134 C PHYSICS IN CANADA / VOL. 63, NO. 3 ( July-Sept. 2007 ) lzheimer's disease (AD), the most common form of dementia, affects thought, memory and lan- guage but cannot be diagnosed with certainty until after death. Currently the only sure diag- nosis is pathology of brain tissue taken post-mortem. Beta-amyloid (Aβ) plaques are a signature pathological feature of AD. Only recently have these been imaged in living, transgenic mice using Magnetic Resonance Imaging (MRI) [1-5] . To determine if Aβ plaques occur early or late in the clin- ical progression of AD, behavioral tests need to be per- formed in parallel with imaging studies to establish whether Aβ plaques precede or follow memory deficits. This study follows Aβ plaques in transgenic APP/PS1 mice, and is the first to combine imaging over an extend- ed period of time with Morris Water Maze (MWM) tests being run in parallel with MRI studies. THEORY Beta-amyloid is a fragment of a larger protein called the Amyloid Precursor Protein (APP). In its complete form, APP spans the fatty cell membrane, extending from the inside to the outside of a brain cell. While the precise physiological role of APP is unknown, recent experiments indicate roles for APP fragments in axonal transport, cell adhesion, cell survival, cholesterol metabolism, gene tran- scription, and cognitive processes [6] . When APP is acti- vated (to perform its physiological role), it is cut by enzymes to form separate fragments. Under some circum- stances, one of the fragments produced is the insoluble beta-amyloid protein. Beta-amyloid accumulates in microscopic plaques inside the brain. According to the amyloid hypothesis, beta-amyloid plaques clog cell-to-cell SUMMARY In vivo MRI and ex vivo histology visualize beta-amyloid plaques in a mouse model of Alzheimer's disease. Behavioural tests detect spatial memory deficits. A BY JONATHAN D. THIESSEN, KATHRYN A. COLLISTER, LARYSSA M. KURJEWICZ, MARC R. DEL BIGIO, BENEDICT C. ALBENSI, AND MELANIE MARTIN MAGNETIC RESONANCE IMAGING AND BEHAVIOURAL TEST COMPARISONS IN A MOUSE MODEL OF ALZHEIMER’S DISEASE communications, disrupting cells and activating immune responses that kill and remove disabled cells [7] . If the amyloid hypothesis is correct, in vivo visualization of Aβ plaques will advance the current understanding of AD's progression in the brain and aid in both the diagnosis and treatment of this debilitating disease. Aβ plaques have a diameter ranging from 5-200 μm in transgenic mice [1,4] . In MRI, the basis for contrast between individual plaques and normal background tissue is related to the higher iron content of the plaques [8,9] , which affects the T 2 and T 2 * parameters of MRI. In T 2 - and T 2 *-weighted images, plaques appear as dark spots devoid of MRI signal. Prior to this work, plaques have been successfully identi- fied in mice ex vivo [1,8-13] and in vivo [2-4] without contrast agents. Other in vivo visualization methods have utilized contrast agents [1,5,14-16] . With methods applied to human patients, it is important to be as non-invasive as possible, especially considering their age and possible symptoms related to AD. Thus, there are obvious benefits in having a method that does not require exogenous contrast agents to visualize Aβ plaques. Performing behavioural tests in conjunction with imaging can determine whether plaques precede memory deficits, supporting the amyloid hypothesis, or follow memory deficits, in which case, Aβ plaques might be a side effect of some larger physiological process. The MWM is a behavioural task to test spatial reference memory, which depends on proper functioning of the hippocampus [17] . According to the amyloid hypothesis, transgenic mice should perform more poorly than control mice, due to the presence of beta-amyloid plaques in the hippocampus. METHODS Transgenic Mouse Model of Alzheimer's Disease In order to develop visualization and testing methods for AD, we used a double transgenic APPSwe/PS1 mouse model, strain 00462, from Jackson Laboratories (Bar Harbor, Maine). PS1 is a mutant form of human presenilin 1 linked to early-onset AD. APPSwe is the "Swedish" FEATURE ARTICLE Jonathan D. Thiessen a <jonathan.thiessen@ gmail.com>, Kathryn A. Collister b,c , Laryssa M. Kurjewicz a,d , Marc R. Del Bigio e , Benedict C. Albensi b,c,f and Melanie Martin a,b ; a Physics, University of Winnipeg; b Pharmacology and Therapeutics, Univ. of Manitoba; c Division of Neurodegenerative Disorders, St. Boniface Research Centre; d Medical Biophysics, Univ. of Western Ontario; e Pathology, Univ. of Manitoba; f Centre on Aging, Univ. of Manitoba