Time

Prog #

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.

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.

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.

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 ìMRI 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.

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.

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.

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.

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.

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.

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.