|AD: Of Mice & Men|
|Novel Method for in Vitro Evaluation of Amyloid
Plaque Binding Contrast Agents in Alzheimer's Disease
Malgorzata Marjanska1, Emily J. Gilles2, Ryan Chamberlain1, Denise A. Reyes2, Thomas M. Wengenack2, Michael Garwood1, Clifford R. Jack, Jr. 2, Joseph F. Poduslo2
1Center for Magnetic Resonance Research, Minneapolis, Minnesota, USA; 2Mayo Clinic College of Medicine, Rochester, Minnesota, USA
Currently, no in vivo diagnostic method exists for Alzheimer’s disease (AD). Molecular imaging may provide a method to not only visualize plaques but also diagnose AD at much earlier stage. One important problem in development of targeted contrast agents is an ability to assess binding properties of the contrast agent to the tissue or cellular target of interest. The technique described here is a novel in vitro assay to evaluate the effectiveness of contrast agent binding to the target of interest. This method involves gentle homogenization of unfixed AD mouse brain, incubation of the homogenate with a contrast agent, removal of unbound contrast agent by centrifugation and washing, and resuspension of the homogenate in gelatin in an MRI compatible glass tube.
Targeting Alzheimer's Plaques with Dysprosium Based
Youssef Zaim Wadghiri1, Moustafa Douadi1, Jing Yang1, Yeliz Utku2, Kent Kirshenbaum2, Thomas Wisniewski1
1NYU School of Medicine, New York, New York, USA; 2New York University, New York, New York, USA
MRI has been successfully used in transgenic mice for visualizing amyloid plaques, one of the hallmarks of Alzheimer’s Disease (AD). However, the plaque load remains underestimated using either endogenous iron detection or with the help of gadolinium-labeled targeted peptides, suggesting the need of increasing the sensitivity of the magnetic label. We demonstrate that dysprosium labeling of our amyloid probes is a great alternative to increasing the transverse relaxation rate hence increasing sensitivity without compromising the required physicochemical attributes critical for efficient plaque visualization.
Micro MR Imaging of Beta-Amyloid Plaques
and Co-Registration with Iron Deposition and Histological Analysis in
Both Human Alzheimer’s Disease and APP/PS1 Transgenic Mice
Mark D. Meadowcroft1, 2, James R. Connor1, Michael B. Smith2, Qing X. Yang1
1Penn State College of Medicine, Hershey, Pennsylvania, USA; 24. Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts, USA
Here we present data using a magnetic resonance microscopy (MRM) histological coil to view plaques in both human Alzheimer’s and APP/SP1 transgenic mice without contrast agents. The results indicate that iron in the plaques plays a role in observing A β plaque distribution in human Alzheimer’s samples with MRI. However, transgenic APP/PS1 mice show very little focal iron in plaques yet they are seen in the MR data. The data suggest that iron load alone does not account for the hypo-intensities that are observed in the T2* weighted images while plaque morphology and overall size of the plaques also do.
Correlation Between Neurochemical Changes and
Development of Alzheimer’s Plaques with Age Monitored by in Vivo High
Resolution Magnetic Resonance Microimaging and Spectroscopy
Niels Braakman1, Jörg Matysik1, Huub JM De Groot1, Reinhard Schliebs2, A Alia1
1Leiden University, Leiden, Netherlands; 2University of Leipzig, Leipzig, Germany
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the presence of β-amyloid plaques in the brain. Recent studies have shown that the neurochemical profile changes with the progression of AD. However, relationship between the development of β-amyloid plaques and changes in the metabolic profile with age has not yet been explored. In this study we optimized high resolution MRS and ěMRI sequences to explore the correlation between in vivo Alzheimer’s plaque development and neurochemical changes with age in the same transgenic mouse model of AD. Our results show clear relationship between increase in Alzheimer’s plaque load and changes in neurochemical composition of the brain with age.
Assessment of Cerebrovascular Reactivity as a
Function of Age in a Transgenic Mouse Model of Alzheimer’s Disease
Displaying Significant Vascular Pathology Using Acetazolamide
Felicitas Laura Kranz1, 2, Thomas Mueggler1, 2, Marlen Knobloch2, Roger M. Nitsch2, Markus Rudin1, 2
1University and ETH Zurich, Zurich, Switzerland; 2University Zurich, Zurich, Switzerland
Cerebral amyloid angiopathy (CAA) and parenchymal amyloid plaques are the most specific pathological hallmarks of Alzheimer’s Disease. arcAβ mice develop a high vascular plaque load in an age dependent manner. Injection of acetazolamide leads to vasodilation and hence to CBV increase. Two parameters can be derived from dynamic CBV profiles: the rate of vasodilation (vascular reactivity) and the maximal CBV-value (vascular reserve capacity). Vascular reactivity was found to be impaired in arcAβ mice compared to age-controlled littermates, an effect which tended to increase with increasing age or CAA-load respectively. Maximal CBV-values tended to be lower in arcAβ compared to controls.
Cerebral Perfusion, Blood Volume, Vessel Size, and
Vessel Density in the B6.PS2APP Mouse Model for Alzheimer's Disease
Claudia Weidensteiner1, Friedrich Metzger1, Basil Kuennecke1, Markus von Kienlin1
1F. Hoffmann-La Roche Ltd, Basel, Switzerland
Functional and structural parameters of brain vasculature were studied with MRI in double-transgenic B6.PS2APP mice serving as an amyloid-bearing model of Alzheimer’s disease. Brain perfusion, blood volume, vessel size, and vessel density were assessed and compared to those in wild-type controls. Decreased perfusion was observed in B6.PS2APP mice in the dorsal part of the cortex at age 10, 12, and 17 months. This finding was corroborated by a decrease in blood volume detected in the same region in B6.PS2APP mice at age 17 months. No significant differences in vessel size or vessel density were observed.
Diffusion Tensor Imaging (DTI) Reveals
Evolving White Matter Abnormalities in Patients with Alzheimer’s Disease
Jiangyang Zhang1, Can Ceritoglu2, Kazi D. Akhter1, Michael I. Miller2, Marilyn Albert1, Peter C.M. van Zijl1, 3, Susumu Mori1, 3
1Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; 2Johns Hopkins University, Baltimore, Maryland, USA; 3Kennedy Krieger Institute, Baltimore, Maryland, USA
We studied the evolution of diffusion tensor images for a population of Alzheimer’s disease (AD) patients (n=12) and normal elderly controls (n=18) over a period of one year. The multiple scan results were normalized to our single-subject DTI atlas using non-linear diffeomorphic mapping and cross-sectional and longitudinal analyses were performed simultaneously. These initial data suggest that there are evolving white matter abnormalities in a section of the corpus callosum in AD patients.
Biphasic Changes of Functional Hippocampal
Connectivity Identifies AD Risks
Zhilin Wu1, Yin Xu1, Gaohong Wu1, Piero Antuono1, Shi-Jiang Li1
1Medical College of Wisconsin, Milwaukee, Wisconsin, USA
The functional brain networks have been shown to be organized as anticorrelated networks with biphasic characteristics. In this study, we found that the hippocampal connectivity in the age-matched cognitively normal (CN) subjects consists of significant anticorrelated networks, which are similar to the default mode network. The Alzheimer’s disease (AD) subjects suffer a disrupted network in both positive and negative correlation to the hippocampus, while the amnestic mild cognitive impaired (aMCI) subjects mainly suffer the disrupted network in negative correlation to hippocampus. The hippocampal connectivity index (HCI) within the network can differentiate the three groups. These results suggest that the biphasic characteristics of the resting-state brain network are important in healthy CN subjects and are deteriorated along with AD progression.
|Hippocampal Atrophy Patterns in Mild Cognitive
Impairment and Alzheimer’s Disease
Susanne G. Mueller1, Norbert Schuff, Sky Raptentsetsang, Kristine Yaffe, Catherine Madison, Bruce Miller, Michael Weiner
1Center for Imaging of Neurodegenerative Diseases, San Francisco, California , USA
Hippocampal subfields and total hippocampal volume were measured on high resolution MRIs in 47 controls, 14 MCI and 14 AD. AD had significantly smaller ERC, subiculum, CA1, CA1-2 transition and total hippocampal volumes and MCI had smaller CA1 and CA1-2 transition volumes than controls. This patterns is consistent with patterns of neuronal cell loss in histopathological studies. Discriminant analysis showed that CA1-2 was superior to total hippocampal volume for distinction between controls and subjects diagnosed with MCI. These findings suggest that hippocampal subfield volumetry might be a better measure for diagnosis of early AD than measurement of total hippocampal volume.
The Dynamics of Olfactory FMRI BOLD Response
Differentiate Early AD and MCI from Healthy Controls
Lindsi Anne DeArment1, Paul J. Eslinger1, Erin K. Zimmerman1, Robert Grunfeld1, Jeffrey Vesek1, Mark D. Meadowcroft1, Michael B. Smith1, Jianli Wang1, James R. Connor1, Qing X. Yang1
1Penn State University College of Medicine, Hershey, Pennsylvania, USA
The goal of this study was to investigate the pathophysiology of olfactory brain structures in early Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) with olfactory fMRI. The distinctive profiles of AD and MCI BOLD responses are uniquely different from one another and from age-matched control groups. These findings provide neurobiological validation of the behavioral olfactory deficits identified in AD and are promising since olfactory stimulation requires minimal active participation of subjects and allows a direct bioassay in the brain structures that are most vulnerable to early AD pathology.