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The Canine (Dog) Model of Human Aging and Disease: Dietary, Environmental and Immunotherapy Approaches
Abstract
Aged dogs (beagles) develop losses in executive function, learning and memory. The severity of decline in these cognitive domains represents a spectrum that captures normal aging, mild cognitive impairment and early/mild Alzheimer's disease (AD) in humans. In parallel, dogs naturally accumulate several types of neuropathology (although not all) consistent with human brain aging and AD including cortical atrophy, neuron loss, loss of neurogenesis, amyloid-beta (Abeta) plaques, cerebral amyloid angiopathy and oxidative damage. Many of these neuropathological features correlate with the extent of cognitive decline in a brain region-dependent manner. Dogs are ideally suited for longitudinal studies, and we provide a summary of the beneficial effects of an antioxidant diet, behavioral enrichment, and Abeta immunotherapy. In addition, combinatorial treatment approaches can be a powerful strategy for improving brain function through enhancement of multiple molecular pathways.
... The fMRI has become the primary means of non-invasively identifying the location of specific neuronal activities, e.g., in response to certain sensory stimuli or in connection with some task-driven motor activity (Cox & Savoy, 2003;Logothetis & Pfeuffer, 2004;Ulmer & Jansen, 2013). Similarities between humans and dogs regarding development, aging, and certain disorders affecting the central nervous system led researchers to focus on a deeper understanding of the canine brain (Adams et al., 2000;Cotman & Head, 2008;Head, 2013;Su et al., 1998). Various MRI-based canine brain templates have been developed, but the corresponding label maps either lack the level of detail required for an efficient fMRI analysis (Datta et al., 2012;Nitzsche et al., 2018) or they ...
... The canine brain has previously been examined with CT and MRI in several studies in the recent decades (Couturier et al., 2005;Hecht et al., 2019;Kärkkäinen et al., 1991;Kraft et al., 1989;Leigh et al., 2008;Martín-Vaquero et al., 2011) and has been presented in textbooks (Elliott & Skerritt, 2010;Gavin & Bagley, 2009;Wisner & Zwingenberger, 2015) and in histological (Palazzi, 2011) and diagnostic imaging atlases (Assheuer & Sager, 1997;Datta et al., 2012;Gomercic et al., 2009;Mai, 2018;Nitzsche et al., 2018;Schmidt & Kramer, 2015). Furthermore, due to similarities in development, aging and comorbidity between humans and dogs, investigations have recently focused on the canine central nervous system (Adams et al., 2000;Cotman & Head, 2008;Datta et al., 2012;Head, 2013;Su et al., 1998), and veterinary educational modules have also been published to aid in graduate learning (Christ et al., 2018;Raffan et al., 2017). Compared to the previously mentioned studies, one of the advantages of our 3D modelling methodology is that the created structures are more realistic due to the higher level of detail and surface morphology because of the original high-resolution cryosectioned images. ...
... Compared to the previously mentioned studies, one of the advantages of our 3D modelling methodology is that the created structures are more realistic due to the higher level of detail and surface morphology because of the original high-resolution cryosectioned images. Using the dog as a good translational model for human research is increasingly accepted (Andics et al., 2014;Andics & Miklósi, 2018;Bunford et al., 2017;Cotman & Head, 2008;Head, 2013;Khanna et al., 2006). Canine cognitive dysfunction (CCD) syndrome (Landsberg et al., 2017(Landsberg et al., , 2012Madari et al., 2015) also has some characteristics that are analogous to the early stages of human Alzheimer's disease, which indicates dogs as a promising model to more comprehensively study this disorder. ...
Our aim was to create high-quality macro-anatomical cross-sectional images and 3-dimensional (3D) models of a canine brain that could be paired with the results of magnetic resonance imaging (MRI) and computed tomography (CT) techniques from the same specimen. In this way, multimodal and multiplanar imaging was possible, and by segmenting certain structures various 3D models could be visualised together with the 2D image sets.
... Dogs with CCD exhibit signs of dementia, such as disorientation, anxiety, loss of learned behaviors, and changes in sleep cycles associated with neuronal loss and corresponding cortical atrophy within brain areas such as the prefrontal and frontal cortex, hippocampus, and limbic system [10][11][12]. The marked similarity of amyloid beta pathology between dogs and humans has led to the adoption of the dog as a model of early Alzheimer's disease [13][14][15][16][17][18][19]. As another parallel, dogs with DM develop an upper motor neuron paraparesis that progresses to generalized lower motor neuron tetraplegia over a period of 18-24 months. ...
... The Canine Dementia Scale evaluates seventeen items, distributed into four domains associated with behavioral changes (spatial orientation, social interactions, sleepwake cycles, and house soiling) and grades (normal, mild, moderate, and severe) are assigned for each item. The CADES score was used to classify dogs as normal (0-7), mild (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), moderate (24-44), or severe (45-95) cognitive impairment. ...
... The assessment of the efficacy of novel therapies for AD and ALS requires proper models and sensitive biomarkers that would reflect particular life stage and presymptomatic phases of the disease in a condensed period of time. Aging pet dogs represent a valuable model of spontaneously occurring neurodegenerative diseases due to the similarities in neurobiology and molecular cascades, the shared environmental risk factors between pet dogs and humans, comparable clinical phenotypes and pathology, the ability to provide advanced medical care in a manner comparable with human medical care, the beneficial genetic makeup of dog breeds, and the relatively truncated canine lifespan [8,16,18,38]. ...
Age is a primary risk factor for multiple comorbidities including neurodegenerative diseases. Pet dogs and humans represent two populations that have experienced a significant increase in average life expectancy over the last century. A higher prevalence of age-related neurodegenerative diseases has been observed across both species, and human diseases, such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), have canine analogs, canine cognitive dysfunction (CCD), and degenerative myelopathy (DM) respectively. In humans, protein biomarkers have proved useful in the prediction and diagnosis of neurodegeneration. Molecular signatures of many proteins are highly conserved across species. In this study, we explored the potential of the neuronal cytoskeletal protein neurofilament light chain (NfL) as a biomarker of neuro-aging in dogs using an ultrasensitive single-molecule array assay to measure plasma concentrations. Healthy dogs of different ages and dogs affected with CCD and DM were evaluated. The mean plasma NfL concentrations in the different age groups of the healthy population were as follows: 4.55 ± 1.70 pg/mL in puppy/junior group (0.43–2 years), 13.51 ± 6.8 pg/mL in adult/mature group (2.1–9 years), and 47.1 ± 12.68 pg/mL in geriatric/senior group (9.3–14.5 years). Concentrations in dogs with DM (7.5–12.6 years) and CCD (11.0–15.6 years) were 84.17 ± 53.57 pg/mL and 100.73 ± 83.72 pg/mL, respectively. Plasma NfL increases in an age-dependent manner and is significantly elevated in dogs diagnosed with neurodegenerative disease. This work identified plasma NfL as a key clinical index of neuro-aging and neurodegeneration in pet dogs. Our findings mirror recent reports from human neurodegenerative diseases.
... Canines share aging-related neuropathological features with humans, making for a valuable translational model for Alzheimer's disease (AD). Aging canines intrinsically develop diffuse β-amyloid (Aβ) pathology that is associated with cognitive decline akin to human mild cognitive impairment (MCI; Cotman and Head, 2008). Furthermore, cognitive functions tested in beagles that are relevant in AD, including spatial memory and executive function, are vulnerable to aging and Aβ burden Chan et al., 2002;Tapp et al., 2003;Rofina et al., 2006;Studzinski et al., 2006). ...
... Our negative finding with the current volumetric analysis is not surprising considering that tacrolimus, Q134R, and other peptide-based strategies targeting CN/NFAT-related signaling are known to affect cytoarchitectural and biochemical features including synaptic plasticity, neuroinflammation, and glutamate regulation (Dineley et al., 2007;Furman et al., 2012;Hudry et al., 2012;Sompol et al., 2017) that macrostructural measurements derived from T1-weighted imaging cannot detect. Furthermore, the majority of the dogs in this study had not yet reached the typical age where the effects of increasing Aβ burden such as oxidative stress, neurotoxicity, and neuronal loss become more prevalent, which begins ∼9 years old for beagles (developmentally similar to 60-year-old humans; Cotman and Head, 2008). Thus, the final two MRI sessions for the dogs collected at mean ages of 10.5 and 11.5 years will offer greater insights into whether chronic CN/NFAT inhibition ameliorates impairments related to Aβ burden and/or ultimately slows the trajectory of age-related cortical and subcortical atrophy. ...
Aging dogs serve as a valuable preclinical model for Alzheimer's disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that the frontal lobe showed accelerated atrophy with age, while the caudate nucleus remained relatively stable. Remarkably, the hippocampus increased in volume in all dogs. None of these changes were influenced by tacrolimus or Q134R treatment. Our results suggest that behavioral enrichment can prevent atrophy and increase the volume of the hippocampus but does not prevent aging-associated prefrontal cortex atrophy.
... Given the similarities between human and canine cognition that have been found across multiple domains, such as cognitive aging [19] and social cognition [20] we might expect a similar development in dogs: fewer separable factors in young dogs, with an increase in structural complexity in adult dogs. However, EFs that emerge later in human development are typically higher order EFs, such as Self-Monitoring (i.e., ability to monitor effects of behaviour on others) and Organisation of Materials, [i.e. ...
... This has mainly been shown in working dogs [26,27]. Additionally, a myriad of studies has demonstrated a decline in EF skills during aging in pet and laboratory dogs [19,[28][29][30][31][32][33][34][35]. There is evidence that training might mitigate cognitive decline during aging [30], but few studies have attempted to follow the trajectory of cognitive skills throughout the whole lifespan in dogs. ...
Executive Functions (EFs) are needed for effortful self-regulation of behaviour and are known to change over the lifespan in humans. In domestic dogs, EFs can be assessed through behavioural rating scales, such as the Dog Executive Function Scale (DEFS). The primary aim of this study was to investigate whether the DEFS, developed initially using a sample of adult dogs, can be used in juvenile (<1 year) and senior (>8 years) dogs. Confirmatory factor analysis of a juvenile and senior dog sample led to good model fit indices, indicating that juvenile and senior dogs’ EF structure follows the same functional organisation as found in the DEFS. The secondary aim was to analyse the lifespan development of EFs. Analysis of subscale scores revealed multifaceted relationships with age for four subscales. Working Memory and Attention Towards Owner showed the u-shaped curve traditionally associated with the lifespan development of EFs. Forms of inhibition showed complex associations with age, i.e., Delay Inhibition declined in aging and Motor Regulation increased during aging. Training history and Working Status influenced performance independent of age. More highly trained dogs and working dogs exhibited higher EF skills. Training history appeared more important for EF in non-working dogs than working dogs, perhaps because all working dogs receive a high level of training.
... The rapid development of veterinary medicine and continuous research towards human Alzheimer's disease (AD) are the main reasons why Canine Cognitive Dysfunction (CCD) syndrome is becoming more recognized (Cotman & Head, 2008;Head, 2011;Landsberg, 2005). The most reported symptoms in dogs are impairment in the behavioral categories of orientation, social interactions, house training, and sleep-wake cycle (Bain et al., 2001;Laubner et al., 2015). ...
... In vivo, MR imaging can be used to detect novel, indicative CCD signs like cortical, hippocampal atrophy, ventriculomegaly, diminution of interthalamic adhesion size, or presence of microhemorrhages. These parameters are also used to rule out other diseases such as neoplasia, infectious or inflammatory causes of the clinical representation (Cotman & Head, 2008;Dewey et al., 2020Dewey et al., , 2021Hasegawa et al., 2005;Kimotsuki et al., 2005;Madari et al., 2015;Tapp et al., 2006). ...
Canine Cognitive Dysfunction is a neurological condition, that causes dogs to experience a wide variety of clinical signs. On rare occasions the symptoms may be unusual and severe, therefore they reminiscent of another disease. In this case report a 16 year and 8-month-old intact female poodle presented with circling, head pressing, and generalized ataxia. Prior clinical and neurologic examinations indicated the neurolocalisation to be forebrain. Morphometric brain parameters in MRI indicated otherwise. Quantitative MRI parameters such as the ventricle-brain index, interthalamic adhesion thickness, area, and the ratio of the interthalamic adhesion thickness to brain height may aid in the diagnosis of CCD.
... The rapid development of veterinary medicine and continuous research towards human Alzheimer's disease (AD) are the main reasons why Canine Cognitive Dysfunction (CCD) syndrome is becoming more recognized (Cotman & Head, 2008;Head, 2011;Landsberg, 2005). The most reported symptoms in dogs are impairment in the behavioral categories of orientation, social interactions, house training, and sleep-wake cycle (Bain et al., 2001;Laubner et al., 2015). ...
... In vivo, MR imaging can be used to detect novel, indicative CCD signs like cortical, hippocampal atrophy, ventriculomegaly, diminution of interthalamic adhesion size, or presence of microhemorrhages. These parameters are also used to rule out other diseases such as neoplasia, infectious or inflammatory causes of the clinical representation (Cotman & Head, 2008;Dewey et al., 2020Dewey et al., , 2021Hasegawa et al., 2005;Kimotsuki et al., 2005;Madari et al., 2015;Tapp et al., 2006). ...
Canine Cognitive Dysfunction is a neurological condition, that causes dogs to experience a wide variety of clinical signs. On rare occasions the symptoms may be unusual and severe, therefore they reminiscent of another disease. In this case report a 16 year and 8-month-old intact female poodle presented with circling, head pressing, and generalized ataxia. Prior clinical and neurologic examinations indicated the neurolocalisation to be forebrain. Morphometric brain parameters in MRI indicated otherwise. Quantitative MRI parameters such as the ventricle-brain index, interthalamic adhesion thickness, area, and the ratio of the interthalamic adhesion thickness to brain height may aid in the diagnosis of CCD.
... Beagle dogs were chosen because they are commonly used for both PK and toxicology studies (18). More relevant to the present study, dogs are known to spontaneously develop cognitive deficit with age, as well as certain neuropathological hallmarks seen in aged human brain, particularly in the brains of AD patients (19,20). These include Aβ pathology, reduced brain volume, neuronal loss, and impaired neurogenesis (20,21). ...
... More relevant to the present study, dogs are known to spontaneously develop cognitive deficit with age, as well as certain neuropathological hallmarks seen in aged human brain, particularly in the brains of AD patients (19,20). These include Aβ pathology, reduced brain volume, neuronal loss, and impaired neurogenesis (20,21). In addition, several Aβ species, including Aβ40 and Aβ42, with an identical sequence to humans (22,23) are also present in dog's cerebrospinal fluid (CSF) and their profiles are similar between the canine and human CSF (18,24). ...
Purpose
We have recently demonstrated the brain-delivery of an Amyloid-ß oligomer (Aßo)-binding peptide-therapeutic fused to the BBB-crossing single domain antibody FC5. The bi-functional fusion protein, FC5-mFc-ABP (KG207-M) lowered both CSF and brain Aß levels after systemic dosing in transgenic mouse and rat models of Alzheimer’s disease (AD). For development as a human therapeutic, we have humanized and further engineered the fusion protein named KG207-H. The purpose of the present study was to carry out comparative PK/PD studies of KG207-H in wild type rat and beagle dogs (middle-aged and older) to determine comparability of systemic PK and CSF exposure between rodent species and larger animals with more complex brain structure such as dogs.
Method
Beagle dogs were used in this study as they accumulate cerebral Aß with age, as seen in human AD patients, and can serve as a model of sporadic AD. KG207-H (5 to 50 mg/kg) was administered intravenously and serum and CSF samples were serially collected for PK studies and to assess target engagement. KG207-H and Aβ levels were quantified using multiplexed selected reaction monitoring mass spectrometry.
Results
After systemic dosing, KG207-H demonstrated similar serum pharmacokinetics in rats and dogs. KG207-H appeared in the CSF in a time- and dose-dependent manner with similar kinetics, indicating CNS exposure. Further analyses revealed a dose-dependent inverse relationship between CSF KG207-H and Aß levels in both species indicating target engagement.
Conclusion
This study demonstrates translational attributes of BBB-crossing Aβ-targeting biotherapeutic KG207-H in eliciting a pharmacodynamic response, from rodents to larger animal species.
... The ability to learn simple tasks such as simple associative learning is not affected in healthy senior dogs, however, senior dogs have decreased ability to learn prefrontal-dependent tasks [1]. Senior dogs showed deficits in learning, memory, executive function, and attention [21,[64][65][66]. Based on cognitive performance, senior dogs can be classified into successful agers, mild cognitive impairment, and cognitive dysfunction syndrome (CDS) [9,10]. ...
... The neuron density was significantly reduced in the brains of dogs with CDS compared with age-matched control dogs. [1,4,8,[21][22][23][24]113] Cerebral amyloid angiopathy Amyloid (Aβ1-40) deposits in blood vessel walls. ...
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.
... There are common pathologies between familial AD and sporadic AD, such as the deposition of Aβ, the hyperphosphorylation of Tau, and neuronal loss, but their differences cause failure in the development of therapeutic drugs [55]. Recently, many studies have focused on ideal AD animal models, including natural aging-based AD-like canine models, to overcome the limitations of treatment and predict validity in human clinical applications [56,57]. Aged dogs offer an advantage over nontransgenic aged rodent species because they naturally produce Aβ, which has an identical amino acid sequence to the human protein and results from similar biochemical processing of the amyloid precursor protein. ...
... Aged dogs offer an advantage over nontransgenic aged rodent species because they naturally produce Aβ, which has an identical amino acid sequence to the human protein and results from similar biochemical processing of the amyloid precursor protein. Aged beagles have been shown to develop cognitive dysfunction associated with neuropathology that resembles certain aspects of human AD-related cognitive deficits [57]. Moreover, guinea pigs are a developing animal model of AD featuring a human-like Aβ sequence with age-dependent diffuse accumulation of amyloid pathology [58]. ...
Background
Stem cell transplantation is a fascinating therapeutic approach for the treatment of many neurodegenerative disorders; however, clinical trials using stem cells have not been as effective as expected based on preclinical studies. The aim of this study is to validate the hypothesis that human neural crest-derived nasal turbinate stem cells (hNTSCs) are a clinically promising therapeutic source of adult stem cells for the treatment of Alzheimer’s disease (AD).
Methods
hNTSCs were evaluated in comparison with human bone marrow-derived mesenchymal stem cells (hBM-MSCs) according to the effect of transplantation on AD pathology, including PET/CT neuroimaging, immune status indicated by microglial numbers and autophagic capacity, neuronal survival, and cognition, in a 5 × FAD transgenic mouse model of AD.
Results
We demonstrated that hNTSCs showed a high proliferative capacity and great neurogenic properties in vitro . Compared with hBM-MSC transplantation, hNTSC transplantation markedly reduced Aβ42 levels and plaque formation in the brains of the 5 × FAD transgenic AD mice on neuroimaging, concomitant with increased survival of hippocampal and cortex neurons. Moreover, hNTSCs strongly modulated immune status by reducing the number of microglia and the expression of the inflammatory cytokine IL-6 and upregulating autophagic capacity at 7 weeks after transplantation in AD models. Notably, compared with transplantation of hBM-MSCs, transplantation of hNTSCs significantly enhanced performance on the Morris water maze, with an increased level of TIMP2, which is necessary for spatial memory in young mice and neurons; this difference could be explained by the high engraftment of hNTSCs after transplantation.
Conclusion
The reliable evidence provided by these findings reveals a promising therapeutic effect of hNTSCs and indicates a step forward the clinical application of hNTSCs in patients with AD.
... In this regard, family dogs living as animal companions with their owners could be even more relevant than laboratory dogs (Kaeberlein, 2016). Although laboratory dogs had been traditionally used for a wide range of investigations, including aging research (Cotman and Head, 2008), they have some major limitations. For example, they experience a less complex nutritional and environmental history during their life course than family dogs do, which could lead to major deviances in their base level behavioral parameters. ...
... The mean lifespan of companion dogs (purebred and crossbred together) from Europe and Japan were shown to be 12 and 13.7 years, respectively (O'Neill et al., 2013;Inoue et al., 2018), while the mean lifespan of European humans is 77.2, according to a UN report (Anon, 2019) and is around 83 years for Japanese people (Tokudome et al., 2016). Therefore, follow-up studies are much easier in the case of dogs, and have already been performed by several research groups to measure immunological, neuropathological, and metabolomic changes related to canine aging (Su et al., 2005;Greeley et al., 2006;Cotman and Head, 2008). 2. The fact that the mean lifespan of dogs can range from 5.5 to 14.5 years (Michell, 1999;O'Neill et al., 2013;Jimenez, 2016), depending on body size and breed, suggests that dogs, sharing their lives with humans, gained considerable advantages from this alliance by doubling their mean expected lifespan compared to wild wolves (Mech, 2006). ...
Aging research has experienced a burst of scientific efforts in the last decades as the growing ratio of elderly people has begun to pose an increased burden on the healthcare and pension systems of developed countries. Although many breakthroughs have been reported in understanding the cellular mechanisms of aging, the intrinsic and extrinsic factors that contribute to senescence on higher biological levels are still barely understood. The dog, Canis familiaris, has already served as a valuable model of human physiology and disease. The possible role the dog could play in aging research is still an open question, although utilization of dogs may hold great promises as they naturally develop age-related cognitive decline, with behavioral and histological characteristics very similar to those of humans. In this regard, family dogs may possess unmatched potentials as models for investigations on the complex interactions between environmental, behavioral, and genetic factors that determine the course of aging. In this review, we summarize the known genetic pathways in aging and their relevance in dogs, putting emphasis on the yet barely described nature of certain aging pathways in canines. Reasons for highlighting the dog as a future aging and gerontology model are also discussed, ranging from its unique evolutionary path shared with humans, its social skills, and the fact that family dogs live together with their owners, and are being exposed to the same environmental effects.
... Therefore, a comprehensive approach involving thorough epidemiological and clinical evaluations was adopted. In addition, the results could provide interesting insights on human aging as dogs are recognized as a valuable model due to their similar illnesses, shared lifestyle patterns with their owners (including material and social environments, and activity levels), and their capacity for human-like social relationships [19,20]. ...
Background
As dogs age, they face various health challenges, and preventive care may be overlooked, impacting their quality of life. Frailty, a concept established in human medicine, has recently been applied to dogs using validated tools like the frailty index and frailty phenotype. This study aims to characterize frailty in senior pet dogs and investigate associated factors. To achieve this goal, 88 apparently healthy dogs, as reported by their owners, voluntarily participated in thorough consultations. These consultations included supplementary examinations such as urinary analyses, hematological assessments, and blood biochemistry. Additionally, owners completed questionnaires addressing their dog's overall health, cognitive and locomotor status, as well as their own attachment to the dog and personality traits. Subsequently, each dog was classified as robust or frail based on the presence of multiple criteria out of a set of five. All collected data underwent preliminary screening by a multiple factorial analysis, followed by binomial logistic regression to model frailty.
Results
The final population consisted of 74 dogs, with a frailty prevalence of 41.9% (95% CI: 30.5 – 53.9). In the statistical analysis, older age of the dog, lower owner attachment score, lack of regular deworming, and a disparity in extraversion between owner and dog were identified as contributing factors to frailty.
Conclusions
This study emphasizes the importance of regular deworming and strong owner-pet attachment in reducing frailty in dogs. It underscores the significance of proactive pet care and highlights the complex relationship between owner-dog personalities and canine frailty. This research advocates for a holistic approach that considers both human and canine traits to promote better health outcomes.
... As this damage increases with age [83], a diet enriched with antioxidants, such as vitamins C and E, can slow the progression of cognitive decline and promote healthy aging [17]. Especially when combined with environmental enrichment, antioxidants have been shown to improve the learning ability and memory of old dogs [26,37,43,84]. In human medicine, various studies show that deficiencies in vitamin B may lead to cognitive impairment [51,85] and the supplementation of this vitamin can slow cognitive decline [86]. ...
Simple Summary
Canine cognitive dysfunction is considered the canine equivalent to human Alzheimer’s disease. It is a growing concern in veterinary medicine, as it affects many aged dogs. Dietary intervention with different diets and supplements may improve clinical signs and prevent further degeneration. Using an online questionnaire, we found that even though few owners were willing to change their dog’s main diet, many of them added supplements such as oils and vitamins. Consulting a veterinary surgeon when using dietary supplements is important as it allows for evidence-based recommendations to be made.
Abstract
Canine cognitive dysfunction (CCD) is becoming increasingly recognized in veterinary medicine, as dogs live longer and with CCD being highly prevalent among the elderly dog population. Various studies have shown that diet and dietary supplementation can positively influence the clinical signs of CCD, especially if given at an early stage. The aim of this study was to investigate owner use of dietary supplements (DSs) in dogs with age-related behavioral changes. An observational study based on an online questionnaire for owners of dogs with age-related behavioral changes was performed. Out of a total of 394 owners who completed the survey, after noticing age-related behavioral changes, over half of the dogs received DSs (54%), whereas only 8% reported changing their dog’s base diet. The most used DS was fish oil (48%). The use of DSs should be discussed with and monitored by veterinary surgeons since many geriatric patients have multi-morbidities, may have specific nutritional requirements and receive multi-faceted medications.
... 62 In the context of aging, dogs have been considered as suitable models for preclinical studies of AD, to investigate effects of dietary factors, behavior, and therapies targeting Aβ aggregation. [63][64][65] To quantify the extent to which AD models can reflect human AD pathologies, integrated omics platforms for studying the molecular signatures of neurodegenerative diseases in preclinical models and post mortem human brains have proven useful, 66 ...
INTRODUCTION
Experimental models are essential tools in neurodegenerative disease research. However, the translation of insights and drugs discovered in model systems has proven immensely challenging, marred by high failure rates in human clinical trials.
METHODS
Here we review the application of artificial intelligence (AI) and machine learning (ML) in experimental medicine for dementia research.
RESULTS
Considering the specific challenges of reproducibility and translation between other species or model systems and human biology in preclinical dementia research, we highlight best practices and resources that can be leveraged to quantify and evaluate translatability. We then evaluate how AI and ML approaches could be applied to enhance both cross‐model reproducibility and translation to human biology, while sustaining biological interpretability.
DISCUSSION
AI and ML approaches in experimental medicine remain in their infancy. However, they have great potential to strengthen preclinical research and translation if based upon adequate, robust, and reproducible experimental data.
Highlights
There are increasing applications of AI in experimental medicine.
We identified issues in reproducibility, cross‐species translation, and data curation in the field.
Our review highlights data resources and AI approaches as solutions.
Multi‐omics analysis with AI offers exciting future possibilities in drug discovery.
... For example, aged dogs mainly accumulate Aß deposits with a similar amino acid sequence to the human protein which is an advantage over transgenic mouse models. But, Tau pathology, including aggregated intraneuronal topographies and pre-tangles is very limited in aged dogs [125,133,134]. Aß is also presented in canine's CSF and the ratio of Aß42/Aß40 declines with age [125]. ...
A form of dementia distinct from healthy cognitive aging, Alzheimer's disease (AD) is a complex multi-stage disease that currently afflicts over 50 million people worldwide. Unfortunately, previous therapeutic strategies developed from murine models emulating different aspects of AD pathogenesis have failed. Consequently, researchers are now developing models that express several aspects of pathogenesis that better reflect the clinical situation in humans. As such, this review seeks to provide insight regarding current applications of mammalian models in AD research by addressing recent developments and characterizations of prominent transgenic models and their contributions to pathogenesis as well as discuss the advantages, limitations, and application of emerging models (hAβ-KI) that better capture genetic heterogeneity and mixed pathologies observed in the clinical situation.
... Since epigenetic responses to environmental factors occur actively in dogs as in humans, comparative medical studies using dogs have been conducted on aging, tumor biogenesis, and inflammatory diseases [13]. It has been reported that dogs might be helpful animal models for immunotherapy studies because they are immune-competent, and their tumor biology is similar to that of humans [14]. ...
Background:
Genome-wide dysregulation of CpG methylation accompanies tumor progression and characteristic states of cancer cells, prompting a rationale for biomarker development. Understanding how the archetypic epigenetic modification determines systemic contributions of immune cell types is the key to further clinical benefits.
Results:
In this study, we characterized the differential DNA methylome landscapes of peripheral blood mononuclear cells (PBMCs) from 76 canines using methylated CpG-binding domain sequencing (MBD-seq). Through gene set enrichment analysis, we discovered that genes involved in the growth and differentiation of T- and B-cells are highly methylated in tumor PBMCs. We also revealed the increased methylation at single CpG resolution and reversed expression in representative marker genes regulating immune cell proliferation (BACH2, SH2D1A, TXK, UHRF1). Furthermore, we utilized the PBMC methylome to effectively differentiate between benign and malignant tumors and the presence of mammary gland tumors through a machine-learning approach.
Conclusions:
This research contributes to a better knowledge of the comprehensive epigenetic regulation of circulating immune cells responding to tumors and suggests a new framework for identifying benign and malignant cancers using genome-wide methylome.
... This questionnaire evaluates four domains of behavioral changes (spatial orientation, social interaction, sleep-wake cycles and house soiling) across seventeen questions. The total score ranges from 0 to 95 and allows classification of the dogs into four categories: normal (0-7), mild (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), moderate or severe (45-85) cognitive dysfunction. ...
Maintaining an active lifestyle is considered a hallmark of successful aging. Physical activity significantly reduces the risk of cognitive decline and Alzheimer’s disease in humans. However, pain and lack of motivation are important barriers to exercise. Dogs are a remarkable model for translational studies in aging and cognition as they are prone to Canine Cognitive Dysfunction syndrome, which has many similarities with Alzheimer’s disease. According to owner reports, changes in activity levels are characteristic of this syndrome, with decreased daytime activity, but also excessive pacing, especially at sleep time. We used physical activity monitors to record the activity of 27 senior dogs and evaluated the association between activity level and age, fractional lifespan, cognitive status measured by an owner questionnaire and cognitive tests. We also assessed the relationship between activity and joint/spinal pain, and the off/on leash gait speed ratio (a potential marker of gait speed reserve and motivation). We found that activity patterns in dogs are associated with fractional lifespan and working memory. Additionally, dogs with higher on/off leash gait speed are more active in the afternoon of weekdays. These results encourage future studies evaluating how physical activity can improve or delay cognitive impairment in senior dogs.
... Since epigenetic responses to environmental factors occur actively in dogs as in humans, comparative medical studies using dogs have been conducted on aging, tumor biogenesis, and in ammatory diseases [13]. It has been reported that dogs might be helpful animal models for immunotherapy studies because they are immune-competent, and their tumor biology is similar to that of humans [14]. ...
Background
Genome-wide dysregulation of CpG methylation accompanies tumor progression and characteristic states of cancer cells, prompting a rationale for biomarker development. Understanding how the archetypic epigenetic modification determines systemic contributions of immune cell types is the key to further clinical benefits.
Results
In this study, we characterized the differential DNA methylome landscapes of peripheral blood mononuclear cells (PBMCs) from 76 canines using methylated CpG-binding domain sequencing (MBD-seq). Through gene set enrichment analysis, we discovered that genes involved in the growth and differentiation of T- and B-cells are highly methylated in tumor PBMCs. We also revealed the increased methylation at single CpG resolution and reversed expression in representative marker genes regulating immune cell proliferation (BACH2, SH2D1A, TXK, UHRF1). Furthermore, we utilized the PBMC methylome to effectively differentiate between benign and malignant tumors and the presence of mammary gland tumors through a machine-learning approach.
Conclusions
This research contributes to a better knowledge of the comprehensive epigenetic regulation of circulating immune cells responding to tumors and suggests a new framework for identifying benign and malignant cancers using genome-wide methylome.
... Cognitive tests represent a method of direct evaluation of dogs that allows for the assessment of their cognitive state. Several cognitive tests that measure the learning abilities and spatial memory of dogs have been used and provide valuable information on cognitive impairment [15][16][17][18][19]. It was observed, for example, that aged dogs usually do not demonstrate decline in simple tasks as a spatial memory task, such as when they are repetitively rewarded for approaching one of two different locations [20]. ...
Cognitive dysfunction syndrome is the most common cause of cognitive decline in aged dogs. Early diagnosis is crucial because the sooner treatment is implemented, the greater the chance of slowing the progression of the disease. Assessment tools to assess cognitive decline may differ depending on the environment in which the dogs live. The aims of this study were threefold, first, to describe two feasible methods to evaluate cognitive impairment in aged dogs living in different environments: (i) a Canine Cognitive Assessment Scale (CCAS) for dogs living in a home environment and (ii) a practical cognitive test (PCT) potentially useful for dogs not living in a home environment (NHE); second, to assess the effect of age on the outcome of both tools and, finally, to compare the results of the CCAS with those of the PCT. Both methods were found to be practical to perform. Age was found to significantly predict the score obtained by the CCAS (p = 0.0011) and the outcome of the PCT (p = 0.009). However, the reversal phase from the PCT did not significantly predict the outcomes of the CCAS (p = 0.97). Taken together, these findings suggest that the CCAS is a practical method to evaluate age related cognitive changes in owned dogs. The fact that the PCT has not been proven to be related with the CCAS calls into question the use of the PCT as a sensitive tool to assess cognitive impairment. Further studies in this field are suggested.
... Dozens of studies have shown that signs of age-related neurodegeneration in dogs are often accompanied by cognitive dysfunction in learning and memory analogous to impairments often seen in human aging and Alzheimer's disease [24][25][26][27][28]. Although the full complement of Alzheimer's disease neuropathology has yet to be consistently observed in any naturally occurring nonhuman animal model, Alzheimer-like pathology, e.g., Aβ 1-42, increases with age in companion dogs [29,30] and has been described in the context of diffuse plaque deposition that has been related to cognitive decrements in older dogs [31]. There is also preliminary evidence for tauopathy, another feature of Alzheimer-like pathology, in the brains of dogs diagnosed with canine cognitive dysfunction [32]. ...
Canine cognitive dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer's disease. Given that physical activity is believed to reduce risk of Alzheimer's disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity-with several important covariates-as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = - 0.10, 95% CI: - 0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = - 0.07, 95% CI: - 0.09 to - 0.05, p < 0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p < 0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer's disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical activity interventions.
... Using a model based on Canis familiaris (dog) material, we aimed to investigate the molecular basis of ASC differentiation into chondrocytes, to serve as a transcriptomic reference for further research aiming to introduce ASC into treatment of cartilage related veterinary diseases, such as osteoarthritis. The canine model was chosen due to the wide availability of dog adipose tissue, a remnant material of routine surgeries, as well as the possibility of use of the obtained results as a reference for further in vivo and clinical studied in the field of veterinary medicine [18,19]. Furthermore, there is an added potential of future cross-referencing of the knowledge obtained with similar datasets regarding other experimental models, such as mice, or even humans. ...
The interest in stem cell research continuously increased over the last decades, becoming one of the most important trends in the 21st century medicine. Stem cell-based therapies have a potential to become a solution for a range of currently untreatable diseases, such as spinal cord injuries, type I diabetes, Parkinson’s disease, heart disease, stroke, and osteoarthritis. Hence, this study, based on canine material, aims to investigate the molecular basis of adipose-derived stem cell (ASC) differentiation into chondrocytes, to serve as a transcriptomic reference for further research aiming to introduce ASC into treatment of bone and cartilage related diseases, such as osteoarthritis in veterinary medicine. Adipose tissue samples were harvested from a canine specimen subjected to a routine ovariohysterecromy procedure at an associated veterinary clinic. The material was treated for ASC isolation and chondrogenic differentiation. RNA samples were isolated at day 1 of culture, day 30 of culture in unsupplemented culture media, and day 30 of culture in chondrogenic differentiation media. The resulting RNA was analyzed using RNAseq assays, with the results validated by RT-qPCR. Between differentiated chondrocytes, early and late cultures, most up- and down-regulated genes in each comparison were selected for further analysis., there are several genes (e.g., MMP12, MPEG1, CHI3L1, and CD36) that could be identified as new markers of chondrogenesis and the influence of long-term culture conditions on ASCs. The results of the study prove the usefulness of the in vitro culture model, providing further molecular insight into the processes associated with ASC culture and differentiation. Furthermore, the knowledge obtained could be used as a molecular reference for future in vivo and clinical studies.
... They have a lifespan of 12 to 14 years, individuals over 9 years are considered "old", being associated with people between 66 and 96 years (26,33). As in humans, the cognitive and neurobiological changes are observed in dogs from middle age (6-8 years) and become more visible as they age, some dogs developing the early stages and symptoms of Alzheimer's disease (7,16). Because the duration of studies on ageing in Beagle dogs is time consuming and leads to huge costs, scientists have resorted to models of accelerated ageing caused experimentally by chemical compounds, such as D-galactose (29). ...
The paper reviews literature data with respect to the importance of studies performed on dogs for indepth knowledge of their behaviour and behavioural expression. Given the close cohabitation of dogs and humans, the study of dogs' behaviour is an important
goal in selecting specialized breeds for various activities related to humans, where an aggressive or an unstable temperament should be avoided. Moreover, the nowadays dogs' lifestyle is similar to humans being even reported some behavioural disorders or developmental pathologies similar to humans. Therefore, considering the conditions and causes of these issues, most often similar to humans, the control, therapy or prevention of them in both humans and dogs may be discussed.
... Finding an appropriate animal model with a higher predictive capacity would greatly augment the development of drugs and other forms of interventions. Laboratory dogs have already been traditionally used as preclinical models to test drugs, and many studies have investigated aspects of brain aging in laboratory dog populations [9,10]. However, keeping laboratory dogs for aging and dementia research would not necessarily be a cost-effective solution as the spatial, time, and financial requirements greatly exceed the needs of smaller laboratory animals. ...
Dogs may possess a unique translational potential to investigate neural aging and dementia because they are prone to age-related cognitive decline, including an Alzheimer’s disease–like pathological condition. Yet very little is known about the molecular mechanisms underlying canine cognitive decline. The goal of the current study was to explore the transcriptomic differences between young and old dogs’ frontal cortex, which is a brain region often affected by various forms of age-related dementia in humans. RNA isolates from the frontal cortical brain area of 13 pet dogs, which represented 7 different breeds and crossbreds, were analyzed. The dogs were euthanized for medical reasons, and their bodies had been donated by their owners for scientific purposes. The poly(A) tail RNA subfraction of the total transcriptome was targeted in the sequencing analysis. Cluster analyses, differential gene expression analyses, and gene ontology analyses were carried out to assess which genes and genetic regulatory mechanisms were mostly affected by aging. Age was the most prominent factor in the clustering of the animals, indicating the presence of distinct gene expression patterns related to aging in a genetically variable population. A total of 3436 genes were found to be differentially expressed between the age groups, many of which were linked to neural function, immune system, and protein synthesis. These findings are in accordance with previous human brain aging RNA sequencing studies. Some genes were found to behave more similarly to humans than to rodents, further supporting the applicability of dogs in translational aging research.
... For example, mice do not naturally develop age-related AD-like pathology, and consequently, all currently used mouse models have been genetically engineered to specifically develop various aspects of AD-like pathology [6,7]. Laboratory Beagle dogs do spontaneously develop AD-like pathology as they age [8]; however, they are kept in a laboratory setting that fails to model the environmental variation experienced by people. Similarly, both AD-model mouse strains and laboratory Beagle dogs are relatively genetically inbred and fail to capture the impact of genetic diversity on AD progression and clinical presentation. ...
Alzheimer’s disease (AD) is a significant burden for human health that is increasing in prevalence as the global population ages. There is growing recognition that current preclinical models of AD are insufficient to recapitulate key aspects of the disease. Laboratory models for AD include mice, which do not naturally develop AD-like pathology during aging, and laboratory Beagle dogs, which do not share the human environment. In contrast, the companion dog shares the human environment and presents a genetically heterogeneous population of animals that might spontaneously develop age-associated AD-like pathology and cognitive dysfunction. Here, we quantitatively measured amyloid beta (Aβ42 or Abeta-42) levels in three areas of the companion dog brain (prefrontal cortex, temporal cortex, hippocampus/entorhinal cortex) and cerebrospinal fluid (CSF) using a newly developed Luminex assay. We found significant positive correlations between Aβ42 and age in all three brain regions. Brain Aβ42 abundance in all three brain regions was also correlated with Canine Cognitive Dysfunction Scale score in a multivariate analysis. This latter effect remained significant when correcting for age, except in the temporal cortex. There was no correlation between Aβ42 in CSF and cognitive scores; however, we found a significant positive correlation between Aβ42 in CSF and body weight, as well as a significant negative correlation between Aβ42 in CSF and age. Our results support the suitability of the companion dog as a model for AD and illustrate the utility of veterinary biobanking to make biospecimens available to researchers for analysis.
... In addition, dysfunction of gut-brain axis has been associated with neurodegenerative disorders [21,22]. In old dogs, a cognitive decline can be observed through human-like learning and memory deficits [23]. ...
Since dogs are part of many peoples’ lives, research and industry related to their health and longevity are becoming a rising topic. Although gut microbiota (GM) is a key contributor to host health, limited information is available for canines. Therefore, this study characterized GM according to individual signatures (e.g., breed, age, and body condition score—BCS) of dogs living in the same environment. Fresh fecal samples from 96 healthy dogs were analyzed by sequencing the V3-V4 region of the 16S rRNA gene. The major microbial phyla were Firmicutes, Bacteroidetes, Fusobacteria, Proteobacteria, and Actinobacteria. In the comparison by breeds, relative abundance of Fusobacterium was significantly differed. Interestingly, Fusobacterium perfoetens abundance was positively correlated with age (p = 0.018), being significantly more enriched in the 6–10-year-old group (14.3%) than in the 0.5–1-year-old group (7.2%). Moreover, despite the healthy appearance of dogs in all age (0.5–10 years) and BCS (3–6) groups, the gut microbial environment may be disadvantageous in older dogs or in dogs with an abnormal BCS. These findings broaden our understanding of gut microbial ecology according to individual characteristics of dogs and may be used as a reference for providing customized-care to companion animals.
... Therefore, to enable the widespread adoption of this cell type in routine medical practice, a significant amount of wide-scale studies of the processes occurring during the procedures associated with current and potential applications of these cells are still needed to fully discover their actual clinical usefulness, as well as the possible risks associated with their grafting. The canine (Canis familiaris) source of stem cells is a relatively widely available model for human studies while also allowing for understanding canine stem cells as a potentially effective treatment in veterinary medicine [4,20,21]. ...
Next-generation sequencing (RNAseq) analysis of gene expression changes during the long-term in vitro culture and osteogenic differentiation of ASCs remains to be important, as the analysis provides important clues toward employing stem cells as a therapeutic intervention. In this study, the cells were isolated from adipose tissue obtained during routine surgical procedures and subjected to 14-day in vitro culture and differentiation. The mRNA transcript levels were evaluated using the Illumina platform, resulting in the detection of 19,856 gene transcripts. The most differentially expressed genes (fold change >|2|, adjusted p value < 0.05), between day 1, day 14 and differentiated cell cultures were extracted and subjected to bioinformatical analysis based on the R programming language. The results of this study provide molecular insight into the processes that occur during long-term in vitro culture and osteogenic differentiation of ASCs, allowing the re-evaluation of the roles of some genes in MSC progression towards a range of lineages. The results improve the knowledge of the molecular mechanisms associated with long-term in vitro culture and differentiation of ASCs, as well as providing a point of reference for potential in vivo and clinical studies regarding these cells’ application in regenerative medicine.
... Studies have shown that aged dogs experience a decline in EF skills, and that environmental enrichment, such as exercise, play, social contact, and diet can influence individuals' EF skills in aging dogs. This phenomenon has been intensively studied and reviewed (Adams et al. 2000a, b;Chapagain et al. 2018a, b;Cotman and Head 2008;Cotman et al. 2002;Davis et al. 2017;de Rivera et al. 2005;Fahnestock et al. 2012;Head et al. 2012). However, much less is known about how experiences during the dog's puppyhood, adolescence and early adult life shape its EFs. ...
Executive functions (EFs) are a set of cognitive processes used for effortful self-regulation of behaviour. They include inhibition, working memory, cognitive flexibility and, in some models, attention. In humans, socioeconomic factors and life experiences shape development of EFs. Domestic dogs (Canis familiaris) must often regulate their behaviour in the human environment (e.g. no jumping up on humans or chasing cats), and life experiences also probably influence the development of EFs in dogs. Research into dog cognition and behaviour has been thriving, and some methods used to explore these concepts (e.g. object-choice task, questionnaires measuring traits like distraction and aggression) are likely to be sensitive to differences in EFs, even if that is not their stated aim. Here we examine relevant studies to identify experiential factors which may influence the development of EFs in dogs living in human care. These are early experience, training, housing and stress. We conclude that the development of dogs’ EFs may be negatively affected by hardships, and positively by surmountable challenges, early in life. Training methods appear important, with punishment-based methods leading to poorer dog EFs. Kennel environments seem to affect dog EFs negatively. While mild stressors might enhance the development of EFs, too much stress seems to have negative effects. Regulation of behaviour, a key outcome of EFs, is crucial for dogs’ integration into human society. We should, therefore, strive to better understand how the environment shapes dogs’ EFs.
... The domestic dog is one of very few species that spontaneously develop agedependent dementia, coined CCD, with a relatively well-defined clinical phenotype. With respect to clinical hallmarks and neuropathology, CCD shares many characteristics with sporadic AD in its early stages, and dogs suffering from this condition may therefore hold potential as a nonexperimental large animal model that might help to fill the translational gap between AD patients and AD models, either in vitro or transgenic rodent in vivo platforms (Cummings et al., 1996b;Cotman and Head, 2008;Yu et al., 2011;Schütt et al., 2018). 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). ...
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.
... Aged beagles have been shown to develop cognitive dysfunction associated with neuropathology that resembles certain aspects of human AD-related cognitive deficits. 21 In addition, diet notwithstanding, domesticated dogs are also are exposed to environmental risk factors that are more similar to humans than in rodent models. 22 The pattern of Aβ deposition in aged dogs correlates positively with cognitive impairment and negatively with CSF levels of Aβ42. ...
Over 5 million Americans and 50 million individuals worldwide are living with Alzheimer's disease (AD). The progressive dementia associated with AD currently has no cure. Although clinical trials in patients are ultimately required to find safe and effective drugs, animal models of AD permit the integration of brain pathologies with learning and memory deficits that are the first step in developing these new drugs. The purpose of the Alzheimer's Association Business Consortium Think Tank meeting was to address the unmet need to improve the discovery and successful development of Alzheimer's therapies. We hypothesize that positive responses to new therapies observed in validated models of AD will provide predictive evidence for positive responses to these same therapies in AD patients. To achieve this goal, we convened a meeting of experts to explore the current state of AD animal models, identify knowledge gaps, and recommend actions for development of next-generation models with better predictability. Among our findings, we all recognize that models reflecting only single aspects of AD pathogenesis do not mimic AD. Models or combinations of new models are needed that incorporate genetics with environmental interactions, timing of disease development, heterogeneous mechanisms and pathways, comorbidities, and other pathologies that lead to AD and related dementias. Selection of the best models requires us to address the following: (1) which animal species, strains, and genetic backgrounds are most appropriate; (2) which models permit efficient use throughout the drug development pipeline; (3) the translatability of behavioral-cognitive assays from animals to patients; and (4) how to match potential AD therapeutics with particular models. Best practice guidelines to improve reproducibility also need to be developed for consistent use of these models in different research settings. To enhance translational predictability, we discuss a multi-model evaluation strategy to de-risk the successful transition of pre-clinical drug assets to the clinic.
... This is due to the combined efforts of researchers conducting veterinary and human pre-clinical studies. Dogs are commonly used as pre-clinical models of cancer [25], heart disease [26], and other disorders [27]. There is also a body of literature describing drug transport into the mammary gland of cattle because of the obvious economic and human health concerns related to this issue [28,29]. ...
Xenobiotic transport proteins play an important role in determining drug disposition and pharmacokinetics. Our understanding of the role of these important proteins in humans and pre-clinical animal species has increased substantially over the past few decades, and has had an important impact on human medicine; however, veterinary medicine has not benefitted from the same quantity of research into drug transporters in species of veterinary interest. Differences in transporter expression cause difficulties in extrapolation of drug pharmacokinetic parameters between species, and lack of knowledge of species-specific transporter distribution and function can lead to drug–drug interactions and adverse effects. Horses are one species in which little is known about drug transport and transporter protein expression. The purpose of this mini-review is to stimulate interest in equine drug transport proteins and comparative transporter physiology.
... 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. ...
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.
... The domestic dog is one of very few species that spontaneously develop agedependent dementia, coined CCD, with a relatively well-defined clinical phenotype. With respect to clinical hallmarks and neuropathology, CCD shares many characteristics with sporadic AD in its early stages, and dogs suffering from this condition may therefore hold potential as a nonexperimental large animal model that might help to fill the translational gap between AD patients and AD models, either in vitro or transgenic rodent in vivo platforms (Cummings et al., 1996b;Cotman and Head, 2008;Yu et al., 2011;Schütt et al., 2018). 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). ...
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.
... The study population of dogs and humans included a wide range of ages; however, the range in age between boxers and nonboxers was different and likely responsible for the difference in the relationship of age to time domain indices of heart rate variability. Equating dog age to human age is known to be difficult, non-linear and highly variable depending on the breed of dog (Cotman and Head, 2008). Consequently, attempts to compare the influence of age between the dog and human from our study is not possible. ...
The human and dog have sinus arrhythmia; however, the beat-to-beat interval changes were hypothesized to be different. Geometric analyses (R–R interval tachograms, dynamic Poincaré plots) to examine rate changes on a beat-to-beat basis were analyzed along with time and frequency domain heart rate variability from 40 human and 130 canine 24-h electrocardiographic recordings. Humans had bell-shaped beat-interval distributions, narrow interval bands across time with continuous interval change and linear changes in rate. In contrast, dogs had skewed non-singular beat distributions, wide interval bands {despite faster average heart rate of dogs [mean (range); 81 (64–119)] bpm compared to humans [74.5 (59–103) p = 0.005]} with regions displaying a paucity of intervals (zone of avoidance) and linear plus non-linear rate changes. In the dog, dynamic Poincaré plots showed linear rate changes as intervals prolonged until a point of divergence from the line of identity at a mean interval of 598.5 (95% CI: 583.5–613.5) ms (bifurcation interval). The dog had bimodal beat distribution during sleep with slower rates and greater variability than during active hours that showed singular interval distributions, higher rates and less variability. During sleep, Poincaré plots of the dog had clustered or branched patterns of intervals. A slower rate supported greater parasympathetic modulation with a branched compared to the clustered distribution. Treatment with atropine eliminated the non-linear patterns, while hydromorphone shifted the bifurcated branching and beat clustering to longer intervals. These results demonstrate the unique non-linear nature of beat-to-beat variability in the dog compared to humans with increases in interval duration (decrease heart rate). These results provoke the possibility that changes are linear with a dominant sympathetic modulation and non-linear with a dominant parasympathetic modulation. The abrupt bifurcation, zone of avoidance and beat-to-beat patterning are concordant with other studies demonstrating the development of exit block from the sinus node with parasympathetic modulation influencing not only the oscillation of the pacing cells, but conduction to the atria. Studies are required to associate the in vivo sinus node beat patterns identified in this study to the mapping of sinus impulse origin and exit from the sinus node.
... background Dogs (Canis familiaris) have been proposed as natural models of several human diseases, including age-related pathologies [1][2][3][4][5], and offer many advantages over canonical laboratory model organisms in regard to translatability [6,7]. Laboratory dogs have 3 already been utilized to study various aspects of cognitive aging [8,9]. However, recently pet dogs have been proposed as even more valuable models in this field to study aging, dementia and possible interventions [6,7,10,11]. ...
Background: Dogs ( Canis familiaris ) are natural models of several human diseases, including age-related dementia. However, the molecular techniques, which are routinely applied in invertebrate and rodent models to study disease pathologies and mechanisms, has limited applicability in dogs, mainly because of ethical reasons. In the case of humans, the limited accessibility of tissue samples is at least partly solved by biobanks, which collect and store tissues and organs from voluntary donations. A similar approach with pet dogs could support both translational and veterinary research goals by providing access to good quality biological materials obtained from a wide range of dogs with known ancestry, life history and medical background. Therefore, we have established an initiative, the Canine Brain and Tissue Bank, to collect and store biological samples from pet dogs.
Objectives: The molecular qualities of tissue samples collected and stored on a tissue bank are crucial for reliable downstream applications. We used quantitative Real-Time PCR methodology to assess the stability of mRNA content in our stored samples. Three previously validated reference genes, GAPDH , HMBS and HPRT1 were chosen as targets.
Results: The tested reference genes showed expression patterns and stability values that were consistent with the literature.
Conclusions: Based on the results, the molecular quality of tissues collected in the CBTB’s donations system can fit in the standards of dog gene expression analyses.
... The brain of the dog as a species was previously examined with CT and MRI in several journal publications during the last decades [51,52,60,76,77], it was compared in textbooks [78][79][80], and histological [42] and diagnostic imaging atlases [61][62][63][64]72,81]. Furthermore, due to similarities in development, aging and comorbidity between humans and dogs, investigations have been recently focused on the canine central nervous system [63,[82][83][84][85]. Veterinary educational modules are also published recently to help graduate learning [86,87]. ...
Introduction. Creating a novel anatomical atlas requires a technique showing an organ in a different perspective, or that the applied method results in an enhanced image quality compared to previous work. We visualized a canine brain with multimodal imaging techniques for comparative studies.
Materials and Methods. A two-year-old female Beagle dog was scanned ante- and post mortem with CT and MRI. Arteries of the head were filled with red polyurethane resin through the common carotid arteries post mortem. Followed by freezing to -80°C, a neurocranial block was made and was embedded into a water-gelatin-mix. Using a special milling device and a Nikon D800 DSLR camera we obtained high-resolution (300 dpi and 24-bit color, 7360x4912 pixel) cryosections from the block with 100 µm layer thickness. The RGB images were post-processed in Adobe Photoshop CS3, where arteries and veins were selectively filtered. Images from CT, MRI and cryosectioning were imported into Thermo Scientific Amira 6.0, where all the volumes were co-registered, then segmentation of selected structures were carried out. Finally, surface models were created and refined using Amira and Autodesk Meshmixer.
Results. Cryosectioning resulted 1112 RGB-images from the neurocranium in high-detail (pixel size was only 19.5x19.5 µm). Co-registration in Amira with the CT and the T1- and T2-weighted MRI-series made it possible to visualize the structures in any arbitrary plane, allowing direct comparison between different imaging modalities. Segmentation and 3D surface modeling of the arteries, veins, brain and skull was done in the same coordinate system. This altogether gave a unique possibility to demonstrate the canine brain’s macro-anatomical structures and compare with the result of the diagnostic imaging techniques.
Conclusion. Images produced by this method could be the base of multimodal comparative canine brain atlas, and the upgraded technique of the cryomacrotomisation could be used for future similar studies.
Despite extensive studies published on the canine brain, inconsistencies and disagreements in the nomenclature and representation of various cerebral structures continue to exist. This study aimed to create a comprehensive mapping of the external architecture of the mesocephalic canine brain with a focus on the major gyri and sulci. Standardized dissection techniques were used on 20 ethically sourced brains obtained from 6 to 10-year-old dogs that were free of neurological disorders. Distinct gyri and sulci with unique locations and bordering structures were observed. Thus, it was possible to identify the often-ignored subprorean gyrus. In addition, this study was able to illustrate the unique locations and bordering structures of gyri and sulci. The findings can contribute to a consensus among researchers on the canine brain anatomy and assist in clarifying the inconsistencies in cerebral structure representation. Furthermore, the results of this study may hold significant implications for veterinary medicine and neuroscience and serve as a foundation for the development of diagnostic and therapeutic approaches for various neurological diseases in dogs. Our findings offer valuable insights into the unique evolutionary adaptations and specialized behaviors of the canine brain, thereby increasing awareness about the neural structures that enable dogs to demonstrate their unique traits.
Research into cognition in cats and the impact of nutrition on cat cognitive health lags behind that in dogs but is receiving increased attention. In this review, we discuss the evolutionary history of the domesticated cat, describe possible drivers of domestication, and explore the interrelationships between nutrition and cat cognition. While most cat species are solitary, domesticated cats can live in social groups, engage in complex social encounters, and form strong attachments to humans. Researchers have recently started to study cat cognition using similar methods as those developed for dogs, with an initial primary focus on perception and social cognition. Similar to dogs, cats also show cognitive and behavioral changes associated with stress and aging, but these signs are often gradual and often considered a consequence of natural aging. Despite the fundamental role of nutrition in cognitive development, function, and maintenance, research into the association between nutrition and cognition in cats is only preliminary. Ultimately, additional research is needed to gain a full understanding of cat cognition and to explore the role of nutrition in the cognitive health of cats to help improve their welfare.
Age-related decline in mobility and cognition are associated with cellular senescence and NAD + depletion in dogs and people. A combination of a novel NAD + precursor and senolytic, LY-D6/2, was examined in this randomized controlled trial. Seventy dogs with mild to moderate cognitive impairment were enrolled and allocated into placebo, low or full dose groups. Primary outcomes were change in cognitive impairment measured with the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale and change in activity measured with physical activity monitors. Fifty-nine dogs completed evaluations at the 3-month primary endpoint, and 51 reached the 6-month secondary endpoint. There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint (p = 0.02) with the largest decrease in the full dose group. No difference was detected between groups using in house cognitive testing. There were no significant differences between groups in changes in measured activity. The proportion of dogs that improved in frailty and owner-reported activity levels and happiness was higher in the full dose group than other groups, however this difference was not significant. Adverse events occurred equally across groups. All groups showed improvement in cognition, frailty, and activity suggesting placebo effect and benefits of trial participation. We conclude that LY-D6/2 improves owner-assessed cognitive function over a 3-month period and may have broader, but more subtle effects on frailty, activity and happiness as reported by owners.
Age-related decline in mobility and cognition are associated with cellular senescence and NAD+ depletion in dogs and people. A combination of a novel NAD+ precursor and senolytic, LY-D6/2 was examined in this randomized controlled trial. Seventy dogs were enrolled and allocated into placebo, low or full dose groups. Primary outcomes were change in cognitive impairment measured with the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale and change in activity measured with physical activity monitors. Fifty-nine dogs completed evaluations at the three-month primary endpoint, and 51 reached the six-month secondary endpoint. There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint (p=0.02) with the largest decrease in the full dose group. There were no significant differences between groups in changes in measured activity. However, the proportion of dogs that improved in frailty and owner-reported activity levels and happiness was higher in the full dose group than other groups. Adverse events occurred equally across groups. All groups showed improvement in cognition, frailty, and activity suggesting placebo effect and benefits of trial participation. We conclude that LY-D6/2 significantly improves owner-assessed cognitive function and may have broader effects on frailty, activity and happiness as reported by owners.
A form of dementia distinct from healthy cognitive aging, Alzheimer's disease (AD) is a complex multi-stage disease that currently afflicts over 50 million people worldwide. Unfortunately, previous therapeutic strategies developed from murine models emulating different aspects of AD pathogenesis were limited. Consequently, researchers are now developing models that express several aspects of pathogenesis that better reflect the clinical situation in humans. As such, this review seeks to provide insight regarding current applications of mammalian models in AD research by addressing recent developments and characterizations of prominent transgenic models and their contributions to pathogenesis as well as discuss the advantages, limitations, and application of emerging models that better capture genetic heterogeneity and mixed pathologies observed in the clinical situation.
Current advances in geroscience are due in part to the discovery of biomarkers with high predictive ability in short-lived laboratory animals such as flies and mice. These model species, however, do not always adequately reflect human physiology and disease, highlighting the need for a more comprehensive and relevant model of human aging. Domestic dogs offer a solution to this obstacle, as they share many aspects not only of the physiological and pathological trajectories of their human counterpart, but also of their environment. Furthermore, they age at a considerably faster rate. Studying aging in the companion dog provides an opportunity to better understand the biological and environmental determinants of healthy lifespan in our pets, and to translate those findings to human aging. Biobanking, the systematic collection, processing, storage, and distribution of biological material and associated data has contributed to basic, clinical, and translational research by streamlining the management of high-quality biospecimens for biomarker discovery and validation. In this review, we discuss how veterinary biobanks can support research on aging, particularly when integrated into large-scale longitudinal studies. As an example of this concept, we introduce the Dog Aging Project Biobank.
Brain is a vital organ that always has high oxygen demands and is highly vulnerable to injury caused by reactive oxygen species (ROS). The hippocampus is a complex structure seen deep in the temporal lobe which is constituted by the dentate gyrus, hippocampus proper (Cornu Ammonis- CA1-CA4) and subiculum. The important functions of the hippocampus are learning and memory. Age-influenced pathological lesions in the hippocampus and variation in the number of neurons in the hilus are the main discussion of this study. The major gross lesions observed in the brain of both younger and older dogs were cerebral congestion, thickened meninges and cerebral edema. The major histopathological findings in the hippocampus were thickened blood vessels, accumulation of lipofuscin pigments in the neuronal cytoplasm, satellitosis, gliosis, neurons with the vesicular nucleus, chromatolysis and neuronophagia. A statistically significant reduction in the number of neurons in the hilar region of the hippocampus was observed in aged dogs.
Background:
Microglia contribute to Alzheimer's disease (AD) pathogenesis by clearing amyloid-β (Aβ) and driving neuroinflammation. Domestic dogs with age-related dementia (canine cognitive dysfunction (CCD)) develop cerebral amyloidosis like humans developing AD, and studying such dogs can provide novel information about microglial response in prodromal AD.
Objective:
The aim was to investigate the microglial response in the cortical grey and the subcortical white matter in dogs with CCD versus age-matched cognitively normal dogs.
Methods:
Brains from aged dogs with CCD and age-matched controls without dementia were studied. Cases were defined by dementia rating score. Brain sections were stained for Aβ, thioflavin S, hyperphosphorylated tau, and the microglial-macrophage ionized calcium binding adaptor molecule 1 (Iba1). Results were correlated to dementia rating score and tissue levels of Aβ.
Results:
Microglial numbers were higher in the Aβ plaque-loaded deep cortical layers in CCD versus control dogs, while the coverage by microglial processes were comparable. Aβ plaques were of the diffuse type and without microglial aggregation. However, a correlation was found between the %Iba1 area and insoluble Aβ 42 and N-terminal pyroglutamate modified Aβ(N3pE)-42. The %Iba1 area was higher in white matter, showing phosphorylation of S396 tau, versus grey matter. Perivascular macrophage infiltrates were abundant in the white matter particularly in CDD dogs.
Conclusion:
The results from this study of the microglial-macrophage response in dogs with CCD are suggestive of relatively mild microglial responses in the Aβ plaque-loaded deep cortical layers and perivascular macrophage infiltrates in the subcortical white matter, in prodromal AD.
White matter dysfunction and degeneration have been a topic of great interest in healthy and pathological aging. While ex vivo studies have investigated age-related changes in canines, little in vivo canine aging research exists. Quantitative diffusion MRI such as diffusion tensor imaging (DTI) has demonstrated aging and neurodegenerative white matter changes in humans. However, this method has not been applied and adapted in vivo to canine populations. This study aimed to test the hypothesis that white matter diffusion changes frequently reported in human aging are also found in aged canines. The study used Tract Based Spatial Statistics (TBSS) and a region of interest (ROI) approach to investigate age related changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD) and radial diffusivity (RD). The results show that, compared to younger animals, aged canines have significant decreases in FA in parietal and temporal regions as well as the corpus callosum and fornix. Additionally, AxD decreases were observed in parietal, frontal, and midbrain regions. Similarly, an age- related increase in RD was observed in the right parietal lobe while MD decreases were found in the midbrain. These findings suggest that canine samples show commonalities with human brain aging as both exhibit similar white matter diffusion tensor changes with increasing age.
In this study, it was aimed to investigate the effects of EVOO, rosmarinic acid and donepezil in Alzheimer's model to be created with AlCl3 in rats. For this reason, administration of 100 mg/kg aluminum chloride (AlC3) for 15 days to Sprague Dawley adult male rats; donepezil, Extra-virgin olive oil (EVOO) and rosmarinic acid were administered to three different groups for 21 days by applying treatment protocols. With this study, we were able to demonstrate that cognitive impairment has been occurred after 15 days of AlCl3 administration by oral gavage and treatment protocols prevented the occurrence of AD pathology histopathologically. We also showed that oxidative damage findings which are positively Congo-red stained cell cytoplasm and impaired cell integrity have been observed in serum and hippocampus. Besides, treatment groups showed better cognitive and motor performance, and there was no damage to the cells in control and treatment groups. In the rotarod motor performance test, a significant increase was observed in the donepezil group compared to the AlCl3 group at speeds of 26 and 30 rpm. In MVM, on the 5th day of the experiment, a significant increase was observed in the donepezil group compared to the AlCl3 group, as they were spending more time in the hidden platform area. These results show that 15 days of aluminum exposure is effective in creating a moderate Alzheimer’s pathology, but further chronic research is necessary to explain the efficiencies of rosmarinic acid and EVOO in treatment.
Cognitive dysfunction syndrome (CDS) is an established condition in cats that shares many similarities with human Alzheimer's disease (AD), where cognitive decline ultimately results in dementia. Cats with CDS display behavioural abnormalities, including excessive Vocalisation, altered Interaction with owners (increased affection/attention), altered Sleep‐wake cycles, House‐soiling, Disorientation (spatial and/or temporal), alterations in Activity, Anxiety, and/or Learning/memory deficits (i.e., VISHDAAL). These cats develop neuropathologies, such as accumulation of β‐amyloid and hyperphosphorylated tau deposits. Because of its similarities to those in the brains of people with cognitive impairment and AD, the domestic cat could be a natural model for human dementia studies. It is important to diagnose CDS promptly in cats, ruling out other causes for these behavioural changes, to provide effective management. Interventions include environmental enrichment (e.g., easy access to key resources, calming pheromones), dietary supplementations (e.g., Senilife, Aktivait for cats, SAMe), specific diets (e.g., containing antioxidants, medium‐chain triglycerides) and, potentially, medication (e.g., selegiline or propentofylline). This article reviews the literature about CDS in cats, its causes, neuropathology, clinical signs, diagnosis and potential management options. By doing so, it furthers our understanding of this condition and allows improved health, welfare and quality of life of affected cats.
Aged dogs naturally develop cognitive dysfunction and represent a valuable spontaneous animal model for studying normal aging and neurodegeneration. Elderly canines also share neuropathological hallmarks similar to those observed in humans, especially Alzheimer’s disease-like pathology or amyotrophic lateral sclerosis. In addition, pet dogs share similar living conditions and diets to humans. Increasing oxidative damage, as well as alterations of the intracellular protein quality control system, including ubiquitin-proteasome system (UPS) and Heat shock proteins (Hsp), have been observed in the brain of aged dogs. Thus, future researches carried out on the canine spontaneous model may be useful to define the involvement of age-related alterations in Hsp expression and UPS activity in the pathogenesis of neurodegenerative diseases, as well as to perform translational antioxidant treatment/prevention studies. The possibility to design novel therapeutic approaches, including Hsp-based therapies, may help to increase chaperone protection against proteotoxic stress occurring in human and canine brain during aging.
Background
Little is known about the effect of sex on age-related changes in brain structure.Methods
Quantitative magnetic resonance imaging of the brain was performed in 330 elderly (age range, 66-96 years) volunteers living independently in the community, all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images by means of computer-assisted edge detection and trace methods. High measurement reliabilities were obtained.Results
Age-specific changes in brain size were significantly greater in men than women for the peripheral (sulcal) cerebrospinal fluid volume, the lateral (sylvian) fissure cerebrospinal fluid volume, and the parieto-occipital region area. Main effects of age were observed for all the remaining brain regions examined (cerebral hemisphere volume, frontal region area, temporo-parietal region area, lateral ventricular volume, and third ventricle volume), but these effects were similar in men and women. Asymmetries in brain structures were not affected by aging in either sex.Conclusions
Our results are generally consistent with the few published studies on sex differences in brain aging and suggest that, for at least some structures, aging effects may be more apparent in men than women. The neurobiological bases and functional correlates of these sex differences require further investigation.
Immunisation of patients with Alzheimer's disease with full-length amyloid-beta peptide (Abeta(42)) can clear amyloid plaques from the brain. Our aim was to assess the relation between Abeta(42) immune response, degree of plaque removal, and long-term clinical outcomes.
In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Abeta(42) (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Abeta immunostaining (Abeta load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model.
20 participants--15 in the AN1792 group, five in the placebo group--died before follow-up started. A further 22 patients--19 in the AN1792 group, three in the placebo group--died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Abeta load was lower than in an unimmunised control group that was matched for age at death (2.1% [SE 0.7] in treated participants vs 5.1% [0.9] in controls; mean difference 3.0%, 95% CI 0.6-5.4; p=0.02). Although there was considerable variation in Abeta load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0.02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0.93, 95% CI 0.43-3.11; p=0.86) or of an improvement in the time to severe dementia (1.18, 0.45-3.11; p=0.73) in the AN1792 group versus the placebo group.
Although immunisation with Abeta(42) resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.
The cognitive hallmark of early Alzheimer's disease (AD) is an extraordinary inability to form new memories. For many years, this dementia was attributed to nerve-cell death induced by deposits of fibrillar amyloid beta (Abeta). A newer hypothesis has emerged, however, in which early memory loss is considered a synapse failure caused by soluble Abeta oligomers. Such oligomers rapidly block long-term potentiation, a classic experimental paradigm for synaptic plasticity, and they are strikingly elevated in AD brain tissue and transgenic-mouse AD models. The current work characterizes the manner in which Abeta oligomers attack neurons. Antibodies raised against synthetic oligomers applied to AD brain sections were found to give diffuse stain around neuronal cell bodies, suggestive of a dendritic pattern, whereas soluble brain extracts showed robust AD-dependent reactivity in dot immunoblots. Antigens in unfractionated AD extracts attached with specificity to cultured rat hippocampal neurons, binding within dendritic arbors at discrete puncta. Crude fractionation showed ligand size to be between 10 and 100 kDa. Synthetic Abeta oligomers of the same size gave identical punctate binding, which was highly selective for particular neurons. Image analysis by confocal double-label immunofluorescence established that >90% of the punctate oligomer binding sites colocalized with the synaptic marker PSD-95 (postsynaptic density protein 95). Synaptic binding was accompanied by ectopic induction of Arc, a synaptic immediate-early gene, the overexpression of which has been linked to dysfunctional learning. Results suggest the hypothesis that targeting and functional disruption of particular synapses by Abeta oligomers may provide a molecular basis for the specific loss of memory function in early AD.
The development of Alzheimer's disease (AD) later in life may be reflective of environmental factors operating over the course of a lifetime. Educational and occupational attainments have been found to be protective against the development of the disease but participation in activities has received little attention. In a case-control study, we collected questionnaire data about 26 nonoccupational activities from ages 20 to 60. Participants included 193 people with probable or possible AD and 358 healthy control-group members. Activity patterns for intellectual, passive, and physical activities were classified by using an adaptation of a published scale in terms of “diversity” (total number of activities), “intensity” (hours per month), and “percentage intensity” (percentage of total activity hours devoted to each activity category). The control group was more active during midlife than the case group was for all three activity categories, even after controlling for age, gender, income adequacy, and education. The odds ratio for AD in those performing less than the mean value of activities was 3.85 (95% confidence interval: 2.65–5.58, P < 0.001). The increase in time devoted to intellectual activities from early adulthood (20–39) to middle adulthood (40–60) was associated with a significant decrease in the probability of membership in the case group. We conclude that diversity of activities and intensity of intellectual activities were reduced in patients with AD as compared with the control group. These findings may be because inactivity is a risk factor for the disease or because inactivity is a reflection of very early subclinical effects of the disease, or both.
Visual memory in monkeys was examined under four different conditions, each with a separate group. In all conditions, the delay between sample and choice was 10 sec, and the delay between trials was 30 sec. The procedural differences were matching or nonmatching with the same two objects presented repeatedly and matching or nonmatching with trial-unique objects. With the customary repetitive stimuli, whether in matching or nonmatching, most monkeys either required prolonged training to solve the problem (over 40 sessions) or failed to solve it, corroborating the learning difficulties reported earlier by others. With trial-unique stimuli, by contrast, most monkeys learned quickly (matching, under 20 sessions; nonmatching, under 5 sessions). Furthermore, in nonmatching with trial-unique stimuli, scores averaged 80% correct in the first session, even though the monkeys were experimentally naive. The results indicate that recognition of a stimulus as familiar or novel is highly developed in monkeys, and that their difficulty with the customary nonspatial visual memory tasks stems from a retardation in noticing and using the mnemonic cue of recovery of presentation. Evidence is presented that this difficulty can be overcome, however, by a simple training procedure that exploits their proficiency at distinguishing familiar from novel stimuli.
The relationship between Alzheimer disease (AD) and aging is not currently known. In this study, postmortem frontal- and occipital-pole brain samples were obtained from 16 subjects with AD, 8 age-matched controls, and 5 young controls. These samples were analyzed both for protein oxidation products (carbonyl) and the activities of two enzymes vulnerable to mixed-function oxidation, glutamine synthetase and creatine kinase. Glutamine synthetase is more sensitive to mixed-function oxidation than creatine kinase. Carbonyl content rises exponentially with age, at double the rate in the frontal pole compared with the occipital pole. Compared with young controls, both aged groups (AD and age-matched controls) have increased carbonyl content and decreased glutamine synthetase and creatine kinase activities, which are more marked in the frontal than occipital pole in all instances. We conclude that protein oxidation products accumulate in the brain and that oxidation-vulnerable enzyme activities decrease with aging in the same regional pattern (frontal more affected than occipital). However, only glutamine synthetase activity distinguishes AD from age-matched controls: Because glutamine synthetase activity is differentially reduced in the frontal pole in AD, we suggest that AD may represent a specific brain vulnerability to age-related oxidation.
Experimental paradigms adopted from animal models were used to compare the neuropsychological mechanisms underlying the dementias of Alzheimer's and Parkinson's diseases. Two tasks were selected because characteristic profiles of impairment in nonhuman primates are seen following selective lesions of frontal cortex, temporal cortex, and fornix. The tasks consisted of a spatial and a visual learning problem, each with two components: (1) original learning and (2) reversal of the original learning. The Alzheimer's patients were significantly impaired on original learning and reversal learning in the visual modality compared with demented Parkinson's patients, even though both groups were equated for severity of dementia. On the spatial tasks, both the Alzheimer's and the demented Parkinson's patients were impaired on reversal learning but not on original learning. The profile of deficits on the visual tasks may serve to differentiate Alzheimer's from Parkinson's dementia and may reflect selective orbitofrontal system lesions in the former.
Purpose of review Exciting new therapeutic approaches to the treatment or prevention of Alzheimer's disease involve preventing, slowing or reversing beta-amyloid accumulation. These interventions may also apply to the treatment of Alzheimer's disease in Down syndrome. The purpose of the current review is therefore to summarize developments and advances in our understanding of beta-amyloid pathogenesis in Down syndrome over the past year. Recent findings A shift in research to a focus on early events in beta-amyloid pathogenesis in Down syndrome has led to several novel observations. Several authors have reported the accumulation of both soluble and intracellular beta-amyloid before extracellular beta-amyloid (senile plaques) in Down syndrome. Increases in beta-amyloid levels in Down syndrome may reflect the increased expression and protein levels of beta-site amyloid precursor protein cleavage enzyme 2 on chromosome 21. The impact of the accumulation of beta-amyloid may have differential effects on development and aging in Down syndrome. Summary The past year has seen significant advances in our understanding of beta-amyloid pathogenesis and the functional consequences of beta-amyloid accumulation in Down syndrome. However, there are still large gaps in our knowledge of the pathways involved in beta-amyloid degradation and clearance. It will be critical to conduct clinical trials to test therapeutic strategies that may reduce beta-amyloid in Down syndrome directly to determine the optimal age and dose for specific interventions. Given the differences in the mechanism of beta-amyloid accumulation in Down syndrome, careful consideration needs to be given to potential clinical trials to treat this disorder.
Spatial discriminations can be performed using either egocentric information based on body position or allocentric information based on the position of landmarks in the environment. Beagle dogs ranging from 2 to 16 years of age were tested for their ability to learn a novel egocentric spatial discrimination task that used two identical blocks paired in three possible spatial positions (i.e. left, center and right). Dogs were rewarded for responding to an object furthest to either their left or right side. Therefore, when the center location was used, it was correct on half of the trials and incorrect on the other half. Upon successful acquisition of the task, the reward contingencies were reversed, and the dogs were rewarded for responding to the opposite side. A subset of dogs was also tested on an allocentric spatial discrimination task, landmark discrimination. Egocentric spatial reversal learning and allocentric discrimination learning both showed a significant age-dependent decline, while initial egocentric learning appeared to be age-insensitive. Intra-subject correlation analyses revealed a significant relationship between egocentric reversal learning and allocentric learning. However, the correlation only accounted for a small proportion of the variance, suggesting that although there might be some common mechanism underlying acquisition of the two tasks, additional unique neural substrates were involved depending on whether allocentric or egocentric spatial information processing was required. (c) 2005 Elsevier Inc. All rights reserved.
This chapter discusses color discrimination, visual cognition, object recognition, and spatial localization. It also includes the discussion of the behavioral evidence for deficits, the relation of visual dysfunction to cognitive impairment, the brain bases of the deficits, the clinical relevance of impaired vision, and higher-order visual cognition in the disorder. The neuropathology of this disorder usually affects several brain areas which are devoted to visual processing of low-level visual functions along with higher-order visual cognition. Color discrimination deficits take place in a significant proportion of individuals with Alzheimer's disease (AD). Use of clinical tests of color discrimination or psychophysical assessments reveals the impairments, principally along the tritan color axis. Poor object recognition resulting from impaired inputs to temporal cortex as well as degeneration of that cortex itself leads to the expectation of deficient functional interaction with everyday objects.
The morphology, incidence and distribution of plaques and diffuse amyloid deposits in the brains of seven old dogs (18.5–26.5 years of age) were examined on tissue sections immunocytochemically stained with two monoclonal antibodies to two distinct epitopes of the beta-protein. Amyloid deposits were found in all seven brains examined. Amyloid occurred in three morphological forms: 1. focal amyloid deposits (plaques), 2. large diffuse amyloid deposits and 3. amyloid angiopathy. The number of these deposits was comparable to the numbers of all three types of amyloid deposits seen in the brains of people with Alzheimer’s disease. The number and type of morphological forms of the amyloid deposits depends on topography and the age of the animals. The number of plaques was highest in the brains of the animals 18.5–21 years of age. The oldest animals (21.5, 24 and 26.5 years of age) had a smaller number of amyloid deposits. With age, the number of plaques decreased in superficial layers of the cerebral cortex (II–III) and increased in the deeper layers (IV–VI). In the oldest animals, diffuse amyloid deposits in the deeper layers of the cortex predominated. Our studies suggest that the frequency and the extent of amyloid deposits in the brains of aged dogs are much wider than so far appreciated. It thus appears that aged dogs may be suitable as an animal model for the study of pathomechanisms involved in beta-protein amyloidogenesis.
Endogenous proteins are highly susceptible to modification by ROS produced as byproducts of normal metabolic processes, or upon exposure to oxidative stress and atmospheric pollutants. The ROS-mediated modification of proteins may lead to loss of biological function and to conversion of the proteins to forms that are rapidly degraded by endogenous proteases, especially by the multicatalytic protease. One of many different kinds of protein modification elicited by ROS is the oxidation of some amino acid side chains to carbonyl derivatives. The carbonyl content of protein is therefore a convenient marker of ROS-mediated protein damage. By means of highly sensitive methods for the detection and quantitation of protein carbonyl groups, it has been established in several different animal models that there is an exponential increase in the level of oxidized protein during aging and that elevated levels of oxidized proteins are associated with a number of diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, diabetes, muscular dystrophy, and cataractogenesis, to name a few. Although protein oxidation probably contributes to the biological dysfunction associated with these diseases, a causal relationship between protein oxidation and the etiology or progression of a disease has not been established. Nevertheless, in the case of some neurological disorders, there is a positive correlation between the loss of a particular biological function and an elevation of the level of oxidized protein in the brain (153) and in specific regions of the brain that control that function (154). Finally, because oxidized proteins are readily degraded by endogenous proteases, the steady state intracellular level of oxidized proteins is a complex function of a multiplicity of factors that govern the generation of ROS, the antioxidant systems that scavenge ROS, the susceptibility of proteins to oxidative modification, and the activities of the proteases that degrade oxidized proteins. Accordingly, the accumulation of oxidized protein that occurs during aging and in various diseases is likely attributable to the accumulated genetic damage (ROS-mediated mutations?) that affects one or more of the numerous factors that determine the balance between protein oxidation on the one hand and the degradation of oxidized proteins on the other.
In order to observe changes owing to aging and Alzheimer's disease (AD) in the volumes of subdivisions of the hippocampus and the number of neurons of the hippocampal formation, 18 normal brains from subjects who died of nonneurological causes and had no history of long-term illness or dementia (ten of these brains comprised the aged control group) and 13 AD brains were analyzed. An optimized design for sampling, measuring volume by using the Cavalieri principle, and counting the number of neurons by using the optical disector was implemented on 50 μm-thick cresyl-violet sections. The mean total volume of the principal subdivisions of the hippocampal formation (fascia dentata, hilus, CA3-2, CA1, and subiculum) showed a negative correlation with age in normal subjects (r = −0.56, 2P < 0.05), and a 32% mean reduction in the AD group compared with controls (P < 0.001). This finding supports the measurement of the coronal cross-sectional area and the volume of the hippocampal formation in the clinical diagnosis of AD. There was an inverse relationship between the age of normal subjects and the number of neurons in CA1 (r = −0.84 2P < 0.0001) and subiculum (r = −0.49, 2P < 0.05) but not in other subdivisions. Pronounced AD-related reductions in neuron number were found only in the subiculum and the fascia dentata. Compared with controls, both losses represented 23% of neurons (P < 0.05). These results 1) confirm that AD is a qualitatively different process from normal aging and 2) reveal the regional selectivity of neuron loss within the hippocampal formation in aging and AD, which may be relevant to understanding the mechanisms involved in the neuron loss associated with the two processes. J. Comp. Neurol. 379:482–494, 1997.
Background
Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials.Objective
To characterize clinically subjects with MCI cross-sectionally and longitudinally.Design
A prospective, longitudinal inception cohort.Setting
General community clinic.Participants
A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.Main Outcome Measures
The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively.Results
The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.Conclusions
Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
A cognitive neuroscience perspective provides a valuable framework for organizing data on the behavioral consequences of aging in nonhuman primates. Growing evidence suggests that working memory processes known to depend on the functional integrity of the prefrontal cortex are particularly susceptible to aging in the monkey. By comparison, the status of memory supported by the hippocampus and related medial temporal lobe structures appears more variable across aged individuals. Combined with recent conceptual advances in the broader field of learning and memory research, these findings provide a solid foundation for developing new strategies to establish a complete neuropsychological account of cognitive aging in the monkey.
Oxidative balance is emerging as an important issue in understanding the pathogenesis of Alzheimer’s disease. Examination of Alzheimer’s disease brain has demonstrated a great deal of oxidative damage, associated with both hallmark pathologies (senile plaques and neurofibrillary tangles) as well as in normal appearing pyramidal neurons. While this suggests that oxidative stress is a proximal event in Alzheimer’s disease pathogenesis, the mechanisms by which redox balance is altered in the disease remains elusive. Determining which of the proposed sources of free radicals, which include mitochondrial dysfunction, amyloid-β-mediated processes, transition metal accumulation and genetic factors like apolipoprotein E and presenilins, is responsible for redox imbalance will lead to a better understanding of Alzheimer’s disease pathogenesis and novel therapeutic approaches.
Because aged nonhuman primates show β-amyloid (Aβ) deposition in senile plaques and blood vessels similar to that seen in human aging and AD, we used C-terminal specific antibodies to Aβ40 and Aβ42 to investigate Aβ peptide length in the brains of 11 aged rhesus monkeys and a 59-year-old chimpanzee. In contrast to AD, where the earliest and most prominent form of Aβ in senile plaques is Aβ42, in the monkey, Aβ40-positive plaques predominated. The ratio of Aβ4): Aβ42-positive plaques averaged 2.08 in the monkey, as compared to a mean ratio of 0.37 in 68 human AD subjects (p < 0.001). Aβ40 was also more prominent in the chimpanzee than in humans. Possible explanations for these findings include species differences in the cleavage of Aβ from the amyloid precursor protein or in the activity of a putative carboxy peptidase forming Aβ40 from Aβ42 in situ.
To study the pathogenesis of cerebral amyloid angiopathy (CAA), organ cultures of canine leptomeninges were incubated with fluorescein-conjugated amyloid beta-protein (FA beta, residues 1-40; 10 nM to 200 mu M). Fluorescence microscopy showed focal and dose-dependent FA beta binding to blood vessels affected by CAA at FA beta-concentrations as low as 10 nM. The new A beta deposits appeared to be extracellular and were localized to the middle and outer layers of leptomeningeal arterioles. FA Rho partially co-locaiized with apolipoprotein E (ApoE) as revealed by confocal microscopy, suggesting that A beta in situ binds to ApoE. Young dogs or old dogs without CAA showed no deposition of FA beta. Our results indicate that after initiation of CAA pathology, physiological concentrations of soluble A beta are sufficient to sustain its further deposition and therefore the progression of CAA.
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.
Cortical patterns of β-amyloid (Aβ) deposition were evaluated in 40 beagle dogs ranging in age from 2 to 18 years. Aβ deposition in the prefrontal, occipital, parietal and entorhinal cortices was visualized by using an antibody against Aβ1–42. A logistic regression was used to estimate differences in age-at-onset and rate of deposition of Aβ as a function of brain region. The earliest and most consistent site of Aβ deposition with age was in the prefrontal cortex. Entorhinal Aβ deposition was not consistently observed until the age of 14 years, but was present in a subset of dogs under the age of 14 years. These regional vulnerabilities to Aβ accumulation are similar to those seen in the aging human. By using parameters derived from regression analyses, it may be possible to predict the presence of Aβ within specific brain regions in individual dogs. We propose that these models will be a useful tool to evaluate interventions that delay the age of onset or slow the rate of accumulation of Aβ in the dog.
This chapter discusses the functional neurobiology of aging in other vertebrate species. The primary focus of the chapter is on the dog along with the descriptions of sheep, goat, wolverine, bear, and cat. Both cats and dogs are the appropriate models for the essential study of aging in humans because they share many of the same age-related diseases and disorders such as arthritis, cancer, bone loss, and hypertension. The chapter also describes many of the other vertebrate species that develop some of the hallmark lesions of both normal and pathological aging in the human brain. The underlying strategy for studying aging in the dog is to use a clinical-neuropathology approach in which dogs are given a battery of tasks in an effort to test the function of several cognitive domains such as spatial attention or learning. Ccognitive evaluations of dogs determine whether it is possible to detect various forms of pathology in the brain on the basis of behavior.
In recent years, patients who are at high risk for developing Alzheimer's disease (AD) have become a focus of study. Several research groups have identified these patients, developed diagnostic criteria, and followed the patients longitudinally. These patients therefore constitute a clinical entity that is suitable for therapeutic interventions. In this article, we report our 5-year experience at the Mayo Clinic in characterizing a group of patients with mild cognitive impairment. These subjects were recruited from community-dwelling individuals who were receiving general medical care in the Department of Internal Medicine. They received the diagnosis of mild cognitive impairment if they met the following criteria: (a) complaint of defective memory, (b) normal activities of daily living, (c) normal general cognitive function, (d) abnormal memory function for age, and (e) absence of dementia. In following more than 75 of these patients, some of whom have been studied for as long as 5 years, it appears that approximately 10% to 15% of the subjects evolve to AD each year. We therefore evaluated the cognitive profiles of these patients at the time of their initial diagnosis in an attempt to predict who would remain stable and who would evolve to AD. Certain features of learning and memory performance indicated patients who were more likely to progress, but the strongest predictor was their apolipoprotein E status. The patients who possessed an ε4 allele were more likely to convert to AD at a more rapid rate then those who were not carriers. Our results and similar data from other study groups indicate that diagnostic criteria can be defined for patients who are likely to convert to AD; the natural history of these patients is becoming apparent, and variables that predict ultimate conversion can be defined. Consequently, patients with mild cognitive impairment constitute an important group for study, particularly from the aspect of therapeutic interventions.
Anti-oxidative stress enzymes were immunohistochemically detected in the brain from young to very-aged dogs. More than half of the neurons in the cerebral cortex of the young dogs (< 5 years old) were positive for copper (Cu), zinc (Zn) superoxide dismutase (SOD), and the staining intensity was strong. The number of Cu, Zn SOD-positive neurons decreased with age, and only 10–50% of neurons were positive for SOD in the aged and very aged (> 9 years old) dogs. In contrast, no glial cells were immunostained for Cu, Zn SOD in the young dogs, and the number, as well as the staining intensity, increased with age, reaching > 50% in the aged and very aged dogs. Apoptotic brain cells, which were conspicuous in the aged dog brain, were negative for Cu, Zn SOD. The Cu, Zn SOD immunoreactions were also observed in the degenerative neurites of amyloid type senile plaques, vessels affected with cerebral amyloid angiopathy (CAA) and reactive astroglia around these amyloid plaques and CAA in the aged and very aged dog brains. Diffuse type senile plaques were negative for Cu, Zn SOD. The number of catalase- or glutathione peroxidase-positive cells varied among dogs regardless of their age. An age-related decrease in number of Cu, Zn SOD-positive neurons may enhance the toxicity of oxygen free radicals, resulting in neuronal cell death.
In order to clarify the tau phosphorylation in aged non-human animal brains, paraffin sections of human and non-human animal brains were examined immunohistochemically using two antibodies against tau. The monoclonal antibody (mAb) tau-2 is known to bind non-phosphorylated and phosphorylated forms of tau protein and to recognize neurofibrillary tangles (NFT) in the human brain, whereas rabbit antiserum against tau recognizes the protein in a wide variety of mammalian species. In this study, both antibodies recognized axons, neurites, and cytoplasm of neuronal cells together with oligodendrocytes in non-human animal brains as reported in human brains, suggesting that the distribution of normal tau is quite similar between human and non-human animal brains. Neurofibrillary tangles detected by the Gallyas method were not found in non-human animal brains. Tau-2 intensely labeled NFT in the human brain and neurons of brain stem nuclei in the canine brain. The results may suggest very early stage of abnormal tau phosphorylation leading to NFT formation in the aged canine brain. It is probable that phosphorylation develops over a long period of time (more than 25–30 years) and as a result abnormal tau becomes apparent in humans because they have a long life-span in comparison with most non-human animals.
BACKGROUND
Prostate cancer and benign prostatic hyperplasia are important age-related prostatic diseases that are under the influence of testicular hormones. However, the disparity between male and female life expectancy within the human population cannot be explained solely by the prevalence of prostatic disease-related mortality. The purpose of this paper is to explore the possibility that the testis exerts a detrimental effect on life span.METHODS
First, we review previously published and unpublished data on the influence of the testis on the life span of dogs and men. Aging in pet dogs and men is then discussed in terms of evolutionary theory, emphasizing the significance of a prolonged postreproductive life span and possible consequences of late-acting deleterious genes in these two species. Finally, we present preliminary data that orchiectomy can reduce DNA damage within the brain of elderly male dogs.RESULTS AND CONCLUSIONS
Taken together, these observations raise the intriguing possibility that interventions to antagonize the testis might have much broader therapeutic applications that will extend well beyond the treatment of prostate cancer. Prostate 43:272–277, 2000. © 2000 Wiley-Liss, Inc.
Cerebral amyloid angiopathy (CAA) is a neuropathological feature of Alzheimer's disease and a common cause of cerebral hemorrhage in the elderly. The pathogenetic mechanisms leading to the deposition of Alzheimer amyloid β-protein (Aβ) in cortical and leptomeningeal vessel walls are unknown. There are no experimental models which reproduce the pathological changes of CAA. In this study, leptomeninges from young and old dogs with pre-existing CAA were cultured in cell culture medium or cerebrospinal fluid and their viability, histological appearance and metabolic activity were analyzed during the culture. In addition, living leptomeninges of old and young dogs were incubated with fluorescein-conjugated Aβ and the uptake of Aβ was studied by fluorescence microscopy. Leptomeninges from young and old dogs were viable up to 8 weeks in culture. They contain many small- and medium-sized arterioles, the main vessel type affected by CAA. Histology and immunohistochemistry showed excellent preservation of the vessel wall microarchitecture up to 4 weeks in culture. The cultures were metabolically active as shown by the de novo production of β-amyloid precursor protein. Exogenously added Aβ was focally deposited in the vessel walls of old, but not young dogs. In conclusion, the organ culture of canine leptomeninges is easy to perform and appears suitable to investigate the pathogenesis and the progression of CAA.
It is well known that β-amyloid accumulates abnormally in Alzheimer's disease; however, β-amyloid's relationship to cognitive dysfunction has not been clearly established and is often confounded by the presence of neurofibrillary tangles. We used canines to investigate the relationship between β-amyloid accumulation and cognitive function in an animal model of aging lacking neurofibrillary tangles. The performance of 20 canines (11 purebred beagles and 9 mongrels) on a battery of six cognitive tasks was measured. These tasks included Reward Approach and Object Approach learning, as well as Discrimination, Reversal, Object Recognition, and Spatial learning and memory. Aged canines were impaired on some tasks but not others. β-Amyloid-immunopositive plaques were found in many of the older animals. Plaques were all of the diffuse subtype and many contained intact neurons detected with double-labeling for neurofilaments. No neurofibrillary tangles were detected. β-Amyloid was also associated with the processes of many neurons and with blood vessels. Using computerized image analysis, we quantified the area occupied by β-amyloid in entorhinal cortex, frontal cortex, and cerebellum. Controlling for age-related increases in β-amyloid, we observed that increased β-amyloid deposition is strongly associated with deficits on Discrimination learning (r= .80), Reversal learning (r= .65), and Spatial learning (r= .54) but not the other tasks. There were a few differences between breeds which are discussed in the text. Overall, these data suggest that β-amyloid deposition may be a contributing factor to age-related cognitive dysfunction prior to the onset of neurofibrillary tangle formation.
β-Amyloid (Aβ) is a constituent of senile plaques found with increasing age in individuals with Down syndrome (DS) and in the canine model of aging. Sections of DS and dog brain were immunostained using an affinity-purified polyclonal antibody for a posttranslationally modified Aβ with a racemized aspartate at position 7 (d7C16). The immunostaining characteristics of d7C16 Aβ in DS and dog brain indicate that it is present in all plaque subtypes, including the thioflavin-S-negative diffuse plaques that develop with age in dogs. The youngest DS case exhibited weak immunolabeling for d7C16 but the extent of d7C16-positive plaques increased with age. In addition, d7C16-positive plaques were initially found in clusters in the superficial layers of the frontal and entorhinal cortex but, with advancing age, increasing numbers appeared in deeper layers, suggesting a progression of Aβ deposition from superficial to deeper cortical layers. Ultrastructural studies in DS brain were confirmed using perfused dog brain and provided consistent results; thioflavin-S-negative diffuse plaques consist of fibrillar Aβ and racemized Aβ is a