Clinical Phenotype
Canine cognitive dysfunction (CCD) is an age-related neurodegenerative condition characterised by a progressive decline in cognitive functioning, which is clinically expressed as changes in certain learned behaviors and daily routines. Similarities to the early stages of human Alzheimer’s disease (AD) have been found in relation to both the clinical course and to some pathological findings. Consequently, synonyms of CCD include canine counterpart of senile dementia of the Alzheimer’s type, canine dementia, and canine dysfunction syndrome. The prevalence of CCD ranges from 14 to 35% in dogs more than eight years of age, and the risk of developing CCD increases exponentially with increasing age. Thus, age is considered as the most important risk factor. It has been found that a diagnosis of CCD does not affect survival compared to healthy aging control dogs. The clinical phenotype of CCD is characterised by a slowly progression of specific behavioural alterations such as aimless wandering/pacing, staring into space, decreased social interaction, house-soiling, and disturbances in the sleep-wake cycle. Additionally, signs of fear and anxiety that have not been present earlier and difficulty in finding dropped food have also been reported as common signs for dogs suffering from CCD. Clinical signs of the cognitive decline are cumulative and will worsen over time.
Diagnostic Work-up and Associated Challenges
Obtaining a final diagnosis of CCD can only be done via a post-mortem brain biopsy. Thus, in affected dogs the optimal diagnostic approach is to exclude systemic and intracranial diseases mimicking the clinical signs related to CCD. Common differential diagnoses include brain tumors, endocrine and metabolic disorders, chronic pain conditions, or vision/hearing loss. When excluding differential diagnoses relevant investigations should include a thorough clinical and neurological examination plus para-clinical tests such as a complete blood count, serum biochemistry, thyroid profile, urinalysis, magnetic resonance imaging (MRI) of the neurocranium, and possibly cerebrospinal fluid analysis. Obtaining a detailed history focusing on signs that may be associated with CCD is essential. Several owner-based screening questionnaires exist, and these may prove very useful when evaluating a dog with suspected CCD. An obstacle, however, is that there that there is a great variability between these questionnaires with respect to design and scoring method. Other complicating issues are that no systematic international consensus on the evaluation criteria for establishing an ante-mortem diagnosis of CCD exists. Additionally, cognitive tasks which appropriately measures decline in cognitive abilities, memory, and spontaneous activity in companion dogs are still in development and are not yet applicable in a clinical setting.
Therapeutic Interventions
As for humans suffering from AD, there is presently no cure for CCD. Selegiline, also known as L-deprenyl, is the only drug which in some countries has been approved for CCD. This drug may have a symptomatic effect by slowing down the cognitive decline in some dogs. Preventive approaches, such as supplement of antioxidants, L-carnitine or omega-3 fatty acids may have a beneficial effect in some dogs. Mental stimulation, such as training and playing, and keeping daily routines may help in maintaining a good quality of life. Finally, adjunctive therapy targeting the specific clinical signs is considered key when managing dogs that present in the clinic with signs compatible with CCD.
Neuropathology in the Aging Canine Brain
Examples of neurodegenerative changes that have been identified in the aging dog brain includes neuronal loss and thereby cortical atrophy oxidative damage, dysfunction in the neurotransmitter systems, plus deposition of amyloid-beta Aβ protein as extracellular plaques in the cerebral cortex and in the walls of both parenchymal and meningeal vessels. The amino acid sequence of canine Aβ peptide is identical to the human sequence. However, plaques have only been found to be of the diffuse type and not as neuritic plaques which can be found in the aging human brain. As in human AD research, the majority of focus has been on the association between quantification of the Aβ plaque load and degree of cognitive impairment. Results and conclusions from these studies vary as all studies can demonstrate a positive correlation between plaque load and increasing age, but not all studies can find a positive correlation to the degree of cognitive decline. The same discrepancy has been demonstrated between studies investigating the association of neuropathological features and cognition in humans suffering from AD. Accumulation of hyperphosphorylated tau protein inside the neurons leading to neurofibrillary tangles and neuronal death is one of the other pathological hallmarks in human AD. In the aging dog brain, neurofibrillary tangles have not been demonstrated although few studies have demonstrated a presence of phosphorylated tau inside the neurons. This may indicate some kind of pre-tangle tau pathology. The reason for the presumed lack of neurofibrillary tangles in the canine brain has not yet been fully clarified. The issue whether neuroinflammation is involved in the pathogenesis related to CCD is sparsely documented. Very few studies have investigated a potential glia-mediated inflammatory response in the aging dog brain and with conflicting results.
Comparative Aspects to Early Stage Alzheimer’s Disease
The clinical phenotype and progression pattern described for affected dogs are very similar to the clinical features described for humans suffering from AD dementia. Furthermore, the most striking similarity to AD neuropathology is the characteristics of the extensive Aβ deposition. Accordingly, the dog is considered a promising spontaneous model for the Aβ related pathology associated with early stage AD and human brain aging. The presently used transgenic rodent models of AD are seen as mechanistic models. These animal models have contributed significantly to the current knowledge of the neuropathology associated with AD, and they are nothing less than essential in translational AD research and in the drug development phase. However, modelling the impact of environmental factors and the complex cognition of humans is challenging in such animal models. The fact that the companion dogs can now be studied as a spontaneous animal model for early Alzheimer’s disease has therefore been welcomed into the scientific world. Through research, the hope is that we in future will know more about the phenotype, clinical course, and pathophysiology of CCD.
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