The reliability of and age effects on CSF measures of beta-amyloid 42 in beagle dogs: Implications for a natural animal model of Alzheimer's disease progression

Abstract

Background: Canine aging parallels several features of Alzheimer’s disease (AD) including decline in cognitive function, decreased brain volume, oxidative damage, cellular apoptosis, neuronal loss, and betaamyloid (A b) deposits. Moreover, several biomarkers of AD progression also map onto canine aging, including decreasing CSF levels of A b 42 and brain atrophy as measured by MR. Therefore the aged dog serves as a natural model of AD progression. In addition to cognitive decline and CSF biomarkers, decreased cerebral glucose metabolism measured by 18 F-FDG uptake and PET scanning is also reported in human aging. The current study sought to establish the feasibility of using 18 F-FDG PET-MR imaging techniques as an objective marker of functional brain decline in canine aging. Methods: An isotropic anatomical atlas of the canine brain was developed using six T 1-weighted anatomical MR scans registered to form an average MR brain template. 18 F-FDG PET-MR data were acquired on six young (mean age 2.3 years) and six aged (mean age 12.6 years) dogs. Repeatability was examined using two scans separated by 48 hours, and effect of cognitive load was assessed following simple object discrimination learning and more complex variable object discrimination. Effect of age and task on region specific uptake (% ID/g normalized to cerebellum) was evaluated using repeated-measures ANOVA. Results: Repeatability at 48 hours was excellent (p<0.002) and significant age differences were found across several brain regions including, the cingulate (p<0.01), claustrum (p<0.05), and dorsolateral prefrontal cortex (p<0.05). Uptake in the forebrain was significantly increased following the more complex task compared to the simple task (p<0.001) and mean rest (p<0.001). Also, there were interactions suggesting region specific increases or decreases in uptake in young, but not old dogs; larger numbers of subjects are required to confirm these potential ageand task-dependent responses. Conclusions: The current study demonstrates that brain metabolism is significantly decreased in old dogs and that 18 F-FDG PET-MR techniques can be readily incorporated into ADNI-like studies further characterizing the aged canine model of AD progression and possibly as an endpoint for translational drug discovery.