P32
Saturday, July 13, 2013: Alzheimer’s Imaging Consortium Poster Presentations: IC-P
Figure 2. Across-session test-retest % reproducibility errors of FA, MD, AD and RD averaged across white matter ROIs on eight 3T MRI sites.
CT/MRI fused data was co-registered to an MRI atlas for parcellation of specific brain regions. After decay of the isotope, the animals were perfused, the brains removed and cut in 40 um serial sections which were stained, using immunohistochemical methods, for Ab and microglia (Iba-1). Visuospatial learning and memory and motor ability were assessed with the Morris water maze and rota-rod, respectively. Results: FDG-PET imaging of the 5XFAD mice revealed a pattern of age-dependent altered brain metabolism compared to age-matched controls. b-amyloid staining revealed significant and widespread accumulation of Ab plaques throughout the brain in the 5XFAD mice. Microglial response was elevated in aged animals and may be a contributing factor to the FDG uptake patterns observed in the brain. Modest impairments in learning and memory were observed at 6 months of age in the 5XFAD mice, while severe motor impairments were present after 12 months of age. Conclusions: The 5XFAD mouse develops an AD phenotype early in life. Similar to human AD, altered brain metabolism was observed in these mice compared to age matched controls. The 5XFAD mice displayed robust plaque pathology and microglial response that recapitulated characteristics of human AD. The most profound change in behavioural phenotype was motor impairment after 12 months of age. The 5XFAD mouse model may be a powerful tool for assessing efficacy of diagnostic and therapeutic agents being developed for AD.
IC-P-046
VISUALIZING ALZHEIMER’S DISEASE PATHOLOGY WITH CHOLINESTERASE IMAGING AGENTS
Ian Macdonald1, Andrew Reid1, Ian Pottie2, Earl Martin2, Sultan Darvesh1, Dalhousie University, Halifax, Nova Scotia, Canada; 2Mount Saint Vincent University, Halifax, Nova Scotia, Canada. Contact e-mail: Ian.
[email protected]
1
Figure 3. Means of tSNR (left) and across-session tSNR reproducibility errors (center) and full-brain histogram of reproducibility errors (right).
IC-P-045
CEREBRAL GLUCOSE METABOLISM, PATHOLOGY AND BEHAVIOR IN THE 5XFAD MOUSE MODEL OF ALZHEIMER’S DISEASE
Ian Macdonald1, Drew DeBay2, Tim O’Leary1, Andrew Reid1, Meghan Cash1, Courtney Jollymore1, George Mawko1, Steve Burrell1, Chris Bowen2, Earl Martin3, Richard Brown1, Sultan Darvesh1, 1Dalhousie University, Halifax, Nova Scotia, Canada; 2National Research Council, Halifax, Nova Scotia, Canada; 3Mount Saint Vincent University, Halifax, Nova Scotia, Canada. Contact e-mail:
[email protected] Background: A pathological hallmark of Alzheimer’s disease (AD) is the deposition of b-amyloid (Ab) plaques in the brain. The five times familial AD (5XFAD) mouse model is an aggressive model of brain amyloidosis. We hypothesized that the 5XFAD mouse would display changes in brain glucose metabolism compared to age-matched controls, and that these changes would be correlated with brain pathology and behavioural dysfunction. Recapitulating aspects of human AD in a mouse model at an early age will facilitate evaluation of diagnostics and therapeutics for this disease. Methods: Male 5XFAD mice and age-matched wild-type controls were injected with 18 F-FDG and imaged using PET, CT and MRI scans. The PET/
Background: Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are serine hydrolase enzymes that accumulate in b-amyloid plaques and tau neurofibrillary tangles in the Alzheimer’s disease (AD) brain. Cognitively normal individuals may also have plaques and tangles in the brain however, AChE and BuChE are generally not associated with these structures. Thus, imaging cholinesterase activity associated with plaques and tangles in the brain has the potential to provide definitive diagnosis of AD during life and distinguish those individuals with plaque and tangle pathology but not cognitive decline. This would be advantageous since, at present, confirmation of AD relies on detecting pathology through postmortem examination of the brain. We propose that cholinesterase-binding radiopharmaceuticals can be used in SPECT or PET imaging to detect these enzymes associated with AD pathology in the living brain. We have developed cholinesterase imaging agents with the ability to bind AD pathology in rodent and human brain tissues. Methods: Cholinesterase ligands were synthesized and evaluated for binding potency and specificity using enzyme kinetic analysis. These compounds were rapidly radiolabelled and purified. 123 I radiolabelled molecules were injected intravenously in wild-type or AD mouse models and also incubated with mouse and human brain tissues. The distribution of radioactivity was determined via autoradiography and cholinesterase inhibitors were used to evaluate the specificity of these radioligands for such enzyme activity. Tissues were then stained for b-amyloid with thioflavin-S to visualize plaque deposition for comparison with radioligand uptake. Results: Compounds were synthesized and exhibited binding to cholinesterases. 123 I was successfully incorporated into these cholinesterase ligands. Analysis of AD mouse brain sections with autoradiography indicated radioactivity accumulation in areas known to contain cholinesterase activity and plaque pathology. Furthermore, incubation of the radiolabelled molecules with human tissue revealed accumulation of radioactivity in thioflavin-S-positive plaques. Conclusions: Ligands specific for cholinesterases can be synthesized, radiolabelled and purified in an efficient manner for timely use in neuroimaging. These compounds can detect cholinesterases associated with b-amyloid plaques in AD brain tissues. Because of the presence of these enzymes in AD pathological structures, such radioligands have the potential to provide a non-invasive means for early diagnosis of this disease using brain scanning.
