Edited by: Marietta Zille, Universität zu Lübeck, Germany
Reviewed by: Ling Li, University of Minnesota Twin Cities, United States; Wolfgang Härtig, Leipzig University, Germany; Björn Nitzsche, Leipzig University, Germany
This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Neurodegenerative diseases present a major and increasing burden in the societies worldwide. With aging populations, the prevalence of neurodegenerative diseases is increasing, yet there are no effective cures and very few treatment options are available. Alzheimer’s disease is one of the most prevalent neurodegenerative conditions and although the pathology is well studied, the pathogenesis of this debilitating illness is still poorly understood. This is, among other reasons, also due to the lack of good animal models as laboratory rodents do not develop spontaneous neurodegenerative diseases and human Alzheimer’s disease is only partially mimicked by transgenic rodent models. On the other hand, older dogs commonly develop canine cognitive dysfunction, a disease that is similar to Alzheimer’s disease in many aspects. Dogs show cognitive deficits that could be paralleled to human symptoms such as disorientation, memory loss, changes in behavior, and in their brains, beta amyloid plaques are commonly detected both in extracellular space as senile plaques and around the blood vessels. Dogs could be therefore potentially a very good model for studying pathological process and novel treatment options for Alzheimer’s disease. In the present article, we will review the current knowledge about the pathogenesis of canine cognitive dysfunction, its similarities and dissimilarities with Alzheimer’s disease, and developments of novel treatments for these two diseases with a focus on canine cognitive dysfunction.
Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, and others are a major growing public health problem associated with aging, as aging is the greatest risk factor for neurodegeneration. The global number of people living with dementia more than doubled from 1990 to 2016 (
Neurodegenerative diseases do not occur spontaneously in laboratory mice and rats, but do occur in several other mammalian species. Studies of neurodegenerative diseases in animals have shown strong similarities between cognitive dysfunction in dogs and human AD and between AD in humans and most other primates (
In dogs and humans, dementia often affects cerebral gyri (cerebral atrophy) and shows as widening of sulci together with ventricular enlargement (
Protein aggregation is an established pathogenic mechanism in AD, although little is known about the initiation of this process
In general, age-related neurodegenerative disorders are complex and multifaceted pathologies, wherein the formation of large aggregates and/or high concentrations of toxic proteins prevent the proper function of neuronal cells, leading to ischemia and eventually tissue removal. The spread of AD pathology follows a characteristic topographic pattern, different for the two proteins involved in the pathology, Aβ and TAU (
The most prominent neuropathological signs of AD are accumulation of Aβ in a form of extracellular plaques in the brain parenchyma and also in the walls of blood vessels (cerebral amyloid angiopathy, CAA), and abnormally phosphorylated protein TAU that accumulates in NFTs (
Protein sequences alignments between dog and human amyloid-beta precursor protein (APP) and TAU.
Amyloid-β was found to be present in the form of insoluble plaques in the area of the cerebral cortex in humans and dogs, and cognitive impairment in elderly dogs was in some studies strongly associated with the accumulation of Aβ in the brain (
In dogs, formation and maturation of Aβ deposits was observed by immunostaining throughout the canine cortical gray matter layers in a four-stage distribution, which is also characteristic for human AD, and this, according to some studies, correlates with the severity of cognitive deficit in the dog (
Presence of Aβ in the cerebral cortex of a dog with CCD. The dense plaques detected in superficial cortical layers and diffuse plaques in deeper layers of prefrontal cortex. The dog was 17-years-old of a mixed breed. Immunoperoxidase staining with antibodies against Aβ (purified anti-β-Amyloid, 17-24 Antibody, BioLegend, #800701) with diaminobenzidine (DAB) as chromogen (brown), counter stained with hematoxylin. Original microphotograph made by the authors.
Affected brain regions and underlying cognitive deficits in dogs.
Prefrontal cortex | Aβ | Executive function, behavioral changes [cognitive performance, loss of previously learned behaviors (e.g., house soiling)], motor skills, attention, emotions and impulse control (fearfulness, aggression, stereotypic pacing or circling) | |
Frontal cortex | Aβ | Changes in executive functions (inhibitory control and complex working memory) | |
Parietal cortex | Aβ | Sensory association, learning and memory | |
Entorhinal cortex | Aβ, NFTs* | Visual learning, memory | |
Occipital cortex | Aβ | Learning and memory (visual association area, visual cortex) | |
Temporal cortex | Aβ, NFTs* | Visual memory (facial recognition), emotions | |
Hippocampus | Aβ, NFTs* | Changes in sleep–wake cycles, appetite control, complex working memory | |
Cerebral cortex (not further specified) | Aβ | Disorientation, decrease in social interactions, changes in sleep–wake cycles, loss of prior housetraining, increased anxiety, changes in level of activity | |
Cerebral capillaries and arteries | Aβ - CAA | Lower perceptual speed and episodic memory | |
Meningeal blood vessels | Aβ - CAA |
Besides Aβ plaques, recruitment and activation of astrocytes and microglial cells has been noticed in dogs with CCD (astrocytosis, microgliosis) (
Aged dogs with cognitive impairment exhibit degeneration of noradrenergic neurons, which correlates with higher levels of Aβ deposits in the prefrontal cortex (
TAU protein, another important factor in neurodegenerative diseases, is encoded by
Neurodegenerative diseases occur spontaneously in other domestic animals, especially in cats (
Neurodegenerative diseases most likely occur in many other mammalian species, but there are very limited reports about these. The reports are focusing on the presence of Aβ deposits and phosphorylated TAU and/or NFTs, which are detected post mortem, not describing the cognitive deficit, this is of course more difficult to observe in wild life animals or in this aspect less characterized species. Diffuse deposits of Aβ were observed in the parietal cortex of dolphins and more compact senile plaques in their cerebellum (
There have been speculations on the reasons for the lack of NFTs in the canine brain and in the brains of other animals (
In patients with AD, accumulation of Aβ is often observed in the walls of blood vessels in the brain. This is called CAA and is caused by pathological deposits of Aβ and other proteins in the cerebral arterioles and capillaries of the leptomeninges and cortex. It is considered as an early and integral part of AD pathogenesis and the prevalence of CAA in AD is over 70% (
In aged dogs Aβ deposits are detected both in the brain parenchyma and in the walls of cerebral blood vessels (
Amyloid beta (red) detected by immunofluorescence staining in the wall of a leptomeningeal blood vessel in the frontal cortex from a 15-years-old Pit Bull Terrier. Nuclei were counterstained with DAPI (blue). The antibody employed is the same as in
Pathological hallmarks of CCD and/or AD.
Cognitive decline | + | + |
Brain atrophy | + | + |
Neuronal damage and death | + | + |
Aβ accumulation in brain parenchyma | + | + |
Diffuse Aβ plaques | + | + |
Dense-core Aβ plaques | − | + |
Aβ accumulation in blood vessel walls (CAA) | + | + |
Neurofibrillary tangles (NTFs) formation | − | + |
Microglial dysfunction | + | + |
Astrocyte dysfunction | + | + |
Astroglial hypertrophy and hyperplasia | + | + |
Oxidative brain damage | + | + |
Mitochondrial dysfunction | + | + |
Cholinergic dysfunction | + | + |
Impaired neuronal glucose metabolism | + | + |
The incidence of human neurodegeneration and associated dementias is sporadic and is only rarely due to hereditary changes that are linked with genetic mutations. The majority of AD cases are sporadic late-onset (LOAD) with an unknown etiology (
Some presenilin mutations and mutations in
No mutations in specific genes have been reported in dogs with CCD so far. The only neurodegenerative disease in dogs that has been linked to specific mutation is degenerative myelopathy (DM), a condition caused by both demyelination and axonal loss in the canine spinal cord. In dogs with this disease, mutations have been found in a gene SOD1, coding for superoxide dismutase enzyme (
Neurodegenerative diseases are particularly challenging diseases, as they are difficult to diagnose in the initial stages. Although many years of research have been devoted to the identification of suitable biomarkers, preferably in blood, that would allow early diagnosis or even prediction of AD in humans, such markers remain elusive. Numerous candidates have been identified in both blood and CSF, but none of the markers identified so far have been used routinely in the clinics. CSF levels of Aβ, total TAU and hyperphosphorylated TAU are the most often monitored variables, along with PET molecular imaging of amyloid and TAU deposition, in diagnosis of early stages of AD (
In dogs there are no biological markers that would allow accurate and early diagnosis of CCD. In most cases assessment of cognitive functions through several neuropsychological tests and excluding other conditions with overlapping symptoms is sufficient to confirm diagnosis when the disease has progressed, but markers for detecting disease in early stages would be very useful in veterinary medicine.
In dogs with CCD, plasma Aβ42, a longer Aβ isoform which is more fibrillogenic and associated with disease, was monitored as a biomarker potentially linked to CCD (
In healthy aged dogs with age related Aβ deposits, a decrease in levels of Aβ42, but not Aβ40 was detected in CSF (
Although CCD is highly prevalent the disease is severely under-diagnosed, affecting a growing population of aged dogs. The diagnosis of CCD is a diagnosis of elimination. The illness exacerbating symptoms, commonly also observed in CCD, must be excluded, such as brain tumors, hypertension, other neurological conditions, metabolic and hormonal imbalances, etc. Screening and diagnosis of CCD is primarily based on observation of clinical signs which are summarized by the acronym DISHAA [Disorientation, altered social Interactions, altered Sleep–wake cycles, House soiling and loss of other learned behaviors, altered Activity levels and increasing Anxiety (
The diagnosis depends largely on the owners and the veterinarians to observe and diagnose the disease, which is in most cases overlooked and symptoms attributed to the aging of dogs. To facilitate the detection of CCD, veterinarians can use a screening questionnaire that includes a list of possible signs. Several questionnaires are available and based on the scores the stage of dog’s cognitive decline can be identified (
MRI diagnosis is only rarely performed in dogs, due to possible complications during anesthesia and cost restraints. In dogs with CCD, as in humans with AD, MRI shows brain atrophy and include ventricular enlargement as well as widened and well-demarcated cerebral sulci. Measuring the thickness of the interthalamic adhesion in CCD was employed as a parameter for quantifying canine brain atrophy (
In general, the diagnosis of human AD is set similarly. First by ruling out other possible causes for symptoms and then by detection of CSF and plasma biomarker levels, tests of memory, problem solving, attention, counting, and language, which can be followed by MRI and PET scans (
Current treatment approaches for AD in humans are focused on helping people maintain mental function, manage behavioral symptoms, and slow or delay the symptoms of the disease. Unfortunately, there is no effective treatment for AD. Drugs that are used today in the management of AD can only alleviate the symptoms, and even that only temporarily. Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) have been approved for the management of AD in humans. Drugs acting as acetylcholinesterase inhibitors reduce the activity of the acetylcholine esterase which degrades acetylcholine, thus increasing the amount of acetylcholine available in the brain and therefore stimulate brain cells which receive more synaptic inputs (reviewed in
Current treatment options for CCD target prevention, slowing and/or improving the cognitive decline in dogs. Some drugs or food supplements are available for senior dogs and might act neuroprotective. Some enhance the blood flow into the brain, others work as antioxidants and more effort is now directed to slowing the progression of the disease instead of providing only symptomatic treatment. One commonly prescribed drug for cognitive impaired dogs is selegiline, which acts as an inhibitor of monoamine oxidase B (MAOB), thus reducing degradation of several neurotransmitters in the brain, and may have neuroprotective effects on dopaminergic, noradrenergic and cholinergic neurons (
There are also some nutraceutical preparations available for dogs, which are based on natural products and/or supplement formulations. Behavioral enrichment alongside with antioxidant-rich diet and exercise is an approach for maintaining cognitive function and slowing the progression of CCD in senior pets. As means of preventative intervention, aging beagles were fed a diet rich in antioxidant, which improved cognition, maintained cognition and reduced oxidative damage and Aβ pathology in treated dogs (
In comparison to transgenic mouse models, natural animal models better represent the pathophysiology of AD. Models of “physiologically” aged rats, degus and dogs are useful for studying mechanistic aspects of AD, which are also very valuable in the development of therapeutics that would alleviate age-related declines in cognitive function. Mouse models for AD research carry mutations, found in familial AD, and are artificially accumulating Aβ plaques and NFTs. Whether mice are good models have been thoroughly discussed elsewhere (
To date, most of the drugs in development for AD treatment have been directed toward the removal of amyloid plaques or NFTs, not taking into the account the multifactorial causation of the disease. Several experimental drugs that have successfully removed plaques from mouse brains have not lessened the symptoms of AD in people. For instance, drugs acting as BACE1 (beta-site amyloid precursor protein cleaving enzyme-1) inhibitors had failed in Phase II/III clinical trials (
As canine cognitive decline and human Alzheimer’s disease show neuropathological, cognitive and behavioral parallels, the testing of products for the treatment of AD in canine model could be useful to determine the efficacy of these compounds in humans, and also to develop novel therapeutic agents for the treatment of senior dogs. Several drugs have been tested in elderly dogs and their suitability and effectiveness correlated with results obtained in human trials, when available. Drugs tested in dogs are listed in
Pharmacological interventions tested in dogs with cognitive decline.
LY2886721 | BACE1 inhibitor | Pharmacology study in dogs and clinical trial in healthy volunteers | Aβ lowering in plasma and CSF | |
Selegiline ( |
MAOB inhibitor | Longitudinal study | Higher life expectancy (cognitive status not monitored) | |
Selegiline ( |
MAOB inhibitor | Performance studies | Improved visuospatial working memory (in only a subset of dogs) | |
Atorvastatin | Reduction of Aβ and BACE1 | Longitudinal study | Neuroprotective | |
Adrafinil | A wakefulness-promoting agent (eugeroic) with nootropic effects | Longitudinal study; pharmacological study | A significant increase in locomotion; improved learning; impaired working memory | |
Ampakine | Positive modulator of AMPA receptors (enhance excitatory glutamatergic neurotransmission) | Pharmacological study | Decrease of performance accuracy; may have memory impairing effects | |
CP-118,954 | Acetylcholinesterase inhibitor | Pharmacological study | Minimal cognitive enhancing effects | |
Phenserine | Acetylcholinesterase inhibitor | Pharmacological study; performance study | Enhancing effects on memory and learning; improved performance (only in a subset of dogs treated) | |
Donepezil | Acetylcholinesterase inhibitor | Performance study | memory enhancement | |
CNP520 | BACE1 inhibitor | Dogs, human | Safe to use in dogs; tolerated in healthy humans; ongoing clinical trials | |
Antioxidant-rich diet with cognitive enrichment | / | Dogs | Improved cognition | |
Anti-Aβ immunotherapy | Passive vaccination with injections of antibodies against Aβ42 | Dogs | Reduced amyloid plaques and reduced astrogliosis |
BACE1 is a protease that controls the formation of Aβ and most likely plays an important role in the development of pathogenesis in AD. The usefulness of BACE1 small-molecule inhibitor LY2886721 has been tested in a dog model and in humans in the first clinical phase (
Testing the same compounds in dogs and humans provided similar findings also in other studies. CP-118,954, an acetylcholinesterase inhibitor, showed minimal cognitive enhancing effects in dogs and human clinical trials were discontinued (
Besides BACE1 and cholinesterase inhibitors several attempts have been made to develop immunotherapy treatments directed against Aβ or TAU (
In dogs, Aβ immunotherapy could reduce the presence of amyloid plaques and astroglial reaction in aged individuals (
Risks for age-related AD and CCD are a complicated interplay between aging, genetic risk factors and environmental influences. CCD in dogs is similar to human AD with respect to APP processing, amyloid plaque deposition and cognitive dysfunction. As dogs age, they have been shown to accumulate amyloid plaques, but, dissimilar to human AD patients, dog brain rarely contains NFTs. Aβ peptide accumulates in the canine brain extracellular space in the form of soluble oligomers, fibrils and Aβ plaques. Its toxic accumulation is believed to be responsible for the neuronal dysfunction and degeneration although the severity of the disease does not always correlate with amyloid burden, but might correlate with toxic fibril polymorphs.
Dogs over 7–8 years seem to be interesting, naturally occurring model organism for aging/dementia that fairly faithfully recapitulate human disease. They are potentially much more useful as rodent models as in laboratory rodents neurodegenerative diseases do not occur spontaneously. Furthermore, genetically modified mice used in research often show very different neurodegeneration courses, as seen in humans. Dogs also spontaneously develop vasculopathies, such as CAA, and perhaps vascular dementia although this has not yet been truly studied, and are therefore also valuable as models to decipher the age and/or dementia related cerebrovascular changes that often accompany or even precede neurodegeneration in human patients.
There are no effective treatments for neurodegenerative disorders, practically all currently available treatments are symptomatic. This is partially related to the poor understanding of the pathogenesis of these diseases, and partly due to the lack of good animal models. Cholinesterase or secretase inhibitor therapy or immunotherapy has been attempted in dogs with CDD, with overlapping results to human AD trials. The neuroprotective effects of cognitive enrichment, alongside with antioxidant-rich diet, show benefits in managing the disease progression and severity in both humans and dogs. Similar results with various drugs do suggest that dogs are useful model to study both pathogenesis and novel treatments for AD in the future.
Taken together, animal studies are important to dissect the molecular and cellular processes specific to AD pathology. Dogs with CCD not only develop isomorphic changes in human cognition and brain pathology, but also accurately predicted the efficacy of known AD treatments and would be therefore good models for testing new substances that affect the lowering of Aβ levels or the reduction or degradation of aggregates associated with AD. This would benefit human patients, but could also help dog patients as any successful treatments could be also introduced into clinical veterinary medicine with the aim to successfully treat this debilitating disease in canine patients.
Both authors have made a substantial contribution to this work.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.