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Canine cognitive dysfunction (CCD) is a clinical condition, which impacts significantly on the lives of elderly dogs and their owners. It is hypothesised that nutritional supplementation can be used in the management of the condition and this trial was designed to investigate the therapeutic effects of a specific supplement when compared to a placebo. The trial was conducted in a clinical context and involved 20 UK veterinary practices, giving geographical spread across the country. The duration of the trial was 56 days, including a baseline period of 7 days and a post trial period of 7 days. There was a significant difference between the treated and the placebo groups in relation to improvement in their scores for disorientation, changes in interaction and house soiling behaviour at day 21, day 28 and day 42. These results support the clinical practice of nutritional supplementation as a valuable component of the therapeutic approach in cases of canine cognitive dysfunction.
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... A SDCC acomete cães com média de onze anos de idade (7), principalmente fêmeas castradas (18), mas há relatos de animais com sete anos que apresentaram sinais de declínio da cognição (7,17). A prevalência mundial da doença é desconhecida e variável, mas na Austrália, em cães com mais de sete anos é estimada em 14%, no Reino Unido em 20-30% em cães da mesma faixa etária, e nos EUA em 22% dos cães entre 11 e 14 anos (14,19). ...
... A nutrição é um fator auxiliar importante no tratamento, sendo indicado o uso de antioxidantes, visando diminuir a ação deletéria dos radicais livres (19,24,27,28). Os suplementos nutricionais indicados são a vitamina E, vitamina C, selênio, e beta caroteno (1). ...
... Os suplementos nutricionais indicados são a vitamina E, vitamina C, selênio, e beta caroteno (1). Na Europa existe um suplemento nutricional que contém selênio, N acetilcisteína, ácido α-lipoico, vitaminas C, E, L-carnitina e coenzima Q10, além de ácidos graxos, cujo uso experimental obteve resultados benéficos em alguns aspectos comportamentais (19). A S-adenosilmetionina (SAMe) é um precursor da glutationa com propriedades antioxidantes, e em um estudo utilizando apenas essa medicação em 17 cães com mais de oito anos, tratados por dois meses com dose de 18mg/ kg, foi observado melhora da cognição (32). ...
Várias afecções podem afetar a porção tálamo-cortical do encéfalo do cão idoso, ocorrendo alterações do estado mental, comportamento ou andar compulsivo, entre outros sinais clínicos. Dentre essas doenças, a síndrome da disfunção cognitiva canina (SDCC) é uma das mais enfatizadas atualmente, no entanto, ou-tras doenças, como a encefalopatia hepática, neoplasias encefálicas e hipotireoidismo devem ser conside-radas como diagnósticos diferenciais. O diagnóstico da SDCC só pode ser realizado após outras afecções intra e extracranianas serem excluídas, assim o objetivo desse trabalho é revisar os aspectos importantes destas diversas afecções quanto aos sinais clínicos, métodos de diagnóstico, tratamento e prognóstico. Palavras-chave: geriatria, encéfalo, sistema nervoso cão.
... 5,6 A wide variety of supplement therapies, including nutraceuticals, herbal extracts, and vitamins, have been suggested to improve or prevent declining cognitive function. 6 Vitamins B, E, and C, carotenoids, flavonoids, phospatidilserine, and omega 3 fatty acids have antioxidant properties and neuroprotective effects in dogs and people. 7,8 In people with cognitive dysfunction (CD), administration of these compounds has been reported to improve social interactive behavior, memory, and learning. ...
... 7,8 In people with cognitive dysfunction (CD), administration of these compounds has been reported to improve social interactive behavior, memory, and learning. 9 In dogs, an antioxidantenriched diet leads to easier learning and memory improvements, 6 and it has also been reported that antioxidants may be beneficial for promoting physiologic brain aging and reducing the risk of neurodegenerative disease.  Finally, it has been shown that medium-chain triglyceride supplementation improves visuospatial function and learning ability in healthy old dogs. ...
Several studies indicate that changes in cerebrospinal fluid (CSF) composition depend on the disease stage and reflect modification of brain energy metabolism (BEM). Also, it has been reported that a decline in cognitive functions may be mitigated by incorporating nutraceuticals in the diet.
Assuming the beneficial effect of nutraceuticals on BEM and oxidative damage, the aim of this study was to determine if the administration of a nutraceutical compound results in changes of select CSF biomarkers in healthy adult Beagle dogs.
Two separate CSF and blood samples were obtained from 11 healthy adult Beagle dogs, before and after 50 days of treatment with a veterinary combined nutraceutical. CSF analysis included a total nucleated cell count, total protein, glucose, sodium, chloride, potassium, pyruvate, and lactate concentrations, and calculation of lactate/pyruvate ratio. CBC and serum biochemistry were also performed. The Wilcoxon test was used to analyze the significance of the changes after nutraceutical treatment.
All studied variables remained within reference intervals, before and after treatment. A significant increase in CSF sodium and glucose concentration, and a decrease in lactate levels, was observed after treatment (P < .05), and the lactate/pyruvate ratio was decreased after treatment (P = .05). In serum, sodium and chloride concentrations were significantly increased (P < .05), and creatinine concentration was significantly decreased (P < .05) after treatment.
After 50 days of treatment with a nutraceutical compound, CSF glucose, sodium, and lactate concentrations, and L/P ratio were significantly different, suggesting an influence of nutraceuticals' administration on CSF composition.
... After three months of feeding, dogs fed the test diet had significantly better spatial attention. A clinical study was conducted to determine the effects of Aktivait on the clinical symptoms of CDS in old dogs . Aktivait contained four categories of nutrients including brain strengthening components (DHA/EPA, phosphotidylserine), signaling enhancers (phosphotidylserine, acetyl-L-carnitine, L-carnitine, CoQ10), metabolic enhancers (acetyl-L-carnitine, L-carnitine, CoQ10), and antioxidants (vitamin C, vitamin E, selenium, N-acetyl cysteine, alpha-lipoic acid). ...
... Aktivait contained four categories of nutrients including brain strengthening components (DHA/EPA, phosphotidylserine), signaling enhancers (phosphotidylserine, acetyl-L-carnitine, L-carnitine, CoQ10), metabolic enhancers (acetyl-L-carnitine, L-carnitine, CoQ10), and antioxidants (vitamin C, vitamin E, selenium, N-acetyl cysteine, alpha-lipoic acid). Significant improvement was observed in CDS scores for disorientation, changes in interaction, and house soiling behavior at day 21, day 28, and day 42 between the test and the placebo groups . ...
Due to a difference in genetics, environmental factors, and nutrition, just like in people, dogs age at different rates. Brain aging in people and dogs share similar morphological changes including irreversible cortical atrophy, cerebral amyloid angiopathy, and ventricular enlargement. Due to severe and irreversible brain atrophy, some aging dogs develop cognitive dysfunction syndrome (CDS), which is equivalent to dementia or Alzheimer’s disease (AD) in people. The risk factors and causes of CDS in dogs have not been fully investigated, but age, gender, oxidative stress, and deficiency of sex hormones appears to be associated with increased risk of accelerated brain aging and CDS in dogs. Both AD and CDS are incurable diseases at this moment, therefore more efforts should be focused on preventing or reducing brain atrophy and minimizing the risk of AD in people and CDS in dogs. Since brain atrophy leads to irreversible cognitive decline and dementia, an optimal nutritional solution should be able to not only enhance cognitive function during aging but also reduce irreversible brain atrophy. Up to now, only one nutritional intervention has demonstrated both cognition-enhancing benefits and atrophy-reducing benefits.
... Therefore, our objectives in this study were to examine the changes in discrimination learning in older pet dogs of various breeds and to test whether a dietary intervention can counteract potential age-associated decline in learning and learning from feedback (cognitive flexibility) while taking also the dogs' lifelong training experiences into account. In contrast with other studies in pet dogs (Dodd et al., 2003;Heath et al., 2007) that studied the effect of dietary supplements over shorter periods (42 and 60 days) and measured changes in dog behavior by means of questionnaires filled in by the owners, we fed the dogs with two kinds of diet for 1 year and used objective measures of changes in learning. In a recent study using 185 pet dogs aged over 6 years (Chapagain et al., 2017), we have found that lifelong training had a positive effect on sustained and selective attention probably due to the stimulation provided by these interactions. ...
... However, other studies conducted on laboratory dogs have shown positive effect of enriched diet with antioxidants and mitochondrial co-factors already after feeding for 3 months (Milgram et al., 2002a), 6 months (Milgram et al., 2002b) and 1 year (Milgram et al., 2004). Additionally, there are two studies in pet dogs (Dodd et al., 2003;Heath et al., 2007) that have shown beneficial effects of nutritional supplement as early as 2 months of feeding. Noteworthy, these studies, however, relied completely on the owners' assessment of dogs' behavioral changes and used no objective measurement of cognitive functions with specific tests. ...
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.
... A number of clinical trials have shown improvements in signs associated with CDS in dogs using dietary supplements containing phosphatidylserine, a membrane phospholipid. 73,74 One product (Senilife; CEVA Animal Health, Libourne, France) was tested in aged dogs using a cross-over design in which DNMP memory performance was improved after 60 days of treatment with Senilife. 75 Although labeled for use in cats, efficacy studies are not published. ...
... Another product containing phosphatidylserine (Activait; Vet Plus Ltd, Lytham St. Annes, UK) demonstrated significant improvement over placebo on signs of disorientation, social interactions, and house soiling in dogs. 74 A feline version of Activait, with no alpha-lipoic acid, is also available but has not been tested in clinical trials. ...
Brain aging is a degenerative process manifest by impairment of cognitive function; although not all pets are affected at the same level, once cognitive decline begins it is generally a progressive disorder. Diagnosis of cognitive dysfunction syndrome (CDS) is based on recognition of behavioral signs and exclusion of other medical causes that might mimic CDS or complicate its diagnosis. Drugs, diets, and supplements are now available that might slow CDS progression by various mechanisms including reducing oxidative stress and inflammation or improving mitochondrial and neuronal function. Moreover, available therapeutics may provide some level of improvement in cognitive and clinical signs of CDS.
... While many studies on the prevalence of CDS have identified CDS as a common problem in old dogs (Neilson et al 2001, Osella et al 2007, Azkona et al 2009, epidemiology studies suggest that the disease is under-diagnosed in up to 85% of potentially affected animals (Salvin et al 2010). Its prevalence has not been established in many countries of Europe or America, but a poll taken by 981 owners of dogs older than 7 years in the United Kingdom suggested that approximately one-third of the dogs showed signs of confusion, restlessness and less enjoyment of life, while 1 out of 5 showed an increase in the incidence of habitual hygiene problems (Heath et al 2007). A study conducted in Italy that included 124 geriatric dogs showed a CDS prevalence of nearly 50%, in which 75 dogs over 7 years old showed signs that correlated with the disease (Osella et al 2007). ...
Improvements in veterinary medicine, nutrition and the enrichment of the domestic environment have helped more dogs reach to their senile phase. However, greater longevity leads to a higher prevalence of cognitive problems in our pets. Throughout their geriatric lives, dogs are more vulnerable to suffering progressive neurodegenerative dementia syndromes. Due to its high prevalence, cognitive dysfunction syndrome is one of the most studied neurodegenerative diseases. This disease is a neurobehavioral entity that presents itself in senile dogs, and it is characterized by a deficit in learning, memory and the dog's spatial awareness. It is a clinical disorder that has a significant impact on older dogs and their owners. There is a lack of reliable diagnostic tests that can guarantee the presence of the disease, provide early identification of the clinical signs of this disease, or establish a prognosis in terms of the recovery and expansion of the quality of life of the affected patient. Treatment should be directed at slowing down the progression of cognitive loss through the establishment of techniques and programs that improve physical activity, nutrition and the animal's environment. Therefore, future research on the knowledge, control and prevention of this pathology are necessary to lower the impact generated by its effects on the quality of life of the animal.
... A alteração dos padrões de sono é talvez a mais difícil de relacionar com o déficit de função cognitiva. No entanto, esta é uma alteração que ocorre também em humanos com a doença de Alzheimer, possivelmente devido a uma perturbação do ciclo circadiano(Heath, Barabas & Craze, 2007). Apesar da desorientação poder ser devida ou intensificada pelo enfraquecimento da visão e/ou da audição, na maioria dos casos não está relacionada com estes factores(Neilson, 2001). ...
... Several clinical trials have shown improvements in clinical signs associated with CDS in dogs using dietary supplements containing phosphatidylserine, a membrane phospholipid. 10,76,77 One product, Senilife (CEVA Animal Health) was tested on dogs using a memory task after administration of 60 days of either a placebo or the product. 78 An example of a cat performing a memory task in a laboratory model may be viewed online (within this article at www.vetsmall.theclinics.com, ...
Physical signs of old age may be obvious, but mental and cognitive changes require more careful observation. Changes in behavior may represent the earliest indications of medical problems, or disorders of the central nervous system, and these may be bidirectional. Cognitive dysfunction syndrome is underdiagnosed and affects a substantial portion of aged companion animals. This article describes potential treatment regimens to address age-related behavioral problems, as well as a framework for investigating differential diagnoses. Early identification of changes in behavior is essential for the adequate treatment and management of medical and behavioral problems, and for monitoring outcomes.
... In this case the use of single nutraceuticals can be an alternative. Phosphatidylserine is a phospholipid that improves social interactions, house soiling and orientation in dogs (Heath et al. 2007). In a study of aged beagles fed with phosphatidylserine, Gingko biloba, vitamin E and pyridoxine an improvement in their short term memory was observed (Dowling and Head 2012). ...
p>Canine Cognitive Dysfunction Syndrome (CCD) is a neurodegenerative disease affecting aging dogs. CCD is an underdiagnosed disease that involves at least 14% of geriatric dogs, but apparently less than 2% of diseased dogs are diagnosed. There are several physiopathological similarities between Alzheimer disease (AD) and CCD, developing amyloid-β deposits in brain parenchyma and blood vessels, brain atrophy and neuronal loss. The clinical signs lead to behavioural changes. They are unspecific and could appear as soon as seven years of age, but are more relevant in senior dogs. The abnormal behaviour could be classified following the acronym DISHA: Disorientation in the immediate environment; altered Interactions with humans and other animals; Sleep-wake cycle disturbances; House-soiling; and changes in Activity levels. There is no specific diagnostic test or biomarker to demonstrate the presence of CCD; therefore, it is often assessed by ruling out other diseases that may cause similar behavioural changes. Veterinarians have to be able to make an accurate account of veterinary history asking for abnormal behaviour that could be misreported by the owners. CCD is a neurodegenerative disorder that cannot be cured. It is possible to delay the progression of the clinical signs and improve the quality of life of patients, but like in AD, the progression of the illness will depend on the individual. There are three treatment pathways, which could be used in combination: drug therapy to improve cognition and reduce anxiety, antioxidant diet and nutraceutical supplements to reduce the progression of the illness, and finally, environmental enrichment to maintain brain activity. The aim of this review article is to contribute to the knowledge of the illness, presenting recent advances in the pathophysiology, diagnosis and treatment of the disease.</p
... In a double-blind, placebo-controlled trial, a multicomponent supplement improved two out of six owner-assessed behaviors in dogs with clinical cognitive dysfunction (16). Another preparation was used in open, non-controlled trials (17,18). ...
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
... To be efficient, this nutritional intervention must be started as early as possible and should also be used in combination with environmental enrichment (4) . Supplementation with antioxidant combinations (4) , phospholipids such as phosphatidylserine (5) , α-lipoic acid (6) , S-adenosyl-L-methionine (7) or curcumin (8) has been claimed to provide protection against oxidative and inflammation-induced damage in both brain and vascular tissues in aged dogs. On the other hand, another well-studied strategy in dogs consists of providing the brain with an alternative energy source in the form of medium-chain TAG (9) . ...
Cellular oxidative damage is thought to be one of the key mechanisms underlying age-related cognitive impairment in dogs. Several nutritional interventions to limit cognitive decline are reported in the literature. To our knowledge, the association of grape and blueberry extracts has never been tested in aged dogs. Our objective was to evaluate the effect of a polyphenol-rich extract from grape and blueberry (PEGB) on oxidative status and cognitive performances in aged dogs. A total of thirty-five beagle dogs (aged 8·0–14·5 years) were fed a basal diet with PEGB at either 0 parts per million (ppm) ( n 11; control), 240 ppm ( n 12; PEGB1) or 480 ppm ( n 12; PEGB2) for 75 d. To investigate the effects of PEGB supplementation on cognition and oxidative status, a delayed non-matching to position (DNMP) test and RT-PCR on genes involved in oxidative stress were evaluated. The dogs fed PEGB1 showed a higher superoxide dismutase mRNA expression compared with dogs fed PEGB2 ( P = 0·042) and with the control group ( P = 0·014). Moreover, the dogs fed PEGB2 showed higher nuclear factor-like 2 (Nrf2) mRNA expression compared with the dogs fed PEGB1 ( P = 0·027). Concerning the DNMP test, the proportion of dogs showing cognitive improvements relative to their baseline level was significantly higher in dogs fed the PEGB, regardless of the dosage, than in dogs receiving no supplementation ( P = 0·030). The results obtained in the DNMP test suggested a potential benefit of the PEGB on working memory. However, this hypothesis should be further investigated to confirm this cognitive effect.
... Another product containing phosphatidylserine combined with omega-3 fatty acids, vitamins E and C, l-carnitine, alpha-lipoic acid, coenzyme Q and selenium (Activait; Vet Plus) demonstrated significantly superior results compared with placebo in terms of improving signs of disorientation, social interactions and house soiling in dogs. 63 A feline version of Activait, which does not contain alpha lipoic acid, is also available, but likewise has not been tested in clinical trials. In a placebo-controlled trial in dogs with CDS, S-adenosyl-l-methionine (SAMe) improved activity and awareness. ...
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.
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.
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.
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.
... Aktivait ® (VetPlus Ltd.) which contains phosphatidylserine, omega-3 fatty acids, vitamins E and C, L-carnitine, alpha-lipoic acid, coenzyme Q, and selenium has also demonstrated significant improvement over placebo in improving social interactions, disorientation, and house soiling in dogs with CDS (Heath et al. 2007). The feline version of the product does not contain alpha-lipoic acid because of potential for toxicity; however, efficacy has not yet been evaluated in controlled trials (Hill et al. 2004). ...
Treatment options for cognitive dysfunction syndrome (CDS) could target prevention, slowing decline and improving clinical signs. However, while prompt diagnosis and early initiation of treatment have the greatest potential for success, most owners do not report signs until they are significantly advanced and veterinarians fail to educate owners about the importance of early reporting. Both laboratory trials in beagle dogs and cats using neuropsychological assessment tools to assess learning and memory as well as clinical trials and in some cases both have been used to assess effect of therapeutics.
... Moreover, Heath S. (Heath et al., 2007) hypothesized that nutritional supplementation can be used in the management of the condition and their trial was designed to investigate the therapeutic effects of a specific supplement when compared to a placebo. The trial was conducted in a clinical conte t and involved 20 UK veterinary practices, giving geographical spread across the country. ...
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that usuallyaffects individuals of an older age. Aged dogs spontaneously develop many featuresof human aging and Alzheimer’s disease (AD) including cognitive decline andneuropathology. AD is accompanied by progressive dementia and the accumulationof senile pla
... So far, one study has shown that lifelong training can delay the aging of attentional capture, sustained attention, and selective attention in pet dogs of various breeds  , and two studies have looked at the effect of nutritional supplementation on pet dogs exhibiting symptoms of cognitive dysfunction. Heath et al.  investigated the use of "Aktivait" containing a range of antioxidants, freeradical scavengers, vitamins C and E, fatty acids, and phosphatidylserine in 44 pet dogs of different breeds for 42 days. They monitored the behavior of the dogs for 56 days via questionnaires and reported that there was a significant improvement in the dogs' behavior as noted by the owners during the trial period. ...
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.
... S-adenosyl-l-methionine (SAMe) (NoviSAMe; generic SAMe) helps to maintain the fluidity of cell membranes and enhances the production of the antioxidant glutathione, 66 and when given to elderly cats, there was an improvement in cognitive tests, including object discrimination and reversal learning; the effects were most evident in cats with mild CDS, suggesting that it is more likely to help early in disease. 67 While proprietary dietary supplements, such as Senilife (CEVA Animal Health), 8,68 and Aktivait (VetPlus), 69 have been shown to reduce signs of CDS in dogs, there is little evidence of their efficacy in cats. Senilife contains Gingko biloba, D-α -tocopherol, vitamins B6 and E, and resveratrol, amongst other components. ...
Cognitive dysfunction syndrome (CDS) is an established condition in cats that shares many similarities with human Alzheimer's disease (AD), where cognitive decline ultimately results in dementia. Cats with CDS display behavioural abnormalities, including excessive Vocalisation, altered Interaction with owners (increased affection/attention), altered Sleep‐wake cycles, House‐soiling, Disorientation (spatial and/or temporal), alterations in Activity, Anxiety, and/or Learning/memory deficits (i.e., VISHDAAL). These cats develop neuropathologies, such as accumulation of β‐amyloid and hyperphosphorylated tau deposits. Because of its similarities to those in the brains of people with cognitive impairment and AD, the domestic cat could be a natural model for human dementia studies. It is important to diagnose CDS promptly in cats, ruling out other causes for these behavioural changes, to provide effective management. Interventions include environmental enrichment (e.g., easy access to key resources, calming pheromones), dietary supplementations (e.g., Senilife, Aktivait for cats, SAMe), specific diets (e.g., containing antioxidants, medium‐chain triglycerides) and, potentially, medication (e.g., selegiline or propentofylline). This article reviews the literature about CDS in cats, its causes, neuropathology, clinical signs, diagnosis and potential management options. By doing so, it furthers our understanding of this condition and allows improved health, welfare and quality of life of affected cats.
... Pesquisas confirmam que cães com sinais clínicos sugestivos de SDCC podem apresentar melhora dos sinais clínicos se enriquecida dieta com suplemento alimentar (Landsberg, 2005;Heath et al., 2007). Constituintes do produto comercial utilizado incluem vitaminas, como a vitamina A, C, E, Beta-caroteno (sequestram os radicais livres) e taurina, os quais exercem uma função protetora contra as doenças neurodegenerativas (Bianchi e Antunes, 1999;Heaton et al., 2002). ...
O alto nível de relação entre humanos e animais de companhia intensificou a preocupação de alguns tutores com as desordens relacionadas ao envelhecimento. Durante a velhice, além de mudanças fisiológicas, alterações patológicas como a Síndrome da Disfunção Cognitiva Canina (SDCC) são comuns. Essa doença é caracterizada por processos degenerativos que culminam em perda gradual da função cognitiva, sendo frequentemente confundida com o processo natural de envelhecimento. Neste contexto, objetivou-se avaliar a ação de um suplemento nutricional à base de aminoácidos, prebióticos e ácidos graxos para cães idosos na evolução clínica da SDCC. Foram avaliados 67 cães em idade sênior (> 7 anos) para positividade aos sinais clínicos da SDCC. Posteriormente, os animais positivos (n=15 / 22%) foram alocados em dois grupos experimentais, controle (C) e tratamento (T- utilização do suplemento nutricional). Observou-se melhora, relatada pelos tutores, de sinais clínicos associados à SDCC em 80% dos animais tratados, no entanto mais estudos são necessários para elucidar o efeito de suplementos nutricionais na regressão da sintomatologia clínica de cães com sinais clínicos sugestivos da doença.
... Dogs with CDS present with clinical signs in a number of behavioral domains including disorientation, altered social interactions, sleep/wake disturbances, house soiling, anxiety and activity, which may be referred to by the acronym DISHAA (1,2,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Therefore, for this clinical study we used a questionnaire (35) that incorporated all 6 DISHAA categories (Supplementary Table 1), including questions from all previously validated questionnaires to have a complete and sensitive screening tool for identifying dogs that had levels ranging from mild to severe (27,(36)(37)(38)(39). ...
Cognitive dysfunction syndrome (CDS) is a common condition in senior dogs, which may be analogous to dementia such as Alzheimer's disease (AD) in people. In humans, AD has been associated with many risk factors such as reduced cerebral glucose metabolism, docosahexaenoic acid (DHA) deficiency, chronic oxidative stress, and chronic inflammation. By targeting some of these risk factors, we have developed two nutritional solutions (medium chain triglyceride, MCT and Brain Protection Blend, BPB) to enhance cognitive function and slow aging-induced cognitive decline. These have been positively evaluated in colony housed senior dogs and cats. The objective of this clinical study was to evaluate the effects of diets with MCTs and the BPB on client-owned dogs with CDS. Participating veterinary clinics screened senior dogs for signs of CDS as determined by a Senior Canine Behavior Questionnaire and a Canine Medical Health Questionnaire. Eighty-seven dogs were randomly enrolled into one of three diet groups with 29 dogs per group: Control, 6.5% MCT oil + BPB (6.5% MCT diet), 9% MCT oil + BPB (9% MCT diet). Diets were fed for a period of 90 days, and each dog's CDS signs were re-evaluated at day 30 and day 90. All 6 categories of the CDS signs were significantly improved (p <0.05) in the dogs given the 6.5% MCT diet at the end of the 90-day study. Control only improved in 4 out 6 categories. The 9% MCT diet only improved in dogs that accepted the diet. The results from this dog study confirm the benefits of MCT and BPB in managing clinical signs of CDS in dogs. The results support our hypothesis that targeting known risk factors associated with brain aging and AD is able to improve symptoms of CDS in dogs. These data may facilitate the development of similar nutrient blends to manage MCI and AD.
... Dogs with CDS present with clinical signs in a number of behavioral domains including disorientation, altered social interactions, sleep/wake disturbances, house soiling, anxiety and activity, which may be referred to by the acronym DISHAA (1,2,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Therefore, for this clinical study we used a questionnaire (35) that incorporated all 6 DISHAA categories (Supplementary Table 1), including questions from all previously validated questionnaires to have a complete and sensitive screening tool for identifying dogs that had levels ranging from mild to severe (27,(36)(37)(38)(39). ...
These proceedings contain oral and poster presentations from various experts on animal behaviour and animal welfare in veterinary medicine presented at the conference.
... 35,132 Many nutraceutical products currently available to veterinarians and pet owners include a combination of several ingredients, including antioxidants, minerals, and vitamins. Use of a combination nutraceutical d significantly improved a number of cognitive dysfunction syndrome-associated signs in aged dogs in a multicenter, double-blinded, placebo-controlled clinical trial 133 ; however, the dogs relapsed once administration of the nutraceutical was discontinued. ...
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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.
... 39 A study using a supplement containing phosphatidylserine, omega 3 fatty acids, Lcarnitine, co-enzyme Q10, selenium, vitamins E and C, plus alpha lipoic acid (Aktivait, VetPlus) resulted in improved social interactions, house soiling, and disorientation in dogs. 40 Because alpha-lipoic acid is toxic in cats, a feline version has been commercially released, but has not been tested for safety or efficacy. ...
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.
... In dogs with CDS, several studies have shown behavioural improvements and reduced amyloid deposition when giving supplements or diets with various combinations of antioxidants, vitamins, essential fatty acids and other potentially useful components (Hill's b/d; Senilife™; Purina Pro Plan Veterinary Diets Neurocare ® ; CEVA Animal Health; Aktivait™; VetPlus) [41,43,. A recent prospective double-blinded placebo controlled clinical study on dogs with CDS showed benefits from a diet with added medium chain triglyceride and Brain Protection Blend in managing clinical signs of CDS . ...
The objectives of this study were to explore owner perception of the causes of increased vocalisation in cats diagnosed with cognitive dysfunction syndrome (CDS) and consider what impact this vocalisation may have on the cat’s household. Owners of cats diagnosed with CDS that presented with increased vocalisation were invited to complete an online survey. The survey consisted of 28 questions including the cat’s signalment, its medical history, and questions pertaining to the owner’s perception of what motivated their cat´s increased vocalisation. This was determined by looking at the cat’s behaviour when vocalising, where it was looking when it was vocalising, and if the vocalisation stopped when the owner interacted with it, e.g., petting or feeding it. The owners were also asked how stressful they found their cat’s vocalisation. There were 37 responses. The majority of owners reported that the main cause of their cat’s vocalisation appeared to be disorientation (40.5%) or attention seeking (40.5%). Seeking a resource such as food was reported in 16.2%, and pain was perceived to be the cause in only 2.7% of cats. However, the majority of owners (64.8%) believed there was >1 cause of their cat’s increased vocalisation. Importantly, when owners were asked how stressful they found their cat’s increased vocalisation, 40.5% scored ≥3 (where 1 = not stressful; 5 = significantly stressful). This study provides novel insight into owner perception of feline CDS, as well as potential causes for increased vocalisation; this will allow veterinarians to better advise owners on how to manage their cat with CDS.
... The gut microbiome of dogs is more similar to that of humans than that of mice and pigs . Although studies on dogs' microbiota and their connection to disease prevalence and aging are still scarce [21,22], they suggest that nutritional supplements may improve some of the symptoms of age-related pathological cognitive decline in dogs . ...
Gut microbiota can crucially influence behavior and neurodevelopment. Dogs show unique similarities to humans in their physiology and may naturally develop dementia-like cognitive decline. We assessed 29 pet dogs’ cognitive performance in a memory test and analyzed the bacterial 16S rRNA gene from fecal samples collected right after the behavioral tests. The major phyla identified in the dog microbiomes were Bacteroidetes, Firmicutes, and Fusobacteria, each represented by >20% of the total bacterial community. Fewer Fusobacteria were found in older dogs and better memory performance was associated with a lower proportion of Actinobacteria. Our preliminary findings support the existence of links between gut microbiota, age, and cognitive performance in pet dogs.
... At present, the treatment of vascular dementia focuses mainly on symptomatic management and significant brain injury reduction. In the brain tissue and blood vessels, antioxidants like Se and vitamins E and C protect the organ from oxidative injury and inflammation-induced degradation (17)(18)(19)(20)(21)(22) in middleaged and elderly cats (23). Approved treatments, however, are still limited in medical practice. ...
In our study, we evaluated the beneficial effect of luteolin in the treatment of cognitive dysfunction in rat models induced by cerebral hypoperfusion by two-vessel occlusion (2-VO).
Material and Methods
Seventy-five male Sprague Dawley rats were subjected to 2-VO surgery, in all but 15 (the sham group, group I) the ligation being permanent to impair cognitive abilities. The sham group rats received saline instead of a drug; 15 2-VO rats were not injected at all (the model group, group II); 15 2-VO rats were administered luteolin at 50 mg/kg b.w. (the lut 50 group, group III); to a further 15 luteolin was given at 100 mg/kg b.w. (the lut 100 group, group IV); and the final 15 received nimodipine at 16 mg/kg b.w. as positive controls (the nimodipine group, group V). Object recognition and Morris water maze tests were performed to investigate memory ability. A Western blot test was also conducted to assess expression of phosphatidylinositol 3-kinase (PI3K), its downstream target protein kinase B (Akt), and the phosphorylated form (P-Akt) in cerebral cortex and hippocampus tissue samples.
Significant variations in the discrimination index in the object recognition test, the escape latencies in the Morris water maze test, and expression levels of PI3K-p110α and PI3K-p85 were observed three months after 2-VO surgery in both lut groups, with a significant change in the nimodipine group compared to the model group. P-Akt and Akt were expressed significantly higher in both lut groups and the nimodipine group than in the model group.
Luteolin treatment of rats cognitively dysfunctional after experimental cerebral hypo perfusion was neuroprotective by activating the PI3K/Akt signals which inhibit neuronal death in the cerebral cortex and hippocampal region.
... Diets supplemented with MCTs have been shown to improve memory in humans with AD. 7 Tynes & Landsberg behavioral symptoms of cognitive dysfunction related to disorientation, social interactions, sleep-wake cycles, and house soiling, there was significant improvement in all 4 categories compared with placebo, and significant improvements in age-related behavior and quality of life reported by both owners and veterinary staff. 58 S-adenosyl-L-methionine (SAMe) is a metabolite found in all cells, where it functions as a methyl donor. SAMe-dependent methylation reactions are particularly important in the CNS, where they play an important role in maintaining the integrity of cellular membranes and are required for the synthesis and inactivation of neurotransmitter monoamines such as noradrenaline, adrenaline, dopamine, serotonin, and histamine. ...
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.
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.
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.
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.
Age-related behavioural changes should be considered by practicing veterinarians because of their relative high prevalence among geriatric dogs, especially in females.
Veterinarians need to be prepared to provide nutritional advice for healthy pets as well as for pets that are ill. Before instituting a dietary change in any patient, especially an older dog or cat, a nutritional evaluation should be completed. This should include an evaluation of the patient, the current diet, and feeding management. Diets should be appropriate to the unique needs of the individual patient. Many diseases in senior pets are “diet-sensitive” meaning that diet can play a role in managing the effects of the disease. Common examples discussed include cognitive dysfunction of aging, osteoarthritis, and obesity.
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.
Increasing numbers of cats are living to become elderly and they commonly develop behavioral changes. The objectives of this article are to consider the possible causes and prevalence of behavioral problems in pet cats, to describe how cognitive dysfunction syndrome (CDS) typically presents, and how its diagnosis and management are often complicated by the concurrent presence of multiple interacting disease processes. The most frequently reported behavioral problems in old cats are loss of litter box training and crying out loudly at night. The most common causes of these problems are CDS, osteoarthritis, systemic hypertension (commonly secondary to chronic kidney disease or hyperthyroidism), hyperthyroidism (even without hypertension), deafness, and brain tumors. These conditions all occur frequently in older cats, many of which suffer from a number of concurrent interacting conditions. Owners and veterinary surgeons often mistake these for "normal aging changes," so many treatable conditions are neglected and go untreated. Almost one third of cats 11 to 14 years of age develop at least one geriatric-onset behavior problem that appears to relate to CDS, and this increases to over 50% for cats 15 years of age or older. For optimum management of elderly cats with behavioral problems, all interacting conditions need to be diagnosed and addressed concurrently with management for CDS.
With improvements in nutrition and veterinary medicine the life expectancy of pet cats is increasing. Accompanying this growing geriatric population there are increasing numbers of cats with signs of apparent senility. A recent study suggests that 28 per cent of pet cats aged 11 to 14 years develop at least one geriatric onset behavioural problem, and this increases to over 50 per cent for cats of 15 years of age or older. While behavioural changes may result from systemic illness, organic brain disease or true behavioural problems, the possibility of age-related cognitive dysfunction is often overlooked. Studies have revealed a number of changes in the brains of geriatric cats that showed signs of cognitive dysfunction, and potential causes include vascular insufficiency leading to hypoxia, increased free radical damage and the deposition of beta-amyloid plaques and/or the modification of other proteins. By recognising the importance of behavioural changes in old cats, investigating them fully for potentially treatable medical conditions, and instigating dietary and environmental modifications to meet their changing needs, we can make the lives of our geriatric cats much more comfortable and rewarding.
Oxidative stress (OS) impairs organic function and is considered causally related to cellular senescence and death. This study aims to evaluate if the redox balance varies in relation to age and gender in healthy cats. To quantify the oxidative status of this species we determined the oxidative damage as serum reactive oxygen metabolites (ROM) and the total serum antioxidant capacity (SAC). In addition, we used the ratio of ROM to SAC as a measure of the oxidative balance, with higher values meaning higher oxidative stress (oxidative stress index). Our results suggest that the male population is at oxidative risk when compared with females, especially between the age of 2 and 7 years. Nutritional strategies in this population looking for additional antioxidant support would probably avoid the oxidative stress status that predisposes to chronic processes in senior male cats. Further clinical trials in this field are recommended.
Cognitive dysfunction syndrome, a neurodegenerative disease, is relatively common in older dogs including a constellation of behavioral and cognitive deficits. An earlier diagnosis and adequate therapeutic protocol could help to improve the quality of life of the dogs as well as the relationships with their owners.
The aim of this study was to investigate the prevalance of behavioral changes associated with age in dogs and their relationship to sex, reproductive status, weight, housing and feeding. About 134 dogs older than 7 years were included in this study. Owners of dogs were interviewed and gather information about signs: sleep/wake cycle, social interaction, learning and house training and disorientation. Forty seven dogs (35.07%) were found to have shown behavioural changes associated with age-related cognitive impairment. Prevalance increased with age. There were no significant effects of sex, weight, housing (inside/outside) and feeding (dry food/home made) on behavioral changes. According to categories, 20 dogs had alterations in one category, 7 dogs had two categories, 12 dogs with three categories and 7 dogs had four categories. The most impaired behavioral categories were changes in sleep/wake cycles (32%) and social interaction (30%) followed by disorientation (20%) and learning and house training (18%). The results of this study suggest that estimates of the prevalance of various degrees of age-related behavioral changes. Veterinarian and dog owner should be aware of this problem.
There are a number of correlations between the pathophysiology and behavioral expression of early Alzheimer disease in humans and age-related cognitive dysfunction in dogs and cats. Changes in social interaction and the reduced ability to cope with everyday situations are difficulties experienced in human, canine, and feline age-related cognitive decline. Anxiety, distress, and confusion commonly precede diagnosis. Information obtained from family members, carers, or owners may be key to identifying early behavioral markers and allowing early management or treatment.Environment may predispose to or protect from cognitive decline over time. Neuroinflammation associated with air pollution or excessive noise can lead to oxidative damage within the cerebrum and development of β-amyloid plaques. Targeted programs promoting mental exercise may be used to delay progression once clinical signs have been presented.Pharmacological interventions in humans have focused mainly on augmenting neuronal efficacy by using agents to increase the chemical communication, whereas in veterinary medicine cerebral vasodilators are commonly used. Preclinical and mildly impaired patients have limited options in human medicine, whereas there is a trend in veterinary medicine to offer targeted nutritional supplements that include antioxidants, L-carnitine, or omega-3 fatty acids.Comparing treatment options in species provides opportunities to identify new methods of controlling age-related cognitive decline.
Canine cognitive dysfunction (CCD) is a condition seen in aged dogs. The causes, signs and development of the disease must be well understood for correct diagnosis and treatment to be considered. The disease can impact greatly on the dog's quality of life and the owner–animal relationship as loss of learned behaviours and reduced social interaction can be frustrating, especially if the cause is unknown. Drug therapy and dietary modification have been proven to be successful in slowing the progression of the disease and improving brain function when used alongside behavioural modification.
Phosphatidylserine, a constituent of the cell membrane, has an essential role in ageing of the brain. Phosphatidylserine maintains the fluidity of membranes, due in part to its antioxidant role, and it is involved in the function of structural proteins, ionic channels, enzymes, receptors, release of neurotransmitters, and synaptic plasticity. Phosphatidylserine is a cofactor in activation of protein kinase C isoforms, stimulating the dependant Na/K-ATPase and increasing the release of catecholamine and acetylcholine, and muscarinic NMDA and NGF receptor density involved in neuroprotection. Experimental and clinical studies have shown efficacy in the prevention of cognitive decline. In this regard, phosphatidylserine acts as a nootropic, facilitating learning and memory.
Dog husbandry and housing in shelters has changed over the years to parallel the changes in veterinary care and animal sheltering that have gone from essentially "one size fits all" to adapting to meet the needs of the individual animal. The Association of Shelter Veterinarians' (ASV) Guidelines state that primary enclosures must provide sufficient space to allow each animal, regardless of species, to make normal postural adjustments, for example, to turn freely and to easily stand, sit, stretch, move their head without touching the top of the enclosure, etc. The primary enclosure, regardless if it is a pen, cage, condo unit, or double-sided compartment, should be made from durable nonporous materials that are easily disinfected, safe, and sturdy. Staffs who are administering vaccinations and any prophylactic and targeted treatments must take into account the dog's behavior and demeanor as well as their physical condition to minimize their stress when handling them.
Canine cognitive dysfunction (CCD) is a behavioural change that can occur in geriatric dogs, and is associated with impairments in learning and memory. CCD can impact the human–animal bond due to the reduction in the animal’s quality of life and the owner being unable to cope with behavioural changes associated with CCD. However, early diagnosis of CCD is key in managing the condition, as its progression can be delayed with diet, medical and behavioural interventions.
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.
Thirty-two typical patients with breast cancer, aged 32-81 years and classified 'high risk' because of tumor spread to the lymph nodes in the axilla, were studied for 18 months following an Adjuvant Nutritional Intervention in Cancer protocol (ANICA protocol). The nutritional protocol was added to the surgical and therapeutic treatment of breast cancer, as required by regulations in Denmark. The added treatment was a combination of nutritional antioxidants (Vitamin C: 2850 mg, Vitamin E: 2500 iu, beta-carotene 32.5 iu, selenium 387 micrograms plus secondary vitamins and minerals), essential fatty acids (1.2 g gamma linolenic acid and 3.5 g n-3 fatty acids) and Coenzyme Q10 (90 mg per day). The ANICA protocol is based on the concept of testing the synergistic effect of those categories of nutritional supplements, including vitamin Q10, previously having shown deficiency and/or therapeutic value as single elements in diverse forms of cancer, as cancer may be synergistically related to diverse biochemical dysfunctions and vitamin deficiencies. Biochemical markers, clinical condition, tumor spread, quality of life parameters and survival were followed during the trial. Compliance was excellent. The main observations were: (1) none of the patients died during the study period. (the expected number was four.) (2) none of the patients showed signs of further distant metastases. (3) quality of life was improved (no weight loss, reduced use of pain killers). (4) six patients showed apparent partial remission.
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.
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.
Age-stratified cohort study.
63 spayed female and 47 castrated male dogs 11 to 14 years of age.
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.
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.
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.
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.
Accumulation of oxidative damage to mitochondria, protein, and nucleic acid in the brain may lead to neuronal and cognitive dysfunction. The effects on cognitive function, brain mitochondrial structure, and biomarkers of oxidative damage were studied after feeding old rats two mitochondrial metabolites, acetyl-l-carnitine (ALCAR) [0.5% or 0.2% (wt/vol) in drinking water], and/or R-alpha-lipoic acid (LA) [0.2% or 0.1% (wt/wt) in diet]. Spatial memory was assessed by using the Morris water maze; temporal memory was tested by using the peak procedure (a time-discrimination procedure). Dietary supplementation with ALCAR and/or LA improved memory, the combination being the most effective for two different tests of spatial memory (P < 0.05; P < 0.01) and for temporal memory (P < 0.05). Immunohistochemical analysis showed that oxidative damage to nucleic acids (8-hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine) increased with age in the hippocampus, a region important for memory. Oxidative damage to nucleic acids occurred predominantly in RNA. Dietary administration of ALCAR and/or LA significantly reduced the extent of oxidized RNA, the combination being the most effective. Electron microscopic studies in the hippocampus showed that ALCAR and/or LA reversed age-associated mitochondrial structural decay. These results suggest that feeding ALCAR and LA to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function.
We test whether the dysfunction with age of carnitine acetyltransferase (CAT), a key mitochondrial enzyme for fuel utilization, is due to decreased binding affinity for substrate and whether this substrate, fed to old rats, restores CAT activity. The kinetics of CAT were analyzed by using the brains of young and old rats and of old rats supplemented for 7 weeks with the CAT substrate acetyl-l-carnitine (ALCAR) and/or the mitochondrial antioxidant precursor R-alpha-lipoic acid (LA). Old rats, compared with young rats, showed a decrease in CAT activity and in CAT-binding affinity for both substrates, ALCAR and CoA. Feeding ALCAR or ALCAR plus LA to old rats significantly restored CAT-binding affinity for ALCAR and CoA, and CAT activity. To explore the underlying mechanism, lipid peroxidation and total iron and copper levels were assayed; all increased in old rats. Feeding old rats LA or LA plus ALCAR inhibited lipid peroxidation but did not decrease iron and copper levels. Ex vivo oxidation of young-rat brain with Fe(II) caused loss of CAT activity and binding affinity. In vitro oxidation of purified CAT with Fe(II) inactivated the enzyme but did not alter binding affinity. However, in vitro treatment of CAT with the lipid peroxidation products malondialdehyde or 4-hydroxy-nonenal caused a decrease in CAT-binding affinity and activity, thus mimicking age-related change. Preincubation of CAT with ALCAR or CoA prevented malondialdehyde-induced dysfunction. Thus, feeding old rats high levels of key mitochondrial metabolites can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction.
Mitochondrial-supported bioenergetics decline and oxidative stress increases during aging. To address whether the dietary addition of acetyl-l-carnitine [ALCAR, 1.5% (wt/vol) in the drinking water] and/or (R)-alpha-lipoic acid [LA, 0.5% (wt/wt) in the chow] improved these endpoints, young (2-4 mo) and old (24-28 mo) F344 rats were supplemented for up to 1 mo before death and hepatocyte isolation. ALCAR+LA partially reversed the age-related decline in average mitochondrial membrane potential and significantly increased (P = 0.02) hepatocellular O(2) consumption, indicating that mitochondrial-supported cellular metabolism was markedly improved by this feeding regimen. ALCAR+LA also increased ambulatory activity in both young and old rats; moreover, the improvement was significantly greater (P = 0.03) in old versus young animals and also greater when compared with old rats fed ALCAR or LA alone. To determine whether ALCAR+LA also affected indices of oxidative stress, ascorbic acid and markers of lipid peroxidation (malondialdehyde) were monitored. The hepatocellular ascorbate level markedly declined with age (P = 0.003) but was restored to the level seen in young rats when ALCAR+LA was given. The level of malondialdehyde, which was significantly higher (P = 0.0001) in old versus young rats, also declined after ALCAR+LA supplementation and was not significantly different from that of young unsupplemented rats. Feeding ALCAR in combination with LA increased metabolism and lowered oxidative stress more than either compound alone.
Antioxidants may protect the aging brain against oxidative damage associated with pathological changes of Alzheimer disease (AD).
To examine the relationship between antioxidant supplement use and risk of AD.
Cross-sectional and prospective study of dementia. Elderly (65 years or older) county residents were assessed in 1995 to 1997 for prevalent dementia and AD, and again in 1998 to 2000 for incident illness. Supplement use was ascertained at the first contact.
Cache County, Utah.
Among 4740 respondents (93%) with data sufficient to determine cognitive status at the initial assessment, we identified 200 prevalent cases of AD. Among 3227 survivors at risk, we identified 104 incident AD cases at follow-up.
Diagnosis of AD by means of multistage assessment procedures.
Analyses of prevalent and incident AD yielded similar results. Use of vitamin E and C (ascorbic acid) supplements in combination was associated with reduced AD prevalence (adjusted odds ratio, 0.22; 95% confidence interval, 0.05-0.60) and incidence (adjusted hazard ratio, 0.36; 95% confidence interval, 0.09-0.99). A trend toward lower AD risk was also evident in users of vitamin E and multivitamins containing vitamin C, but we saw no evidence of a protective effect with use of vitamin E or vitamin C supplements alone, with multivitamins alone, or with vitamin B-complex supplements.
Use of vitamin E and vitamin C supplements in combination is associated with reduced prevalence and incidence of AD. Antioxidant supplements merit further study as agents for the primary prevention of AD.
An introductory review of phospholipid biochemistry and pharmacology is given, with particular reference to the biological and pharmacological effects of phosphatidylserine in normal animals. Phosphatidylserine, isolated from bovine brain and administered parenterally, exerts neurochemical, neuroendocrine, behavioural and electrophysiological effects in experimental animals. The molecular basis for these effects is sought in the activation of neuronal membrane-mediated release of intracellular amine stores. Realization that the activity is localized on the neuronal membranes has led to further research in the field of brain ageing, on the basis of the membrane hypothesis of ageing.
This double- blind study assesses the therapeutic efficacy and the safety of oral treatment with phosphatidylserine (BC- PS) vs placebo (300 mg/day for 6 months) in a group of geriatric patients with cognitive impairment. A total of 494 elderly patients (age between 65 and 93 years), with moderate to severe cognitive decline, according to the Mini Mental State Examination and Global DeteriorationScale, were recruited in 23 Geriatric or General Medicine Units in Northeastern Italy. Sixty- nine patients dropped out within the 6- month trial period. Patients were examined just before starting therapy, and 3 and 6 months thereafter. The efficacy of treatment compared to placebo was measured on the basis of changes occurring in behavior and cognitive performance using the Plutchik Geriatric Rating Scale and the Buschke Selective Reminding Test. Statistically significant improvements in the phosphatidylserine- treated group compared to placebo were observed both in terms of behavioral and cognitive parameters. In addition, clinical evaluation and laboratory tests demonstrated that BC- PS was well tolerated. These results are clinically important since the patients were representative of the geriatric population commonly met in clinical practice. (Aging Clin. Exp. Res. 5: 123- 133, 1993).
There is considerable controversy over whether nutrition in early life has a long-term influence on neurodevelopment. We have shown previously that, in preterm infants, mother's choice to provide breast milk was associated with higher developmental scores at 18 months. We now report data on intelligence quotient (IQ) in the same children seen at 7 1/2-8 years. IQ was assessed in 300 children with an abbreviated version of the Weschler Intelligence Scale for Children (revised Anglicised). Children who had consumed mother's milk in the early weeks of life had a significantly higher IQ at 7 1/2-8 years than did those who received no maternal milk. An 8.3 point advantage (over half a standard deviation) in IQ remained even after adjustment for differences between groups in mother's education and social class (p less than 0.0001). This advantage was associated with being fed mother's milk by tube rather than with the process of breastfeeding. There was a dose-response relation between the proportion of mother's milk in the diet and subsequent IQ. Children whose mothers chose to provide milk but failed to do so had the same IQ as those whose mothers elected not to provide breast milk. Although these results could be explained by differences between groups in parenting skills or genetic potential (even after adjustment for social and educational factors), our data point to a beneficial effect of human milk on neurodevelopment.
The effects of phosphatidylserine (BC-PS) on cognitive, affective and behavioural symptoms were studied in a group of 10 elderly women with depressive disorders. Patients were treated with placebo for 15 days, followed by BC-PS (300 mg/day) for 30 days. The Hamilton Rating Scale for Depression, Gottfries-Bråne-Steen Rating Scale, Nurse's Observation Scale for Inpatient Evaluation and Buschke Selective Reminding Test were administered before and after placebo and after BC-PS therapy, to monitor changes in depression, memory and general behaviour. At the same time, basal plasma levels of noradrenaline, MHPG, DOPAC, HVA and 5-HIAA, and GH/beta-endorphin/beta-lipotropin responses to clonidine stimulation were measured. BC-PS induced consistent improvement of depressive symptoms, memory and behaviour. No changes in amine metabolite levels or in hormonal responses to alpha 2-adrenoceptor stimulation were observed.
The release of total acetylcholine (ACh) and [3H]ACh was investigated in electrically stimulated cortical slices prepared from 4- and 18-month-old male Wistar rats. The slices were prelabeled with [3H]choline ([3H]Ch) and perfused with Krebs solution containing physostigmine. Total ACh was measured and the nature of the tritium efflux identified by HPLC. The total tritium content in the slices at the end of the incubation period was half as great in the old as in young rats. A linear relationship was found between stimulation frequencies (2, 5, and 10 Hz) and fractional [3H]ACh release in both young and old rats. In the latter the release was significantly smaller. At 10 Hz stimulation frequency the ratio between the two 2-min stimulation periods, S2/S1, was higher in the 18-month-old rats than in the young rats. Specific activity of the evoked ACh release was significantly smaller in S2 than in S1 in 4-month-old rats only. These findings indicate that the young synthetize ACh from endogenous unlabeled Ch more than older rats. In 18-month-old rats both the evoked total ACh and [3H]ACh release, expressed as picograms per minute, showed an approximately 50% decrease in both S1 and S2 stimulation periods, with no significant difference in specific activity. Phosphatidylserine (PtdSer) administration (15 mg/kg, i.p. daily) for 1 week to 18-month-old rats prevented the reduction in total evoked ACh release but not the reduction in evoked [3H]ACh release. The specific activity of ACh release was therefore significantly smaller than that of the young and untreated old rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Relationships of nutrition and vitamins to the genesis and prevention of cancer are increasingly evident. In a clinical protocol, 32 patients having -"high-risk"- breast cancer were treated with antioxidants, fatty acids, and 90 mg. of CoQ10. Six of the 32 patients showed partial tumor regression. In one of these 6 cases, the dosage of CoQ10 was increased to 390 mg. In one month, the tumor was no longer palpable and in another month, mammography confirmed the absence of tumor. Encouraged, another case having a verified breast tumor, after non-radical surgery and with verified residual tumor in the tumor bed was then treated with 300 mg. CoQ10. After 3 months, the patient was in excellent clinical condition and there was no residual tumor tissue. The bioenergetic activity of CoQ10, expressed as hematological or immunological activity, may be the dominant but not the sole molecular mechanism causing the regression of breast cancer.
This double-blind study assesses the therapeutic efficacy and the safety of oral treatment with phosphatidylserine (BC-PS) vs placebo (300 mg/day for 6 months) in a group of geriatric patients with cognitive impairment. A total of 494 elderly patients (age between 65 and 93 years), with moderate to severe cognitive decline, according to the Mini Mental State Examination and Global Deterioration Scale, were recruited in 23 Geriatric or General Medicine Units in Northeastern Italy. Sixty-nine patients dropped out within the 6-month trial period. Patients were examined just before starting therapy, and 3 and 6 months thereafter. The efficacy of treatment compared to placebo was measured on the basis of changes occurring in behavior and cognitive performance using the Plutchik Geriatric Rating Scale and the Buschke Selective Reminding Test. Statistically significant improvements in the phosphatidylserine-treated group compared to placebo were observed both in terms of behavioral and cognitive parameters. In addition, clinical evaluation and laboratory tests demonstrated that BC-PS was well tolerated. These results are clinically important since the patients were representative of the geriatric population commonly met in clinical practice.
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.
Docosahexaenoic acid (DHA) is essential for the growth and functional development of the brain in infants. DHA is also required for maintenance of normal brain function in adults. The inclusion of plentiful DHA in the diet improves learning ability, whereas deficiencies of DHA are associated with deficits in learning. DHA is taken up by the brain in preference to other fatty acids. The turnover of DHA in the brain is very fast, more so than is generally realized. The visual acuity of healthy, full-term, formula-fed infants is increased when their formula includes DHA. During the last 50 years, many infants have been fed formula diets lacking DHA and other omega-3 fatty acids. DHA deficiencies are associated with foetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis, phenylketonuria, unipolar depression, aggressive hostility, and adrenoleukodystrophy. Decreases in DHA in the brain are associated with cognitive decline during aging and with onset of sporadic Alzheimer disease. The leading cause of death in western nations is cardiovascular disease. Epidemiological studies have shown a strong correlation between fish consumption and reduction in sudden death from myocardial infarction. The reduction is approximately 50% with 200 mg day(-1)of DHA from fish. DHA is the active component in fish. Not only does fish oil reduce triglycerides in the blood and decrease thrombosis, but it also prevents cardiac arrhythmias. The association of DHA deficiency with depression is the reason for the robust positive correlation between depression and myocardial infarction. Patients with cardiovascular disease or Type II diabetes are often advised to adopt a low-fat diet with a high proportion of carbohydrate. A study with women shows that this type of diet increases plasma triglycerides and the severity of Type II diabetes and coronary heart disease. DHA is present in fatty fish (salmon, tuna, mackerel) and mother's milk. DHA is present at low levels in meat and eggs, but is not usually present in infant formulas. EPA, another long-chain n-3 fatty acid, is also present in fatty fish. The shorter chain n-3 fatty acid, alpha-linolenic acid, is not converted very well to DHA in man. These longchain n-3 fatty acids (also known as omega-3 fatty acids) are now becoming available in some foods, especially infant formula and eggs in Europe and Japan. Fish oil decreases the proliferation of tumour cells, whereas arachidonic acid, a longchain n-6 fatty acid, increases their proliferation. These opposite effects are also seen with inflammation, particularly with rheumatoid arthritis, and with asthma. DHA has a positive effect on diseases such as hypertension, arthritis, atherosclerosis, depression, adult-onset diabetes mellitus, myocardial infarction, thrombosis, and some cancers.
Glutathione deficiency has been associated with a number of neurodegenerative diseases including Lou Gehrig's disease, Parkinson's disease, and HIV. A crucial role for glutathione is as a free radical scavenger. Alzheimer's disease (AD) brain is characterized by oxidative stress, manifested by protein oxidation, lipid oxidation, oxidized glutathione, and decreased activity of glutathione S-transferase, among others. Reasoning that elevated levels of endogenous glutathione would offer protection against free radical-induced oxidative stress, rodents were given in vivo injections of N-acetylcysteine (NAC), a known precursor of glutathione, to study the vulnerability of isolated synaptosomal membranes treated with Fe2+/H2O2, a known hydroxyl free radical producer. Protein carbonyls, a marker of protein oxidation, were measured. NAC significantly increased endogenous glutathione levels in cortical synaptosome cytosol (P < 0.01). As reported previously, protein carbonyl levels of the Fe2+/H2O2-treated synaptosomes were significantly higher compared to that of non-treated controls (P < 0.01), consistent with increased oxidative stress. In contrast, protein carbonyl levels in Fe2+/H2O2-treated synaptosomes isolated from NAC-injected animals were not significantly different from saline-injected non-treated controls, demonstrating protection against hydroxyl radical induced oxidative stress. These results are consistent with the notion that methods to increase endogenous glutathione levels in neurodegenerative diseases associated with oxidative stress, including AD, may be promising.
The etiology of Alzheimer disease (AD) is not well understood; therefore, neither prevention strategies nor long-term effective treatment modalities are available for this disease. Based on laboratory and clinical studies, it appears that reactive oxygen species (ROS) and reactive nitrogen species (RNS) that are generated extracellularly and intracellularly by various mechanisms are among the major intermediary risk factors that initiate and promote neurodegeneration in idiopathic AD. Therefore, multiple antioxidant supplements could be useful in the prevention of AD, and as an adjunct to standard therapy in the treatment of AD. The products of inflammatory reactions such as prostaglandins (PGs; PGE1 and PGA1), free radicals, cytokines, and complement proteins are neurotoxic. Nonsteroidal antiinflammatory drugs (NSAIDs), which inhibit the synthesis of PGs, reduce the rate of deterioration of cognitive functions in patients with advanced AD. Cholinergic drugs are routinely used in the treatment of AD to improve cognitive functions. Therefore, we propose that a combination of multiple antioxidants and NSAIDs may be more beneficial in the prevention of AD, and that this combination taken together with cholinergic drugs may be more effective in the treatment of AD than the individual agents alone. We also hypothesize that, in idiopathic AD, epigenetic components of neurons such as mitochondria, membranes, other membranous structures, and protein modifications--rather than the genes of neurons--are the primary targets for the action of neurotoxins including free radicals. In some familial AD, mutations in amyloid precursor protein and presenilins are associated with the risk of early onset of this disease; however, their mechanisms of action are not fully understood.
Linoleic and alpha-linolenic acid are essential for normal cellular function, and act as precursors for the synthesis of longer chained polyunsaturated fatty acids (PUFAs) such as arachidonic (AA), eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), which have been shown to partake in numerous cellular functions affecting membrane fluidity, membrane enzyme activities and eicosanoid synthesis. The brain is particularly rich in PUFAs such as DHA, and changes in tissue membrane composition of these PUFAs reflect that of the dietary source. The decline in structural and functional integrity of this tissue appears to correlate with loss in membrane DHA concentrations. Arachidonic acid, also predominant in this tissue, is a major precursor for the synthesis of eicosanoids, that serve as intracellular or extracellular signals. With aging comes a likely increase in reactive oxygen species and hence a concomitant decline in membrane PUFA concentrations, and with it, cognitive impairment. Neurodegenerative disorders such as Parkinson's and Alzheimer's disease also appear to exhibit membrane loss of PUFAs. Thus it may be that an optimal diet with a balance of n-6 and n-3 fatty acids may help to delay their onset or reduce the insult to brain functions which these diseases elicit.
Harman first suggested in 1972 that mitochondria might be the biological clock in aging, noting that the rate of oxygen consumption should determine the rate of accumulation of mitochondrial damage produced by free radical reactions. Later in 1980 Miquel and coworkers proposed the mitochondrial theory of cell aging. Mitochondria from postmitotic cells use O2 at a high rate, hence releasing oxygen radicals that exceed the cellular antioxidant defences. The key role of mitochondria in cell aging has been outlined by the degeneration induced in cells microinjected with mitochondria isolated from fibroblasts of old rats, especially by the inverse relationship reported between the rate of mitochondrial production of hydroperoxide and the maximum life span of species. An important change in mitochondrial lipid composition is the age-related decrease found in cardiolipin content. The concurrent enhancement of lipid peroxidation and oxidative modification of proteins in mitochondria further increases mutations and oxidative damage to mitochondrial DNA (mtDNA) in the aging process. The respiratory enzymes containing the defective mtDNA-encoded protein subunits may increase the production of reactive oxygen species, which in turn would aggravate the oxidative damage to mitochondria. Moreover, superoxide radicals produced during mitochondrial respiration react with nitric oxide inside mitochondria to yield damaging peroxynitrite. Treatment with certain antioxidants, such as sulphur-containing antioxidants, vitamins C and E, or the Ginkgo biloba extract EGb 761, protects against the age-associated oxidative damage to mtDNA and the oxidation of mitochondrial glutathione. Moreover, the EGb 761 extract also prevents changes in mitochondrial morphology and function associated with aging of the brain and liver.
Research indicates that vulnerability to oxidative stress (OSV) may increase in aging, suggesting that age-related neurodegenerative diseases such as Alzheimer's disease (AD) or vascular dementia (VAD) may be superimposed upon a vulnerable neuronal environment. Determinations in cell models have suggested that the enhanced OSV may be the result of, (a) increases in membrane lipids, especially sphingomyelin and the sphingomyelin metabolite, sphingosine-1-phosphate, (b) decreases in glutathione, and (c) CNS distribution of OS-sensitive neuronal muscarinic receptor subtypes (e.g. M1, M2 and M4). These changes appear to enhance, (a) decrements in cellular calcium buffering following KCl-induced depolarization, and (b) cell death under OS conditions. Among the most effective agents that antagonized cellular OSV were the combination of polyphenolics found in fruits (e.g. blueberry extract) with high antioxidant activity. Subsequent experiments using dietary supplementation with fruit (strawberry) or vegetable (spinach) extracts have shown that such extracts are also effective in forestalling and reversing the deleterious effects of behavioral aging in F344 rats. Thus, it appears that the beneficial effects of the polyphenolics found in fruits and vegetables in neuronal aging and behavior may be similar to those seen with respect to carcinogenesis and cardiovascular disease.
To determine dietary factors involved in the pathological process of Alzheimer's disease (AD), we analyzed food consumption and intake of nutrients using Self-administered Diet History Questionnaire (DHQ) developed for Japanese. Sixty four AD patients and 80 age-matched healthy subjects were enrolled in this study. AD was diagnosed according to the criteria of DSM-IV. Dietary behaviors of AD patients was markedly deviated from those of age-matched healthy elderly. AD patients disliked fish and green-yellow vegetables and took more meats than controls. Energy-adjusted analysis of nutrients revealed that AD patients took less vitamin C and carotene. Most conspicuously, AD patients took significantly smaller amount of n-3 polyunsaturated fatty acid (PUFA) reflecting low consumption of fish, and their n-6/n-3 ratio was significantly increased. These habits started from 3 months to 44 years before the onset of dementia, suggesting these dietary abnormalities are not merely the consequence of dementia. Rather, it implies that AD might be a life style-related disease such as coronary heart disease, western style diet-associated cancer and hyperallergy. To see if cognitive function was improved by correcting the n-6/n-3 ratio, we prescribed eicossapentaenoic acid (EPA), one type of n-3 PUFA, for AD patients. Cognitive function was evaluated using MMSE. Administration of EPA (900 mg/day) improved MMSE significantly with maximal effects at 3 months and the effects lasted 6 months. However, the score of MMSE decreased after 6 months. The present study showed that nutritional intervention is useful for the prevention of AD, and also for the therapy of dementia, though it has some limitation.
Soybean lecithin transphosphatidylated phosphatidylserine (SB-tPS) was prepared from soybean lecithin and L-serine by a transphosphatidylation reaction, and its effect on age-related memory impairment was evaluated in rats by the Morris water maze test. Continuous oral administration of SB-tPS (60 mg x kg(-1) x d(-1) for 60 d) to male aged rats (24-25 mo) significantly improved performance in the water maze escape test (P < 0.01 vs. control aged rats) similar to bovine brain cortex-derived phosphatidylserine, which restores cognitive function in patients with senile dementia. SB-tPS also increased acetylcholine release and the Na(+), K(+)-ATPase activity of the synaptosomes prepared from these aged rats to the level in young rats. The nootropic actions of SB-tPS in the present study can be partly explained by the changes in these biochemical activities.
Advanced age is accompanied by cognitive decline indicative of central nervous system dysfunction. One possibly critical causal factor is oxidative stress. Accordingly, we studied the effects of dietary antioxidants and age in a canine model of aging that parallels the key features of cognitive decline and neuropathology in humans. Old and young animals were placed on either a standard control food, or a food enriched with a broad spectrum of antioxidants and mitochondrial enzymatic cofactors. After 6 months of treatment, the animals were tested on four increasingly difficult oddity discrimination learning problems. The old animals learned more slowly than the young, making significantly more errors. However, this age-associated decline was reduced in the animals fed the enriched food, particularly on the more difficult tasks. These results indicate that maintenance on foods fortified with complex mixtures of antioxidants can partially counteract the deleterious effects of aging on cognition.
The landmark discrimination learning test can be used to assess the ability to utilize allocentric spatial information to locate targets. The present experiments examined the role of various factors on performance of a landmark discrimination learning task in beagle dogs. Experiments 1 and 2 looked at the effects of age and food composition. Experiments 3 and 4 were aimed at characterizing the cognitive strategies used in performance on this task and in long-term retention. Cognitively equivalent groups of old and young dogs were placed into either a test group maintained on food enriched with a broad-spectrum of antioxidants and mitochondrial cofactors, or a control group maintained on a complete and balanced food formulated for adult dogs. Following a wash-in period, the dogs were tested on a series of problems, in which reward was obtained when the animal responded selectively to the object closest to a thin wooden block, which served as a landmark. In Experiment 1, dogs were first trained to respond to a landmark placed directly on top of coaster, landmark 0 (L0). In the next phase of testing, the landmark was moved at successively greater distances (1, 4 or 10 cm) away from the reward object. Learning varied as a function of age group, food group, and task. The young dogs learned all of the tasks more quickly than the old dogs. The aged dogs on the enriched food learned L0 significantly more rapidly than aged dogs on control food. A higher proportion of dogs on the enriched food learned the task, when the distance was increased to 1cm. Experiment 2 showed that accuracy decreased with increased distance between the reward object and landmark, and this effect was greater in old animals. Experiment 3 showed stability of performance, despite using a novel landmark, and new locations, indicating that dogs learned the landmark concept. Experiment 4 found age impaired long-term retention of the landmark task. These results indicate that allocentric spatial learning is impaired in an age-dependent manner in dogs, and that age also affects performance when the distance between the landmark and target is increased. In addition, these results both support a role of oxidative damage in the development of age-associated cognitive dysfunction and indicate that short-term administration of a food enriched with supplemental antioxidants and mitochondrial cofactors can partially reverse the deleterious effects of aging on cognition.
The effects of long-term treatment with both antioxidants and a program of behavioral enrichment were studied as part of a longitudinal investigation of cognitive aging in beagle dogs. Baseline performance on a battery of cognitive tests was used to assign 48 aged dogs (9-12 years) into four cognitively equivalent groups, of 12 animals per group: Group CC (control food-control environment), group CE (control food-enriched environment); Group AC (antioxidant fortified food-control environment); Group AE (fortified food-enriched environment). We also tested a group of young dogs fed the control food and a second group fed the fortified food. Both groups of young dogs received a program of behavioral enrichment. To evaluate the effects of the interventions on cognition after 1 year, the dogs were tested on a size discrimination learning task and subsequently on a size discrimination reversal learning task. Both tasks showed age-sensitivity, with old dogs performing more poorly than young dogs. Both tasks were also improved by both the fortified food and the behavioral enrichment. However, in both instances the treatment effects largely reflected improved performance in the combined treatment group. These results suggest that the effectiveness of antioxidants in attenuating age-dependent cognitive decline is dependent on behavioral and environmental experience.
Oxidative stress is important in the pathogenesis of Alzheimer's disease (AD). The brain contains high levels of oxidizable lipids that must be protected by antioxidants. Low concentrations of vitamin E, quantitatively the major lipophilic antioxidant in the brain, are frequently observed in cerebrospinal fluid (CSF) of AD patients, suggesting that supplementation with vitamin E might delay the development of AD. In a placebo-controlled trial, vitamin E (2000 IU/day, 2 years) slowed (-53%) functional deterioration in patients with moderate AD (Sano et al., N. Engl. J. Med. 336: 1216-1222, 1997). Recently, use of vitamin E and vitamin C supplements in combination was found to be associated with reduced prevalence (-78%) and incidence (-64%) of AD in elderly population (Zandi et al., Arch. Neurol. 61: 82-88, 2004). These results are consistent with the ability of the supplementation with vitamin E (400 IU/day, 1 month) to increase its levels in CSF (123%) and plasma (145%) of AD patients and, in combination with vitamin C (1000 g/day), to decrease the susceptibility of CSF lipoproteins (up to -32%) to in vitro oxidation (Kontush et al., Free Radic. Biol. Med. 31: 345-354, 2001). In addition, vitamin E reduced lipid peroxidation and amyloid deposition in a transgenic mice model of AD (Sung et al., FASEB J. 18: 323-325, 2004). Computer modeling of the influence of vitamin E on lipoprotein oxidation reveals that the vitamin develops antioxidative activity in CSF lipoproteins in the presence of physiologically relevant, low amounts of oxidants. By contrast, under similar conditions, vitamin E behaves as a pro-oxidant in plasma lipoproteins, consistent with the model of tocopherol-mediated peroxidation (Stocker, Curr. Opin. Lipidol. 5: 422-433, 1994). This distinction is related to major differences in the levels of vitamin E (50 nM vs. 30 microM) and oxidizable lipids (4 microM vs. 2.5 mM) between CSF and plasma, which result in major differences in oxidative conditions (per unit of vitamin E) between CSF and plasma in the presence of similar amounts of oxidants. Altogether, these data suggest that vitamin E may be effective against in vivo oxidation of CSF lipoproteins and brain lipids, and offer new perspectives in the treatment of AD and other neurodegenerative disorders.
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.
Visuospatial learning and memory impairments are an early marker for age-related cognitive decline and Alzheimer's disease. Similar to humans, aged dogs show visuospatial learning and memory deficits (). One hundred and nine beagle dogs ranging between 0.25 and 11.99 years were tested on a visuospatial delayed non-matching to position (DNMP) task to better characterize the progression of visuospatial deficits in the dog. Age predicted 48.2% of the variability in learning the DNMP, with dogs ranging from 1 to 11.99 years generally making more errors with increasing age. By contrast, puppies (<1 year) likely were showing developmental deficits, possibly due to an immature prefrontal cortex. Mild visuospatial deficits were detected by 6 years, which precedes the typical onset of amyloid-beta (Abeta) accumulation in the dog brain by two years, and can serve as an early marker for cognitive decline in the dog. These findings suggest that (1) age-related changes in visuospatial function in the dog models that seen in humans, further validating the dog as a model for human aging and dementia; and (2) other mechanisms, such as oxidative stress, soluble Abeta oligomers or cholinergic deficits, are likely contributing to the early impairment.
Improvement in daytime sleep pattern—mean daily scores (outliers removed) Differences from pre-trail week. Error bars represent 95% confidence intervals using the combined standard error Predicting behavioural changes associated with age-related cognitive impairment in dogs
Fig. 1. Improvement in daytime sleep pattern—mean daily scores (outliers removed). Differences from pre-trail week. Error bars represent 95% confidence intervals using the combined standard error. References Bain, M.J., Hart, B.L., Cliff, K.D., Ruehl, W.W., 2001. Predicting behavioural changes associated with age-related cognitive impairment in dogs. J. Am. Vet. Med. Assoc. 218, 1792–1795.
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