Christa M. Studzinski

Visuospatial function in the beagle dog: An early marker of cognitive decline in a model of human aging and dementia

Visuospatial learning and memory impairments are an early marker for age-related cognitive decline and Alzheimers disease. Similar to humans, aged dogs show visuospatial learning and memory deficits (). One hundred and nine beagle dogs ranging between 0.25 and 11.99 years were tested on a visuospatial delayed non-matching to position (DNMP) task to better characterize the progression of visuospatial deficits in the dog. Age predicted 48.2% of the variability in learning the DNMP, with dogs ranging from 1 to 11.99 years generally making more errors with increasing age. By contrast, puppies (<1 year) likely were showing developmental deficits, possibly due to an immature prefrontal cortex. Mild visuospatial deficits were detected by 6 years, which precedes the typical onset of amyloid-beta (Abeta) accumulation in the dog brain by two years, and can serve as an early marker for cognitive decline in the dog. These findings suggest that (1) age-related changes in visuospatial function in the dog models that seen in humans, further validating the dog as a model for human aging and dementia; and (2) other mechanisms, such as oxidative stress, soluble Abeta oligomers or cholinergic deficits, are likely contributing to the early impairment.

The canine model of human cognitive aging and dementia: Pharmacological validity of the model for assessment of human cognitive-enhancing drugs

For the past 15 years we have investigated the aged beagle dog as a model for human aging and dementia. We have shown that dogs develop cognitive deficits and neuropathology seen in human aging and dementia. These similarities increase the likelihood that the model will be able to accurately predict the efficacy of Alzheimers disease (AD) treatments as well as detect therapeutics with limited or no efficacy. Better predictive validity of cognitive-enhancing therapeutics (CETs) could lead to enormous cost savings by reducing the number of failed human clinical trials and also may reduce the likelihood of negative outcomes such as those recently observed in the AN-1792 clinical trials. The current review assesses the pharmacological validity of the canine model of human aging and dementia. We tested the efficacy of (1) CP-118,954 and phenserine, two acetylcholinesterase inhibitors, (2) an ampakine, (3) selegiline hydrochloride, two drugs that have failed human AD trials, and (4) adrafinil, a putative CET. Our research demonstrates that dogs not only develop isomorphic changes in human cognition and brain pathology, but also accurately predict the efficacy of known AD treatments and the absence or limited efficacy of treatments that failed clinical trials. These findings collectively support the utilization of the dog model as a preclinical screen for identifying novel CETs for both age-associated memory disorder and dementia.

Amyloid-β Peptide and Oligomers in the Brain and Cerebrospinal Fluid of Aged Canines

The study of Alzheimers disease (AD) pathogenesis requires the use of animal models that develop some amount of amyloid pathology in the brain. Aged canines (beagles) naturally accumulate human-type amyloid-beta peptide (Abeta) and develop parallel declines in cognitive function. However, the type and quantity of biochemically extracted Abeta in brain and cerebrospinal fluid (CSF), its link to aging, and similarity to human aging has not been examined systematically. Thirty beagles, aged 4.5-15.7 years, were studied. Abeta40 and Abeta42 were measured in CSF by ELISA, and from SDS and formic acid extracted prefrontal cortex. A sample of the contralateral hemisphere, used to assess immunohistochemical amyloid load, was used for comparison. In the brain, increases in Abeta42 were detected at a younger age, prior to increases in Abeta40, and were correlated with an increased amyloid load. In the CSF, Abeta42 decreased with age while Abeta40 levels remained constant. The CSF Abeta42/40 ratio was also a good predictor of the amount of Abeta in the brain. The amount of soluble oligomers in CSF was inversely related to brain extractable Abeta, whereas oligomers in the brain were correlated with SDS soluble Abeta42. These findings indicate that the Abeta in the brain of the aged canine exhibits patterns that mirror Abeta deposited in the human brain. These parallels support the idea that the aged canine is a useful intermediate between transgenic mice and humans for studying the development of amyloid pathology and is a potentially useful model for the refinement of therapeutic interventions.

A comparison of egocentric and allocentric age-dependent spatial learning in the beagle dog

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.

Changes in cognition and amyloid-β processing with long term cholesterol reduction using atorvastatin in aged dogs

Human studies suggest either a protective role or no benefit of statins against the development of Alzheimers disease (AD). We tested the hypothesis that statin-mediated cholesterol reduction in aged dogs, which have cognitive impairments and amyloid-β (Aβ) pathology, would improve cognition and reduce neuropathology. In a study of 12 animals, we treated dogs with 80 mg/day of atorvastatin for 14.5 months. We did not observe improvements in discrimination learning; however, there were transient impairments in reversal learning, suggesting frontal dysfunction. Spatial memory function did not change with treatment. Peripheral levels of cholesterol, LDLs, triglycerides, and HDL were significantly reduced in treated dogs. Aβ in cerebrospinal fluid and brain remained unaffected. However, β-secretase-1 (BACE1) protein levels and activity decreased and correlated with reduced brain cholesterol. Finally, lipidomic analysis revealed a significant decrease in the ratio of omega-6 to omega-3 essential fatty in temporal cortex of treated aged dogs. Aged beagles are a unique model that may provide novel insights and translational data that can predict outcomes of statin use in human clinical trials. Treatment with atorvastatin may be beneficial for brain aging by reducing BACE1 protein and omega6:omega3 ratio, however, the potential adverse cognitive outcomes reported here should be more carefully explored given their relevance to human clinical outcomes.

Assessment of nutritional interventions for modification of age-associated cognitive decline using a canine model of human aging

The present review focuses on the utility of a canine model in evaluating nutritional interventions for age-related cognitive dysfunction. Aged dogs demonstrate progressive cognitive decline with concurrent amyloid-beta pathology that parallels the pathology observed in aging humans. Dogs, therefore, provide a natural model of human pathological aging. We have and are in the process of evaluating several nutritional-based interventions aimed at preventing cognitive decline and brain aging. In a three-year longitudinal study, we examined the effects of a diet enriched with antioxidants and mitochondrial cofactors on several measures of cognition and brain aging. Compared to controls, aged dogs on the enriched diet demonstrated both short- and long-term cognitive benefits, as well decreased deposition of amyloid-beta protein. The diet also reduced behavioral signs associated with canine Cognitive Dysfunction Syndrome when assessed in veterinary clinical trials. We also have preliminary evidence suggesting a beneficial effect of a proprietary blend of docosahexaenoic acid and phospholipids on both cognitive and physiological measures. Collectively, our data indicate (1) that the dog, either in the laboratory or in the clinic, provides an important tool for assessing nutritional interventions and (2) that combination interventions aimed at several mechanisms of pathological aging may prove more effective than single nutritive components in human trials.

P2-389: Metabolic treatments for Alzheimer's disease

Lauren C. Costantini, C.M. Studzinski, J.A. Araujo, W.A. MacKay, R.L. Webb, T.L. Beckett, M.P. Murphy, P.G. Sullivan, W.M. Burnham, N.W. Milgram, J. Vogel, L. Barr, S.T. Henderson, Accera, Inc., Broomfield, CO, USA; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; CanCog Technologies Inc, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada; Department of Molecular and Cellular Biochemistry, University of Kentucky, Kentucky, KY, USA; Spinal Cord and Brain Injury Research Center, University of Kentucky, Kentucky, KY, USA; CanCog Technologies Inc., Toronto, ON, Canada. Contact e-mail: lcostantini@accerapharma.com