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Abstract

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.

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... Just like in humans, senior dogs can be classified into successful agers, mild cognitive impairment, and severe cognitive impairment called cognitive dysfunction syndrome (CDS) [9,10]. With increased longevity in dogs, higher incidence of CDS has been reported in senior dogs [11][12][13]. Clinical symptoms in dogs with CDS include disorientation, reduced social interaction, increased anxiety, disrupted sleep/wake cycle, change in activity, and loss of house training [13][14][15][16]. Since the aging-induced neurodegenerative process is gradual and irreversible, more efforts should be made to develop solutions that are able to slow down brain aging and brain atrophy [17,18] and an optimal nutritional solution should be able to both enhance cognitive function and reduce the irreversible brain atrophy. ...
... Another study reported that changes in social interaction (37.7%) and loss of house training (37.7%) were the most common signs, followed by disrupted sleep/wake cycle (20.2%) and disorientation (16.4%) in dogs with CDS [11]. CDS adversely affects the quality of life of both dogs and their owners. ...
... Gender appears to be a significant risk factor for AD in people and the incidence of AD in females is almost twice of that in male subjects [70]. Similarly, the incidence of CDS in female dogs was more than twice that in male dogs [11]. Menopause is associated with increased risk of AD in people [71,72]. ...
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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.
... Cognitive dysfunction syndrome (CDS) is a major condition affecting senior dogs (1,2) that has parallels to human dementia. Both CDS in dogs and Alzheimer's disease (AD) in humans share similar neuropathological changes including severe cortical atrophy, cerebral amyloid angiopathy and ventricular enlargement (3)(4)(5). ...
... 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). ...
... This is in comparison to the control diet in which disorientation and social interactions did not improve significantly. As pet owners are particularly sensitive to changes in social interactions, it is perhaps not surprising that they are the most frequently reported signs in mild cognitive decline and amongst the most commonly reported signs (1,27). Additionally, signs of disorientation are indicative of more advanced stages of dementia and amongst the most common signs in severe CDS (1,27,28,36). ...
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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.
... Canine cognitive dysfunction (CCD) or 'canine dementia' is a recognised neurobehavioural syndrome in aged dogs, characterized by deficits in learning, memory and spatial awareness, as well as changes to social interactions and sleeping patterns [29]. CCD is common in aged dogs [30][31][32], but underdiagnosed [33] with a large community-based sample estimating it affects~12% of dogs greater than 10 years and doubling in prevalence every 2 years thereafter [34]. In addition, anxiety has been observed in around half of CCD cases, as also seen in Alzheimer's disease in humans [35]. ...
... The current study identified age as a major predictor of CCD risk, as has been reported in previous studies [31][32][33]. In control dogs, CCD prevalence was observed to increase with age, as has been previously documented, with peak prevalence observed in dogs aged >14 years old in both this study and a previous cross-sectional study [33]. ...
... Lighter dogs were found to be at an increased risk of CCD in this study, when accounting for age. In a previous study, small dogs (<15kg) had a significantly greater prevalence of CCD than medium-large dogs (>15kg) [32]. In contrast, two previous studies did not find an effect of size on CCD risk, when measured by height at the withers [33] and body weight [31]. ...
Article
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Globally, epilepsy is a common serious brain disorder. In addition to seizure activity, epilepsy is associated with cognitive impairments including static cognitive impairments present at onset, progressive seizure-induced impairments and co-morbid dementia. Epilepsy occurs naturally in domestic dogs but its impact on canine cognition has yet to be studied, despite canine cognitive dysfunction (CCD) recognised as a spontaneous model of dementia. Here we use data from a psychometrically validated tool, the canine cognitive dysfunction rating (CCDR) scale, to compare cognitive dysfunction in dogs diagnosed with idiopathic epilepsy (IE) with controls while accounting for age. An online cross-sectional study resulted in a sample of 4051 dogs, of which n = 286 had been diagnosed with IE. Four factors were significantly associated with a diagnosis of CCD (above the diagnostic cut-off of CCDR ≥50): (i) epilepsy diagnosis: dogs with epilepsy were at higher risk; (ii) age: older dogs were at higher risk; (iii) weight: lighter dogs (kg) were at higher risk; (iv) training history: dogs with more exposure to training activities were at lower risk. Impairments in memory were most common in dogs with IE, but progression of impairments was not observed compared to controls. A significant interaction between epilepsy and age was identified, with IE dogs exhibiting a higher risk of CCD at a young age, while control dogs followed the expected pattern of low-risk throughout middle age, with risk increasing exponentially in geriatric years. Within the IE sub-population, dogs with a history of cluster seizures and high seizure frequency had higher CCDR scores. The age of onset, nature and progression of cognitive impairment in the current IE dogs appear divergent from those classically seen in CCD. Longitudinal monitoring of cognitive function from seizure onset is required to further characterise these impairments.
... This assumption may be more true of animals in some age classes than others, as surveys of pain in aged human populations suggest >70% of elderly humans experience some form of physical pain regularly [23,24]. Necropsies of aged domestic pets as well as zoo animals indicate high prevalence of conditions at time of death likely to cause pain [2,[25][26][27]. Thus, animals in different age classes may require different care or opportunities to support positive welfare, with aged animals potentially being at greater risk for negative welfare experiences such as pain or distress. ...
... Many characteristics of animals' circadian rhythms change as they age, and changes to various sleep characteristics have been noted in elderly humans and animals [125]. Aged animals may spend more time awake during their typical sleep period (e.g., diurnal animals awake at night or nocturnal animals awake during the day) or engage in shorter bouts of sleep at varied times throughout the day [2,26,35,125]. As restful sleep is important to physical and psychological well-being, providing flexibility in daily schedules for older animals is important [126]. ...
... It is also possible that social interactions can become more important to animals as they age because social interactions can be a significant source of comfort for some species [129][130][131]. Ageing animals may also commonly become less interested in joining in with a group [26,45]. Similar changes are possible related to an animal's interest in interacting with caretakers-the animal may become less interested or more interested in interacting with caretakers as it ages [32,35,44]. ...
Article
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Simple Summary Many animals experience physical and behavioral changes as they age. Age-related changes in physical or mental ability can limit the opportunities for animals to experience positive well-being. As animals in zoos are living longer than ever, understanding common physical, cognitive, and behavioral changes associated with ageing across species can help inform management practices. This review aggregates information about common age-related changes across a wide number of species, discusses the potential welfare impacts of these changes for ageing animals, and suggests methods for caretakers to maximize positive welfare opportunities for ageing animals under human care. Abstract Improvements in veterinary care, nutrition, and husbandry of animals living in zoos have led to an increase in the longevity of these animals over the past 30 years. In this same time period, the focus of animal welfare science has shifted from concerns over mitigating negative welfare impacts to promoting positive welfare experiences for animals. For instance, providing opportunities for animals to exert agency, solve problems, or acquire rewards are all associated with positive welfare outcomes. Many common age-related changes result in limitations to opportunities for positive welfare experiences, either due to pain or other physical, cognitive, or behavioral limitations. This review aggregates information regarding common age-related physical and behavioral changes across species, discusses how age-related changes may limit positive welfare opportunities of aged animals in human care, and suggests potential management methods to help promote positive welfare for animals at all life stages in zoos and aquariums.
... Cognitive dysfunction syndrome (CDS) is a major condition affecting senior dogs (1,2) that has parallels to human dementia. Both CDS in dogs and Alzheimer's disease (AD) in humans share similar neuropathological changes including severe cortical atrophy, cerebral amyloid angiopathy and ventricular enlargement (3)(4)(5). ...
... 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). ...
... This is in comparison to the control diet in which disorientation and social interactions did not improve significantly. As pet owners are particularly sensitive to changes in social interactions, it is perhaps not surprising that they are the most frequently reported signs in mild cognitive decline and amongst the most commonly reported signs (1,27). Additionally, signs of disorientation are indicative of more advanced stages of dementia and amongst the most common signs in severe CDS (1,27,28,36). ...
Chapter
These proceedings contain oral and poster presentations from various experts on animal behaviour and animal welfare in veterinary medicine presented at the conference.
... There was no significant difference in mean age between groups (control group mean 11.63 years ± 2.36 and CS group mean 11.73 years ± 2.29; P = 0.27); in sex (both groups with 79% females and 21% males; P = 1.00), and in reproductive status (both groups with 89.5% neutered and 10.5% unneutered animals; P = 1.00). This matching procedure was important because dogs, just like most mammals, have aging-related neuropathologic disorders, which hinder cognitive function, making age a risk factor for diseases that coexist with cognitive and behavioral dysfunctions such as Alzheimer's disease (AD) in humans and its equivalent in dogs -CD ( Azkona et al., 2009 ;Landsberg et al., 2012 ). Apart from age, Azkona et al. (2009) reported that being female, similarly to what has been observed for AD in women, and neutering, are risk factors for the development of cognitive disorders, demonstrating in their study a higher incidence of cognitive dysfunction in bitches. ...
... This matching procedure was important because dogs, just like most mammals, have aging-related neuropathologic disorders, which hinder cognitive function, making age a risk factor for diseases that coexist with cognitive and behavioral dysfunctions such as Alzheimer's disease (AD) in humans and its equivalent in dogs -CD ( Azkona et al., 2009 ;Landsberg et al., 2012 ). Apart from age, Azkona et al. (2009) reported that being female, similarly to what has been observed for AD in women, and neutering, are risk factors for the development of cognitive disorders, demonstrating in their study a higher incidence of cognitive dysfunction in bitches. Interestingly, neutered dogs had a twice as high risk to develop CD compared to the unneutered ones. ...
... A higher score for cognitive impairment in dogs with hypercortisolism corroborates the finding in humans, since NOCS affects mainly spayed female ( Pöppl et al., 2016 ;Carotenuto et al., 2019 ). Hence, the population at risk for developing CS is similar to the population at greater risk for developing CD, as pointed out by Azkona et al. (2009) . ...
Article
Hypercortisolism has been associated with impairment of cognitive function in humans with Cushing's syndrome (CS), but there are currently no studies looking into this effect in dogs with CS. The present study evaluated the pattern of cognitive deficits and behavioral changes in dogs with naturally-occurring CS (NOCS). A previously published questionnaire (DISHA - disorientation, changes in interactive behavior, sleep-wake cycle disturbances, house-soiling, and changes in activity) was used to assess cognitive dysfunction (CD) in dogs with recently diagnosed CS, and in age-, sex-, and gonadal status-matched dogs (1:2), according to their owners’ perception. The questionnaire consisted of 32 multiple-choice questions, scored 0 to 96. The higher the score, the higher the severity of CD. The questionnaire included eight categories of behavioral signs, namely: disorientation, social interactions, sleep-wake cycles, house-soiling, compulsive behaviors, depressive behaviors, anxiety, and memory and learning. Of the 57 dogs assessed in the study, 19 were included in the CS group and 38 in the control group. Exclusion criteria for the control group were animals suspected of having CS, chronic glucocorticoid therapy, or glucocorticoid exposure in the past month. Dogs with CS exhibited a higher final score (Wilcoxon test) of cognitive dysfunction (W = 149, p = 0.001), especially, higher memory dysfunction (W = 96, p = 0.01), compulsive behaviors (W = 93, p = 0.04), depressive behaviors (W = 86, p = 0.03), and anxiety (W = 117, p=0.001). There was no correlation between age and CD score in dogs with NOCS (r = 0.32, p = 0.465) and neither control dogs (r = 0.18, p = 0.051). Results suggest hypercortisolism may accelerate neurodegenerative process, thus resulting in more intense behavioral and cognitive changes than those observed in age-matched dogs without CS.
... (46). An interview study of owners of dogs aged older than 9 years classified dogs into three unlabeled age groups (9-11, 12-14, and 15-17 years) and found that each group showed a greater incidence of cognitive impairment than the previous (47). However, there were no dogs with "severe" cognitive impairments in the 9-11 age group compared with 3.3% aged 12-14 years classified as "severe" and 14.3% of the 15-17-yearold population. ...
... In accepting that dogs should be considered "Mature adults" when aged between 2 and 6 years, it is suggested here that dogs aged 7-11 years could be considered "Senior, " whereas dogs aged 12+ years be considered "Geriatric" based upon the greater incidence of cognitive impairments in dogs of that age (13,40,46,47) and the greater likelihood of death past the age of 12 years (3,48). For studies of senior dogs where finer detail is desired, the senior period between 7 and 11 years of age could be split into Early-senior (7-9 years) and Late-senior (10-11 years), as significant differences have been found between dogs in these age groups (7,43,46). ...
... In a group of Japanese dogs of various breeds, the physical signs of canine cognitive dysfunction, a behavioral syndrome affecting old dogs, increased steadily from the age of 10 years, whereas confirmed diagnoses of canine cognitive dysfunction increase sharply from 15 years of age (8). Severe cognitive impairments have also been found more commonly in dogs aged 15-17 years, with 47.6% of dogs in this age group showing some signs of cognitive impairment (47). ...
Article
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Behavioral development is a lifelong process where cognitive traits such as learning and memory may be expected to take quadratic or linear trajectories. It is common practice for operational purposes to reduce study subjects into chronological categories when conducting research. However, there are no agreed-upon thresholds for this practice, and the lack of standardization may hinder comparison between studies of normative and pathological aging. In this perspective review, chronological categories have been identified that can be considered to represent normative cognitive and neurological aging in domestic family dogs. These categories work to capture age-related developmental trajectories for the majority of dog breeds. It is encouraged that researchers studying cognition and behavior, pathological cognitive deficits, or welfare of dogs across age categories utilize the categories presented here to best enable comparison between studies. The proposed groups could also support education programs informing owners of what behavioral changes to expect in their dog as they age, but they cannot be used to reflect health-based needs associated with breed-specific morbidity. The use of the age categories proposed here highlights significant welfare issues for breeds with the shortest average lifespans (e.g., the Great Dane). Studies show no evidence of an increased rate of behavioral or cognitive aging in short-lived breeds, and the shortest-lived breeds are most likely to die when classified by the proposed categories as Mature Adults. Adoption of these chronological categories in future research would aid comparison between studies and identification of non-normative age-related pathologies.
... The diagnosis of CCD is a diagnosis of elimination. The illness exacerbating symptoms, commonly also observed in CCD, must be excluded, such as brain tumors, hypertension, other neurological conditions, metabolic and hormonal imbalances, etc. Screening and diagnosis of CCD is primarily based on observation of clinical signs which are summarized by the acronym DISHAA [Disorientation, altered social Interactions, altered Sleep-wake cycles, House soiling and loss of other learned behaviors, altered Activity levels and increasing Anxiety (Ruehl et al., 1995;Neilson et al., 2001;Azkona et al., 2009;Rosado et al., 2012;Fast et al., 2013b;Madari et al., 2015)]. Sleeping during the day and restless at night, decreased interaction, disorientation at home and anxiety are common symptoms (Fast et al., 2013b). ...
... To facilitate the detection of CCD, veterinarians can use a screening questionnaire that includes a list of possible signs. Several questionnaires are available and based on the scores the stage of dog's cognitive decline can be identified (Colle et al., 2000;Neilson et al., 2001;Osella et al., 2007;Azkona et al., 2009;Golini et al., 2009;Salvin et al., 2011;Landsberg et al., 2012;Rosado et al., 2012;Fast et al., 2013b;Madari et al., 2015). Madari et al. (2015) have proposed criteria for discrimination of three stages of the disease, these are mild cognitive impairment, moderate cognitive impairment, and severe cognitive impairment. ...
Article
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Neurodegenerative diseases present a major and increasing burden in the societies worldwide. With aging populations, the prevalence of neurodegenerative diseases is increasing, yet there are no effective cures and very few treatment options are available. Alzheimer's disease is one of the most prevalent neurodegenerative conditions and although the pathology is well studied, the pathogenesis of this debilitating illness is still poorly understood. This is, among other reasons, also due to the lack of good animal models as laboratory rodents do not develop spontaneous neurodegenerative diseases and human Alzheimer's disease is only partially mimicked by transgenic rodent models. On the other hand, older dogs commonly develop canine cognitive dysfunction, a disease that is similar to Alzheimer's disease in many aspects. Dogs show cognitive deficits that could be paralleled to human symptoms such as disorientation, memory loss, changes in behavior, and in their brains, beta amyloid plaques are commonly detected both in extracellular space as senile plaques and around the blood vessels. Dogs could be therefore potentially a very good model for studying pathological process and novel treatment options for Alzheimer's disease. In the present article, we will review the current knowledge about the pathogenesis of canine cognitive dysfunction, its similarities and dissimilarities with Alzheimer's disease, and developments of novel treatments for these two diseases with a focus on canine cognitive dysfunction.
... Canine Cognitive Dysfunction Syndrome (CCDS) is a syndrome of progressive deterioration in cognition associated with amyloid deposition and cortical atrophy and it is considered the canine analog to Alzheimer's Disease in humans (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The symptoms associated with CCDS fall into the following domains: disorientation, social interaction changes, sleep/wake cycle alterations, house soiling, activity changes, anxiety, and deficits in learning and memory (4,5,(8)(9)(10)15). ...
... One study estimated a prevalence of 14.2-22.5% in animals 8 years and older (4), while another reported that 23% of dogs 11-12 years old and 68% of dogs 15-16 years old had at least 1 sign consistent with CCDS (15). Several studies have reported a dramatic increase in prevalence associated with increased age of dogs (7,10,15). However, while there are numerous studies documenting owner reported signs, studies aimed at quantifying behavioral and cognitive changes using specific validated testing are currently lacking (12,16,17). ...
Article
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Canine Cognitive Dysfunction Syndrome (CCDS) is a syndrome of progressive cognitive decline comparable to Alzheimer's Disease. The sustained gaze test captures attention loss associated with CCDS in laboratory settings, and adapting the sustained gaze test for use by owners at home could greatly increase the data generated on CCDS. We hypothesized that it would be feasible for owners to perform the sustained gaze test at home, and that results would be reliable over repeated trials. Training materials were developed and dog owners underwent training and performed the test in triplicate at weekly intervals for 3 weeks. Gaze videos and a CAnine DEmentia Scale (CADES) questionnaire were submitted each week. Videos were examined for inclusion and duration of gaze was recorded. One observer repeated video assessments twice, 1 week apart; five different observers assessed videos once. Outcome measures included the relationship between CADES and gaze duration, test-retest reliability of owner-performed sustained gaze testing, and intra- and inter-rater reliability. Twenty dogs aged 7–15.5 years completed testing. The majority of videos were acceptable (162/183). Within dog test-retest reliability was excellent (ICC = 0.96). Intra- and interobserver reliability for determining video validity for inclusion were substantial ( k = 0.76 and 0.78, respectively); for duration of gaze these were excellent (ICC = 0.99 and 0.96, respectively). Gaze duration was significantly associated with CADES ( p = 0.0026). We conclude that owners can perform the sustained gaze test at home and that data generated are reliable and correlate to CADES, a validated measure of dementia.
... To compare specific brain MRI anatomic measurements between three groups of 33 geriatric (> 8yrs) dogs: 1) neurologically impaired dogs with presumptive spontaneous brain 34 microhemorrhages and no clinical evidence of canine cognitive dysfunction 2) dogs with canine 35 cognitive dysfunction 3) dogs without clinical evidence of cognitive impairment or abnormalities 36 on neurologic examination (control dogs). MR images from 46 geriatric dogs were reviewed and 37 measurements were obtained of interthalamic adhesion height (thickness) and mid-sagittal 38 interthalamic adhesion area for all dogs, in addition to total brain volume. ...
... This 289 phenomenon has been documented with canine cognitive dysfunction. [20][21][22][23]35,36 In one study of 290 putative microhemorrhages in dogs 17 , affected dogs were significantly older than unaffected 291 dogs, but an increasing tendency for brain microhemorrhages to occur with aging has not yet 292 been established in this species. Another possibility is that a lower age limit of 8 years is too low 293 for a definition of "geriatric" in dogs. ...
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The objective of this study was to compare specific brain MRI anatomic measurements between three groups of geriatric ( > 8yrs) dogs: 1) neurologically impaired dogs with presumptive spontaneous brain microhemorrhages and no clinical evidence of canine cognitive dysfunction 2) dogs with canine cognitive dysfunction 3) dogs without clinical evidence of cognitive impairment or abnormalities on neurologic examination (control dogs). MR images from 46 geriatric dogs were reviewed and measurements were obtained of interthalamic adhesion height (thickness) and mid-sagittal interthalamic adhesion area for all dogs, in addition to total brain volume. Interthalamic adhesion measurements, either absolute or normalized to total brain volume were compared between groups. Signalment (age, breed, sex), body weight, presence and number of SBMs, as well as other abnormal MRI findings were recorded for all dogs. All interthalamic adhesion measurement parameters were significantly (p<0.05) different between control dogs and affected dogs. Both dogs with cognitive dysfunction (12/13; 92 %) and dogs with isolated brain microhemorrhages had more microhemorrhages than control dogs (3/19; 16%). Affected dogs without cognitive dysfunction had more microhemorrhages than dogs with cognitive dysfunction. In addition to signs of cognitive impairment for the CCD group, main clinical complaints for SBM and CCD dogs were referable to central vestibular dysfunction, recent-onset seizure activity, or both. Geriatric dogs with spontaneous brain microhemorrhages without cognitive dysfunction have similar MRI abnormalities as dogs with cognitive dysfunction but may represent a distinct diseasecategory.
... Alzheimer's, biomarkers, canine, cerebrospinal fluid, dementia, diagnostic tool, ELISA, plasma fragments 1 | INTRODUCTION Geriatric veterinary medicine is becoming increasingly important as a form of medical care for companion animals, which has led to the prolongation of their life expectancy. 1 Canine cognitive dysfunction syndrome (CDS) is a highly prevalent condition that affects 14% to 60% of aged dogs; however, less than 2% are actually diagnosed. [1][2][3][4][5][6] Canine cognitive dysfunction syndrome is a progressive neurodegenerative syndrome that affects dogs older than 8 years with representing signs associated with the gradual and progressive loss of cognitive functions. Disorientation, changes in sleepwake cycles, social interaction disturbances, loss of house training and other learned behaviors, activity variations, and increased anxiety are the main indicators of the disease in dogs. ...
Article
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Background Cognitive dysfunction syndrome (CDS) is a common progressive neurodegenerative disease that is poorly defined. Specific multitargeted protocols do not exist for setting the diagnosis and the prognosis of the syndrome. Hypothesis/Objectives To quantify Aβ42 and Aβ40 peptides in blood and cerebrospinal fluid (CSF) and to investigate their contribution to CCDS. Animals A total of 61 dogs from a hospital population. Methods Case‐control study. Six young (YG: 0‐4 years old), 8 middle‐aged (4‐8 years old), 17 cognitively unimpaired and aged (CU: 8‐20 years old), and 30 cognitively impaired and aged (CI: 8‐17 years). From the CI group, 10 dogs exhibited mild impairment (CI‐MCI) and 20 exhibited severe impairment (CI‐SCI). Cognitive status was assessed using a validated owner‐based questionnaire. Direct and indirect Aβ markers were determined in plasma fractions (total‐TP, free‐FP, bound to plasma components‐CP) and CSF using commercial ELISA assays (AΒtest, Araclon Biotech). Results TPAβ42/40 facilitated discrimination between CI‐MCI and CU aged dogs with area under curve ≥ 0.79. CSFAβ42 levels were higher (P = .09) in CU (1.25 ± 0.28 ng/mL) than in MCI (1.04 ± 0.32 ng/mL) dogs. CSF Aβ42 levels were correlated with the CP fragment (CPAβ40: P = .02, CPAβ42: P = .02). CPAβ42 was higher in the CI‐MCI (23.03 ± 11.79 pg/μL) group compared to the other aged dogs (CU: 10.42 ± 7.18 pg/μL, P = .02, SCI: 11.40 ± 12.98 pg/μL, P = .26). Conclusion and Clinical Importance The Aβ should be determined in all of the 3 plasma fractions (TP, FP, CP). In the clinical approach, TPAβ42/40 could be used as an efficient preselection tool for the aged canine population targeting dogs with mild cognitive impairment.
... One possibility is that both brain disorders investigated in this report are more likely to occur with increasing age. This phenomenon has been documented with CCD (Landsberg, Nichol & Araujo, 2012;Dewey et al., 2019;Dewey, 2016;Schutt, Toft & Berendt, 2015;Salvin et al., 2010;Azkona et al., 2009). In one study of putative microhemorrhages in dogs (Kerwin et al., 2017), affected dogs were significantly older than unaffected dogs, but an increasing tendency for brain microhemorrhages to occur with aging has not yet been established in this species. ...
Article
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Objective Spontaneous brain microhemorrhages in elderly people are present to some degree in Alzheimer’s disease patients but have been linked to brain atrophy in the absence of obvious cognitive decline. Brain microhemorrhages have recently been described in older dogs, but it is unclear whether these are associated with brain atrophy. Diminution of interthalamic adhesion size-as measured on MRI or CT-has been shown to be a reliable indicator of brain atrophy in dogs with canine cognitive dysfunction (CCD) in comparison with successfully aging dogs. We hypothesized that aging dogs with brain microhemorrhages presenting for neurologic dysfunction but without obvious features of cognitive decline would have small interthalamic adhesion measurements, like dogs with CCD, compared with control dogs. The objective of this study was to compare interthalamic adhesion size between three groups of aging (>9 years) dogs: (1) neurologically impaired dogs with presumptive spontaneous brain microhemorrhages and no clinical evidence of cognitive dysfunction (2) dogs with CCD (3) dogs without clinical evidence of encephalopathy on neurologic examination (control dogs). MR images from 52 aging dogs were reviewed and measurements were obtained of interthalamic adhesion height (thickness) and mid-sagittal interthalamic adhesion area for all dogs, in addition to total brain volume. Interthalamic adhesion measurements, either absolute or normalized to total brain volume were compared between groups. Signalment (age, breed, sex), body weight, presence and number of SBMs, as well as other abnormal MRI findings were recorded for all dogs. Results All interthalamic adhesion measurement parameters were significantly ( P < 0.05) different between control dogs and affected dogs. Both dogs with cognitive dysfunction (12/15; 80%) and dogs with isolated brain microhemorrhages had more microhemorrhages than control dogs (3/25; 12%). Affected dogs without cognitive dysfunction had significantly more microhemorrhages than dogs with cognitive dysfunction. In addition to signs of cognitive impairment for the CCD group, main clinical complaints for SBM and CCD dogs were referable to central vestibular dysfunction, recent-onset seizure activity, or both. Geriatric dogs with spontaneous brain microhemorrhages without cognitive dysfunction have similar MRI abnormalities as dogs with cognitive dysfunction but may represent a distinct disease category.
... The exact pathogenesis remains undetermined but is believed to be due to the neurotoxic effects of beta-amyloid protein accumulation in the brain. The prevalence of CCD in dogs over the age of 8 ranges from 14 to 60% (25)(26)(27)(28). Dogs naturally accumulate amyloid-β peptide in their brains, with an identical amino acid sequence to humans and similar amounts of deposition associated with cognitive impairment (29)(30)(31)(32)(33). ...
Article
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Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the pathophysiology of the human conditions they are designed to mimic. Naturally occurring large animal models have predominantly been found in companion animals or livestock because of their emotional or economic value to modern society and, unlike mice, often recapitulate the human disease state. In particular, numerous models have been discovered in dogs and have a fundamental role in bridging proof of concept studies in mice to human clinical trials. The present article is a review that highlights current canine models of human diseases, including Alzheimer's disease, degenerative myelopathy, neuronal ceroid lipofuscinosis, globoid cell leukodystrophy, Duchenne muscular dystrophy, mucopolysaccharidosis, and fucosidosis. The goal of the review is to discuss canine and human neurodegenerative pathophysiologic similarities, introduce the animal models, and shed light on the ability of canine models to facilitate current and future treatment trials.
... Some literature exists on the impact of gonadectomy on cognitive function in dogs, most notably regarding Canine Cognitive Dysfunction (CCD), which is a behavioral syndrome affecting older dogs that shares many pathophysiological and behavioral hallmarks with human Alzheimer's Disease (AD), including progressive cognitive impairment, loss of normal sleep patterns, increased anxiety, and aimless wandering as well as Amyloid-beta and possibly tau pathology in the brain [230][231][232]. In this context, female and gonadectomized dogs have been shown to be significantly more likely to show signs of CCD than intact and male dogs in a study of n = 325 geriatric dogs aged nine or older [233]. CCD has also been shown to progress more rapidly in gonadectomized male dogs that already have signs of mild cognitive impairment compared to intact males with mild cognitive impairment during a 12-18 month follow-up period [234]. ...
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Simple Summary: Desexing is a general term for interventions suppressing fertility in dogs, most commonly by surgically removing the testes or ovaries ("gonadectomy"). Desexing is promoted for population control, health benefits, and behavior modification. Surprisingly, the existing evidence shows no effect of desexing on population size in companion or shelter dogs; however, an effect has been shown for desexing female free-roaming dogs. Desexing has consistently been shown to change various health risks, including a reduction in pyometra and mammary tumor risk, as well as an increased risk of cranial cruciate ligament rupture, several forms of cancer, and obesity in both sexes. Other health effects vary considerably between breeds and sexes. A lifespan advantage in desexed dogs has consistently been shown in females, while the evidence is inconsistent in males, and the effect is smaller in studies that found one. There is more literature on behavioral effects in males than in females, and the evidence suggests reduced libido, roaming, conspecific mounting, and urinary marking in a large percentage of gonadectomized males, and reduced male dog aggression in a majority of males gonadectomized because of behavioral problems. The decision whether to desex dogs needs to be individualized based on the available evidence. Abstract: Background: Desexing dogs is promoted for population control, preventative healthcare, and behavior modification. Common methods are orchiectomy and ovariectomy/ovariohysterectomy. GnRH superagonist implants are available in some areas. Alternative methods like vasectomy and salpingectomy/hysterectomy are uncommon. The terminology used to describe desexing is inconsistent and contradictory, showing a need for the adaption of standardized terminology. Population Control: Surprisingly, empirical studies show no effects of desexing on population control in companion and shelter dogs despite desexing being consistently recommended in the literature. There is evidence for a population control effect in free-roaming dogs, where desexing also has benefits on zoonotic disease and bite risk. Population control in free-roaming dogs is mostly correlated with female, not male desexing. Health and Lifespan: Desexing affects numerous disease risks, but studies commonly neglect age at diagnosis and overall lifespan, age being by far the most important risk factor for most diseases. We argue that lifespan is a more important outcome than ultimate cause of death. A beneficial effect of desexing on lifespan is consistently demonstrated in females, while evidence for a beneficial effect in males is inconsistent. Studies are likely biased in desexing being a proxy for better care and desexed dogs having already lived to the age of desexing. Desexing reduces or eliminates common life-limiting diseases of the female reproductive system such as pyometra and mammary tumors, while no analogous effect exists in males. Disease risks increases across sexes and breeds include cruciate ligament rupture, various cancers, and obesity. Urinary incontinence risk is increased in females only. Various other disease risk changes show considerable variability between breeds and sexes. Behavioral Effects: Desexed males show reduced libido, roaming, conspecific mounting, and urinary marking frequency, as well as reduced male dog-directed aggression in a majority of males desexed for behavioral reasons. There is a detrimental effect on the risk and progression of age-related cognitive dysfunction. Desexed dogs may be less likely to cause bite injuries across sexes. The evidence for other effects such as human-directed aggression, human or object mounting, resource Animals 2019, 9, 1086 2 of 28 guarding, or shyness and anxiety is inconsistent and contradictory. There are few studies specific to females or individual breeds. Conclusions: The evidence for a beneficial effect of desexing is stronger in female than in male dogs; however, there is significant variation between breeds and sexes, and more research is needed to further elucidate these differences and to arrive at individualized evidence-based recommendations for clinical practice.
... 11 The prevalence of cognitive dysfunction syndrome was reported to be 22.5% in dogs older than 9 years and 68% in 15−16 years old dogs. 12,13 The incidence of brain tumours in adult dogs has been reported to be 2.8%-4.5%, with gliomas representing 36%-70% of primary brain tumours in dogs. ...
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Background: Detailed analysis of archived brain tissue is fundamental to advancing the understanding of neurological disease. The development of the UK Brain Bank Network (UBBN) has provided an invaluable resource to facilitate such research in the human medical field. Similar resources are needed in veterinary medicine. However, collection and archiving of companion animal brain tissue is a potentially sensitive area for pet owners and veterinary professionals. Methods: Using an online survey, we aimed to study pet owners' perceptions of brain banking. The survey included information on respondents, their views on organ donation, the UBBN and the Royal Veterinary College's Companion Animal Brain Bank (RVC CABB). Results: In total 185 respondents were included. The use of brain tissue from pets for research was supported by 87% of respondents, and 66% of respondents felt that they were highly likely or likely to donate their pet's brain tissue to a CABB. Furthermore, 94% felt that more information on tissue banking in companion animals should be readily available. Conclusions: We found that the perceptions of companion animal brain banking were positive in our respondents. Open dialogue and clear information provision on the process and benefits of the CABB could enhance awareness and thus facilitate brain donation for translational research.
... The most prevailing signs in dogs affected by CCD have been described by the acronym DISHAA (Disorientation, Interactions with people or other pets, Sleep-wake cycles, House soiling and loss of other learned behaviours, Activity levels (increased or decreased), and Anxiety [1,[8][9][10][11][12][13]. Changes may also be seen with self-hygiene (i.e., increased or reduced), appetite or drinking behaviours, and response to stimuli (i.e., exaggerated or reduced) [14]. ...
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The objective of this research was to investigate the efficacy of DìSeniorTM, a nutraceutical formulated to improve cognitive functions in elderly dogs. To this purpose, some clinical and metabolic investigations and a spatial navigation test were performed in treated and untreated dogs. Moreover, the nutraceutical was also tested on primary hippocampal neuron cultures. Results showed no adverse effects on the dogs’ health and a positive effect on learning. In vitro effects on neuron cultures showed an increase in the level of cFOS in treated neurons compared with the vehicle, suggesting that DiSeniorTM has also a positive effect on neuronal functions. Overall, this study suggests that DiSeniorTM can exert a beneficial effect on aged dogs by preventing the negative effects of aging on cognition. Further studies are needed to assess the mechanisms by which it acts on neurons and the specific effect of the different components alone or combined.
... Furthermore, older dogs that exhibit changes in mental status may suffer from the canine equivalent of Alzheimer's disease, which is called canine cognitive dysfunction. Cognitive dysfunction is prevalent among 14.2-22.5% of all geriatric dogs (36,37). The condition is characterized by altered sleep cycles, decreased social interactions, disorientation, anxiety, and house soiling. ...
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Assistance animals play significant roles in human therapy and well-being and represent a rapidly growing demographic of animals in society. Most research in the field of assistance animals has been focused on the effect of these animals on people. Only recently has there been a growing interest in the welfare and well-being of these animals and the effect of the work on the animals themselves. The concept of retirement, or withdrawing the animal from its working life, is an important welfare consideration that has received minimal discussion in the scientific literature. The notion of retirement is typically regarded as a reward earned after a lifetime of work, but this inevitable phase of an animal's working life has positive and negative implications for both animal and handler. Some of these implications include recognizing the emotional impact of this life-altering event on both animal and handler. The decisions of when and how to appropriately retire an animal are typically made at the discretion of the assistance animal agencies and handlers, but standard evidence-based guidelines for the proper retirement of assistance animals are currently unavailable. This review will provide considerations and recommendations for the retirement that assistance animals deserve.
... Such assessments may help to clarify the relationships between age-related cognitive deficits, behavioral changes, and neurological changes in pet dogs. Used in combination with physiological tests and questionnaires, cognitive assessments may also aid in the diagnosis of CDS (Wallis et al. 2016), thereby facilitating veterinary care for millions of pet dogs (for prevalence estimates, see Azkona et al. 2009;Salvin 2010). Moreover, physicians use a number of tools to diagnose AD including behavioral questionnaires, psychometric assessments, physiological assays, and neurological imaging. ...
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Assessments for spatial working memory (SWM) in pet dogs that can detect age-related cognitive deficits in a single session may aid in diagnosing canine dementia and may facilitate translational research on Alzheimer’s disease in humans. Adaptive testing procedures are widely used in single-session assessments for humans with diverse cognitive abilities. In this study, we designed and deployed two up-down staircase assessments for SWM in which 26 pet dogs were required to recall the location of a treat hidden behind one of two identical boxes following delays of variable length. In the first experiment, performance tended to decline with age but few dogs completed the test (n = 10). However, all of the dogs that participated in the second experiment (n = 24) completed the assessment and provided reliable evidence of learning and retaining the task. Delay length and age significantly predicted performance supporting the validity of this assessment. The relationships between age and performance were described by inverted U-shaped functions as both old and young dogs displayed deficits in weighted cumulative-scores and trial-by-trial performance. Thus, SWM in pet dogs may develop until midlife and decline thereafter. Exploratory analyses of non-mnemonic fixation strategies, sustained engagement, inhibitory control, and potential improvements for future SWM assessments which adopt this paradigm are also discussed.
... In dogs, however, deficits in spatial flexibility are found at an older age than that spanned by our sample (i.e. > 8 years of age, Mongillo et al., 2013), and the risk of cognitive impairment is greater in female than in male dogs ( Azkona et al., 2009). Based on these studies, and on the age of our subjects, we can exclude that the lower flexibility observed in our males represents a symptom of cognitive impairment. ...
Article
In this study we assessed the effect of sex and gonadectomy on the type of spatial strategy (allocentric or egocentric) preferentially used by dogs in the acquisition of a navigation task and their ability to resort to the non-preferred strategy. Fifty-six dogs were involved in the study, divided in four equally sized groups based on sex and gonadectomy. Dogs initially underwent a learning phase, where they entered a plus-shaped maze from one arm and had to learn the position of a food bowl, which was placed in one of the lateral arms. The task could be achieved by relying on an either egocentric (i.e. learning to turn left or right) or allocentric strategy (i.e. using the external cues provided within the maze as a reference the position of the baited bowl). Following training, dogs were let in the maze from the entrance opposite to the one used in the learning phase, so that use of an egocentric strategy would lead them to search for food in one arm, while using an allocentric strategy would lead them into the opposite arm. Dogs’ choices were used to determine their preferred strategy. In the last training phase, we assessed dogs’ ability to resort to their non-preferred strategy to find the baited food bowl, by removing external cues and placing the baited bowl always at the same side of the dog, for subjects deemed as allocentric, and by keeping external cues and placing the baited bowl in a constant location relative to the cues, for dogs deemed as egocentric. No effect of sex was found on strategy preference, but ovariectomized females were significantly more likely to prefer an egocentric strategy, implying a role of ovarian hormones in biasing navigation strategies. The probability of resorting to the non-preferred strategy increased with aging in females and decreased in males. The higher requirement to cope with unpredictable environments during dispersal may support a predisposition to flexibly use different sources of information in younger males. By contrast, experience may be needed by females to reach the same proficiency, thereby justifying the increase in flexibility with ageing. In addition to increasing our knowledge about navigation, these results highlight effects of sex and ovariectomy on dog cognition, with potentially important implications regarding the management of dogs in different fields.
... There is a considerable body of evidence regarding the influence of sex and gonadectomy on cognition and (by implication) emotion in dogs. For example, we know that female and gonadectomized dogs are more likely to develop CCD than male or intact dogs (Azkona, Garcia-Belenguer et al. 2009). CCD also progresses more rapidly in neutered male dogs compared to intact males (Hart 2001). ...
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Kujala (2017) provides an excellent overview of most aspects of emotion in dogs; however, she does not cover a few fields of research that I think are also relevant to the topic. In this commentary, I discuss the current state of our knowledge regarding cognitive decline and behavioral disorders in dogs as potential models for human neurodegenerative disease and mental illness; how emotion and cognition in dogs interact with sex, gonadectomy, and sexual behavior; as well as the transformative potential of functional MRI imaging of the conscious dog brain in the study of comparative neurophysiology.
... For example, researchers have found that, like humans, dogs experience declines in EF as they age (Cepeda et al. 2001;Mongillo et al. 2013;Tapp et al. 2003;Wallis et al. 2014Wallis et al. , 2016. Researchers have also found canine analogs of attentional deficit hyperactivity disorder (ADHD; Vás et al. 2007) and Alzheimer's disease (canine cognitive dysfunction; Azkona et al. 2009;Landsberg et al. 2003Landsberg et al. , 2012Ruehl et al. 1995). Such research provides a starting point in developing methods of testing various cognitive abilities, as well as the efficacy of interventions, such as those aiming to reduce age-related cognitive decline Milgram 2003;Milgram et al. 2002Milgram et al. , 2005. ...
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Executive function (EF) allows for self-regulation of behavior including maintaining focus in the face of distraction, inhibiting behavior that is suboptimal or inappropriate in a given context, and updating the contents of working memory. While EF has been studied extensively in humans, it has only recently become a topic of research in the domestic dog. In this paper, I argue for increased study of dog EF by explaining how it might influence the owner-dog bond, human safety, and dog welfare, as well as reviewing the current literature dedicated to EF in dogs. In "EF and its Application to "Man's Best Friend" section, I briefly describe EF and how it is relevant to dog behavior. In "Previous investigations into EF in dogs" section, I provide a review of the literature pertaining to EF in dogs, specifically tasks used to assess abilities like inhibitory control, cognitive flexibility, and working memory capacity. In "Insights and limitations of previous studies" section, I consider limitations of existing studies that must be addressed in future research. Finally, in "Future directions" section, I propose future directions for meaningful research on EF in dogs.
... Cognitive function in dogs, like that of other mammals, declines over the course of ageing (1) and accelerated brain ageing in dogs results in cognitive dysfunction syndrome (CDS) (2,3) , a condition similar to human dementia including Alzheimer's disease (AD), which has no known cure. Epidemiological studies have reported CDS in 28-29·5 % of 11-14-year-old dogs and 47·6-68 % of dogs over 15 years (4,5) . For dogs, as humans, CDS is associated with severe brain atrophy due to irreversible loss of brain cells and synapses (6)(7)(8)(9)(10)(11) . ...
Article
This study focused on the hypothesis that cognitive decline in aged dogs could be attenuated by dietary supplementation with a nutrient blend consisting of antioxidants, B vitamins, fish oil and l -arginine, referred to hereafter as the Brain Protection Blend (BPB). Baseline cognitive assessment before the start of treatment was used to establish cognitively equivalent control (10·464+2·33 kg) and treatment (12·118+3·386 kg) groups of aged dogs between 9·1 and 11·5 years of age and with body condition score of 5. After an initial wash-in period, all dogs were tested over a 6-month period on cognitive test protocols that assessed four phases of a landmark discrimination learning protocol, which assessed a spatial learning skill based on utilisation of external cues, and egocentric discrimination task, which assessed spatial learning based on internal body-centred cues. The BPB-supplemented group showed significantly better performance than the controls on the landmark 1 ( P =0·0446) discrimination learning tasks, and on two egocentric discrimination reversal learning tasks ( P =0·005 and P =0·01, respectively). The groups did not differ significantly ( P >0·10) on the landmark zero discrimination task and the egocentric discrimination learning task. These results suggest beneficial effects are positively linked to task complexity. Many of the nutrients supplemented in the BPB diet were significantly higher in plasma, including arginine, α -tocopherol, DHA and EPA. These results indicate that long-term supplementation with the BPB can have cognition-improving effects and support the use of nutritional strategies in targeting brain ageing-associated risk factors as an intervention to delay cognitive ageing.
... In particular, transgenic rodent models, which harbor mutations causing the rare familial early-onset AD, fail to fully recapitulate the complex human AD phenotype (Babcock et al., 2015;Weishaupt et al., 2018). The prevalence of CCD has been estimated to be 14%e22% in dogs older than 8 years and more than 50% in dogs older than 15 years (Osella et al., 2007;Azkona et al., 2009;Salvin et al., 2010). As with sporadic AD, age is a major risk factor for developing CCD (Adams et al., 2000;Murphy et al., 2002;Schütt et al., 2018). ...
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Canine cognitive dysfunction (CCD) is a potential natural model for human Alz- heimer’s disease (AD). In this chapter we are addressing the current procedures of how to obtain canine induced pluripotent stem cells (ciPSCs) from geriatric dogs and the available protocols for differentiation of ciPSC into neurons. Moreover, we present how these neurons derived from ciPSC can be compared to human iPSC (hiPSC)-derived neurons in order to validate dogs with CCD as natural models for AD. This practical example presents the importance to generate species-specific iPSC to broaden our knowledge of cell typeespecific disease models and to investigate, compare, and evaluate the different animal models as appropriate dis- ease models for human diseases.
... Many genetic diseases, such as Alzheimer's disease, retinal atrophy, muscular dystrophy, cancer, obesity, cardiovascular diseases, and diabetes mellitus, affect dogs and humans [121,135,150]. For instance, the neurobehavioral syndrome called canine cognitive dysfunction (CCD), which affects 14.2-22.5% of dogs over eight years old, shares many clinical and neuropathological similarities with human aging and early stages of Alzheimer's Disease [151][152][153][154]. Recently, Hyttel and collaborators [155] aimed to characterize the CCD condition in iPSC-derived neurons from aged demented and healthy dogs, allowing the comparison of CCD with human Alzheimer's at the cellular level. ...
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Over the history of humankind, knowledge acquisition regarding the human body, health, and the development of new biomedical techniques have run through some animal model at some level. The mouse model has been primarily used as the role model for a long time; however, it is severely hampered regarding its feasibility for translational outcomes, in particular, to preclinical and clinical studies. Herein we aim to discuss how induced pluripotent stem cells generated from non-human primates, pigs and dogs, all well-known as adequate large biomedical models, associated or not with gene editing tools, can be used as models on in vivo or in vitro translational research, specifically on regenerative medicine, drug screening, and stem cell therapy.
... dental disease, obesity, cognitive dysfunction, osteoarthritis, heart failure, survival). For example, prevalence estimates of canine cognitive dysfunction syndrome (CDS) in dogs > 8 years of age range from 14 to 60% [41][42][43][44]. Conservatively, assuming a CDS prevalence of 14% at age 8 years, we estimate having 80% power to detect OR> 1.50 for variables that 20-30% of controls are exposed to (Additional file 3). ...
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Background Despite extensive research, many questions remain unanswered about common problems that impact dog welfare, particularly where there are multiple contributing factors that can occur months or years before the problem becomes apparent. The Generation Pup study is the first longitudinal study of dogs that recruits pure- and mixed-breed puppies, aiming to investigate the relative influence of environmental and genetic factors on a range of health and behaviour outcomes, (including separation related behaviour, aggression to familiar/unfamiliar people or dogs and obesity). This paper describes the study protocol in detail. Methods Prior to commencing recruitment of puppies, the study infrastructure was developed, and subject specialists were consulted to inform data collection methodology. Questionnaire content and timepoint(s) for data collection for outcomes and potential predictors were chosen with the aim of providing the best opportunity of achieving the aims of the study, subject to time and funding constraints. Recruitment of puppies (< 16 weeks, or < 21 weeks of age if entering the United Kingdom or Republic of Ireland through quarantine) is underway. By 23 January 2020, 3726 puppies had been registered, with registration continuing until 10,000 puppies are recruited. Data collection encompasses owner-completed questionnaires issued at set timepoints throughout the dog’s life, covering aspects such as training, diet, exercise, canine behaviour, preventative health care, clinical signs and veterinary intervention. Owners can elect to submit additional data (health cards completed by veterinary professionals, canine biological samples) and/or provide consent for access to veterinary clinical notes. Incidence and breed associations will be calculated for conditions for which there is currently limited information (e.g. separation related behaviour). Multivariable statistical analysis will be conducted on a range of outcomes that occur throughout different life stages, with the aim of identifying modifiable risk factors that can be used to improve canine health and welfare. Discussion The Generation Pup project is designed to identify associations between early-life environment, genotypic make-up and outcomes at different life stages. Modifiable risk factors can be used to improve canine health and welfare. Research collaboration with subject specialists is welcomed and already underway within the fields of orthopaedic research, epilepsy, epigenetics and canine impulsivity.
... Aging also significantly impacts visual attention [22][23][24][25][26][27][28][29][30][31] . A generalised slowing of information processing provides an explanation for an overall age-related decline in cognition 25 . ...
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Forming eye contact is important in dog–human communication. In this study we measured what factors affect dogs’ propensity for forming eye contact with an experimenter. We investigated the effect of [1] cephalic index (head shape’s metric, indicator of higher visual acuity at the centre of the visual field), [2] breed function (visual cooperativeness), [3] age and [4] playfulness with strangers in 125 companion dogs. Cephalic index was measured individually and analysed as a continuous variable. Results showed that [1] dogs with a higher cephalic index (shorter head) established eye contact faster. Since cephalic index is highly variable even within a breed, using artificial head shape groups or breed average cephalic index values is not recommended. [2] Breed function also affected dogs’ performance: cooperative breeds and mongrels established eye contact faster than dogs from non-cooperative breeds. [3] Younger dogs formed eye contact faster than older ones. [4] More playful dogs formed eye contact faster. Our results suggest that several factors affect dogs’ interspecific attention, and therefore their visual communication ability.
... For example, while large dogs have shorter life spans and appear to age faster than smaller dogs in some respects, studies of ageassociated cognitive dysfunction are mixed, with some indicating earlier onset in larger dogs and others finding no such association. 53,62,63 This variability suggests a common set of mechanisms underlying aging that is modified in expression in each individual by both intrinsic and environmental factors. While teasing out these factors is an interesting and productive research challenge, drawing a bright line between healthy and unhealthy aging isn't critical from a clinical perspective. ...
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Aging is the single most important cause of disease, disability, and death in adult dogs. Contrary to the common view of aging as a mysterious and inevitable natural event, it is more usefully understood as a set of complex but comprehensible biological processes that are highly conserved across species. Although the phenotypic expression of these processes is variable, there are consistent patterns both within and between species. The purpose of this feature is to describe the patterns currently recognized in the physical and behavioral manifestations of aging in the dog and how these impact the health and welfare of companion dogs and their human caregivers. Important gaps in our knowledge of the canine aging phenotype will be identified, and current research efforts to better characterize aging in the dog will be discussed. This will help set the context for future efforts to develop clinical assessments and treatments to mitigate the negative impact of aging on dogs and humans.
... To our knowledge, there has been no related behavioral research but the studies of Gunn-Moore et al. (2018) and Stylianaki et al. (2019), provide evidence for potential cognitive decline in dolphins. Furthermore, cognitive aging has been documented in other species such as common marmosets (Callithrix jacchus, Sadoun et al. 2019), rhesus monkeys (Macaca mulatta, Herndon et al. 1997), chimpanzee (Pan troglodytes, Hopkins et al. 2021) and domesticated species (Azkona et al. 2009;Bellows et al. 2016). Hence, research on long-term cognitive functions in dolphins should be considered for future direction of cognitive studies. ...
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Alliance formation plays a crucial part in male dolphins’ lives. These partnerships may last for decades or even for a lifetime; thus, partner choice and the maintenance of these relationships are both considered key components of alliance formation. In our previous investigations, pairs of adult male dolphins showed a high success rate in cooperative manipulation of a cognitive enrichment device. Here, we introduced two novel cognitive enrichment devices to the group of five dolphins, facilitating simultaneous actions for not only pairs, but for three or even four dolphins. The devices were made of PVC tubes, fittings and caps equipped with rope handles, creating a three-way (T-shape) and a four-way (TT-shape) device. The devices were filled with fish and ice and were designed to be opened by simultaneous pull of the handles. Both devices were tested in 12 trials (each lasted for 15 min), separately. Only one of the caps could be opened, the others were affixed with the position of the openable cap counter-balanced over the trials. Although the dolphins received no training regarding the manipulation of the devices, they were successful in cooperatively opening the three-way devices in 10/12 of trials (70% by two and 30% by three dolphins) and the four-way devices also in 10/12 trials (50% by two, 40% by three and 10% by four dolphins). The dolphins interacted with the devices during the entire testing time, and this was mostly spent in cooperative play (77% and 56% of the test duration with the three-way and four-way device, respectively). The majority of the cooperative play was observed between one particular pair of dolphins that was temporarily associated with a third or sometimes even with a fourth dolphin. These findings demonstrate the first successful use of multi-partner cooperative enrichment devices, providing information on the social organisation of a male dolphin group.
... Females were significantly more affected than males, as prevalence and severity increased with age. This study's hypothesis was that hormonal and/or genetic factors may influence the development of cognitive signals in elderly female dogs, as well as women with AD [52]. ...
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Episodic memory, in humans, is the memory most affected by age-related deterioration or the constitution of neurodegenerative pathologies, such as Alzheimer's disease. However, it is unknown whether this relationship is also present in nonhuman animals. Since studies in birds, rats, primates, and dogs have been shown to have episodic-like memory, more studies aiming to improve the present understanding of this relationship in nonhuman animals are important to aid the development of new translational models for neurodegenerative disorders. Knowing that dogs (Canis familiaris) represent a promising experimental model for neurodegenerative disorders, a memory retrieval test was conducted with 90 clinically healthy domestic dogs of different ages, both sexes, and distinct breeds, for the purpose of evaluating episodic-like memory. The present study adapted a test that corroborates episodic memory requirements through incidental codification of experienced events. We performed a test with two exposure phases, with different characteristics between them, so that in the third phase it was necessary to integrate previous experiences in order to achieve success in the test. In our study, it was possible to verify the decline of episodic memory in elderly dogs, even clinically healthy, regardless of the dogs' sex and size. This episodic-like memory decline observed in elderly dogs may be related to the physiological process of aging or preclinical pathological manifestation of cognitive impairment, similar as reported in humans. More studies should be carried out evaluating episodic-like memory in dogs with suspected of canine cognitive dysfunction syndrome in order to better understand the physiological and pathological behavior of this type of memory in canine species.
... On the other hand, dogs diagnosed with CDS ranged from 10% (up to 12 years of age) to 61% (13 years old and over) [24,69], with Osella [68] reporting that 33% of the evaluated elderly dog population was affected by this syndrome. It must be mentioned, however, that different authors reported lower data, with cumulative (MCI and CDS) prevalence ranging from 14% [29,70] to 22.5% [71]. ...
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Canine and feline cognitive dysfunction syndrome is a common neurodegenerative disorder of old age and a natural model of human Alzheimer’s disease. With the unavoidable expanding life expectancy, an increasing number of small animals will be affected. Although there is no cure, early detection and intervention are vitally important to delay cognitive decline. Knowledge of cellular and molecular mechanisms underlying disease onset and progression is an equally decisive factor for developing effective approaches. Uncontrolled neuroinflammation, orchestrated in the central nervous system mainly by astrocytes, microglia, and resident mast cells, is currently acknowledged as a hallmark of neurodegeneration. This has prompted scientists to find a way to rebalance the altered crosstalk between these cells. In this context, great emphasis has been given to the role played by the expanded endocannabinoid system, i.e., endocannabinoidome, because of its prominent role in physiological and pathological neuroinflammation. Within the endocannabinoidome, great attention has been paid to palmitoylethanolamide due to its safe and pro-homeostatic effects. The availability of new ultramicronized formulations highly improved the oral bioavailability of palmitoylethanolamide, paving the way to its dietary use. Ultramicronized palmitoylethanolamide has been repeatedly tested in animal models of age-related neurodegeneration with promising results. Data accumulated so far suggest that supplementation with ultramicronized palmitoylethanolamide helps to accomplish successful brain aging.
... Our main goal here was to test how ageing affects the dogs' separation related behaviour with a repeated separation test, in a longitudinal study. We have very little knowledge about the different aspects of age-related changes in separation behaviours, and how dogs' arousal level is coded in occurrences of NLP and spectral noise (Azkona et al., 2009;Neilson et al., 2001;Osella et al., 2007;Salvin et al., 2010). Some authors in cross-sectional studies (Marx et al., 2021;Mongillo et al., 2013) have addressed age effects on separation behaviour, but it is important to support these findings in repeated, longitudinal studies, as these have the potential to indicate the direct effects of ageing (Salthouse, 2019). ...
Article
Separation related problems (SRP) caused by distress associated with separation from the preferred member of the social group, can be characterised by their symptoms e.g., excessive vocalisation. In dogs’ separation whines, nonlinear phenomena (NLP) (abrupt changes in the resonance of the vocal folds) might occur, which could be adaptive in communicating aroused inner states. Previously, using a separation test we found that more dogs that were classified as having SRP by their owner have NLP in their whines than nonaffected dogs and that NLP ratio increases with age, which suggests that separation stress might intensify with age. We repeated the separation test 21.19 ± 9.37 months later with 32 dogs from the previous study to investigate longitudinally how separation behaviour and vocalisations change with age. Beside behaviour, we measured the acoustic structure of the whines (jitter - small-scale irregularity of the pitch, entropy - vocal harshness, call length, pitch (f0) related parameters, and the spectral components) and calculated the NLP ratio. We formed clusters based on the dogs’ behaviour changes from the first test to the second, to see individual ageing patterns. Finally, we compared the dogs’ behaviour and the acoustic structure of their whines in the two occasions. We found that dogs could be clustered by the changes in their separation behaviour. 41 % of the dogs were stable over time, 38 % improved, and 16 % showed an increase in their separation behaviours. 3 % switched from barking to whining. Interestingly, SRP dogs were stable, some of them even showed improvement in their separation behaviour. On the contrary, we also found that SRP dogs tended to have an increased NLP ratio with age from test 1 to test 2 (p = 0.09), showed less escape-related behaviour (p = 0.01), but tended to spend more time passively whining at the door through which the owner left the room (p = 0.05), than non-SRP dogs. The behavioural and vocal results suggest elevated stress levels in SRP dogs with age, although they did not decline but mostly stayed stable in their separation behaviour, confirming that there could be a connection between SRP status, age, and NLP. However, together with the results of the clustering that showed that there are different patterns in dogs’ separation behaviour, we emphasise the importance of individual level longitudinal investigations in order to facilitate the early diagnosis of SRP and to provide a solid basis for the development of individualised treatment plan for SRP dogs.
... Ook voor teven die na de leeftijd van één jaar geovariectomiseerd werden, bleef het risico groter dan bij intacte teven. Daarnaast blijkt dat cognitieve disfunctie, een aandoening die vooral oude, vrouwelijke honden treft, mogelijk vaker gezien wordt na gonadectomie; dit zowel bij de reu als de teef (Azkona et al., 2009). ...
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In recent years, gonadectomy in dogs has become the subject of growing criticism. Novel studies have demonstrated that this type of surgery can have negative effects on the dog's health, effects that at first sight cannot be linked to the removal of the gonads or the absence of sex steroids. In this review, the literature on the long term-health effects of gonadectomy in dogs is described. The most important medical indication for ovariectomy in a bitch is lowering the risk of pyometra and mammary tumors, diseases which arc prevalent in intact bitches. Spaying is often done in young bitches because of the protective effect it has on the development of mammary tumors. However, recent research has shown that orthopedical problems and some non-genital tumors are more prevalent in dogs after gonadectomy, especially if spayed before puberty. Results of these studies also show a major impact of the breed of the dog, hence a general advice for the dog population is not feasible. Veterinarians have to evolve towards a patient-specific advice in this matter.
... For example, researchers have found that, like humans, dogs experience declines in EF as they age (Cepeda et al. 2001;Mongillo et al. 2013;Tapp et al. 2003;Wallis et al. 2014Wallis et al. , 2016. Researchers have also found canine analogs of attentional deficit hyperactivity disorder (ADHD; Vás et al. 2007) and Alzheimer's disease (canine cognitive dysfunction; Azkona et al. 2009;Landsberg et al. 2003Landsberg et al. , 2012Ruehl et al. 1995). Such research provides a starting point in developing methods of testing various cognitive abilities, as well as the efficacy of interventions, such as those aiming to reduce age-related cognitive decline Milgram 2003;Milgram et al. 2002Milgram et al. , 2005. ...
... A prevalência de cães que apresentavam sinais clínicos sugestivos da SDCC no presente estudo (22,38% -15/67) está dentro dos valores encontrados por Azkona et al. (2009) de 22,5%, Heath et al. (2007 de 20 -30% e por Bain et al. (2001) de 22% em cães com idade entre 11 e 14 anos. Quanto maior a idade dos cães, mais alterações comportamentais (Neilson et al., 2001), visto que os idosos demonstram um declínio cognitivo dependente da idade e de afecções cerebrais existentes (Faraco, 2013). ...
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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.
... Many studies have documented that senior dogs may experience canine cognitive dysfunction syndrome (CCDS), also known as "canine dementia." In these dogs, we usually notice behavioral changes that are described in short by the acronym DISHA [Disorientation, altered social Interactions, altered Sleep-wake cycles, House soiling and loss of other learned behaviors, altered Activity levels and increasing Anxiety; (4)(5)(6)(7)(8)], as well as neuropathological changes in the brain. CCDS is observed mainly in large-breed dogs over 8 years of age showing slow onset of behavioral and cognitive changes. ...
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Canine cognitive dysfunction syndrome (CCDS) is a progressive neurodegenerative disorder in senior dogs that is mainly associated with decreased ability to learn and respond to stimuli. It is commonly under-diagnosed because behavioral changes are often attributed to the natural process of aging. In the present study, we used for the first time a comprehensive approach enabling early diagnosis of canine patients with mild cognitive disorders (MiCI). We included CAnine DEmentia Scale (CADES) questionnaires, biochemical parameters, and biomarkers in blood serum, and correlated them with post-mortem histopathological changes. The CADES questionnaires enabled us to identify MiCI dogs developing changes mainly in domains corresponding to social interaction and spatial orientation, which seems to be crucial for delineating early cognitive disorders. Biochemical analyses in these dogs showed slightly elevated liver enzyme parameters (AST and ALT) and significantly decreased sodium and chloride levels in blood serum. Furthermore, we describe for the first time a significant increase of neurofilament light chain (NFL) in blood serum of MiCI dogs, compared to normal aging seniors and young controls, but no changes in TAU protein and amyloid-β (Aβ42) peptide levels. In canine brains with cognitive impairment, amyloid plaques of mainly diffuse and dense types were detected. Furthermore, activated microglia with amoeboid body and dystrophic processes occurred, in some cases with spheroidal and bulbous swellings. On the other hand, no TAU pathology or neurofibrillary tangles were detected. These results suggest that a combination of CADES questionnaire mainly with CNS injury biomarker (NFL) and with biochemical parameters (ALT, AST, Na, and Cl) in blood serum may predict CCDS in senior dogs.
... In dogs, the diagnosis of canine cognitive dysfunction syndrome is based on behavioral signs and exclusion of other medical conditions [24]. Further, it is known clinically that the prevalence and severity of canine cognitive dysfunction increases with the age [25]. Different publications have studied that dogs affected by progressive cognitive impairment share certain histopathological changes including alterations related to the structure of certain proteins as in Alzheimer disease: neuronal loss, astrocytosis, amyloid-β deposition and rarely neurofibrillary tangles [26,27]. ...
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Background Aquaporin-4 (AQP4) is in growing recognition as potential marker for cancer progression, differentiation and therapeutic intervention. No information is available about AQP4 expression in the normal canine brain. The aim of this histopathological study is to confirm the presence of AQP4 by immunohistochemistry technique in a group of non-pathological canine brains and to describe its expression and distribution across the brain. Results Twelve non-pathological canine brains of various ages (ranging from 21 days to 17 years) and breeds were included in the study. Immunohistochemical expression of AQP4 was analyzed using formalin-fixed paraffin-embedded brain tissue sections. The findings were correlated between AQP4 expressing cells and astrocytes using glial fibrillary acidic protein (GFAP). AQP4 expression was more marked in the astrocyte foot processes of subpial, perivascular and periventricular surfaces in all specimens. The majority of the canine brain sections (9/12) presented with an AQP4 predilection for white matter tracts. Interestingly, the two youngest dogs (21 days and 3 months old) were characterized by diffuse AQP4 labelling in both grey and white matter tracts. This result may suggest that brain development and ageing may play a role in the AQP4 distribution throughout the canine brain. Conclusions This is the first study to describe immunohistochemical distribution of AQP4 in normal canine brains. The AQP4 expression and distribution in non-pathological canine brains was comparable to other species. Larger studies are needed to substantiate the influence of breed and ageing on AQP4 expression in the normal canine brain.
... In particular, transgenic rodent models, which harbor mutations causing the rare familial early-onset AD, fail to fully recapitulate the complex human AD phenotype (Babcock et al., 2015;Weishaupt et al., 2018). The prevalence of CCD has been estimated to be 14%e22% in dogs older than 8 years and more than 50% in dogs older than 15 years (Osella et al., 2007;Azkona et al., 2009;Salvin et al., 2010). As with sporadic AD, age is a major risk factor for developing CCD (Adams et al., 2000;Murphy et al., 2002;Schütt et al., 2018). ...
Chapter
Cattle constitute one of the most commercially important livestock species. They are a significant source of nutrition as well has had great economic importance. Through thousands of years of selective breeding humans have shaped cattle into these multipurpose species that are adapted to various environments around the globe. In the past decade, the sequencing of the cattle genome has paved the way for genetic enhancement of existing breeds to increase productivity and sustainability. More recently, developments in genome editing technologies and pluripotent stem cell culture can now be combined to achieve highly commercial goals for the livestock industry. In this chapter, we discuss the basics of these cutting-edge technologies and their applications in cattle. We focus on bovine iPSCs (biPSCs) as they can be generated in theory from any individual long after their genetic value has been proven, and their phenotypic characteristics validated and regardless of their fecundity status. Furthermore, we discuss the various genome editors and how these novel tools can be used for the genetic improvement of cattle.
... Recently, Salvin et al. [32] developed a CDS rating scale for the diagnosis of cognitive dysfunction and reported the prevalence to be 14.2% in pet dogs over the age of 8 years in contrast to the veterinary diagnosis rate of 1.9%. Overall, when including different studies, the prevalence of CDS in the population of senescent dogs ( ≥ 8 years) is estimated to range from 14.2 to 22.5% and to increase exponentially with increasing age [27,[33][34][35] . ...
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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.
Chapter
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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.
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The veterinary and animal science professions are rapidly developing and their inherent and historical connection to agriculture is challenged by more biomedical and medical directions of research. While some consider this development as a risk of losing identity, it may also be seen as an opportunity for developing further and more sophisticated competences that may ultimately feed back to veterinary and animal science in a synergistic way. The present review describes how agriculture-related studies on bovine in vitro embryo production through studies of putative bovine and porcine embryonic stem cells led the way to more sophisticated studies of human induced pluripotent stem cells (iPSCs) using e.g. gene editing for modeling of neurodegeneration in man. However, instead of being a blind diversion from veterinary and animal science into medicine, these advanced studies of human iPSC-derived neurons build a set of competences that allowed us, in a more competent way, to focus on novel aspects of more veterinary and agricultural relevance in the form of porcine and canine iPSCs. These types of animal stem cells are of biomedical importance for modeling of iPSC-based therapy in man, but in particular the canine iPSCs are also important for understanding and modeling canine diseases, as e.g. canine cognitive dysfunction, for the benefit and therapy of dogs.
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As the most phenotypically diverse mammalian species that shares human environments and access to sophisticated healthcare, domestic dogs have unique potential to inform our understanding of the determinants of aging. Here we outline key concepts in the study of aging and illustrate the value of research with dogs, which can improve dog health and support translational discoveries. We consider similarities and differences in aging and age-related diseases in dogs and humans and summarize key advances in our understanding of genetic and environmental risk factors for morbidity and mortality in dogs. We address health outcomes ranging from cancer to cognitive function and highlight emerging research opportunities from large-scale cohort studies in companion dogs. We conclude that studying aging in dogs could overcome many limitations of laboratory models, most notably, the ability to assess how aging-associated pathways influence aging in real-world environments similar to those experienced by humans. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 10 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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With increasing age, humans and animals suffer from partial or complete loss of cognition and memory. As a result, quality of life declines significantly. Among many underlying mechanisms, a significant decline in the neurotransmitter acetylcholine (ACh), an increase in N-methyl-d-aspartate (NMDA), and oxidative stress are the most recognized events involved in cognition impairment, especially memory and learning. Like chronic neurodegenerative Alzheimer’s disease (AD) in humans, canines and felines suffer from memory loss as they become older. Currently, for AD treatment in humans, an NMDA receptor antagonist memantine in combination with the acetylcholinesterase (AChE) inhibitor donepezil, rivastigmine, or galantamine appears to be the best option. A number of therapeutic drugs (selegiline, gabapentin, buspirone, memantine, etc.) are also available for treatment of canine cognition dysfunction (CCD)/cognitive dysfunction syndrome (CDS). A large number of plant extracts, their ingredients, and bioactive compounds of animal origin have been investigated for anticholinesterase (anti-ChE), antioxidative, anti-inflammatory, and immunomodulatory activities, as well as anti-Aβ aggregation and deposition in the brain. Some of these substances have also been shown to normalize the blood-brain barrier permeability and integrity, while others have been demonstrated to restore mitochondrial function. A small number of plant extracts have also shown MAO-B inhibitory property. Currently, dementic dogs and cats are given nutraceuticals and/or a therapeutic diet to improve their cognition and memory. This chapter describes various nutraceuticals and substances that have potential to improve cognition and memory in senior dogs and cats.
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Neurologic conditions represent some of the most confusing, challenging, and frustrating cases to treat. Because of this, it is not surprising that many pet owners turn to alternative therapies, including cannabis, to treat their pets. This chapter provides information on the use of cannabinoid compounds for the treatment or management of common neurologic diseases and disorders of dogs and cats.
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The effect of breed and body weight on longevity in the pet dog was analyzed, and a method was developed to standardize the chronological age of dogs in terms of physiological time, using human year equivalents. Mortality data from 23,535 pet dogs were obtained from a computerized data base of North American veterinary teaching hospitals, and the median age at death was determined for pure and mixed breed dogs of different body weight. Body size in the dog was inversely related to longevity. Within each body weight category, the median age at death was lower for pure breed dogs compared with mixed breed dogs. The difference between the standardized physiological ages of mixed breed dogs of the same chronological age in the smallest and largest body weight categories varied from 8 to > 15 years, and between large and small pure breed dogs, the disparity was even greater. Laboratory research to explore the biological basis for these breed and body weight specific differences in life span among dogs may provide additional clues to genetic factors influencing senescence.
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Recent changes in veterinary medicine have required quantitative epidemiological techniques for designing field surveys, identifying risk factors for multifactorial diseases, and assessing diagnostic tests. Several relevant techniques are brought together in the package of veterinary epidemiological computer software, WIN EPISCOPE 2.0, described in this paper. It is based on Microsoft Windows and includes modules for the design and analysis of field surveys, control campaigns and observational studies, and a simple mathematical model. It provides comprehensive 'Help' screens and should therefore be useful not only in field investigations but also for teaching veterinary epidemiology.
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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.
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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.
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To determine whether gonadectomy predisposes dogs to development of age-related behavioral changes linked to cognitive impairment. Cohort study. 29 sexually intact male dogs, 63 spayed female dogs, and 47 castrated male dogs 11 to 14 years old. Information on possible impairments in 4 behavioral categories linked to cognitive impairment (orientation in the home and yard, social interactions, house training, and sleep-wake cycle) was obtained from owners of the dogs by use of a structured telephone interview format. A second interview was performed 12 to 18 months after the initial interview, and differences in responses were evaluated. Sexually intact male dogs were significantly less likely than neutered dogs to progress from mild impairment (i.e., impairment in 1 category) to severe impairment (i.e., impairment in > or = 2 categories) during the time between the first and second interviews. This difference was not attributable to differences in ages of the dogs, duration of follow-up, or the owners' perceptions of the dogs' overall health. Results suggest that the presence of circulating testosterone in aging sexually intact male dogs may slow the progression of cognitive impairment, at least among dogs that already have signs of mild impairment. Estrogens would be expected to have a similar protective role in sexually intact female dogs; unfortunately, too few sexually intact female dogs were available for inclusion in the study to test this hypothesis. There may be a need to evaluate possible methods for counteracting the effects of loss of sex hormones in gonadectomized dogs.
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Circulating testosterone (T) levels have behavioral and neurological effects in both human and nonhuman species. Both T concentrations and neuropsychological function decrease substantially with age in men. The purpose of this prospective, longitudinal study was to investigate the relationships between age-associated decreases in endogenous serum T and free T concentrations and declines in neuropsychological performance. Participants were volunteers from the Baltimore Longitudinal Study of Aging, aged 50-91 yr at baseline T assessment. Four hundred seven men were followed for an average of 10 yr, with assessments of multiple cognitive domains and contemporaneous determination of serum total T, SHBG, and a free T index (FTI). We administered neuropsychological tests of verbal and visual memory, mental status, visuomotor scanning and attention, verbal knowledge/language, visuospatial ability, and depressive symptomatology. Higher FTI was associated with better scores on visual and verbal memory, visuospatial functioning, and visuomotor scanning and a reduced rate of longitudinal decline in visual memory. Men classified as hypogonadal had significantly lower scores on measures of memory and visuospatial performance and a faster rate of decline in visual memory. No relations between total T or the FTI and measures of verbal knowledge, mental status, or depressive symptoms were observed. These results suggest a possible beneficial relationship between circulating free T concentrations and specific domains of cognitive performance in older men.
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We previously reported that long-term cyclic estrogen (E) treatment reverses age-related impairment of cognitive function mediated by the dorsolateral prefrontal cortex (dlPFC) in ovariectomized (OVX) female rhesus monkeys, and that E induces a corresponding increase in spine density in layer III dlPFC pyramidal neurons. We have now investigated the effects of the same E treatment in young adult females. In contrast to the results for aged monkeys, E treatment failed to enhance dlPFC-dependent task performance relative to vehicle control values (group young OVX+Veh) but nonetheless led to a robust increase in spine density. This response was accompanied by a decline in dendritic length, however, such that the total number of spines per neuron was equivalent in young OVX+Veh and OVX+E groups. Robust effects of chronological age, independent of ovarian hormone status, were also observed, comprising significant age-related declines in dendritic length and spine density, with a preferential decrease in small spines in the aged groups. Notably, the spine effects were partially reversed by cyclic E administration, although young OVX+Veh monkeys still had a higher complement of small spines than did aged E treated monkeys. In summary, layer III pyramidal neurons in the dlPFC are sensitive to ovarian hormone status in both young and aged monkeys, but these effects are not entirely equivalent across age groups. The results also suggest that the cognitive benefit of E treatment in aged monkeys is mediated by enabling synaptic plasticity through a cyclical increase in small, highly plastic dendritic spines in the primate dlPFC. • aging • estradiol • hormone • neocortex • plasticity
Chapter
This chapter discusses the utility of the dog as a model of brain aging. The procedural learning task, designed to assess skill acquisition in the dog, consists of two learning phases: reward-approach and object-approach learning. Aged dogs raised as pets, having diverse and varied life experiences, perform as well as or better than young dogs. Object recognition learning, the ability to classify and register the identity of objects, is examined using a delayed nonmatching to sample (DNMS) paradigm. The correct response for the dog is to choose the novel stimulus. The location of the novel stimulus is randomized across trials, and different stimuli selected from a large pool of objects are used for each trial. One of the most consistent cognitive deficits in old dogs is the ability to acquire and use spatial information. In humans, spatial learning impairments are a common feature of aging and become more severe in neurodegenerative disorders.
Article
This chapter explores the potential of the canine as a model of human age-related cognitive decline (ARCD), dementia, and Alzheimer's disease (AD). It also discuss a number of studies that indicate that some people with dementia and dogs with cognitive dysfunction respond to therapy with the monoamine oxidase inhibitor, 1-deprenyl (selegiline HCl). Results indicate that elderly pet dogs exhibit multiple behavioral or cognitive problems indicative of cognitive dysfunction, which in some canine patients are sufficiently severe to disrupt the dog's function as an adequate pet. In some affected pet dogs, the change in behavior was found to be due to the presence of systemic, non-neurological disease; however, in numerous cases, no such general medical condition was identified, suggesting that the behavioral or cognitive dysfunction may be due to brain pathology. Studies indicate that some cognitive deficits, but not others, are correlated with age and with amyloid accumulation. Screening tests might be developed to predict amyloid accumulation and/or response to therapy in pet dogs. If so, this information might be extrapolated to cognitively impaired people. The dogs in the study presented in the chapter responded quite favorably to once-daily therapy with 0.5 mg/kg 1-deprenyl. Similarly, human patients with dementia of the Alzheimer's type have responded to 1-deprenyl therapy.
Article
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.
Article
The behavior of 25 dogs was indirectly assessed by a formal questionnaire (evaluation of Age-Related Cognitive and Affective Disorders—ARCAD), filled out by the owner. The density of diffuse and vascular deposits was evaluated using four anti-Aβ peptide antibodies, in four temporal areas. Parenchymal, diffuse deposits of Aβ42 peptide were found in all aged animals but one. They were Congo red negative and were not immunostained by the anti-Aβ40 antibody, contrary to the vascular deposits. The densities of vascular and parenchymal deposits were not correlated. The ARCAD score was correlated with age, density of Aβ parenchymal and vascular deposits, and with the number of areas containing deposits (extension index). Multivariate analysis showed that the age and the extension index explained most of the variance. Congo red positivity (indicating that the Aβ peptide has the characteristics of an amyloid substance) is limited in the dog to the vascular wall and is associated, as in man, with the deposition of the Aβ 1–40 isoform. Parenchymal Aβ deposition seems to be a common correlate of behavioral problems in aging dogs.
Article
Recent reports have suggested that β-amyloid (Aβ) species of variable length C-termini are differentially deposited within early and late-stage plaques and the cerebrovasculature. Specifically, longer C-terminal length Aβ423 fragments (i.e., Aβ forms extending to residues 42 and/or 43) are thought to be predominant within diffuse plaques while both Aβ423 and Aβ40 (Aβ forms terminating at residue 40) are present within a subset of neuritic plaques and cerebrovascular deposits. We sought to clarify the issue of differential Aβ deposition using aged canines, a partial animal model of Alzheimer's disease that exhibits extensive diffuse plaques and frequent vascular amyloid, but does not contain neuritic plaques or neurofibrillary tangles. We examined the brains of 20 aged canines, 3 aged felines, and 17 humans for the presence of Aβ immunoreactive plaques, using antibodies to Aβ1–17, Aβ17–24, Aβ1–28, Aβ40, and Aβ42. We report that plaques within the canine and feline brain are immunopositive for Aβ42 but not Aβ40. This is the first observation of nascent AD pathology in the aged feline brain. Canine plaques also contained epitopes within Aβ1–17, Aβ17–24, and Aβ1–28. In all species examined, vascular deposits were immunopositive for both Aβ40 and Aβ42. In the human brain, diffuse plaques were preferentially Aβ42 immunopositive, while neuritic plaques and vascular deposits were both Aβ40 and Aβ42 immunopositive. However, not all neuritic plaques contain Aβ40 epitopes.
Article
Cognitive dysfunction syndrome (CDS) is a progressive neurodegenerative disorder of senior dogs. Since age-related behavioural changes may be useful indicators for early diagnosis and treatment, the first purpose of the present study was to investigate the prevalence of clinical signs of CDS in a general population of aged dogs. The second aim was to evaluate the use of a neuroprotective nutraceutical (Senilife®, Innovet Italia srl, Rubano, Italy) using an open-label clinical pilot trial.Dogs were recruited from a geriatric population not referred for behavioural consultations. A questionnaire with a checklist of behaviours was filled out to evaluate behavioural items grouped in the following categories: disorientation (D), socio-environmental interaction (I), sleep–wake cycles (S), house soiling (H), general activity (A)—(DISHA). Each owner was asked to rate the frequency of the behavioural signs: never, rarely, often, or always.One hundred and twenty-four dogs were assessed in the first survey; 22 of the 124 dogs tested in the survey were ruled out based on exclusion criteria (clinically and/or sensory severe impairment), 42 dogs had alterations in one category and 33 dogs had signs in 2 or more categories. Consequently 75 dogs had signs consistent with CDS.Among this population eight dogs affected by CDS were enrolled for the second step of the project, an open-label clinical pilot trial with the neuroprotective nutraceutical Senilife®. Senilife® contains 25mg phosphatidylserine, 50mg of standardized Ginkgo biloba extract, 33.5mg/d-alpha tocopherol and 20.5mg pyridoxine per capsule and is dosed at one capsule per 5kg body weight. The investigator asked the owners to rate the frequency of behaviours referring to DISHA using a four point frequency scale (never, rarely, often, always). Post-treatment, the owners were asked to evaluate all the signs in each category on a five point scale (much better, slightly better, the same, slightly worse, much worse). At the time of the first visit (V0) the owners were briefed verbally about the procedure; no behavioural advice was given throughout the study time and whenever appropriate therapy with Senilife® (was started. At V0, V1 (28±3 days), V2 (56±3 days) and V3 (84±3 days) a control visit was performed and the owners were interviewed. Dogs treated with Senilife® showed a highly significant difference at V3 compared to V0 (p
Article
Objectives: Recent studies have suggested that estrogen may improve cognitive function or prevent cognitive decline in older women. Little research has been conducted on exogenous or endogenous sex hormones and cognition in older men, yet it has been hypothesized that testosterone, either directly or by conversion to estrogens, may improve cognitive function. We investigated whether serum level of testosterone and estradiol is associated with cognition in older community-dwelling men. Design: A cross-sectional study. Setting: Population-based listings in the Monongahela Valley near Pittsburgh, Pennsylvania. Participants: Three hundred ten men (mean age +/- standard deviation = 73.0 +/- 7.1) who were part of a cohort study. Measurements: We measured cognitive function using the Mini-Mental State Examination (MMSE), Trails B, and Digit Symbol. Sex hormone levels were determined by radioimmunoassay from serum obtained at the time of cognitive testing and analyzed by tertile. Results: No consistent association between total testosterone level and cognitive test scores was observed. However, men with high bioavailable (loosely protein-bound) testosterone had better cognitive test scores on all three tests (P < or =.001). Total estradiol levels were associated with worse cognitive scores on Digit Symbol (P <.001) and Trails B (P =.002), but bioavailable estradiol levels were not associated with cognitive function. Level of sex hormone binding globulin (SHBG) was negatively associated with cognitive scores on all three tests (P < or =.001). After adjusting for age and education, the statistical significance lessened for bioavailable testosterone (MMSE, P =.086; Digit Symbol, P =.047; Trails B, P =.076) and became nonsignificant for SHBG (all cognitive tests P>.10). Conclusions: Our findings support the hypothesis that higher levels of bioavailable testosterone, but not of bioavailable estradiol, are associated with better cognitive function in older men. In addition, bioavailable measures of testosterone may better reflect hormone levels available to the brain and thus be more closely associated with central nervous system outcomes such as cognition. Future studies, especially randomized trials, should be undertaken to determine whether testosterone may protect against cognitive decline in older men.
Article
Among 26 dogs greater than or equal to 10 years old, the most frequent owner complaints relating to behavioral problems were destructive behavior in the house (n = 10), inappropriate urination or defecation in the house (n = 10), and excessive vocalization (n = 7). The most frequent behavioral diagnoses were separation anxiety (n = 13) and breakdown of housetraining (n = 6). Most of the behavioral problems in the 26 dogs began after the dogs reached the age of 10 years, and most of the dogs had been owned for many years without having behavioral problems. Few behavioral problems in old dogs had a medical basis. Most cases of inappropriate urination or defecation in the house were not related to urinary or fecal incontinence, but were exacerbated by problems such as degenerative joint disease and renal disease. Behavioral therapy is appropriate for behavioral problems in old dogs, and, taking into account an old dog's health and physical limitations, techniques used are the same as for younger dogs.
Article
We characterized eight aged beagles (maintained from birth in a laboratory colony) and one black Labrador using Bielschowsky's, thioflavine S, and Congo red staining, and antibodies to the beta-amyloid peptide, dystrophic neurites, and other plaque components. All plaques within these canine brains were of the diffuse subtype and were neither thioflavine S- nor Congo red-positive. The majority of plaques in the entorhinal cortex contained numerous neurons within them while plaques in the dentate gyrus did not. beta-Amyloid immunoreactivity was also present within select neurons and neuronal processes and was detected as a diffuse linear zone corresponding to the terminal fields of the perforant path. There was no significant correlation between extent of beta-amyloid accumulation and neuron number in entorhinal cortex. Neither tau-1, PHF-1, nor SMI-31-immunostaining revealed dystrophic fibers, confirming the classification of these plaques as diffuse. Canine plaques did not appear to contain bFGF- or HS-positive immunostaining. This may explain why neuritic involvement was not detected within these canine plaques. It is possible that the beta-amyloid within the canine brain has a unique primary structure or may not be in an assembly state that adversely affects neurons.
Article
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.
Article
Brains from 41 aged canines (> or = 10 years of age) were examined immunohistochemically to characterize the laminar distribution and age-related progression of beta-amyloid (A beta) in frontal cortex. We classified the A beta patterns into four distinct types. Type I was characterized by small, faint deposits of A beta in deep cortical layers. Type II consisted of diffuse deposits of A beta mainly in layers V and VI. Type III had both dense plaques in superficial layers, and diffuse deposits in deep layers. Finally, Type IV had solely dense plaques throughout all layers of cortex. We compared the A beta distribution pattern between the Old canines (10-15 years, n = 22) and the Very Old canines (> 15 years, n = 19). The Old group primarily had negative staining, or Type I and Type II patterns of amyloid deposition (73%). Conversely, the Very Old group had predominantly Types II, III and IV deposits (89.5%), a difference that was significant (P < 0.05). We suggest that A beta deposition in canine frontal cortex is a progressive age-related process beginning with diffuse deposits in the deep cortical layers followed by the development of deposits in outer layers. In support of this hypothesis, the deeper layer diffuse plaques in the Very Old group of dogs also contain the largest proportion of beta-amyloid with an isomerized aspartic acid residue at position 7, indicating that these deposits had been present for some time. We also observed fiber-like A beta immunoreactivity within regions of diffuse A beta deposits. These fibers appeared to be degenerating neurites, which were negative for hyperphosphorylated tau. Therefore, these fibers may represent a very early form of neuritic change that precede tau hyperphosphorylation or develop by an alternative pathway.
Article
Young, middle-aged, and old beagle dogs were tested on several visual-discrimination tasks: reward- and object-approach learning, object discrimination and reversal, long-term retention of a reversal problem, and a size-discrimination task. Beta-amyloid accumulation in the entorhinal, prefrontal, parietal, and occipital cortices was quantified using immunohistochemical and imaging techniques at the conclusion of cognitive testing. Middle-aged and old dogs were impaired in size-discrimination learning. In each task, a subset of aged dogs was impaired relative to age-matched peers. Beta-amyloid accumulation was age-dependent. However, not all middle-aged and old dogs showed beta-amyloid accumulation in the entorhinal cortex. The error scores from dogs tested with a nonpreferred object during visual discrimination learning and from reversal learning were correlated with beta-amyloid in the prefrontal but not entorhinal cortex. Size-discrimination and reward and object-approach learning error scores were correlated with beta-amyloid accumulation in the entorhinal but not prefrontal cortex. The results of these studies support an association between cognitive test and the location and extent of beta-amyloid pathology.
Article
The objective of this study was to determine whether endogenous sex hormone levels predict cognitive function in older men. Our study design was an exploratory analysis in a population-based cohort in Rancho Bernardo, California. The study participants were 547 community-dwelling men 59-89 yr of age at baseline who were not using testosterone or estrogen therapy. Between 1984 and 1987, sera were collected for measurement of endogenous total and bioavailable testosterone and estradiol levels. Between 1988 and 1991, 12 standard neuropsychological instruments were administered, including two items from the Blessed Information-Memory-Concentration (BIMC) Test, three measures of retrieval from the Buschke-Fuld Selective Reminding Test, a category fluency test, immediate and delayed recall from the Visual Reproduction Test, the Mini-Mental State Examination with individual analysis of the Serial Sevens and the "World" Backwards components, and the Trail-Making Test Part B. In age- and education-adjusted analyses, men with higher levels of total and bioavailable estradiol had poorer scores on the BIMC Test and Mini-Mental State Examination. Men with higher levels of bioavailable testosterone had better scores on the BIMC Test and the Selective Reminding Test (long-term storage). Five associations were U-shaped: total testosterone and total and bioavailable estradiol with the BIMC Test; bioavailable testosterone with the "World" test; and total estradiol with the Trail-Making Test. All associations were relatively weak but independent of age, education, body mass index, alcohol use, cigarette smoking and depression. In these older men, low estradiol and high testosterone levels predicted better performance on several tests of cognitive function. Linear and nonlinear associations were also found, suggesting that an optimal level of sex hormones may exist for some cognitive functions.
Article
Although several studies have suggested that hormone replacement therapy lowers the risk of AD among postmenopausal women, few studies have evaluated the relationship of endogenous estrogen levels and AD. The current study investigated whether serum estrone and estradiol levels were related to the presence of AD among postmenopausal women not currently taking hormone replacement therapy. Using a case-control design, we examined an ethnically diverse sample of postmenopausal women who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD (n = 50) and nondemented controls (n = 93). All women were participants in a study of aging and dementia and were seen consecutively between August 1997 and October 1998. Patients with AD had lower estradiol (F[1,141] = 8.3, p = 0.005) levels than did normal controls. Patients also had lower estrone levels; however, this comparison did not quite meet significance criteria (F[1,141] = 3.6, p = 0.06). Compared to estradiol levels >20 pg/mL, women with AD were four to six times more likely to have levels <20 pg/mL after adjusting for age, years of education, presence of an APOE-epsilon4 allele, ethnicity, and body mass index. There were no significant differences in frequency of AD among women within different quartiles of estrone after adjusting for potential confounds. The results of this preliminary case-control study suggest that estradiol levels may decline significantly in women in whom AD develops.
Article
Previous studies have found no association between serum concentrations of total oestradiol and cognitive function, but these measurements may not reflect concentrations of hormone available to the brain. We tested the hypothesis that concentrations of non-protein-bound (free) and loosely bound (bioavailable) sex hormones are associated with cognitive function in older women. We measured cognitive performance with a modified mini mental status examination (mMMSE) at baseline (1986-88) and 6 years later in 425 women (65 years or older). Concentrations of non-protein-bound and bioavailable oestradiol and total and non-protein-bound testosterone were measured by RIA in serum samples taken at baseline. Initial cognitive scores did not differ by tertile of non-protein-bound oestradiol, bioavailable oestradiol, or testosterone. Cognitive impairment (a decrease of 3 points or more in mMMSE score) occurred in five (5%) of 94 women in the high tertile for non-protein-bound oestradiol and in 17 (16%) of 106 in the low tertile (odds ratio 0.3 [95% CI 0.1-0.8]). After adjustment for age, years of education, body-mass index, current oestrogen use, history of surgical menopause, and baseline mMMSE score, the odds ratio was 0.3 (0.1-0.9). The results were similar for bioavailable oestradiol (five [5%] vs 15 [15%]; adjusted odds ratio 0.3 [0.1-1.0]). There was no association between risk of cognitive impairment and serum testosterone. Women with high serum concentrations of non-protein-bound and bioavailable oestradiol, but not testosterone, were less likely to develop cognitive impairment than women with low concentrations. This finding supports the hypothesis that higher concentrations of endogenous oestrogens prevent cognitive decline.
Article
1. Aged dogs display many of the cognitive impairments associated with aging and dementia. 2. Aged dogs, like humans, display a wide range of individual variability in cognitive functioning (i.e., different cognitive functions decline at different rates in aged dogs). 3. Different categories of aged canines can be identified on the basis of neuropsychological test performance, and these categories can be used to model different subgroups of aged humans (i.e., dementia, mild cognitive impairment and successful aging). 4. Additional research is required to further validate the dog as a model of human cognitive aging and dementia.
Article
Relatively few studies have investigated the relationship between endogenous sex steroid levels and cognition in older people and the reported results have been inconsistent. A number of experimental hormone replacement studies have suggested that estrogen replacement in older women enhances cognition, especially verbal memory. In contrast, little research has been done focusing on men. In the current study the association between endogenous sex steroids (estradiol and testosterone) and cognition was investigated in 38 healthy older women (mean age 68 years) and 30 healthy older men (mean age 69 years). Five cognitive tests measuring verbal memory, spatial memory, verbal fluency, mental rotation, and susceptibility to interference were administered. Results revealed that in women higher estradiol levels as well as testosterone levels were associated with better verbal memory (paired associates and estradiol; r =.38, P < 0.05; paired associates and testosterone; r =.33, P < 0.05;). Moreover estradiol, but not testosterone was associated with less susceptibility to interference (Stroop color word test; r = -0.34, P < 0.05). In men the only significant association was a negative correlation between testosterone and verbal fluency (r = -0.38, P < 0.05). The associations observed in this small study support the notion that estradiol is protecting verbal memory and possibly also frontal lobe mediated functions in older women. In contrast to the positive findings in women endogenous sex steroids do not appear to be closely linked to better cognition in older men.
Article
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.
Article
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.
Article
For the past 15 years we have investigated the aged beagle dog as a model for human aging and dementia. We have shown that dogs develop cognitive deficits and neuropathology seen in human aging and dementia. These similarities increase the likelihood that the model will be able to accurately predict the efficacy of Alzheimer's disease (AD) treatments as well as detect therapeutics with limited or no efficacy. Better predictive validity of cognitive-enhancing therapeutics (CETs) could lead to enormous cost savings by reducing the number of failed human clinical trials and also may reduce the likelihood of negative outcomes such as those recently observed in the AN-1792 clinical trials. The current review assesses the pharmacological validity of the canine model of human aging and dementia. We tested the efficacy of (1) CP-118,954 and phenserine, two acetylcholinesterase inhibitors, (2) an ampakine, (3) selegiline hydrochloride, two drugs that have failed human AD trials, and (4) adrafinil, a putative CET. Our research demonstrates that dogs not only develop isomorphic changes in human cognition and brain pathology, but also accurately predict the efficacy of known AD treatments and the absence or limited efficacy of treatments that failed clinical trials. These findings collectively support the utilization of the dog model as a preclinical screen for identifying novel CETs for both age-associated memory disorder and dementia.
Article
With increasing age, dogs develop a form of neurodegenerative disease which has many similarities to age related cognitive impairment and Alzheimer's disease in humans. A decline in learning and memory can be demonstrated in dogs beginning as young as 7 years of age using a variety of neuropsychological tests. However, clinical cases of cognitive dysfunction syndrome are seldom identified until the age of 11 years or older. This is likely due to the fact that the owners are relying on clinical observations such as house-soiling, sleep-wake cycles and disorientation, rather than tests of learning and memory. On the other hand, dogs that are trained to more exacting tasks such as guide dogs for the visually impaired, or bomb detection and agility trained dogs might be noticed to have a decline in performance at a much earlier age. Through the use of standardized neuropsychological testing protocols, a number of drugs, natural products and supplement formulations have been developed for use in dogs with cognitive dysfunction and, in some cases clinical trials have validated their efficacy. Furthermore, the testing of products currently licensed and in the pipeline for the treatment of cognitive decline and Alzheimer's in humans, may provide additional therapeutic agents for the treatment of senior dogs, as well as provide insight as to the potential for the efficacy of these compounds in humans. This review will examine those products that are now marketed along with some that might be considered for use in senior dogs with cognitive dysfunction as well as the research that has been used to validate the efficacy (or lack thereof) of these compounds.
Article
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.