Phosphatidylserine (PS) as a potential nutraceutical for canine brain aging: A review

Neurodegenerative processes are one of the main age-related features of dogs. Senile neurodegeneration can be clinically asymptomatic, “borderline” (i.e., a condition that is intermediate between normal and disease state) or progress toward overt clinical abnormalities, known as age-related cognitive disorders, cognitive dysfunction syndrome (CDS), or senile dementia. The aim of the present article is to review the rationale for the use of phosphatidylserine (PS), a natural phospholipid, in the management of brain neurodegenerative processes in senior dogs. The preliminary clinical data on PS supplementation in senior dogs will also be reviewed. There is evidence that PS is absorbed rapidly, reaches high concentrations in the brain, and is well tolerated. Phosphatidylserine has emerged to exert several in vitro and in vivo neuroprotective activities. It has been shown to positively affect neurotransmitter release and neurotransmitter receptor density in several brain regions from laboratory animals with memory impairments. Phosphatidylserine also was found to revert experimentally-induced amnesia in rats and improve memory deficits both in old animals and in elderly humans with various degrees of cognitive impairment and Alzheimer's dementia. On the basis of the data reported in the scientific literature, PS stands out as an essential “brain nutrient.” In view of these features, some supplements containing PS have been licensed recently as adjuvant treatment for canine and feline brain aging. The results of the studies on its use in the preventative and combined treatment of dogs with clinical features consistent with the diagnosis of CDS are reported. Although PS-based neuroprotection in dogs and cats is still at its infancy, the preliminary collected data look promising and thus merit further investigation.     

“Didy,” a clinical case of cognitive dysfunction syndrome

The term cognitive dysfunction syndrome (CDS) has been used to refer to the changes of behavior related to aging with cognitive skills deterioration, that do not stem completely from medical conditions and that are a consequence of a degenerative process of the central nervous system. It is known that the CDS in dogs is caused by the physical and chemical changes that take place in the brain due to aging. The aim of this paper is to present a clinical case of CDS which was clinically diagnosed and then confirmed by necropsy at the veterinary hospital of the National Autonomous University of Mexico.     

Prevalence of behavioral changes associated with age-related cognitive impairment in dogs

OBJECTIVE: To determine the prevalence of age-related behavioral changes, namely impairment, in a randomly chosen population of dogs. DESIGN: Age-stratified cohort study. ANIMALS: 97 spayed female and 83 castrated male dogs that were 11 to 16 years old. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS AND CLINICAL RELEVANCE: 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.     

Alleviative effects of gamma-aminobutyric acid (GABA) on behavioral abnormalities in aged dogs

gamma-aminobutyric acid (GABA, 30 mg/kg) was administered to aged dogs with recent history of veterinary clinic visits (mean age: 15.3 years old) once daily for 2 weeks by mixing with food. Their owners subjectively evaluated the effects of GABA on behavioral signs often associated with aging in the dogs. Improvement in some of behavioral signs was notable without any observable adverse effects. Dogs administered with GABA tended to exhibit improvement in emotional states and signs may be caused by neurovegetable dysfunction, though effects on cognitive dysfunction syndrome were not always observed. Thus, GABA administration may be one of the effective means of improving the quality of life of aged dogs.     

Cognitive dysfunction in cats: a syndrome we used to dismiss as 'old age'

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

Effect of gonadectomy on subsequent development of age-related cognitive impairment in dogs.

OBJECTIVE: To determine whether gonadectomy predisposes dogs to development of age-related behavioral changes linked to cognitive impairment. DESIGN: Cohort study. ANIMALS: 29 sexually intact male dogs, 63 spayed female dogs, and 47 castrated male dogs 11 to 14 years old. PROCEDURE: Information on possible impairments in 4 behavioral categories linked to cognitive impairment (orientation in the home and yard, social interactions, house training, and sleep-wake cycle) was obtained from owners of the dogs by use of a structured telephone interview format. A second interview was performed 12 to 18 months after the initial interview, and differences in responses were evaluated. RESULTS: Sexually intact male dogs were significantly less likely than neutered dogs to progress from mild impairment (i.e., impairment in 1 category) to severe impairment (i.e., impairment in > or = 2 categories) during the time between the first and second interviews. This difference was not attributable to differences in ages of the dogs, duration of follow-up, or the owners' perceptions of the dogs' overall health. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that the presence of circulating testosterone in aging sexually intact male dogs may slow the progression of cognitive impairment, at least among dogs that already have signs of mild impairment. Estrogens would be expected to have a similar protective role in sexually intact female dogs; unfortunately, too few sexually intact female dogs were available for inclusion in the study to test this hypothesis. There may be a need to evaluate possible methods for counteracting the effects of loss of sex hormones in gonadectomized dogs.     

Evaluation of interthalamic adhesion size as an indicator of brain atrophy in dogs with and without cognitive dysfunction

Interthalamic adhesion thickness has been previously described as a parameter for quantifying canine brain atrophy and hypothesized to correlate with brain height or ventricular size. However, studies testing this hypothesis are lacking. This retrospective cross‐sectional study aimed to compare interthalamic adhesion thickness, interthalamic adhesion thickness/brain height ratio, and interthalamic adhesion thickness/brain height ratio/lateral ventricle to brain height ratio values in dogs with and without cognitive dysfunction. Medical records for dogs meeting the following inclusion criteria were retrieved from two hospitals: available brain magnetic resonance imaging (MRI) or computed tomography (CT) studies, no cerebral parenchymal lesions, and no prior neurological treatment. For each included dog, values of interthalamic adhesion thickness, interthalamic adhesion thickness/brain height ratio, and interthalamic adhesion thickness/brain height ratio/lateral ventricle to brain height ratio were measured by one observer from transverse CT or MRI images and a consensus was reached. A total of 113 dogs met inclusion criteria. Dogs were divided into three groups based on the following criteria: Young group (no cognitive dysfunction, <9‐year‐old, n = 43), Aging group (no cognitive dysfunction, ≥9‐year‐old, n = 61), and Dementia group (n = 9). All three parameters were significantly lower in the dementia group than in the Young and Aging groups. In the Young and Aging groups, there was significant negative correlation of all three parameters with age and positive correlation of interthalamic adhesion thickness and interthalamic adhesion thickness/brain height ratio/lateral ventricle to brain height ratio with body weight, while there was no correlation of interthalamic adhesion thickness/brain height ratio with body weight (P < 0.05). There were no differences in all three parameters according to skull type or gender. Findings from the current study supported the use of interthalamic adhesion thickness, interthalamic adhesion thickness/brain height ratio, and interthalamic adhesion thickness/brain height ratio/lateral ventricle to brain height ratio for quantifying brain atrophy in dogs with cognitive dysfunction.     

Age-related changes in the brain of the dog.

Although many age-related changes have been described in the nervous system of different species, few authors have specifically studied the topic. Knowledge of such changes is essential to veterinary pathologists, who must distinguish the lesions of specific pathologic processes from those arising as a result of normal aging. The brains of 20 old dogs, ranging in age from 8 to 18 years, were compared with those of 10 young dogs using routine staining techniques (hematoxilin and eosin, periodic acid-Schiff), special staining techniques (periodic acid-methenamine silver stain), and immunohistochemical techniques to detect glial fibrillary acid protein, neurofilaments, ubiquitin, and beta-amyloid. Changes affected meninges and choroid plexuses, meningeal and parenchymal vessels, neurons, and glial cells. Of special interest was the presence of polyglucosan bodies, cerebrovascular amyloid deposition, senile plaques, and ubiquitinated bodies. Some of the age-related changes found, particularly lipofuscin, polyglucosan bodies, and beta-amyloid protein deposition, may play a role in the pathogenesis of the canine cognitive dysfunction syndrome. The dog could be used as a natural animal model for the study of normal aging and human neurodegenerative diseases.     

Concentrations of platelet α2-adrenoceptors,lymphocyte muscarinic receptors,and blood monoamines in dogs (Canis familiaris) affected by canine cognitive dysfunction syndrome

Canine cognitive dysfunction syndrome (CDS) is a neurodegenerative disorder of aged dogs characterized by a progressive decline in cognitive function. In humans and laboratory animals, a variety of neurotransmitter abnormalities have been described in patients affected by age-related dementia. Specifically, the regulatory role of the catecholaminergic, serotonergic, and cholinergic systems has been outlined. The aim of the present study was to measure blood monoamine levels, platelet α₂-adrenergic receptors, and lymphocyte muscarinic receptors in healthy adult and aged dogs and in dogs affected by canine cognitive dysfunction. Based on clinical and behavioral examination, 40 dogs were divided into 3 groups: healthy adults (n = 14), aged dogs (n = 17), and aged dogs affected by canine cognitive dysfunction (n = 9). A significant reduction in plasma levels of norepinephrine and dopamine was observed both in aged dogs (0.16 ± 0.02 ng/mL, P < 0.01; 0.11 ± 02 ng/mL, P < 0.01, respectively) and in CDS dogs (0.14 ± 0.03 ng/mL, P < 0.05; 0.10 ± 00.005 ng/mL, P < 0.01, respectively) compared with adults (0.29 ± 0.04 ng/mL and 0.15 ± 0.02 ng/mL, respectively). No significant differences were observed among groups for α₂-adrenergic receptor concentrations. Canine lymphocytes express 2 distinct classes of muscarinic receptors, characterized by high (HA) and low affinity (LA) for [³H]-N-methyl-scopolamine. A significant age-dependent decrease in HA muscarinic receptors was observed. However, no differences were found between aged dogs (87.65 ± 11.08 sites/cell × 10²) and in CDS dogs (90.17 ± 6.75 sites/cell × 10² ) for HA muscarinic receptor concentrations. As far as LA muscarinic receptors are concerned, CDS dogs showed a significant increase (393.48 ± 63 sites/cell × 10²; P < 0.05) with respect to healthy adult dogs (188.84 ± 16.50 sites/cell × 10²). Our results suggest that the reduction in HA muscarinic receptor-binding sites could be representative of the physiological aging process, whereas the increase in lymphocyte LA muscarinic receptor levels could be related to the cognitive decline.     

Behavior problems in geriatric pets.

Aging pets often suffer a decline in cognitive function (eg, memory,learning, perception, awareness) likely associated with age-dependent brain alterations. Clinically, cognitive dysfunction may result in various behavioral signs, including disorientation; forgetting of previously learned behaviors, such as house training; alterations in the manner in which the pet interacts with people or other pets;onset of new fears and anxiety; decreased recognition of people, places, or pets; and other signs of deteriorating memory and learning ability. Many medical problems, including other forms of brain pathologic conditions, can contribute to these signs. The practitioner must first determine the cause of the behavioral signs and then determine an appropriate course of treatment, bearing in mind the constraints of the aging process. A diagnosis of cognitive dysfunction syndrome is made once other medical and behavioral causes are ruled out.     

Predicting behavioral changes associated with age-related cognitive impairment in dogs

OBJECTIVE: To monitor the progression of age-related behavioral changes in dogs during a period of 6 to 18 months and to determine whether signs of dysfunction in any of 4 behavioral categories can be used to predict further impairment. DESIGN: Age-stratified cohort study. ANIMALS: 63 spayed female and 47 castrated male dogs 11 to 14 years of age. PROCEDURE: Data were collected from randomly selected dog owners who were interviewed by telephone twice at a 12- to 18-month interval; data were included if the dog had lived > or = 6 months between interviews. The interview focused on signs of impairment in the following behavioral categories: orientation in the home and yard, social interactions with human family members, house training, and the sleep-wake cycle. Dogs were determined to have impairment in 0 behavioral categories (on the basis of < or = 1 sign for each category), impairment in 1 category (> or = 2 signs of dysfunction in that category), or impairment in > or = 2 categories. RESULTS: Between interviews, 22% (16/73) of dogs that did not have impairment in a category at the time of the first interview developed impairment in that category by the time of the second interview. Forty-eight percent (13/27) of dogs that had impairment in 1 category at the time of the first interview developed impairment in > or = 2 categories by the time of the second interview and were significantly more likely to develop impairment in > or = 2 categories, compared with dogs that initially had impairment in 0 categories. Dogs with 1 sign of dysfunction in orientation were significantly more likely to develop impairment in that category, compared with dogs that had 0 signs of dysfunction in orientation. CONCLUSIONS AND CLINICAL RELEVANCE: Age-related behavioral changes in dogs are progressive. Clinicians should consider trying to predict which dogs are most likely to become progressively impaired during the subsequent 6 to 18 months.     

Clinical feasibility of cognitive testing in dogs (Canis lupus familiaris)

Several cognitive tests have been developed to evaluate specific aspects of human and animal learning and memory. These tests have been used for early detection of cognitive deficits and to monitor the treatment of dogs with cognitive impairment. Thus, this article evaluated the feasibility of cognitive tests for use in canine neurology clinical routines and the suitability of the different tests to accomplish this aim. Fifteen healthy adult dogs were used for the cognitive tests of reward approach learning, object approach learning, object discrimination learning, reversal learning, delayed non-matched to position, and delayed non-matched to sample to assess different aspects of memory. No difference was observed between tests of delayed non-matched to position (3.13 ± 2.23 days) and delayed non-matched to sample (3.20 ± 2.40 days) (P = 0.944). However, dogs had greater difficulty in reversal learning (8.47 ± 2.61 days) than in object discrimination learning (4.60 ± 1.64 days) (P ≤ 0.001). Based on the tests performed, the delayed non-matched to position test may be performed in clinical routine if the owner and the veterinarian have time available, because this test is sensitive to evaluate dogs with cognitive impairments, but requires approximately 10 days of training. Thus, elderly dogs are excellent experimental models to study pathological aging based on their similarities with some human brain diseases, such as Alzheimer disease.     

Nutrition and behavior in senior dogs

With increasing age, some dogs develop a neurogenerative disease that is commonly referred to as canine cognitive dysfunction syndrome (CDS). Diagnosis of CDS can be clinical or based on laboratory tests. The main behavioral changes associated with CDS are disorientation, altered interactions with people or other animals, sleep-wake cycle alterations, house-soiling, and changes in activity level. Ruling out medical conditions that can cause similar changes in behavior is important when performing a clinical diagnosis. Management of CDS includes dietary and pharmacological intervention. Dietary treatment of CDS has been based on the use of antioxidants and mitochondrial cofactors, and recent work has shown that long-term supplementation with medium-chain triglycerides can improve cognitive function in aged dogs. CDS must be considered an animal welfare issue and the implications of this are discussed in this article.     

Localization of metallothioneins-I & -II and -III in the brain of aged dog.

Localization of metallothionein (MT) -I & -II and MT-III and its significance in the brain aging in dogs were examined using immunohistological and molecular pathological techniques. MT-I & -II immunohistochemistry showed positive staining in the hypertrophic astrocytes throughout the aged dog brains; these MT-I & -II immunoreactive astrocytes were predominant in the cerebral cortex and around the blood vessels in the brain. These findings dominated in the brain regions with severe age-related morphological changes. In situ hybridization using MT-I mRNA riboprobes also demonstrated signals for MT-I mRNA in these hypertrophic astrocytes. Immunohistochemistry using a guinea pig antiserum against a synthetic polypeptide of canine MT-III demonstrated positive MT-III immunoreactivity predominantly in neurons in the Zn-rich regions such as hippocampus and parahippocampus. The findings were supported by in situ hybridization using MT-III mRNA riboprobes. Both MT-III immunoreactivity and signals for MT-III mRNA were demonstrated in neurons in the brain regardless of the intensity of the age-related changes. These results suggest, first, MT-I & -II may be induced in relation to the progress of the age-related morphological changes in the brain, playing an important role in the protection of the brain tissue from the toxic insults responsible for the brain aging, and second, MT-III may play a role in maintenance of Zn-related essential functions of the brain.     

Oxidative stress, aging, and central nervous system disease in the canine model of human brain aging.

Decline in cognitive functions that accompany aging in dogs may have a biologic basis, and many of the disorders associated with aging in dogs may be mitigated through dietary modifications that incorporate specific nutraceuticals. Based on previous research and the results of laboratory and clinical studies, antioxidants may be one class of nutraceutical that provides benefits to aged dogs. Brains of aged dogs accumulate oxidative damage to proteins and lipids, which may lead to dysfunction of neuronal cells. The production of free radicals and lack of increase in compensatory antioxidant enzymes may lead to detrimental modifications to important macromolecules within neurons. Reducing oxidative damage through food ingredients rich in a broad spectrum of antioxidants significantly improves, or slows the decline of, learning and memory in aged dogs.     

MEASUREMENT OF INTERTHALAMIC ADHESION THICKNESS AS A CRITERIA FOR BRAIN ATROPHY IN DOGS WITH AND WITHOUT COGNITIVE DYSFUNCTION (DEMENTIA)

The criteria for brain atrophy in dogs have not yet been established, because of wide variation in the morphology of the ventricles and sulci of the brain depending on the breed and size. In this study, we examined the thickness of the interthalamic adhesion in a transverse magnetic resonance image to investigate normal, to examine the correlation with age, body weight, and breed, and to assess whether measurement would be a useful indicator of brain atrophy. The animals used in this study were of various breeds and weight, and had no identifiable intracranial lesion. They were divided into two groups: a normal group (0.6-15-year-old, n = 66) and a demented aging group (12-18-year-old, n = 12). The interthalamic adhesion thickness in both T1- and T2-weighted transverse images were measured in all dogs. The interthalamic adhesion thickness in the normal and demented groups was 6.79 +/- 0.70 and 3.82 +/- 0.79 mm, respectively. The interthalamic adhesion thickness in the demented group was significantly smaller. In an analysis of the correlation of interthalamic adhesion thickness with age and weight in normal dogs, significant negative and positive correlation was recognized, respectively. However, the strength of these correlations was low. These results suggest that interthalamic adhesion thickness may be a good parameter for evaluating brain atrophy in dogs with cognitive dysfunction.     

Prevalence and risk factors of behavioural changes associated with age-related cognitive impairment in geriatric dogs

O bjectives : The aim of this study was to describe the prevalence and severity of behavioural changes associated with age and their relationship to risk factors such as sex, reproductive status, bodyweight and age.
M ethods : A cross-sectional study design was chosen. A total of 325 geriatric dogs were included. Owners of dogs older than nine years were interviewed by a veterinary behaviourist. Structured phone interviews were used to gather information about four behavioural categories related to cognitive impairment: sleep/wake cycles, social interaction, learning and house training and signs of disorientation.
R esults : Signs of cognitive impairment showed a prevalence of 22·5 per cent in geriatric dogs. Sex and age emerged as significant predictor variables. Females and neutered dogs were significantly more affected than males and entire dogs, respectively. Prevalence and severity increased with age. Although weight was not a statistically significant predictor variable, smaller animals had greater odds of showing age-related cognitive impairment. The most impaired behavioural categories were social interaction and house training.
C linical S ignificance : Age-related behavioural changes should be considered by practicing veterinarians because of their relative high prevalence among geriatric dogs, especially in females.     

Nutraceuticals, aging, and cognitive dysfunction.

Decline in cognitive function that accompanies aging in dogs might have a biological basis, and many of the disorders associated with aging in canines might be preventable through dietary modifications that incorporate specific nutraceuticals. Based on previous research and the results of laboratory and clinical studies, antioxidants might be one class of nutraceutical that benefits aged dogs. Brains of aged dogs accumulate oxidative damage to proteins and lipids, which can lead to dysfunction of neuronal cells. The production of free radicals and lack of increase in compensatory antioxidant enzymes might lead to detrimental modifications to important macromolecules within neurons. Reducing oxidative damage through food ingredients rich in a broad spectrum of antioxidants significantly improves, or slows the decline of, learning and memory in aged dogs; however, determining which compounds, combinations, dosage ranges, when to initiate intervention, and long-term effects constitute critical gaps in knowledge about this subject.     

Improvement of short-term memory performance in aged beagles by a nutraceutical supplement containing phosphatidylserine, Ginkgo biloba, vitamin E, and pyridoxine

Aged dogs demonstrate cognitive decline that is linked to brain aging. The purpose of the present study was to examine if a commercially available nutraceutical supplement that may be neuroprotective and contains phosphatidylserine, Ginkgo biloba, vitamin E, and pyridoxine could improve cognitive function in aged beagles. Nine aged beagles were tested on performance on a delayed-non-matching-to-position task, which is a neuropsychological test of short-term visuospatial memory. All subjects were tested on 5 baseline sessions; then, to assess the supplement, a crossover design was used in which 1 group received the supplement and the other a control substance in the 1st phase, with treatment conditions being reversed in the 2nd phase. Performance accuracy was significantly improved in supplemented dogs compared with control dogs and the effect was long lasting. These findings suggest that the nutraceutical supplement can improve memory in aged dogs.     

Effects of DDAVP administrated subcutaneously in dogs with aspirin-induced platelet dysfunction and hemostatic impairment due to chronic liver diseases

To evaluate the hemostatic effects of desmopressin (DDAVP) in dogs with aspirin-induced platelet dysfunction and hemostatic impairment in chronic liver diseases, 3 microg/kg DDAVP was administrated subcutaneously. In aspirin-induced platelet dysfunction dogs (n=5), prolonged BMBT (buccal mucosal bleeding time) was shortened significantly after DDAVP injection (2.2 +/- 1.2 min, P<0.05). In dogs with chronic liver diseases (n=4), activated partial thromboplastin time (APTT) tended to shorten by 0.9 to 3.0 sec, and prolonged BMBT was shortened in two cases for 4.2 and 1.7 min after DDAVP injection. Therefore, the present results indicated that DDAVP shortened the prolonged BMBT in dogs with aspirin-induced platelet dysfunction and chronic liver disease. DDAVP might be helpful in hemostasis under invasive procedures such as biopsy or surgery for dogs with hemostatic impairment.