Canine Cognitive Decline and Alzheimer’s Disease

Publishing Author : Katherine Compitus, MSEd, MSW
Date Published – September 2013

Millions of older adults are diagnosed each year with Alzheimer’s disease, a serious neurodegenerative condition that results in death.  Early symptoms include a reduction in episodic memory which quickly advances to full-blown dementia.  The cause of Alzheimer’s disease is still not well known; hypothesis focus on cholinergenic changes, amyloid deposits or tau protein abnormalities.  The aging brain of a dog parallels that of a human in many respects, including similar neuropathological changes and an age specific pattern of cognitive decline.  This makes a canine model particularly useful for studying the development and potential treatment options for  Alzheimer’s disease.

As dogs age they may show a severe decline in cognitive functioning including impairment on tests of complex discriminative learning, reversal learning, object recognition memory and visuospatial working memory, while procedural memory and simple discriminative learning remain intact (Adams et al, 2000).  Neurolopatholoical changes in dogs also mimic those in humans; the deposition of amaloid-ß into diffuse plaques has been shown to increase with age and the degree of cognitive impairment in aged dogs correlates with the extent and location of Aß  deposition (Fanhestock et al, 2012).   Additionally, oxidative damage and hilar neuron loss in the hippocampus have also been observed (Fanhestock et al, 2012).  Older dogs naturally develop learning and memory impairments, as well as changes in social interactions.  However, dogs never develop a full-blown Alzheimer’s pathology, instead their symptoms mimic that of early AD in humans and, therefore, dogs are particularly useful to test theories of AD development and early intervention strategies.

The cholinergenic hypothesis is the oldest theory about the cause of AD, but it’s also the most controversial.  AD patients show “reduced post-mortem activity levels of choline acetyltransferase” and the most effective therapeutic interventions to date have targeted

cholinergenic dysfunction (Araujo et al, 2011).  Additionally, a muscarinic cholinergenic antagonist, Scopolamine, can mimic the symptoms of AD in mammals and can cause severe cognitive impairments (Dowling & Head, 2011).  Scopolamine hypersensitivity is believed to be represent age-related cholenergenic dysfunction in humans.  Dowling and Head (2012) found that older dogs demonstrated more scopolamine-induced deficits than younger dogs.  However, the decreased muscarinic receptor density in older dogs suggested that any age-related hypersensitivity to scopolamine may suggest a physiological change in the cholenergenic system.  However, cholenergenic deficits alone cannot account for all the cognitive impairments in Alzheimer’s disease, especially since there is a bidirectional interaction between cholergenic and amaloid events (Araujo et al, 2011).  Sadly, choolinesterase inhibitors are the most popular treatment option for AD and they not only appear to have limited efficacy, but the effectiveness of the treatment shows individual variability (Araujo et al, 2011).

The amyloid hypothesis is one of the most popular theories of AD development and, therefore, the target for new therapeutic interventions.  It postulates that the cause of AD is the “deposition of amyloid-β into senile plaques and the formation of neurofibrillary tangles within the brain” (Araujo et al, 2011).  Dog brains show similar neuropathological changes, including “the deposition of amyloid-β, which is identical in protein sequence and undergoes similar post-translational modifications as that seen in humans” (Araujo et al, 2011).  The levels and numbers of those isoforms is also similar to those seen in human AD patients.  Additionally, in people with mild cognitive impairments and also AD, brain-derived neurotrophic factor (BDNF), mRNA and protein are shown to decrease in the cortex and hypocampus of humans, therefore a reduction is BDNF is highly correlated with cognitive decline (Adams et al, 2000).  Decreased BDNF has also been found in transergenic mice, as well as in older dogs and primates.

Fanhestock et al. (2012) state that “BDNF availability in the brain may be a viable strategy to counteract cognitive decline with aging or AD”.  They suggest noninvasive  approaches such as altering the person (or dog’s) diet, exercise regime and adding both cognitive and environmental enrichment. Current research suggests that the most effective therapies combine both a treatment with an antioxidant diet with a program of behavioral enrichment.  When this combination of treatment modalities is followed, the activity of the Glutathion-S transferase (GST) in the brain is increased, while the GST itself is less oxidized (Opii et al, 2008).  It has been determined that “there is a significant decline in the activity of GST in the amygdala, huppocampus and inferior parietal lobule of patients with AD” (Opii et al, 2008) and the GST is critical to preventing oxidative stress.  The increase in acitivity of the GST could improve the ability of the brain to clear out toxic aldehydes that are impairing memory.  Higher levels of GST in dogs has been shown to reflect lower error scores on discriminative learning tests and other cognitive tasks.  Snigdha et al (2012) believe that behavioral interventions can include social enrichment (housing in pairs), physical enrichment (increased exercise), and cogntive enrichment (training on cognitive tasks).  They suggest that “that the beneficial effects of the two interventions (on cognition) are mediated via distinctly different pathways” and that “downstream signal transduction events mobilized by antioxidants may be separable from those engaged by environmental enrichment. Such events may include activation of protective mechanisms such neurotrophic factor accumulation or even improved synaptic connectivity” (Snigdha et al, 2012) .  However, the combination of an antioxidant diet along with an increase in environmental enrichment has show to reduce and reverse cogntive decline more significantly than either treatment modality alone.

There has been a recent increase in the number of systematic and controled studies of age-related cognitive decleficits in dogs.  These studies have focused on deficits in learning, memory, exectutive, and visuospatial functioning.  Just as in older humans, other aspects of behavior, especially spontaneous activity, appears to be affected by the aging process.  Rosado et al (2012) extensively studied the locomotion, exploratory behavior and social responsiveness of older dogs.  The cognitive decline in older canines is not limited to information processing and studying the change in other habits can provide us even more insight into the variety of ways that human and non-human animals age.    Although cognitive decline in dogs parallels that of humans with Alzheimer’s, dogs never develop full-blown dementia and CD in dogs does not result in dealth.  However, it is estimated that 22% of geriatric dogs suffer from cognitive dysfunction syndrome (CDS), and the percentage of dogs with CDS significantly increases with age (Rosado et al, 2012).  Since CDS does not result in death, scientists are able to study congitive decline more extensively and for a longer period of time than they may with humans.  Rosado et al (2012) found that, in dogs, there were significant differences in spontaneous activity, including locomotion, based on congitive status, not age.  There is some speculation that “increased walking is related to a dysfunction in the behavioural cortrol mechanisms in the prefrontal cortical-striatal-pallidal circutry” (Rosado et al 2012).  This is consistent with studies of humans with AD, since they demostrate different locomotive behavior than those with simple vascular dementia (AD patients are more likely to wander aimlessly than those with vascular dementia).  There was also a decline in exploratory behavior of novel environments and novel objects, with severety of CDS being a more significant factor than age alone.  Older humans with AD also “undergo several changes in social behaviour including aggression, culturally inappropriate behaviours, and affective disturbances” (Rosado, 2012).  A significant difference was also shown in the social behaviors of aging dogs, especially in those with CDS.  Dogs with CDS were more likely to display abnormal social responses incluing altered relationships with family members and unprovoked aggression towards unfamiliar humans and animals.  The sleep-wake cycle, orienation ability and housetraining habits of dogs with CDS and also parallel similar biological changes in human patients with AD (Adams et al, 2000).

As of yet, no cure has been found to treat AD or CDS and current medication appear to have limited efficacy.  Scientitist continue to expolory possible causes in order to determine the most effective treatment for AD/CDS.  Badino et al (2012) suggest that current medications may be targeting the wrong part of the brain and that scientists should make sure to differentiate between normal aging (vascular dementia) and AD.  They believe that “the reduction in HA muscarinic receptor-binding sites could be representative of the physiological agine process, whereas the increase in lymphocyte LA muscarinic receptor levels could be related to the cognitive decline” (Badino et al, 2012).   However, to date Adrenaphil has been the most effective treatment for both AD and CDS.  Adrenaphil is a eugregoric medication, which means that it has behavior activating effects without the side effects most common in most anphetamines (Siwak et all, 2000).  Adrenaphil has been proven to improve locamotor activity, exploratory behavior, discrimination learning and performance motivation in dogs.  It aged people it has also been shown to be “effective in treating deficits in arousal or vigilance, difficulties in attention, sleep memory and mild depression” (Siwak et al, 2000).  Sadly, the efficacy of current medications, such as Adrenaphil, varies from individual to individual.  Since CDS in aging dogs is so simliar to AD in older humans, it is important to continue studying the potential causes and treatment options.  The brain remains a highly mysterious entity and, hopefully, as we unlock more of its secrets we will be able to develop a cure for highly debilitating illnesses such as Alzheimer’s Disease and, of course, Cognitive Dysfunction Syndrome.

References

 

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Adams, B., Chan, A., Callahan, H., Siwak, C., Tapp, D., Ikeda-Douglas, C., Atkinson, P., Head, E., Cotman, C., Milgram, N. (2000). Use of a delayed non-matching to position            task to model age-dependent cognitive decline in the dog. Behavioural Brain      Research, 108, 47–56

 

Araujo, J., Nobrega, J., Raymond, R., Milgram, N. (2011). Aged dogs demonstrate both increased sensitivity to scopolamine impairment and decreased muscarinic receptor density. Pharmacology, Biochemistry and Behavior, 98, 203–209

 

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Rosado, B., Gonzalez-Martinez, A., Pesini, P., Garcia-Belenguer, S., Palacio, J., Villegas, A.,             Suarez, M.-L., Santamarina, G., Sarasa, M. (2012). Effect of age and severity of   cognitive dysfunction on spontaneous activity in pet dogs – Part 2: Social        responsiveness. The Veterinary Journal, 194, 196–201

 

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Snigdha, S., Astarita, G., Piomelli, D., Cotman, C. (2012). Effects of diet and behavioral enrichment on free fatty acids in the aged canine brain. Neuroscience, 202, 326–333

 

Studzinskia, C., Araujoa, J., Milgram, N. (2005). The canine model of human cognitive aging      and dementia: Pharmacological validity of the model for assessment of human cognitive-enhancing drugs. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 29, 489– 498

 

 

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