the greatest effect might be achieved with the combined effects of behavioral enrichment and a blend of ingredients. 46 This possibility is supported by human studies in which physical and mental activity and diets containing fruits, vegetables, seeds, legumes, nuts and fish oils, and a diet with both omega-3 fatty acids and B vitamins, have been shown to reduce cognitive decline. 6,47 Nutritional Support for Cognitive Dysfunction Syndrome Studies in both laboratory models and clinical trials have shown a beneficial effect of nutrition on improving signs and slowing progression of CDS in dogs. ...
... 48 A diet (Hills Prescription Diet b/d Canine) supplemented with fatty acids, antioxidants (vitamins C and E, b-carotene, selenium, flavonoids, carotenoids), and mitochondrial cofactors (DL-alpha-lipoic acid and L-carnitine) was evaluated in a laboratory study of beagles. 46 Over 2 years, discrimination learning was improved with behavioral enrichment, and reversal learning was improved by both behavioral enrichment and diet, whereas the 2 treatments together were more effective than either treatment alone. 46 A blinded, 60-day clinical trial in 125 dogs compared the total number of improved signs in the supplemented diet with the control group, and observed a significant difference in favor of the supplemented food 49 (Table 2 provides a guide to screening for cognitive decline using the mnemonic DISHAA). ...
... 46 Over 2 years, discrimination learning was improved with behavioral enrichment, and reversal learning was improved by both behavioral enrichment and diet, whereas the 2 treatments together were more effective than either treatment alone. 46 A blinded, 60-day clinical trial in 125 dogs compared the total number of improved signs in the supplemented diet with the control group, and observed a significant difference in favor of the supplemented food 49 (Table 2 provides a guide to screening for cognitive decline using the mnemonic DISHAA). ...
There are several natural products and functional ingredients that, either alone or in combination with other ingredients, have shown evidence for decreasing signs associated with cognitive dysfunction and anxiety in dogs and cats, and in management of seizures in dogs with epilepsy. The evidence supporting the role that a healthy gastrointestinal tract plays in behavior is also growing as more is learned about the gut-brain axis. Nutritional support may play an important role in therapy for certain brain disorders and behavioral problems, in conjunction with other aspects of management. A multimodal approach provides the greatest likelihood of success.
... Similarly, dietary manipulations are thought to enhance cognitive abilities by protecting the brain from oxidative damage, promoting repair and counteracting the effects of aging (Gómez-Pinilla, 2008). For example, reduction of oxidative damage and Aβ plaque pathology in the brain as well as reduced mitochondrial dysfunction have been reported in laboratory dogs fed with diets enriched with antioxidants and mitochondrial enzymatic co-factors (Milgram et al., 2005;Opii et al., 2008;Head et al., 2009;Pop et al., 2010). In line with these results, aged rats and laboratory dogs receiving an antioxidant treatment, as compared to subjects receiving a control diet, showed improved cognitive performance in the Morris water maze and in discrimination learning tasks (Socci et al., 1995;Davis and Head, 2014). ...
... Moreover, supplementation of medium chain triglycerides had beneficial effects on the aging brain, as demonstrated by better performance of laboratory dogs in various discrimination tasks (Pan et al., 2010). Finally, a combined treatment of behavioral enrichment (consisting of exercise and cognitive training) and antioxidants diet is thought to have additive effects on synaptic plasticity and cognitive functions in humans and in animal models (Cotman and Berchtold, 2002;Gómez-Pinilla, 2008), and at least in laboratory dogs helps attenuate age-dependent cognitive decline Milgram et al., 2004Milgram et al., , 2005Head et al., 2009). Overall, studies in humans, rats and dogs have provided some evidence of protective effects of diet and exercise on various cognitive functions in the elderly. ...
... Therefore, the discrimination learning tests used by Wallis et al. (2016) has proved suitable to detect age effects. Discrimination learning tasks have also been used to test the influence of dietary supplements on learning and cognitive flexibility in laboratory dogs (Milgram et al., 2002a(Milgram et al., ,b, 2004(Milgram et al., , 2005. In a longitudinal study using laboratory beagles, Milgram et al. (2002a) tested the effectiveness of antioxidants and behavioral enrichment in different cognitive tasks. ...
Aging is associated with a decline in cognitive functions such as learning, memory, attention, cognitive flexibility, and executive functions. Recent evidence indicates that interventions such as exercise, diet and cognitive training can be used to reduce the rate of age-dependent cognitive decline. In this study, we examined the changes in discrimination learning in older pet dogs, tested whether a dietary intervention counteracts a potential decline in learning and evaluated the influence of lifelong training on learning speed and cognitive flexibility. We included 115 pet dogs (>6 years) of 30 different breeds into one of two treatment groups: either a diet enriched with antioxidants, docosahexaenoic acid (DHA), Phosphatidylserine and tryptophan or a control diet for 1 year. Lifelong training was calculated for each dog using a questionnaire where owners filled their dog’s training experiences over years. Dogs were trained to discriminate different pictures at the start of the dietary intervention using a touch screen methodology. After 1 year of dietary intervention, they were tested on a main picture discrimination task where they were confronted with a discrimination of four new pictures. We used the total number of sessions needed to reach learning criterion as a measure of learning speed and the rate of correction trials as a measure of deficit in learning from feedback/cognitive flexibility. In the main discrimination task, we found an influence of neither age nor diet on the speed of learning and deficit in learning from feedback. We did not find any influence of lifelong training either. The null findings were further corroborated by Bayesian statistics. The null findings might be due to the fact that pet dogs live in a stimulating environment which may reduce the rate of cognitive decline and hinder finding an age or diet effect. Also, the similarity between the training and the main discrimination task might have made the main task too easy for the animals to solve. Further studies are warranted to assess the effect of enriched diets on pet dogs using tasks that measure cognitive functions with a higher sensitivity.
... It showed that dogs receiving the fortified diet learned the landmark discrimination learning task more rapidly Milgram, Zicker, et al., 2002), and performed better on the oddity discrimination learning task at higher levels Milgram, Zicker, et al., 2002). Additionally, those receiving the fortified diet in combination with a behavioural intervention performed better on size discrimination reversal-learning task , and on several learning tasks in a two-year follow-up (Milgram et al., 2005). ...
... Similarly, in another trial where 48 dogs were assigned to receive a control diet, the fortified diet, a behavioural enrichment intervention, or a combination of both the fortified diet and behavioural enrichment intervention , those receiving a combined intervention performed significantly better on a size discrimination reversal-learning task than the other three groups at the one-year follow-up. At the two-year follow-up, the combined intervention group also performed significantly better on the black/white discrimination learning task and the reversal-learning task than the control diet group (Milgram et al., 2005). An analysis of brain samples from these Beagles suggested that the improvement of cognitive function, as a result of a combined dietary and behavioural interventions, was mediated by an increased expression of BDNF, a decrease of Aβ plaque deposits and an improvement of the antioxidant reserve system, resulting in a reduction of oxidative damage (Fahnestock et al., 2012;Head et al., 2000;Opii et al., 2008;Pop et al., 2010). ...
Dogs possess the ability to obtain essential nutrients, established by the Association of American Feed Control Officials (AAFCO), from both animal- and plant-based ingredients. There has been a recent increase in the popularity of diets that limit or completely exclude certain plant-based ingredients. Examples of these diets include ‘ancestral’ or ‘evolutionary’ diets, raw meat-based diets and grain-free diets. As compared to animal sources, plant-derived ingredients (including vegetables, fruits, grains, legumes, nuts and seeds) provide many non-essential phytonutrients with some data suggesting they confer health benefits. This review aims to assess the strength of current evidence on the relationship between the consumption of plant-based foods and phytonutrients (such as plant-derived carotenoids, polyphenols and phytosterols) and biomarkers of health and diseases (such as body weight/condition, gastrointestinal health, immune health, cardiovascular health, visual function and cognitive function) from clinical trials and epidemiological studies. This review highlights the potential nutritional and health benefits of including plant-based ingredients as a part of balanced canine diets. We also highlight current research gaps in existing studies and provide future research directions to inform the impact of incorporating plant-based ingredients in commercial or home-prepared diets.
... Researchers have also found canine analogs of attentional deficit hyperactivity disorder (ADHD; Vás et al. 2007) and Alzheimer's disease (canine cognitive dysfunction; Azkona et al. 2009;Landsberg et al. 2003Landsberg et al. , 2012Ruehl et al. 1995). Such research provides a starting point in developing methods of testing various cognitive abilities, as well as the efficacy of interventions, such as those aiming to reduce age-related cognitive decline Milgram 2003;Milgram et al. 2002Milgram et al. , 2005. Increased knowledge of EF in dogs can show us which qualities (and associated brain regions) of this ability are shared between humans and dogs and which are distinct to each species, and inform the conclusions we can draw from research using dogs as models for human cognition and mental illness. ...
... During the reversal phase, subjects must overcome the urge to perform the previously rewarded response in favor of performing the opposite response (e.g., selecting a small block when the large block had previously been rewarded; Tapp et al. 2003). This task has been used with a variety of species to examine how aging affects EF, as well as testing the efficacy of treatments for age-related cognitive decline Milgram 2003;Milgram et al. 2002Milgram et al. , 2005. ...
... In line with these human results, lifelong training helped to retain measures of attentiveness in senior dogs [14]. In laboratory Beagles, a combined treatment of behavioural enrichment (consisting of exercise and cognitive training) and an antioxidant diet has proven to be more effective in attenuating age-dependent cognitive decline than cognitive training alone [36,45]. Reports of the effects of lifelong training on a broader cognitive profile in pet dogs are currently lacking. ...
... Nutritional antioxidants act as free radical scavengers by directly neutralizing free radicals, or reducing the peroxide concentrations and repairing oxidized membranes [47]. Several crosssectional and longitudinal studies in laboratory beagles have reported the positive effects of antioxidant fortified food in attenuating cognitive decline measured in different domains like attention, learning, cognitive flexibility and executive functions [36,45,[48][49][50][51][52] but see Snigdha et al. [53] for negative results. Moreover, reduced oxidative damage and Aβ plaque pathology in the brain, as well as reduced mitochondrial dysfunction have been reported in laboratory dogs fed with an enriched diet containing antioxidants and mitochondrial enzymatic co-factors [46,54,55]. ...
Dogs demonstrate behavioural changes and cognitive decline during aging. Compared to laboratory dogs, little is known about aging in pet dogs exposed to different environments and nutrition. In this study, we examined the effects of age, an enriched diet and lifelong training on different behavioural and cognitive measures in 119 pet dogs (>6yrs). Dogs were maintained on either an enriched diet or a control diet for one year. Lifelong training was calculated using a questionnaire where owners filled in their dog's training experiences to date. Before commencing the diet and after one year of dietary treatment, they were tested in the Modified Vienna Canine Cognitive Battery (MVCCB) consisting of 11 subtests to examine correlated individual differences in a set of tasks measuring general, social and physical cognition and related behaviours. Fourty two behavioural variables were coded and were subjected to principle component analyses for variable reduction. Twelve subtest level components and two Z-transformed variables were subjected to exploratory factor analysis which resulted in six final factors: Problem solving, Trainability, Sociability, Boldness, Activity-independence and Dependency. Problem solving, Sociability, Boldness, and Dependency showed a linear decline with age, suggesting that the MVCCB can be used as a tool to measure behavioural and cognitive decline in aged pet dogs. An enriched diet and lifelong training had no effect on these factors, calling attention to the fact that the real world impact of nutritional and other interventions in possibly counteracting the effects of aging, should be further investigated in pet dogs living under diverse conditions, in order to understand their ultimate effects.
... Over the last two decades, we have seen an increase in attempts to capture how age affects non-pathological canine behavior. Examples span from attention [7,8], memory [9,10], sleep physiology [11], personality [12], and social interaction [13] to higher cognitive functions, such as reasoning by exclusion and reversal learning [10,14,15]. A more practical problem related to the study of canine aging is how to standardize and optimize the behavioral testing protocols toward, for example, creating quick and easy assessment tools for practicing veterinarians. ...
... Many of the test procedures published so far for cognitive aging in dogs could prove costly in terms of both time and finance if applied one on one in the veterinary practice. They involve either expensive and/or complicated devices, such as touch-screen computers [10] or other engineered testing apparatus [14]. Some tests investigating cognitive skills require extensive pre-training before the animals' behavior can be evaluated with the test [10,15]. ...
Over the last few years, several efforts have been undertaken to characterize the aging process in dogs. In the present study, we evaluate a short protocol measuring dogs’ cognitive, social, and physical capacities. Our aim was to develop a feasible test battery, with minimal pre-training requirements, no complex devices, and which is set outdoors (i.e., a specific testing room is not needed). As ageing in dogs is usually associated with a decrease in activity, we also assessed the personality trait activity/excitability with a dog personality questionnaire. Four subtests proved sensitive to the dogs’ age. In particular, old dogs displayed less approaching and following behaviors toward an unknown but friendly human, showed both less avoidance and interest toward a novel object, looked less at the owner when faced with an unsolvable problem, and performed worse on the short-term memory task. Previous test procedures for investigating age-related changes involve expensive and/or complicated devices and extensive pre-training. The main advantage of the proposed battery is to reduce costs and efforts in veterinary assessments. Further tests in same-breed, large samples and between dogs with mild and severe cognitive impairments will be needed in order to further validate the battery.
... Researchers have also found canine analogs of attentional deficit hyperactivity disorder (ADHD; Vás et al. 2007) and Alzheimer's disease (canine cognitive dysfunction; Azkona et al. 2009;Landsberg et al. 2003Landsberg et al. , 2012Ruehl et al. 1995). Such research provides a starting point in developing methods of testing various cognitive abilities, as well as the efficacy of interventions, such as those aiming to reduce age-related cognitive decline Milgram 2003;Milgram et al. 2002Milgram et al. , 2005. Increased knowledge of EF in dogs can show us which qualities (and associated brain regions) of this ability are shared between humans and dogs and which are distinct to each species, and inform the conclusions we can draw from research using dogs as models for human cognition and mental illness. ...
... During the reversal phase, subjects must overcome the urge to perform the previously rewarded response in favor of performing the opposite response (e.g., selecting a small block when the large block had previously been rewarded; Tapp et al. 2003). This task has been used with a variety of species to examine how aging affects EF, as well as testing the efficacy of treatments for age-related cognitive decline Milgram 2003;Milgram et al. 2002Milgram et al. , 2005. ...
Executive function (EF) allows for self-regulation of behavior including maintaining focus in the face of distraction, inhibiting behavior that is suboptimal or inappropriate in a given context, and updating the contents of working memory. While EF has been studied extensively in humans, it has only recently become a topic of research in the domestic dog. In this paper, I argue for increased study of dog EF by explaining how it might influence the owner-dog bond, human safety, and dog welfare, as well as reviewing the current literature dedicated to EF in dogs. In "EF and its Application to "Man's Best Friend" section, I briefly describe EF and how it is relevant to dog behavior. In "Previous investigations into EF in dogs" section, I provide a review of the literature pertaining to EF in dogs, specifically tasks used to assess abilities like inhibitory control, cognitive flexibility, and working memory capacity. In "Insights and limitations of previous studies" section, I consider limitations of existing studies that must be addressed in future research. Finally, in "Future directions" section, I propose future directions for meaningful research on EF in dogs.
... In line with these human results, lifelong training helped to retain measures of attentiveness in senior dogs [14]. In laboratory Beagles, a combined treatment of behavioural enrichment (consisting of exercise and cognitive training) and an antioxidant diet has proven to be more effective in attenuating age-dependent cognitive decline than cognitive training alone [36,45]. Reports of the effects of lifelong training on a broader cognitive profile in pet dogs are currently lacking. ...
... Nutritional antioxidants act as free radical scavengers by directly neutralizing free radicals, or reducing the peroxide concentrations and repairing oxidized membranes [47]. Several crosssectional and longitudinal studies in laboratory beagles have reported the positive effects of antioxidant fortified food in attenuating cognitive decline measured in different domains like attention, learning, cognitive flexibility and executive functions [36,45,[48][49][50][51][52] but see Snigdha et al. [53] for negative results. Moreover, reduced oxidative damage and Aβ plaque pathology in the brain, as well as reduced mitochondrial dysfunction have been reported in laboratory dogs fed with an enriched diet containing antioxidants and mitochondrial enzymatic co-factors [46,54,55]. ...
Cognitive aging in pet dogs of different breeds: effects of an enriched diet and lifelong training
Cognitive decline in dogs has been mostly studied in laboratory dogs, but little is known in pet dogs exposed to different environments and nutrition. In this study, we examined how age, enriched diet and lifelong training influence different behaviours and cognitive functions in 119 pet dogs (>6yrs) of various breeds. Dogs were assigned to one of two treatment groups, and were fed with enriched diet or with a control diet for a year. After one year, they were tested in the Vienna Canine Cognitive Battery (VCCB), a test battery that consists of 11 subtests and aims to examine correlated individual differences in domains of general, social and physical cognition as well as human-animal interactions. Forty behavioral variables were coded and were subjected to principle component analyses (PCA) for variable reduction. The 14 subtest-level components generated from the PCA were then fed into exploratory factor analysis (EFA) to explore the underlying cognitive construct. The EFA yielded six final factors: Problem solving, Social activity, Learning, Boldness, Exploration and Dependency. The effects of age, enriched diet and training were examined in these factors. Results revealed significant age effects on problem solving (p<0.001), boldness (p=0.01) and dependency (p<0.001), and a tendency on learning (p=0.06) and social activity (p=0.06). While enriched diet seemed to influence only social activity (p=0.01), training had no effect on any of the measured cognitive functions. We conclude that VCCB can be used to measure cognitive decline in aged pet dogs, and that dietary enrichment can enhance social activity during aging.
... These researchers used a modified Wisconsin General Testing Apparatus, securing motor and sensory demands of dogs across tests. Aged laboratory dogs showed cognitive decline in tests measuring complex learning, executive function, spatial learning and memory [18,28,43] . Using spatial learning and memory tasks (Delayed Nonmatch to Position (DNMP)), old dogs can be categorized into 3 groups: successful agers, dogs with mild cognitive impairments, and severely impaired dogs [5] . ...
... Aged dogs fed a diet containing medium-chain triglyceride supplementation performed better on various cognitive tasks [51] . Behavioral enrichment (physical exercise, social enrichment, and cognitive enrichment), alone or in combination with an antioxidant diet, also preserves and improves cognitive function in old dogs [43,52] . Since these data have almost exclusively been collected under laboratory conditions and in beagles that were mostly obtained from highly inbred lines and had limited social and environmental experiences, currently we do not know if behavioral enrichment and nutritional treatment have similar effects on pet dogs that live in a physically and socially more stimulating environment posing more cognitive challenges than the life of laboratory dogs. ...
A decline in the physical or mental health of older dogs can be a challenge for the owners, whose relationship with their dog is compromised by the cognitive and behavioral changes in their dogs. Although dog owners tend to consider many physiological and behavioral changes in old dogs as part of the normal aging process, it is important to differentiate between normal aging and pathologic aging, since behavioral changes may be the first indication of declining health and welfare in old dogs. Most reviews on cognitive aging in dogs have focused on translational approaches to human Alzheimer's disease; from a practical perspective, however, understanding normal cognitive aging in pet dogs and screening cognitively affected dogs are important in their own right. Here we review the literature on different cognitive functions that decline during aging, signs of cognitive dysfunction, screening methods, and preventive measures for age-related cognitive decline. Moreover, we discuss the drawbacks of using questionnaires as subjective measures of aging and propose the development of objective methods to distinguish normal cognitive aging from severe cognitive dysfunction. We suggest that multi-targeted approaches that combine owner-evaluated questionnaires with neuropsychological tests can be most effective in screening cognitively affected dogs from normally aging dogs. Regarding preventive measures, we conclude that combinations of dietary intervention and behavioral enrichment may be more beneficial than single-pathway manipulations in delaying cognitive aging or retaining various cognitive functions during aging.
... Thus, the results of many cross-sectional, prospective, and retrospective epidemiological studies in humans have suggested a link between physical activity and cognitive benefits to old adults (for details see Churchill et al., 2002). Similar to humans, Milgram and colleagues in numerous studies have documented benefits of physical activity and cognitive enrichment on the performance of laboratory dogs in different cognitive tasks (Milgram et al., 2002(Milgram et al., , 2004(Milgram et al., , 2005Milgram, 2003). In these studies, they used physical activity and cognitive enrichment as an intervention and assessed their effect on learning and memory task. ...
... Recent studies in pet dogs have provided some examples of the positive effect of lifelong training on performance in different cognitive tasks (Marshall-Pescini et al., 2008, 2009Range et al., 2009). Studies in rats and laboratory beagles have also documented the effect of environmental enrichment, cognitive training and physical activity in improving cognitive performance (Milgram et al., 2005;Kramer et al., 2006;Nippak et al., 2006;Berchtold and Cotman, 2009;Harati et al., 2011;Snigdha et al., 2014). Hence, the dogs that had participated in different forms of training in their life might have benefited from those training experiences, and thus showed increased attention. ...
Aging of attentiveness affects cognitive functions like perception and working memory, which can seriously impact communication between dogs and humans, potentially hindering training and cooperation. Previous studies have revealed that aged laboratory beagles and pet Border collies show a decline in selective attention. However, much less is known about the aging of attentiveness in pet dogs in general rather than in specific breeds. Using 185 pet dogs (75 Border collies and 110 dogs of other breeds) divided into three age groups (late adulthood (6- <8 yr), senior (8- <10 yr) and geriatric (≥10yr)), we assessed the progress of aging of attentional capture, sustained and selective attention in older dogs in order to explore if prior results in Border collies are generalizable and to evaluate the influence of lifelong training on measures of attention. Each dog’s lifelong training score (ranging from 0 to 52) was calculated from a questionnaire filled in by the owners listing what kinds of training the dog participated in during its entire life. Dogs were tested in two tasks; the first, measuring attentional capture and sustained attention towards two stimuli (toy and human); and the second, measuring selective attention by means of clicker training for eye contact and finding food on the floor. In the first task, results revealed a significant effect of age but no effect of lifelong training on latency to orient to the stimuli. Duration of looking decreased with age and increased with lifelong training. In the second task, while lifelong training decreased the latency of dogs to form eye contact, aged dogs needed longer to find food. Border collies did not differ from other dogs in any measures of attention except latency to find food. In conclusion, aged dogs showed a decline in attentional capture and sustained attention demonstrating that these tests are sensitive to detect aging of attentiveness in older pet dogs. Importantly, selective attention remained unchanged with age and lifelong training seemed to delay or reduce the aging of attentiveness, further highlighting the importance of lifelong training in retaining general cognitive functions.
... This has mainly been shown in working dogs [26,27]. Additionally, a myriad of studies has demonstrated a decline in EF skills during aging in pet and laboratory dogs [19,[28][29][30][31][32][33][34][35]. There is evidence that training might mitigate cognitive decline during aging [30], but few studies have attempted to follow the trajectory of cognitive skills throughout the whole lifespan in dogs. ...
Executive Functions (EFs) are needed for effortful self-regulation of behaviour and are known to change over the lifespan in humans. In domestic dogs, EFs can be assessed through behavioural rating scales, such as the Dog Executive Function Scale (DEFS). The primary aim of this study was to investigate whether the DEFS, developed initially using a sample of adult dogs, can be used in juvenile (<1 year) and senior (>8 years) dogs. Confirmatory factor analysis of a juvenile and senior dog sample led to good model fit indices, indicating that juvenile and senior dogs’ EF structure follows the same functional organisation as found in the DEFS. The secondary aim was to analyse the lifespan development of EFs. Analysis of subscale scores revealed multifaceted relationships with age for four subscales. Working Memory and Attention Towards Owner showed the u-shaped curve traditionally associated with the lifespan development of EFs. Forms of inhibition showed complex associations with age, i.e., Delay Inhibition declined in aging and Motor Regulation increased during aging. Training history and Working Status influenced performance independent of age. More highly trained dogs and working dogs exhibited higher EF skills. Training history appeared more important for EF in non-working dogs than working dogs, perhaps because all working dogs receive a high level of training.
... Furthermore, this measure accounted for previous activity (i.e., history of training versus current training regimen) and so, given the timeline, cannot be readily explained by reverse causality. While the literature in humans [73] and laboratory animals [74], including beagles [57,75], supports the idea that enrichment can lead to better cognitive functioning in old age, only two other studies have demonstrated this relationship in companion dogs [45,76], and a third study found no effect of lifelong training on behavioral and cognitive change [77]. Nonetheless, this relationship has interesting potential parallels to associations between cognitive training and educational attainment in the context of dementia and Alzheimer's disease risk in humans [78]. ...
Canine cognitive dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer's disease. Given that physical activity is believed to reduce risk of Alzheimer's disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity-with several important covariates-as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = - 0.10, 95% CI: - 0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = - 0.07, 95% CI: - 0.09 to - 0.05, p < 0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p < 0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer's disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical activity interventions.
... Thus, we predicted that their searching behavior, but not their overall success rate, will differ between light and dark conditions. Based on the evidence of typical dogs' discrimination capacities (Affenzeller et al. 2017;Milgram et al. 2005), we expected that both GWL and T dogs would solve the discrimination task. However, as it is not clear to which extent the verbal labels of the objects influence their mental representations, the two groups may differ in their searching behavior. ...
Little research has been conducted on dogs’ (Canis familiaris) ability to integrate information obtained through different sensory modalities during object discrimination and recognition tasks. Such a process would indicate the formation of multisensory mental representations. In Experiment 1, we tested the ability of 3 Gifted Word Learner (GWL) dogs that can rapidly learn the verbal labels of toys, and 10 Typical (T) dogs to discriminate an object recently associated with a reward, from distractor objects, under light and dark conditions. While the success rate did not differ between the two groups and conditions, a detailed behavioral analysis showed that all dogs searched for longer and sniffed more in the dark. This suggests that, when possible, dogs relied mostly on vision, and switched to using only other sensory modalities, including olfaction, when searching in the dark. In Experiment 2, we investigated whether, for the GWL dogs (N = 4), hearing the object verbal labels activates a memory of a multisensory mental representation. We did so by testing their ability to recognize objects based on their names under dark and light conditions. Their success rate did not differ between the two conditions, whereas the dogs’ search behavior did, indicating a flexible use of different sensory modalities. Little is known about the cognitive mechanisms involved in the ability of GWL dogs to recognize labeled objects. These findings supply the first evidence that for GWL dogs, verbal labels evoke a multisensory mental representation of the objects.
... In both CE types, an animal's cognitive skills are challenged by a new activity or environment (Clark 2011). CE skill is primarily studied in laboratory settings and aims to slow the rate of cognitive decline and/or enhance future cognitive skills (Milgram et al. 2005(Milgram et al. , 2006Frick and Benoit 2010). For example, Milgram et al. (2006) found that aged, laboratory-housed beagle dogs with prior experience of neuropsychological testing performed better on a new cognitive task (size discrimination and reversal) than dogs with no prior experience of neuropsychological testing. ...
Cognitive enrichment is a growing subset of environmental enrichment for captive animals. However, it has been difficult for practitioners to design, implement, and evaluate relevant and appropriate cognitive challenges. Even though pure comparative cognition researchers focus on fundamental evolutionary questions, their knowledge and expertise can also shape the future of cognitive enrichment. This paper describes the motive, means, and opportunity to do so. Taxon-specific summaries of animal cognition (including inter-individual variation in skill and effects of motivation), and experimental designs (including the task itself, training, and reward) need to be accessible to practitioners in applied settings, such as farms, zoos, and sanctuaries. Furthermore, I invite pure researchers to directly evaluate their cognitive research program as enrichment and thus bridge the disciplines of animal cognition and welfare.
... Our lab has similarly demonstrated that antioxidants are effective at improving performance in cognitive tasks. We found that supplementation with antioxidants and mitochondrial cofactors (Vitamins E and C, L-carnitine, alpha lipoic acid and 1% fruit and vegetable granules) improved the performance of aged beagles in a size and black and white discrimination task, but that this improvement was greater when coupled with behavioral enrichment ( Milgram et al., 2005 ). In humans, Vitamin E consumption from food and supplements was associated with a lower rate of cognitive decline in a large-scale longitudinal study, although Vitamin C and carnitine consumption was not ( Morris et al., 2002 ). ...
Reactive oxygen species (ROS) are metabolic byproducts that are necessary for physiological function but can be toxic at high levels. Levels of these oxidative stressors increase gradually throughout the lifespan, impairing mitochondrial function and damaging all parts of the body, particularly the central nervous system. Emerging evidence suggests that accumulated oxidative stress may be one of the key mechanisms causing cognitive aging and neurodegenerative diseases such as Alzheimer's disease (AD). Here, we synthesize the current literature on the effect of neuronal oxidative stress on mitochondrial dysfunction, DNA damage and epigenetic changes related to cognitive aging and AD. We further describe how oxidative stress therapeutics such as antioxidants, caloric restriction and physical activity can reduce oxidation and prevent cognitive decline in brain aging and AD. Of the currently available therapeutics, we propose that long term physical activity is the most promising avenue for improving cognitive health by reducing ROS while promoting the low levels required for optimal function.
... D. Providing for species-specific and cognitive needs Outlets for hunting and seeking drive Mental stimulation decreases the rate of decline of cognitive function in aged animals. 57 Provide opportunities for searching, chasing, and pouncing by using a combination of scatter feeding and food puzzles (shop bought or homemade; Fig. 26, www. foodpuzzlesforcats.com, ...
Caring for an increasingly aging population of pet cats presents challenges. The interplay between emotional and physical health is an important consideration; their ability to cope with stress is reduced. Optimizing the environment can improve quality of life at home and within the clinic, as does early diagnosis and treatment of medical or behavioral problems. This may be complicated by multiple, often interacting diseases, and the overlap of clinical signs, including behavioral change. Client education evenings and elderly cat clinics play a crucial role in making owners aware of normal aging changes. Differential diagnoses behind behavioral changes such are considered.
... Moreover, the standardized keeping conditions are also ideal for studies that require longitudinal design, systematic testing, or extensive training. Thus, kenneled dogs are also often used in research on cognition, such as the effect of age on different cognitive functions (7)(8)(9)(10), or the effect of different training schedules on the acquisition of a task (11). ...
In dogs, the social and spatial restriction associated with living in a kennel environment could lead to chronic stress and the development of abnormal behaviors ("kennel-dog syndrome"). However, little is known about how kenneled dogs differ from their conspecifics living as pets in human families. In the current study, using a test battery exposing the dogs to novel stimuli, we compared the behavior of three groups of beagles: (1) kenneled dogs living in a restricted environment with limited human contact (N = 78), (2) family dogs living in human families as pets (N = 37), and (3) adopted dogs born in the kenneled population but raised in human families (N = 13). We found one factor comprising most of the test behaviors, labeled as Responsiveness. Family dogs and adopted dogs scored higher in Responsiveness than kenneled dogs. However, 23% of the kenneled dogs were comparable to family and adopted dogs based on a cluster analysis, indicating a similar (positive) reaction to novel stimuli, while 77% of the kenneled dogs were unresponsive (mostly immobile) in at least part of the test. To assess if the behavioral difference between the family and kenneled dogs could be due to genetic divergence of these two populations and/or to lower genetic diversity of the kenneled dogs, we analyzed their genetic structure using 11 microsatellite markers. We found no significant difference between the populations in their genetic diversity (i.e., heterozygosity, level of inbreeding), nor any evidence that the family and kenneled populations originated from different genetic pools. Thus, the behavior difference between the groups more likely reflects a G × E interaction, that is, the influence of specific genetic variants manifesting under specific environmental conditions (kennel life). Nevertheless, some kenneled individuals were (genetically) more resistant to social and environmental deprivation. Selecting for such animals could strongly improve the welfare of kenneled dog populations. Moreover, exploring the genetic background of their higher resilience could also help to better understand the genetics behind stress-and fear-related behaviors.
... 16,113,114,116 The improvements were substantially enhanced when the diet was coupled with environmental enrichment, which indicated a complementary and synergistic effect of environmental enrichment and antioxidants. 2,108,114,[116][117][118][119] A subsequent clinical investigation 114,120 of the effects of antioxidants combined with environmental enrichment revealed improvements in age-related behavioral changes in pet dogs as well as improvements in mitochondrial function. Results of an investigation of the effects of α-lipoic acid and acetyl-l-carnitine suggested that these individual components may have improved long-term memory but did not affect other cognitive measures. ...
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Many nutrients are critical for maintaining brain structure and function, including cognition. A deficiency of some nutrients can lead to compromised brain structure and function, which accelerates brain aging. Additional nutrients may have benefits when provided in quantities greater than those listed in recognized requirements, whereas other nutrients that may be beneficial to cognitive function may not be recognized as essential nutrients. The purpose of the information provided here was to summarize the evidence for beneficial effects of nutrients on brain function and cognition, with an emphasis on the aging brain, and to provide evidence on the dietary management of dogs with cognitive dysfunction syndrome.
... Owners have a tendency to spend more time in physical activity than people without dogs (Brown & Rhodes, 2006;Schofield et al., 2005;Serpell, 1991) and experience health benefits (Christian et al., 2016). In dogs, increased physical exercise and a socially stimulating and enriched environment have a positive effect on cognitive ability (Head et al., 2009;Milgram et al., 2005) and the quality of life (McMillan, 2002). ...
Introduction:
The aim of this study was to explore spontaneous social interactions between dyads of unfamiliar adult dogs. Although intraspecific encounters are frequent events in the life of pet dogs, the factors that might influence encounters, such as sex, dyad composition, reproductive status, age, and state of cohabitation (keeping the dogs singly or in groups), remained unexplored.
Methods:
In this study, we assigned unfamiliar, non-aggressive dogs to three types of dyads defined by sex and size. We observed their unrestrained, spontaneous behaviors in an unfamiliar dog park, where only the two dogs, the owners, and experimenter were present.
Results:
We found that the dogs, on average, spent only 17% of the time (less than 1 min) in proximity. Sex, dyad composition, reproductive status, and age influenced different aspects of the interactions in dyads. Female dogs were more likely to initiate the first contact in their dyad but later approached the partner less frequently, were less likely to move apart, and displayed less scent marking. Following and moving apart were more frequent in male-male interactions. Neutered dogs spent more time following the other dog and sniffed other dogs more frequently. The time companion dogs spent in proximity and number of approaches decreased with age.
Conclusion:
The study provides guidance for dog owners about the outcomes of intraspecific encounters based on the dog's age, sex, and reproductive status, as well as the sex of the interacting partner.
... There is good evidence of the potential beneficial impact of interventions on cognitive functioning in older dogs (Milgram, 2003;Milgram, Siwak-Tapp, Araujo, & Head, 2006), and this is of relevance if we wish to maximize the working life of military working dogs. In laboratory dogs, it has been found that enrichment effects interact with diet; for example, the beneficial effect of increasing antioxidant intake in aged dogs is greatly success of scent detection dogs VOLUME 14, 2019 increased when enrichment is added to the dogs' routine (Milgram et al., 2005). Both enrichment and diet have complex effects on cognitive functioning, and simple generalizations are unwise. ...
Scent detection dogs are used in a variety of contexts; however, very few dogs successfully complete their training, and many others are withdrawn from service prematurely due to both detection accuracy issues in the field and wider behavioral issues. This article aims to review our understanding of the factors affecting variation in scent detection dogs' learning of the tasks and performance in the field. For this we deconstructed the scent detection task into its key behavioral elements and examined the literature relating to the factors affecting variation in the dogs' success all across their development. We first consider factors that affect individuality and individual performance, in general, such as temperament, arousal, the handler-dog relationship, training regimes, and the housing and management of scent detections dogs. We then focus on tasks specific to scent detection dogs and critically appraise relevant literature relating to the learning and performance of these tasks by dogs. This includes prenatal and early life exposure and later environment, training regime, and the human-dog relationship, as well as performance limiting factors such as the need to pant in hot environments during work.
... Apesar da SDC não ter cura, o objetivo da terapia é retardar a evolução da enfermidade, de forma que o processo degenerativo evolua lentamente, atenuando os sinais clínicos precocemente. O tratamento indicado para cães com SDC é o enriquecimento ambiental, utilização de medicamentos, dietas suplementadas com antioxidantes e mudanças no manejo dos animais (Milgram et al., 2005;Landsberg et al., 2012). O enriquecimento ambiental inclui novos truques e brincadeiras, passeios, atividade física, entre outras estratégias para estimular a cognição do animal; esses exercícios auxiliam, ainda, no ciclo de sono-vigília. ...
O presente trabalho teve por objetivo dissertar sobre os aspectos atuais acerca do processo de envelhecimento, bem como da síndrome da disfunção cognitiva canina. O processo de envelhecimento cerebral nos cães se caracteriza por alterações como atrofia cortical, mineralização meníngea, lesões perivasculares, angiopatia amiloide cerebrovascular, perda de neurônios, desmielinização, acúmulo de placas senis, danos oxidativos, entre outras. Devido à degeneração patológica que ocorre no cérebro, as alterações comportamentais são os primeiros sinais de declínio cognitivo em cães geriátricos. Desse modo, a síndrome da disfunção cognitiva (SDC) é reconhecida como uma doença neurodegenerativa que acomete animais a partir dos seis anos de idade, sendo seriamente subdiagnosticada, pois os tutores omitem as mudanças comportamentais de seus animais nas consultas veterinárias, acreditando que estas são alterações normais relacionadas ao envelhecimento. Outro fator importante é a falta de questionamento dos médicos veterinários quanto a mudanças que indicam declínio cognitivo. O diagnóstico é complexo e pode envolver exames de imagem, laboratoriais, aplicação de questionários específicos para alterações comportamentais, além da exclusão de outras enfermidades. O tratamento consiste na utilização de fármacos, enriquecimento ambiental, alteração no manejo e na dieta, objetivando retardar a evolução da doença e melhorar a qualidade de vida do paciente.
... Additionally, whether this positive effect is observable when training/enrichment is started in old age (e.g. Milgram et al. (2005) but see Davis et al. (2017)), or it is rather related to cognitive reserve acquired at a young age as suggested in humans (Lenehan et al., 2015), requires further, more detailed studies. ...
To describe the extent of age-related cognitive decline in dogs, information regarding the baseline occurrence of associated behaviours in the general population is necessary. With a seven-item, data driven Age-Related Changes scale, we evaluated the relationship between sensory functions, training, sex, and the occurrence of behavioural signs associated with cognitive decline across the whole adult lifespan. The twofold difference in lifespan between small and large dogs presents challenges for ageing studies, with no widely accepted method to control for body size as it relates to chronological age and longevity, when comparing behavioural signs of cognitive decline. To address this issue, we utilized relative age, calculated using the estimated expected lifespan of the individuals in our questionnaire study. Signs of cognitive decline were already detectable in' Mature' dogs (at 50-75% of the expected lifespan). Visual, auditory and olfactory impairments all resulted in significantly higher scores on the Age-Related Changes scale. Participating in dog training activities was revealed to be protective against behavioural signs of cognitive decline in aged dogs as perceived by the owners. These results revealed possible beneficial effects of training on cognitive ageing and emphasize the importance of routinely screening the sensory capacities of ageing dogs.
... 63 In aged dogs, a diet containing DHA and EPA was shown to reduce signs of ageassociated cognitive decline and improve learning. [28][29][30] However, these diets were also rich in antioxidants and mitochondrial cofactors and contained relatively low amounts of DHA and EPA. 64 This factor suggests that the findings may be more attributable to the antioxidants and mitochondrial cofactors. ...
Behavioral problems of companion animals are becoming more widely recognized. As a result, there are a growing number of behavioral nutraceuticals and diets on the market. These products may be useful for the treatment of mild conditions, for clients who are hesitant to give their pet a psychopharmacologic agent, or sometimes in conjunction with psychopharmacologic agents. Veterinarians should critically review the research associated with nutraceuticals and diets, and have an understanding of the functional ingredients and their mechanisms of action before prescribing treatment. This article provides an overview of nutraceuticals, their mechanisms of action, and relevant research regarding their use.
... Studies in rodents show a positive effect of grape seed proanthocyanidin extract (GSPE) in improving the spatial memory of middle-aged male rats, with the effect related to its antioxidant properties and the enzymatic antioxidant defenses in the cerebral cortex (CC) and HC [18,19]. Furthermore, exercise in conjugation with dietary fortification is reported to enhance aging-related cognitive deficits in older humans [20] and animals [21]. These effects of exercise and supplements such as GSPE together could be synergistic through common pathways. ...
Decline in cognition is one of the earliest signs of normal brain aging. Several dietary and non-pharmacological approaches have been tested to slow down this process. The aim of the present study was to assess the influence of grape seed proanthocyanidin extract (GSPE) either individually or in combination with swimming training on acetylcholine esterase activity (AChE) and m1 acetylcholine receptor (m1AChR) on the extent of cognitive decline with aging. The experimental protocol included the oral administration of GSPE (400 mg/kg body weight) for 14 weeks to 4 (adult) and 18-month-old (middle-aged) male Wistar rats along with swimming training. They were subjected to behavioral testing followed by biochemical and immunohistochemical analysis. The results demonstrated that GSPE supplementation and swimming training either individually or in combination had an improvement on acquisition and working memory with reduced AChE activity in the medial prefrontal cortex (mPFC) and hippocampus (HC). Immunohistochemical and qRT-PCR evaluation showed an increase in m1AChR protein and mRNA in the CA1 region of HC and also mPFC upon swimming training with GSPE treatment. These beneficial and synergistic effects of GSPE and swimming training are suggestive as interventions in modulating the cognitive function, with GSPE alone being more suitable for middle-aged individuals.
... However, as with the mouse models, dogs also failed to reveal the adverse autoimmune responses that occurred in human patients . Aged dogs have also been useful for assessing the impact of non-pharmacological interventions including the benefits of dietary antioxidants and behavioural enrichment in delaying cognitive decline and dementia (Milgram et al., 2002;Milgram et al., 2004;Milgram et al., 2005;Nippak, Mendelson, Muggenburg, & Milgram, 2007;Opii et al., 2008;Siwak et al., 2005). ...
Alzheimer’s disease is a major and increasing burden on families, communities, and national health budgets. Despite intensive and extended research there is still widespread debate about its cause(s) and no effective treatments exist. Familial (inherited, mainly early onset) and sporadic (mainly late onset) forms of the disease exist and it is uncertain to what extent they are related. Transgenic mouse models have dominated the investigation of this disease but their validity can be questioned. Numerous alternative models exist that can provide valuable information on the molecular and cellular basis of Alzheimer’s disease. In this chapter we review the various invertebrate, nonmammalian vertebrate, and mammalian models and how these have been used to investigate this disease. We examine the strengths and weaknesses of these various model systems. Of course, animal models never completely reflect the true nature of a human disease but progress in understanding and finding preventative and ameliorative treatments for Alzheimer’s disease is hindered by the lack of a convincing hypothesis for the cause of this complex condition.
... For example, mice exposed to increased environmental complexity perform better on maze navigation tasks and have increased cellular activity in the brain (Codita et al., 2012). Access to toys and cage-mates maintains the level of cognitive task performance in dogs (beagles) as they age (Milgram et al., 2005), and more formally-educated humans (i.e., those spending more years at school and university) show increased performance in cognitive tasks, and reduced incidence of degenerative brain disease (Dufouil, Alperovitch, & Tzourio, 2003). Despite the benefits of this "broad" form of cognitive enrichment, Milgram et al. (2006) lobby the criticism that it is practically impossible to determine which characteristic(s) of the environment affect cognition. ...
“Cognitive enrichment” is a subset of enrichment that has gained interest from researchers over the past decade, particularly those working in zoos. This review explores the forms of cognitive enrichment that have been attempted for laboratory, farmed and zoo animals with a focus on the latter, including various definitions, aims, and approaches. This review reveals the fundamental theoretical and practical problems associated with cognitive enrichment, leading to recommendations for further research in this field. Critically, more research is needed to elucidate what makes challenges appropriate for certain taxa, acknowledging that individual differences exist. Going forward, we should be prepared to incorporate more computer technology into cognitive tasks, and examine novel welfare indicators such as flow, competence, and agency.
... Furthermore, efficacy as a result of the long-term use of dietary enrichment has been extended to include behavioral outcomes. Learning of the reversal discrimination task was improved relative to controls in animals fed a diet enriched with supplemental antioxidants and mitochondrial enzymatic cofactors in a longitudinal trial [17,37]. Improved utilization of allocentric spatial information has also been demonstrated as a result of dietary fortification with the same antioxidant cocktail [17]. ...
Whole cell Schizochytrium sp. is a rich source of omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) including docosahexaenoic acid (DHA), an important nutrient for brain health. Aged beagle dogs experienced on a visuospatial task of working memory, variable-delay delayed-non-matching-to-position were used to assess efficacy of DHA-rich microalgae based upon DHA wt% of total phospholipids and 8-iso-PGF2α concentrations in plasma, and performance on cognitive assessments of visual object discrimination, learning, and memory consolidation after 25 weeks on fortified diet.
Improved DHA status (p<0.001) and initial learning of the protocols for visual and variable contrast discrimination (p<0.05), but not long-term recall of the concurrent discrimination task were observed in animals fed the algal-fortified diet. Overall, results were consistent with dried Schizochytrium sp. as a source of n-3 LCPUFA nutrition to support DHA status in large mammals, and healthy brain function in a canine model of senescence.
Executive functions (EFs) are cognitive processes that are used to effortfully self-regulate behaviour and might be important for dogs’ success in working and pet roles. Currently, studies are assessing dogs’ EF skills through often laborious cognitive measures, leading to small sample sizes and lacking measures of reliability. A complementary method is needed. The aim of this study was to develop a dog executive function scale (DEFS) for adult dogs. Focus groups were held with people working with dogs professionally to refine a pool of items describing dog behaviours related to EF. A survey was distributed online to a convenience sample of N = 714 owners of adult dogs. Exploratory and confirmatory factor analysis identified six distinguishable factors named behavioural flexibility, motor inhibition, attention towards owner, instruction following, delay inhibition and working memory. These factors appear similar to factors identified in human EF scales. Working dogs exhibit higher EF scores on the DEFS than non-working dogs. Dogs sourced from breeders exhibited higher DEFS scores than dogs sourced from shelters, and the amount of training received positively correlated with dogs’ DEFS scores. The DEFS requires further validation with cognitive measures. The DEFS could then be used by researchers to complement assessment of dogs’ EF skills through cognitive measures or assess dogs’ EF skills in large samples.
The use of psychopharmaceutical agents is a core aspect of treatment in veterinary behavioural medicine. Psychotropic medication use has shifted the focus of treatment from purely behavioural and environmental interventions to a multi-modal approach. Objective measures of efficacy are required for the licensing of medication. Pharmacotherapeutics have come to encompass supplements and diets, in addition to prescription medications. The first part of this paper examines the efficacy of medications, supplements and diets used in behavioural medicine. Foci include the role of evolution in the types of behavioural concerns reported, the importance of defining abnormal or pathological behaviour, use of terminology that supports stratified mechanistic diagnoses aid in understanding presentation and response clusters, and rational use of medication to relieve emotional, mental and behavioural suffering, given these diagnoses and clusters. The second part of this paper examines the extent to which variation in patient response to medication can enlighten us about mechanisms and outcomes of distress using a series of 3 patient populations who are the focus of studies on separation anxiety and noise reactivity. This response surface approach can be useful for understanding differences in populations in susceptibility to behavioural pathology and in medication response, and may suggest new avenues for drug development and application.
As the most phenotypically diverse mammalian species that shares human environments and access to sophisticated healthcare, domestic dogs have unique potential to inform our understanding of the determinants of aging. Here we outline key concepts in the study of aging and illustrate the value of research with dogs, which can improve dog health and support translational discoveries. We consider similarities and differences in aging and age-related diseases in dogs and humans and summarize key advances in our understanding of genetic and environmental risk factors for morbidity and mortality in dogs. We address health outcomes ranging from cancer to cognitive function and highlight emerging research opportunities from large-scale cohort studies in companion dogs. We conclude that studying aging in dogs could overcome many limitations of laboratory models, most notably, the ability to assess how aging-associated pathways influence aging in real-world environments similar to those experienced by humans.
Expected final online publication date for the Annual Review of Animal Biosciences, Volume 10 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Overweight and obesity may damage the cerebrovascular architecture, resulting in a significant reduction in cerebral blood flow. To date, there have been few randomized clinical trials (RCT) examining whether obesity‐related reductions in cerebral blood flow could be modified by weight loss. Further, it is unknown whether the behavioral intervention strategy for weight loss (i.e., diet alone or diet combined with exercise) differentially influences cerebral blood flow in adults with overweight or obesity. The primary aim of this study was to determine whether a 12‐month RCT of exercise and diet increases cerebral blood flow in 125 midlife (Mean age ± SD = 44.63 ± 8.36 years) adults with overweight and obesity. Further, we evaluated whether weight loss via diet combined with aerobic exercise has an added effect on changes in cerebral blood flow compared to weight loss via diet alone and whether there were regionally specific effects of the type of behavioral intervention on cerebral blood flow patterns. Consistent with our predictions, a 12‐month diet and exercise program resulting in 10% weight loss increased cerebral blood flow. These effects were widespread and extended throughout frontal, parietal, and subcortical regions. Further, there was some regional specificity of effects for both diet‐only and diet combined with exercise. Our results demonstrate that weight‐related reductions in cerebral blood flow can be modified by 10% weight loss over the course of 12 months and that interventions involving exercise exposure may provide unique effects on cerebral blood flow compared to interventions involving only diet.
Environmental enrichment is known to reduce stereotypical behaviours in a wide range of captive animals, providing clear welfare benefits in many species. However, one of the most significant stressors faced by captive animals is live transport but whether enrichment can alleviate transport stress is unknown. Using behavioural measures as indicators of fish welfare, we investigated whether the addition of environmental enrichment can improve the welfare of ornamental fish during commercial transport. Pairs of bags containing variatus platy (Xiphophorus variatus) were transported by road with or without enrichment (plastic loops) from a UK wholesaler to one of two stores, the first and the last store on a delivery route. Transport time to the first store was short (< 4 h) and longer (> 6 h) to the second. Fish behaviour and incidences of mortality, disease and injury were recorded immediately following transport and during a four-week recovery period. Immediately post-transport, significantly fewer occurrences of erratic swimming were observed in the enriched group compared to the control group, and lower levels of chasing were recorded in the enriched group during recovery. This study is the first to demonstrate the behavioural benefits of enrichment during live transport of fishes under commercial conditions.
With increasing age, humans and animals suffer from partial or complete loss of cognition and memory. As a result, quality of life declines significantly. Among many underlying mechanisms, a significant decline in the neurotransmitter acetylcholine (ACh), an increase in N-methyl-d-aspartate (NMDA), and oxidative stress are the most recognized events involved in cognition impairment, especially memory and learning. Like chronic neurodegenerative Alzheimer’s disease (AD) in humans, canines and felines suffer from memory loss as they become older. Currently, for AD treatment in humans, an NMDA receptor antagonist memantine in combination with the acetylcholinesterase (AChE) inhibitor donepezil, rivastigmine, or galantamine appears to be the best option. A number of therapeutic drugs (selegiline, gabapentin, buspirone, memantine, etc.) are also available for treatment of canine cognition dysfunction (CCD)/cognitive dysfunction syndrome (CDS). A large number of plant extracts, their ingredients, and bioactive compounds of animal origin have been investigated for anticholinesterase (anti-ChE), antioxidative, anti-inflammatory, and immunomodulatory activities, as well as anti-Aβ aggregation and deposition in the brain. Some of these substances have also been shown to normalize the blood-brain barrier permeability and integrity, while others have been demonstrated to restore mitochondrial function. A small number of plant extracts have also shown MAO-B inhibitory property. Currently, dementic dogs and cats are given nutraceuticals and/or a therapeutic diet to improve their cognition and memory. This chapter describes various nutraceuticals and substances that have potential to improve cognition and memory in senior dogs and cats.
This updated new edition summarizes the latest developments in cognitive neuroscience related to rehabilitation, reviews the principles of successful interventions and synthesizes new findings about the rehabilitation of cognitive changes in a variety of populations. With greatly expanded sections on treatment and the role of imaging, it provides a comprehensive reference for those interested in the science, as well as including the most up-to-date information for the practicing clinician. It provides clear and practical guidance on cognitive rehabilitation’s effectiveness, and the latest research and clinical directions.
Adult brain can generate new neurons (neurogenesis). The process is well defined in terms of specific phases of cell growth but still not completely understood as far as its regulation and functional significance are concerned. "Use it or lose it" rule applies to neurogenesis. Neurogenesis is commonly observed in hippocampus but is also being found in other brain regions. A dogma that neurons in adult mammalian brain cannot regenerate is no longer true. Persistent reports dating back as far as 1962 suggested that some cells in adult brain can divide through mitosis and grow as neurons. Joseph Altman and colleagues reported that incorporation of a DNA-synthesis marker 3H Thymidine did in fact occur in the adult rodent hippocampus and were first to propose that adult neurogenesis is a bona fide phenomenon (Altman, 1962; Altman & Das, 1965, 1967). Although suggestive, these studies were hampered by lack of convincing demonstration that new-born cells were properly matured and functionally relevant neurons. It was not even clear if they were neurons at all. This was in contrast to the common acceptance of proliferation of glial cells within the adult brain, especially after injury. The renaissance in the field became possible with the availability of the novel DNA-synthesis marker bromodeoxyuridine (BrdU) (Gratzner, 1982). Bromodeoxyuridine appears to be more sensitive and selective than 3H Thymidine and allows for colabeling with specific antibodies raised against proteins that are expressed in neurons at specific developmental stages. By now a catalogue of markers is available that can be used to chart the neuronal development as cells divide, differentiate, migrate and mature (Figure 20.1).
Now available in paperback, this updated new edition summarizes the latest developments in cognitive neuroscience related to rehabilitation, reviews the principles of successful interventions and synthesizes new findings about the rehabilitation of cognitive changes in a variety of populations. With greatly expanded sections on treatment and the role of imaging, it provides a comprehensive reference for those interested in the science, as well as including the most up-to-date information for the practising clinician. It provides clear and practical guidance on why cognitive rehabilitation may or may not work. How to use imaging methods to evaluate the efficacy of interventions. What personal and external factors impact rehabilitation success. How biological and psychopharmacological changes can be understood and treated. How to treat different disorders of language and memory, and where the field is going in research and clinical application.
Background: Veterinary professionals have seen a rise in geriatric patients suffering from canine cognitive dysfunction (CCD). Previous literature has supported the use of environmental enrichment therapies which have been considered to reduce the progression of cognitive decline in CCD. However, CCD is commonly undiagnosed within the companion dog population.
Aim: To determine whether owners of older dogs are able to notice behavioural changes, and in addition, explore knowledge around the term environmental enrichment which may help owners slow the progression of CCD through further education.
Method: The study involved quantitative research using a questionnaire with 11 questions. Data were subsequently statistically analysed. Of the participants 16 worked within a veterinary practice, 52 were customers visiting a pet shop and 39 respondents formed a web survey group predominantly of veterinary professionals.
Results: Owners of geriatric dogs working within a veterinary-related field were more likely to notice behavioural changes possibly associated with CCD compared with the average owner of a geriatric dog, and were also more likely to understand the term environmental enrichment.
Conclusion: This study informs the veterinary field that improved education strategies implemented within nurse clinics may help pet owners recognise behavioural indicators of CCD, and treatment recommendations may assist in slowing the progression of CCD in geriatric dogs.
Now available in paperback, this updated new edition summarizes the latest developments in cognitive neuroscience related to rehabilitation, reviews the principles of successful interventions and synthesizes new findings about the rehabilitation of cognitive changes in a variety of populations. With greatly expanded sections on treatment and the role of imaging, it provides a comprehensive reference for those interested in the science, as well as including the most up-to-date information for the practising clinician. It provides clear and practical guidance on why cognitive rehabilitation may or may not work. How to use imaging methods to evaluate the efficacy of interventions. What personal and external factors impact rehabilitation success. How biological and psychopharmacological changes can be understood and treated. How to treat different disorders of language and memory, and where the field is going in research and clinical application.
After brain injury, there is short-term and long-term brain plasticity and reorganization. The brain also alters structurally and dynamically over the normal lifespan. Since more research has been completed in the area of aging, this knowledge serves as a model for understanding brain plasticity after cognitive rehabilitation. Changes in memory with aging have been extensively studied. Most functional neuroimaging research on brain plasticity with aging has been carried out in the memory domain. Both reduced and increased brain activity with aging has been reported. Each is reviewed. The brain is not a static entity, but rather alters its structure and function dynamically over the lifespan (Grady et al., 2006; Raz, 2000; Sowell et al., 2001; Sullivan et al., 1995). Changes also occur in the brain after damage, some of which are the result of the insult itself, and some of which are due to reorganization of neural pathways in response to the damage (Merzenich et al., 1983; Ramachandran, 2005). Studies using functional neuroimaging techniques, such as positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), to study brain plasticity have shown that there are changes in activity patterns due to learning new information or practicing a given task over some period of time (Karni et al., 1995; Raichle et al., 1994). These short-term changes are superimposed over the longer-term plasticity occurring naturally, and it is likely that the two types of plasticity interact with one another. Consideration of all these factors when attempting to understand the effect of brain damage or injury on brain function and how this is influenced by rehabilitation thus becomes a complicated undertaking. Some of these issues have been addressed in functional neuroimaging studies of healthy older adults, so that aging can be used as a model of brain plasticity to help us understand the impact of cognitive rehabilitation on brain function.
Judgments about the clinical effectiveness of interventions are complex and subject to biases. Nothing is so firmly believed as what we least know. (Michel de Montaigne) The practice of evidence-based rehabilitation is based on the "integration of individual clinical experience with the best available external clinical evidence from systematic research" (Sackett et al., 2000, p. 2). In the absence of scientific evidence, claims for the effectiveness of any medical or rehabilitation practice rely upon clinical "expert opinion," typically reflecting the judgments and beliefs acquired by individual clinicians through their professional experience and clinical practice. Unfortunately, clinical judgments are fraught with potential biases (Elstein & Schwarz, 2002) and these appear to be a fundamental aspect of human reasoning and decision making (Ditto & Lopez, 1992; Kahneman, 2003). The impact of potential bias is greatest and is most apparent in situations that require the integration of complex and incomplete information (Elstein & Schwarz, 2002), which, of course, is characteristic of most aspects of rehabilitation planning and decision making. Within the context of rehabilitation, even judgments about patients’ functional status that rely on well-established, standardized instruments are highly susceptible to biases that are difficult to overcome (Wolfson et al., 2000). Clinical experience is generally inadequate to overcome subjective biases, and may even exacerbate errors in judgment. Practicing clinicians frequently fail to initiate a search for relevant information or suppress the recognition of a need for additional information (Cabana et al., 1999) and are less likely to acknowledge information that is inconsistent with their past experience and practices (Burgers et al., 2003).
Now available in paperback, this updated new edition summarizes the latest developments in cognitive neuroscience related to rehabilitation, reviews the principles of successful interventions and synthesizes new findings about the rehabilitation of cognitive changes in a variety of populations. With greatly expanded sections on treatment and the role of imaging, it provides a comprehensive reference for those interested in the science, as well as including the most up-to-date information for the practising clinician. It provides clear and practical guidance on why cognitive rehabilitation may or may not work. How to use imaging methods to evaluate the efficacy of interventions. What personal and external factors impact rehabilitation success. How biological and psychopharmacological changes can be understood and treated. How to treat different disorders of language and memory, and where the field is going in research and clinical application.
It is unwise to prophesy either death or recovery in acute diseases. (Hippocrates: Aphorisms II-19 c. 500 BC) Neurological recovery occurs commonly, and is mediated by many mechanisms from cells to systems. Research is currently trying to clarify which neural mechanisms of recovery are behaviorally significant. It is a common observation on neurology wards that most patients improve after a stroke or a traumatic brain injury. About 80-90% of all stroke patients have motor deficits (or hemiparesis) at onset, while only 40-60% of them have a persistent deficit at 6 months to 1 year (Dobkin, 2005). Similar degrees of recovery occur for language and visuospatial perception (Sarno & Levita, 1971; Stone et al., 1993). Whereas early (1-3 days) recovery may be explained by vascular changes, such as early canalization of an obstructed vessel or reduction in the amount of edema surrounding an ischemic area, recovery that occurs in the weeks and months following the stroke must be explained by different mechanisms. The central nervous system reacts to injuries (stroke, trauma) through changes that occur at the level of brain networks, areas, neurons, connections, molecules and even genes (Carmichael, 2003a; Nudo, 1999; Weiller, 1998). Many of these changes represent "house-keeping" operations unrelated to behavioral recovery. For instance, in the area of ischemic damage an inflammatory reaction is mounted within 24-48 hours that leads to the elimination of vascular and cellular debris. At the level of brain networks, damage to one area may lead to a decrement of synaptic activity downstream in a connected area, which will in turn downregulate its metabolic demands (diaschisis) (Baron et al., 1980).
There is a growing emphasis on healthy aging, with many services and products being developed to respond to this interest. It is essential to understand the scientific evidence on which such products are based. This chapter focuses on the beneficial effects of physical exercise on brain structure and function, with a focus on normal aging. The chapter consists of four sections: molecular and cellular mechanisms evidenced in non-human animals; epidemiological studies of the impact of physical activity and exercise on cognition later in life; cross-sectional studies and randomized clinical trial studies; future directions for research. Given the aging of the population in most industrialized countries (Gokhale & Smetters, 2006) and the fact that the first baby boomers turn 60 in 2006 it is unsurprising that there is an increasing focus on the development of programs and products for healthy aging. This focus has resulted in a dramatic increase in the availability of books, computer programs, nutritional supplements, physical activity programs and other consumer products that claim to provide solutions to the detrimental changes in cognition and brain function that occur during the process of adult aging. For example, a recent search on Amazon.com yielded 175 books that profess to offer successful techniques for maintaining and enhancing memory during aging. An increasing number of computer programs are also available that offer to both track changes in attention, memory, decision making, processing speed and other cognitive processes over time and provide practice and training to ensure maintenance and even enhancement of a variety of cognitive skills and abilities. One recent addition to this rapidly growing field of products to foster healthy aging is a series of games introduced in 2006 by Nintendo.
In the first edition of this book, the chapter on impaired self-awareness (ISA or anosognosia) (Prigatano, 1999a) also included a discussion on how ISA and disturbances of motivation must be addressed in neurorehabilitation. It was noted at that time: "motivation may improve level of performance on specific tasks, without necessarily improving underlying ‘capacity’ or ‘skill.'" (p. 246); "impaired self-awareness can lead to a passive (non-engaging) approach to cognitive rehabilitation and, at times, to clear resistance to such activities" (p. 247); and that "facilitating recovery of impaired self-awareness via a variety of cognitive and interpersonal tasks may aid the process and outcome of neuropsychological rehabilitation, but the data are sparse" (p. 242). This updated/revised chapter will specifically address in more detail the latter observation/claim. It will also address, in light of further evidence, the notion that improving performance on a specific task (e.g., improving self-monitoring on a behavioral task) may not actually alter the underlying capacity of self-awareness in a person with severe traumatic brain injury (TBI). The focus of this chapter will be to provide a summary of current information that will potentially aid the practicing clinician in the rehabilitation of patients who show frank anosognosia and/or its residuals several months, and at times years, post brain disease/disorder. This chapter will not discuss the growing literature on anosognosia for dementia of the Alzheimer’s type (DAT), or the neuroimaging correlates of anosognosia, denial, repression and self-awareness (e.g., Johnson et al., 2002; Schmitz et al., 2006).
Patients with an acquired brain injury may frequently present with abnormalities of mood, affect and motivation. Given the disabling nature of these disturbances, accurate clinical assessment is necessary in planning and implementing a comprehensive rehabilitation strategy. It is important to realise at the outset that abnormalities in each domain may occur independently of one another, although a more common clinical picture is one in which all are affected to varying degrees. The importance in making this clinical distinction cannot be overemphasised for distinct abnormalities in mood, affect and motivation each demand a specific treatment. The clinician who fails to tease out these various features of the mental state thus runs the risk of missing potentially treatable conditions that could derail the rehabilitation process and erode the patient’s quality of life. To better understand how such presentations arise in a clinical setting, reference will be made to the neural circuitry underpinning these abnormalities. While there is sound empirical evidence elucidating the neural pathways controlling mood and motivation, the pathogenesis of disturbances in affect, i.e., the display of emotion as distinct from subjective feeling, is less clearly understood. Therefore, only brief reference will be made to it within a clinical perspective in the section dealing with pseudobulbar affect, also termed pathological laughing and crying.
Animal models are used in preclinical trials to screen compounds before they are tested in humans, and can provide insight into the mechanism of action and rationale for clinical trials. Most animal models are only capable of reproducing certain aspects of a neurological condition; therefore, multiple animal models are needed to analyze different components of a disorder, and to provide a more complete assessment of a compound's pharmacological profile. Determining the best set of models for testing a novel compound can be daunting, especially since new models are constantly being developed. Validation, as well as a detailed understanding of the model's strengths, weaknesses, design characteristics, output measurements, and correlation to the associated human condition, are essential. This chapter reviews the most common animal models used today, as well as the most promising new models representing four major CNS conditions: anxiety disorder, depression, schizophrenia, and Alzheimer's disease.
Brain food for aged dogs Aging in dogs is associated with a decline in cognitive abilities, including learning and memory. Many animals over 7 years of age develop degenerative brain disease. The resulting aberrant behavior includes five categories: impaired sense of direction, loss of interaction with family members, disturbances in sleep, inappropriate toileting and restlessness. The package of a health food reads: " With enhanced botanical oils shown to promote alertness and mental sharpness in dogs 7+, with visible results within 30 days. " For a medical food, available through veterinarians, the manufacturer claims that it " is clinically proven nutrition to help fight age-related behavior changes in older dogs. " The two brain foods contain distinctive ingredient blends that are thought to oppose oxidative damage and enhance energy supply in brain cells. The impact of dietary ingredients and supplements on cognitive function in aged dogs has been evaluated with the use of various laboratory tests. All tests use a food reward to motivate dogs to learn the tasks. Diet-induced learning makes dogs push sooner, with their snouts, objects away from a well that contains palatable food. A laboratory study supports the claim on the health food, but reproducibility is unknown. In aged laboratory dogs, diets comparable to the medical product were effective in about two thirds of the broad span of tests. In pet dogs with clinical cognitive dysfunction, the medical food decreased the severity of only four out of 16 symptoms, while the effect sizes were small. The studies suggest that current brain foods reduce aging-associated cognitive decline in dogs without symptoms of disease. However, these foods only partly rejuvenate the cognitive level of aged dogs, while brain stimulation by social interaction and environment can be more effective. Cohort study: design Milgram et al. (1-7) have performed a series of cognitive tests in a cohort of aged beagles that were housed in pairs and received toys, exercise and regular cognitive testing. Based on baseline tests, two cognitively equivalent dietary groups with mean age of about 10 years were formed. The test food was enriched with antioxidants and mitochondrial cofactors: vitamin E, L-carnitine, DL-alpha-lipoic acid and vitamin C, and flavonoids and carotenoids in the form of spinach, tomato, grape, carrot and citrus preparations. All cognitive tests involved a box with front of vertical bars and a sliding tray. Lifting the bars gave the dog inside access to the tray. The experimenter was separated visually by a screen with one-way mirror and a hinged door on the bottom, to be opened for presentation and removal of the tray. The dog's task was to learn and remember which object covered the food reward in one of the three wells in the tray. Outcome was the number of errors to meet a pre-set criterion level of success. Tests and results
Now available in paperback, this updated new edition summarizes the latest developments in cognitive neuroscience related to rehabilitation, reviews the principles of successful interventions and synthesizes new findings about the rehabilitation of cognitive changes in a variety of populations. With greatly expanded sections on treatment and the role of imaging, it provides a comprehensive reference for those interested in the science, as well as including the most up-to-date information for the practising clinician. It provides clear and practical guidance on why cognitive rehabilitation may or may not work. How to use imaging methods to evaluate the efficacy of interventions. What personal and external factors impact rehabilitation success. How biological and psychopharmacological changes can be understood and treated. How to treat different disorders of language and memory, and where the field is going in research and clinical application.
Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.
Abstract Recent studies have suggested that altered function of apolipoprotein E might lead to Alzheimer's disease via oxidative stress. In this context, the objective of this study was to determine if antioxidative treatment with vitamin E was neuroprotective in apolipoprotein E-deficient mice. For this purpose, 1-month-old control and apolipoprotein E-deficient mice received dietary vitamin E for 12 months. We showed that, compared to apolipoprotein E-deficient mice who received a regular diet, mice treated with vitamin E displayed a significantly improved behavioural performance in the Morris water maze. This improved performance was associated with preservation of the dendritic structure in vitamin E-treated apolipoprotein E-deficient mice. In addition, whilst untreated apolipoprotein E-deficient mice displayed increased levels of lipid peroxidation and glutathione, vitamin E-treated mice showed near normal levels of both lipid peroxidation and glutathione. These results support the contention that vitamin E prevents the age-related neurodegenerative alterations in apolipoprotein E-deficient mice.
The behavior of aged rhesus monkeys (18 years and older) was compared to that of young monkeys (3 to 6 years old) to evaluate their relative abilities to learn a series of visual discrimination and discrimination reversal problems. Using a subject-paced, automated experimental procedure designed to optimize stimulus control and facilitate execution of choice responses, no consistent age-related differences were observed in the ability to learn new color and pattern discrimination problems of varying difficulty. However, a severe and consistent deficity on reversal learning did occur. A detailed analysis of this deficit revealed that not only did the aged monkeys take longer to extinguish the old habit and return to chance performance, but they continued to display a deficit in establishing accurate performance at above-chance levels as well. Since no reliable age differences were observed on the original discrimination learning problems, these data suggest that aging impairs mechanisms involved with response rigidity and/or susceptibility to intertrial proactive interference, more severely than those involved with the simple formation of new associations.
This study investigated the role of low normal cognitive function in the subsequent loss of independence in activities of daily living.
Of the 678 elderly nuns who-completed cognitive and physical function assessments in 1992/93, 575 were reassessed in 1993/94. Mini-Mental State Examination scores were divided into three categories and related to loss of independence in six activities of daily living.
Participants with low normal cognitive function at first assessment had twice the risk of losing independence in three activities of daily living by second assessment relative to those with high normal cognitive function. This relationship was largely due to a progression from low normal cognitive function at first assessment to impaired cognitive function at second assessment and was associated with an elevated risk of losing independence in the six activities.
Progression from low normal to impaired cognitive function was associated with loss of independence in activities of daily living. Thus low normal cognitive function could be viewed as an early warning of impending cognitive impairment and loss of physical function.
The effect of breed and body weight on longevity in the pet dog was analyzed, and a method was developed to standardize the chronological age of dogs in terms of physiological time, using human year equivalents. Mortality data from 23,535 pet dogs were obtained from a computerized data base of North American veterinary teaching hospitals, and the median age at death was determined for pure and mixed breed dogs of different body weight. Body size in the dog was inversely related to longevity. Within each body weight category, the median age at death was lower for pure breed dogs compared with mixed breed dogs. The difference between the standardized physiological ages of mixed breed dogs of the same chronological age in the smallest and largest body weight categories varied from 8 to > 15 years, and between large and small pure breed dogs, the disparity was even greater. Laboratory research to explore the biological basis for these breed and body weight specific differences in life span among dogs may provide additional clues to genetic factors influencing senescence.
The free radical theory of aging, conceived in 1956, has turned 40 and is rapidly attracting the interest of the mainstream of biological research. From its origins in radiation biology, through a decade or so of dormancy and two decades of steady phenomenological research, it has attracted an increasing number of scientists from an expanding circle of fields. During the past decade, several lines of evidence have convinced a number of scientists that oxidants play an important role in aging. (For the sake of simplicity, we use the term oxidant to refer to all "reactive oxygen species," including O2-., H2O2, and .OH, even though the former often acts as a reductant and produces oxidants indirectly.) The pace and scope of research in the last few years have been particularly impressive and diverse. The only disadvantage of the current intellectual ferment is the difficulty in digesting the literature. Therefore, we have systematically reviewed the status of the free radical theory, by categorizing the literature in terms of the various types of experiments that have been performed. These include phenomenological measurements of age-associated oxidative stress, interspecies comparisons, dietary restriction, the manipulation of metabolic activity and oxygen tension, treatment with dietary and pharmacological antioxidants, in vitro senescence, classical and population genetics, molecular genetics, transgenic organisms, the study of human diseases of aging, epidemiological studies, and the ongoing elucidation of the role of active oxygen in biology.
The present study investigated the enduring effects of postnatal handling (administered during the first 21 days of life), and environmental enrichment (for a period of 6 months starting 3 weeks after weaning) on spatial learning in 24-month-old hypoemotional (Roman high-avoidance, RHA/Verh) and hyperemotional (Roman low-avoidance, RLA/Verh) rats. Two groups of 5-month-old rats from both lines were also included in the experiment as young controls. The Roman lines performed differently in the Morris water maze: Path lengths of RLA/Verh rats were shorter and they swam at lower speed than RHA/Verh rats, showing quicker and more efficient learning overall. Postnatal handling improved learning mainly in RHA/Verh rats, whereas environmental enrichment was able to prevent the deficits shown by aged controls of both lines. Young, enriched, and handled plus enriched animals exhibited better performance than impaired aged controls, to the point that aged enriched and handled plus enriched animals did not differ from young controls. Thus, besides indicating that RLA/Verh rats are better learners than RHA/Verh rats in the Morris water maze, this study demonstrates that environmental enrichment prevents the cognitive loss associated with aging, over the long term. Finally, the positive effects obtained with postnatal handling were dependent on the rat line.
Ample research indicates that age-related neuronal-behavioral decrements are the result of oxidative stress that may be ameliorated by antioxidants. Our previous study had shown that rats given dietary supplements of fruit and vegetable extracts with high antioxidant activity for 8 months beginning at 6 months of age retarded age-related declines in neuronal and cognitive function. The present study showed that such supplements (strawberry, spinach, or blueberry at 14.8, 9.1, or 18.6 gm of dried aqueous extract per kilogram of diet, respectively) fed for 8 weeks to 19-month-old Fischer 344 rats were also effective in reversing age-related deficits in several neuronal and behavioral parameters including: oxotremorine enhancement of K(+)-evoked release of dopamine from striatal slices, carbachol-stimulated GTPase activity, striatal Ca(45) buffering in striatal synaptosomes, motor behavioral performance on the rod walking and accelerod tasks, and Morris water maze performance. These findings suggest that, in addition to their known beneficial effects on cancer and heart disease, phytochemicals present in antioxidant-rich foods may be beneficial in reversing the course of neuronal and behavioral aging.
To determine the prevalence of age-related behavioral changes, namely impairment, in a randomly chosen population of dogs.
Age-stratified cohort study.
97 spayed female and 83 castrated male dogs that were 11 to 16 years old.
Data on possible impairment in 4 behavioral categories (ie, orientation in the home and yard, social interaction, house training, and sleep-wake cycle) linked to cognitive dysfunction were obtained from dog owners, using a structured telephone interview. Hospital records of dogs had been screened to exclude dogs with dysfunction in organ systems that may cause behavioral changes. Dogs with behavioral impairment were those with > or = 2 signs of dysfunction within a category. Dogs with impairment in 1 category were considered mildly impaired and those with impairment in > or =2 categories were considered severely impaired.
Age by sex interactions for dogs with impairment in any category were not significant, and, therefore, data on castrated males and spayed females were pooled for analyses across ages. The prevalence of age-related progressive impairment was significant in all categories. The percentage of 11- to 12-year-old dogs with impairment in > or = 1 category was 28% (22/80), of which 10% (8/80) had impairment in > or = 2 behavioral categories. Of 15- to 16-year-old dogs, 68% (23/34) had impairment in > or =1 category, of which 35% (12/34) had impairments in > or = 2 categories. There were no significant effects of body weight on the prevalence of signs of dysfunction in the behavioral categories.
Data collected provide estimates of the prevalence of various degrees of age-related behavioral changes associated with cognitive dysfunction in dogs. Age-related behavioral changes may be useful indicators for medical intervention for dogs with signs of cognitive impairment.
In order to verify whether brain damage caused by chronic oxidative stress induces the impairment of cognitive function, the ability of learning and memory was assessed using the water maze and the eight-arm radial maze tasks. Young rats showed significantly greater learning ability before the stress than the old and vitamin E-deficient rats. At five days after subjection to oxidative stress, the memory function of the young declined toward the level of that in the aged rats maintained under normal condition. This phenomenon is supported by the findings that the delayed-type apoptosis appeared in the CA1 region of the hippocampus of the young at five to seven days after the stress. Vitamin E supplementation to the young accelerated significantly their learning functions before the stress and prevented the deficit of memory caused by the stress. When rats were subjected to stress, thiobarbituric acid-reactive substance (TBARS), lipid hydroperoxides, and protein carbonyls were significantly increased in synaptic plasma membranes. It was found that zeta-potential of the synaptic membrane surface was remarkably decreased. These phenomena were also observed in the aged and vitamin E-deficient rats maintained under normal condition. These results suggest that oxidative damage to the rat synapse in the cerebral cortex and hippocampus during aging may contribute to the deficit of cognitive functions.
Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.
Diets high in antioxidant properties are known to reverse some deficits in neuronal and cognitive function that occur in aging animals. Antioxidants are also known to reduce levels of proinflammatory factors in the CNS. We report here that 6 weeks of a spinach-enriched diet ameliorates deficits in cerebellar-dependent delay classical eyeblink learning and reduces the proinflammatory cytokines tumor necrosis factor alpha (TNFalpha) and TNFbeta in the cerebelli of eyeblink-trained animals. Eighteen-month-old Fischer 344 rats were given spinach-enriched lab chow or regular lab chow for 6 weeks. The rats were then given 6 d of 30 trials per day training using a 3 kHz tone conditioned stimulus and airpuff unconditioned stimulus. Rats were killed 3 weeks after eyeblink training. Cytokine expression was measured using RNase protection assay analysis in the eyeblink-trained animals and in a group of young control animals given regular lab chow diet. Old animals on the spinach-enriched lab chow diet learned delay eyeblink conditioning significantly faster than old animals on the regular diet. Cerebelli from older animals on the spinach-enriched diet had significantly less TNFalpha and TNFbeta than cerebelli from older animals on the control diet.
Cognitive function in older adults is related to independent living and need for care. However, few studies have addressed whether improving cognitive functions might have short- or long-term effects on activities related to living independently.
To evaluate whether 3 cognitive training interventions improve mental abilities and daily functioning in older, independent-living adults.
Randomized, controlled, single-blind trial with recruitment conducted from March 1998 to October 1999 and 2-year follow-up through December 2001.
Volunteer sample of 2832 persons aged 65 to 94 years recruited from senior housing, community centers, and hospital/clinics in 6 metropolitan areas in the United States.
Participants were randomly assigned to 1 of 4 groups: 10-session group training for memory (verbal episodic memory; n = 711), or reasoning (ability to solve problems that follow a serial pattern; n = 705), or speed of processing (visual search and identification; n = 712); or a no-contact control group (n = 704). For the 3 treatment groups, 4-session booster training was offered to a 60% random sample 11 months later.
Cognitive function and cognitively demanding everyday functioning.
Thirty participants were incorrectly randomized and were excluded from the analysis. Each intervention improved the targeted cognitive ability compared with baseline, durable to 2 years (P<.001 for all). Eighty-seven percent of speed-, 74% of reasoning-, and 26% of memory-trained participants demonstrated reliable cognitive improvement immediately after the intervention period. Booster training enhanced training gains in speed (P<.001) and reasoning (P<.001) interventions (speed booster, 92%; no booster, 68%; reasoning booster, 72%; no booster, 49%), which were maintained at 2-year follow-up (P<.001 for both). No training effects on everyday functioning were detected at 2 years.
Results support the effectiveness and durability of the cognitive training interventions in improving targeted cognitive abilities. Training effects were of a magnitude equivalent to the amount of decline expected in elderly persons without dementia over 7- to 14-year intervals. Because of minimal functional decline across all groups, longer follow-up is likely required to observe training effects on everyday function.
Diets high in antioxidant properties are known to reverse some deficits in neuronal and cognitive function that occur in aging animals. Antioxidants are also known to reduce levels of proinflammatory factors in the CNS. We report here that 6 weeks of a spinach-enriched diet ameliorates deficits in cerebellar-dependent delay classical eyeblink learning and reduces the proinflammatory cytokines tumor necrosis factor alpha (TNFalpha) and TNFbeta in the cerebelli of eyeblink-trained animals. Eighteen-month-old Fischer 344 rats were given spinach-enriched lab chow or regular lab chow for 6 weeks. The rats were then given 6 d of 30 trials per day training using a 3 kHz tone conditioned stimulus and airpuff unconditioned stimulus. Rats were killed weeks after eyeblink training. Cytokine expression was measured using RNase protection assay analysis in the eyeblink-trained animals and in a group of young control animals given regular lab chow diet. Old animals on the spinach-enriched lab chow diet learned delay eyeblink conditioning significantly faster than old animals on the regular diet. Cerebelli from older animals on the spinach-enriched diet had significantly less TNFalpha and TNFbeta than cerebelli from older animals on the control diet.
Clinical symptoms of Alzheimer's disease (AD) include a variety of progressive cognitive deficits, particularly memory. Twenty-five patients with mild to moderate AD and their caregivers, who served as controls, participated in a 5 week memory training programme, with a 1 month follow up. Participants were taught strategies that included nameface rehearsal, effortful recall, and a significant event technique. Intervention efficacy was assessed on task specific tests, administered on a weekly basis, and general cognitive measures obtained at the first and last sessions of the intervention. During the memory training programme patients showed improved performance on the recall of names and faces, recognition memory after effortful processing of information, and significant events (p < .05). Controls consistently performed better than the AD group, making few errors. Standardised measures for the AD group improved on the Kendrick Digit Copy and had lower scores on the Geriatric Depression Scale (p < .05). Caregivers also rated patients higher on the Memory Function Questionnaire (MFQ) (p < .05). Thus, a memory training programme can be beneficial for patients with mild to moderate AD to improve some aspects of memory and behaviour. Ultimately, behavioural interventions in conjunction with pharmacological therapies may optimise functional ability and provide a framework to further enhance cognitive function in patients with dementia.
Cortical patterns of β-amyloid (Aβ) deposition were evaluated in 40 beagle dogs ranging in age from 2 to 18 years. Aβ deposition in the prefrontal, occipital, parietal and entorhinal cortices was visualized by using an antibody against Aβ1–42. A logistic regression was used to estimate differences in age-at-onset and rate of deposition of Aβ as a function of brain region. The earliest and most consistent site of Aβ deposition with age was in the prefrontal cortex. Entorhinal Aβ deposition was not consistently observed until the age of 14 years, but was present in a subset of dogs under the age of 14 years. These regional vulnerabilities to Aβ accumulation are similar to those seen in the aging human. By using parameters derived from regression analyses, it may be possible to predict the presence of Aβ within specific brain regions in individual dogs. We propose that these models will be a useful tool to evaluate interventions that delay the age of onset or slow the rate of accumulation of Aβ in the dog.
Spatial learning and memory in young and old dogs was studied in a series of experiments using a delayed non-matching to position (DNMP) paradigm. Past research from our laboratory has suggested that aged dogs perform more poorly on a version of the DNMP task compared to young dogs [Head et al., Spatial learning and memory as a function of age in the dog, Behav. Neurosci. 1995;109(5):851–585]. We have now extended these findings by testing a large number of dogs on three different variations of the DNMP paradigm to evaluate different aspects of spatial learning and memory. Our results indicate that: (1) aged dogs show impaired spatial learning compared to young dogs, (2) aged dogs display spatial working memory deficits compared to young dogs, (3) young dogs have a greater maximum working spatial memory capacity than old dogs and (4) we can use the DNMP paradigm to cognitively categorize different subsets of aged dogs. These data indicate that the DNMP paradigm can serve as a valuable tool to evaluate age-dependent cognitive dysfunction in the canine.
One of the theories involved in the etiology of Alzheimer’s disease (AD) is the oxidative stress hypothesis. The amyloid β-peptide (Aβ), a hallmark in the pathogenesis of AD and the main component of senile plaques, generates free radicals in a metal-catalyzed reaction inducing neuronal cell death by a reactive oxygen species mediated process which damage neuronal membrane lipids, proteins and nucleic acids. Therefore, the interest in the protective role of different antioxidants in AD such as vitamin E, melatonin and estrogens is growing up. In this review we summarize data that support the involvement of oxidative stress as an active factor in Aβ-mediated neuropathology, by triggering or facilitating neurodegeneration, through a wide range of molecular events that disturb neuronal cell homeostasis.
Visual discrimination and reversal learning were assessed in young adult (10-12 years old, n = 4) and aged (23-27 years old, n = 5) female rhesus monkeys. Performance was comparable across age groups in many tasks, suggesting that the acquisition of stimulus-reward associations remains largely intact in the aged monkey. Most older subjects, however, required more training than any young animal to learn an initial pattern discrimination. In combination with previous findings from the same groups of monkeys, these data suggest that deficits in attending to the relevant stimulus features in novel testing procedures may contribute to poor performance in aged subjects across a variety of learning and memory tasks. In addition, preliminary findings from a discrimination probe procedure raise the possibility that aged subjects may adopt alternate testing strategies that compensate for some aspects of age-dependent cognitive dysfunction.
The brains of 7 dogs aged 6 to 18 years have been histochemically and immunohistochemically investigated at the light- and electron microscopy levels for preamyloid deposits and amyloid fibrils to verify the hypothesis that the accumulation of cleavage products of amyloid precursor protein is related not only to Alzheimer's disease but also to the normal aging of the brain. Preamyloid deposits were detected in the neuropil of the cerebral cortex and neostriatum, whereas amyloid fibrils were found in the walls of parenchimal and leptomeningeal vessels. The densities of preamyloid deposits in the neuropil and of deposits of amyloid fibrils in the vessel walls were higher in the brains of the most aged dogs. These findings suggest that aging of the canine brain is characterized by an accumulation of intermediate cleavage products of the amyloid precursor protein in both the neuropil and the vessel walls, and by processing of these products to amyloid fibrils in the vessel walls.
Research in aging has emphasized average age-related losses and neglected the substantial heterogeneity of older persons.
The effects of the aging process itself have been exaggerated, and the modifying effects of diet, exercise, personal habits,
and psychosocial factors underestimated. Within the category of normal aging, a distinction can be made between usual aging,
in which extrinsic factors heighten the effects of aging alone, and successful aging, in which extrinsic factors play a neutral
or positive role. Research on the risks associated with usual aging and strategies to modify them should help elucidate how
a transition from usual to successful aging can be facilitated.
The effects of aging and of housing in an enriched environment on performance in an 8-arm radial maze were evaluated in young adult (7-8 months) and old (30-33 months) male Brown-Norway rats, using a procedure in which the rats were confined for 8 s to the central platform of the maze between consecutive choices. Although the old rats attained a level of performance which was clearly above change, they were shown to perform worse than the young rats. No performance differences were found between differentially housed rats of the same age group. In a second experiment recovery cycles of visual evoked potentials were determined in the same rats by using paired flashes with an interstimulus time of 400, 300, 200, or 100 ms. Recovery was consistently smaller in the old rats as compared to the young ones. No correlation could be demonstrated, however, between radial maze performance or housing condition and recovery functions of the visual evoked potentials. This finding indicates that a decline in visual sensitivity cannot readily explain the impaired radial maze performance of old rats. Evidence which suggests that age-related hippocampal changes play a major role in the radial maze performance deficit is discussed.
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.
As part of the effort to characterize age-related cognitive changes in executive system function in a nonhuman primate model of human aging, the performance of seven rhesus monkeys, 20 to 28 years of age, was compared to that of five young adult monkeys, 6 to 11 years of age, on spatial and object reversal tasks. No differences in performance were found between the two groups in the initial learning of either task. On spatial reversals, aged monkeys were impaired relative to young adults, but there was no difference in overall performance between the groups on object reversals. Central to this article, a perseverative tendency was noted in the aged group on both spatial and object reversal tasks. Changes in executive system dysfunction may represent an important aspect of age-related cognitive decline.
Free radicals and oxidative damage have been implicated in brain aging and several neurodegenerative diseases. The purpose of the present study was to determine whether antioxidants could alleviate age-associated cognitive and motor changes. Aged 24-month-old male Sprague-Dawley rats were treated for 4-5 months with daily i.p. injections of spin-trapping compound phenyl-alpha-tert-butylnitrone (PBN; 32 mg/kg) and alpha-tocopherol (200 mg/kg) or with vehicles. Antioxidant-treated animals also received ascorbate in their drinking water. In Morris water maze testing after two months, antioxidant-treated rats exhibited significantly greater memory retention than vehicle-treated rats in water maze testing. Subsequent tests for passive avoidance behavior and motor activity/skill revealed no effect of antioxidant treatment. In a separate group of aged 33-month-old rats that received the same combination of antioxidants for only 14 days, antioxidant treatment did not affect basal levels of brain lipid peroxidation (as indexed by TBAR formation) compared to controls. The results of this study provide initial evidence that chronic antioxidant treatment can improve cognitive function during aging, thus supporting the 'free radical hypothesis of aging' related to brain function.
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-Alzheimer's. 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.
There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer's disease.
We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimer's disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3).
Despite random assignment, the baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups, and this variable was highly predictive of the primary outcome (P<0.001). In the unadjusted analyses, there was no statistically significant difference in the outcomes among the four groups. In analyses that included the base-line score on the Mini-Mental State Examination as a covariate, there were significant delays in the time to the primary outcome for the patients treated with selegiline (median time, 655 days; P=0.012), alpha-tocopherol (670 days, P=0.001) or combination therapy (585 days, P=0.049), as compared with the placebo group (440 days).
In patients with moderately severe impairment from Alzheimer's disease, treatment with selegiline or alpha-tocopherol slows the progression of disease.
Recent studies have implicated increased oxidative stress in the pathogenesis of Alzheimer's disease (AD). Increased lipid peroxidation and decreased polyunsaturated fatty acid levels have been described in the brain in AD. Four-hydroxynonenal (HNE), an aldehyde product of lipid peroxidation, has been demonstrated to be a neurotoxin in tissue culture and in vivo studies and is elevated in ventricular fluid in AD. We report here an increase in mean free HNE in multiple brain regions in AD compared with age-matched control subjects. These increases reached statistical significance in the amygdala and hippocampus and parahippocampal gyrus, regions showing the most pronounced histopathological alterations in AD. This study, in conjunction with cell culture studies, suggests that HNE may be an important substance in the pathogenesis of neuron degeneration in AD.
Multiple lines of evidence indicate that oxidative stress is a contributor to neuronal death in Alzheimer's disease (AD). The oxidative damage that occurs to DNA may play a role in both normal aging and neurodegenerative diseases, including AD. This is a study of the oxidative damage that occurs in nuclear DNA in the brains of AD patients and cognitively intact, prospectively evaluated, age-matched control subjects. Nuclear DNA from frontal, temporal, and parietal lobes and cerebellum was isolated from 11 control subjects and 9 AD subjects, and oxidized purine and pyrimidine bases were quantitated using gas chromatography/mass spectrometry. Stable isotope-labeled oxidized base analogues were used as internal standards to measure 5-hydroxyuracil, 5-hydroxycytosine, 8-hydroxyadenine, 4,6-diamino-5-formamidopyrimidine (Fapy-adenine), 8-hydroxyguanine, and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-guanine). Statistically significant elevations of 5-hydroxycytosine, 5-hydroxyuracil, 8-hydroxyadenine, and 8-hydroxyguanine were found in AD brain compared with control subjects (p < 0.05). There was an increased trend in the levels of Fapy-adenine in the AD brain, and Fapy-guanine showed a trend toward higher levels in control brains compared with AD. A generally higher level of oxidative DNA damage was present in neocortical regions than cerebellum. No significant correlation was observed between the oxidized bases and neurofibrillary tangle and senile plaque counts. Our results demonstrate that nuclear DNA damage by oxygen-derived radicals is increased in AD and support the concept that the brain is under increased oxidative stress in AD.
Dogs exhibit both neuroanatomical and cognitive changes as a function of age that parallel those seen in aging humans. This study describes in vivo changes in neuroanatomical and cerebrovascular characteristics of the canine brain as a function of age in a group of dogs ranging from 4 to 15 years old. Dynamic contrast-enhanced magnetic resonance imaging (MRI) was used to measure the kinetics of contrast agents in the brain. Measures of vascular volume and blood-brain barrier (BBB) permeability were derived from a pharmacokinetic analysis. Cortical atrophy and ventricular enlargement were characteristic features of the aged canine brain. Vascular volume did not vary as a function of age and BBB permeability exhibited a nonsignificant increasing trend with age. However, BBB dysfunction was detected in one middle-aged dog that in addition to having unusually large ventricles, demonstrated an early onset of diffuse senile plaques at postmortem. These findings indicate that BBB dysfunction detected by magnetic resonance imaging may be useful for predicting and potentially diagnosing early pathological conditions.
Young, middle-aged, and old beagle dogs were tested on several visual-discrimination tasks: reward- and object-approach learning, object discrimination and reversal, long-term retention of a reversal problem, and a size-discrimination task. Beta-amyloid accumulation in the entorhinal, prefrontal, parietal, and occipital cortices was quantified using immunohistochemical and imaging techniques at the conclusion of cognitive testing. Middle-aged and old dogs were impaired in size-discrimination learning. In each task, a subset of aged dogs was impaired relative to age-matched peers. Beta-amyloid accumulation was age-dependent. However, not all middle-aged and old dogs showed beta-amyloid accumulation in the entorhinal cortex. The error scores from dogs tested with a nonpreferred object during visual discrimination learning and from reversal learning were correlated with beta-amyloid in the prefrontal but not entorhinal cortex. Size-discrimination and reward and object-approach learning error scores were correlated with beta-amyloid accumulation in the entorhinal but not prefrontal cortex. The results of these studies support an association between cognitive test and the location and extent of beta-amyloid pathology.
The presence of the biomarkers of oxidative damage, protein carbonyl formation and the inactivation of oxidatively sensitive brain creatine kinase (CK BB, cytosolic isoform), were studied in frontal lobe autopsy specimens obtained from patients with differen