Development of Alzheimer-disease neuroimaging-biomarkers using mouse models with amyloid-precursor protein-transgene expression

doi:10.1016/j.pneurobio.2011.05.004

Progress in Neurobiology

Volume 95, Issue 4, December 2011, Pages 547-556

https://doi.org/10.1016/j.pneurobio.2011.05.004 Get rights and content

Abstract

There are important recent developments in Alzheimer's disease (AD) translational research, especially with respect to the imaging of amyloid pathology in vivo using MRI and PET technologies. Here we exploit the most widely used transgenic mouse models of amyloid pathology in order to relate the imaging findings to our knowledge about the histopathological phenotype of these models. The development of new diagnostic criteria of AD necessitates the use of biological markers to diagnose AD even in the absence of overt dementia or early symptomatic mild cognitive impairment. The validity of the diagnosis will depend on the availability of an in vivo marker to reflect underlying neurobiological changes of AD. Transgenic models with essential features of AD pathology and mechanisms provide a test setting for the development and evaluation of new biological imaging markers.

Among the best established imaging markers of amyloid pathology in transgenic animals are high-field MRI of brain atrophy, proton spectroscopy of neurochemical changes, high-field MRI of amyloid plaque load, and in vivo plaque imaging using radio-labelled ligands with PET. We discuss the implications of the findings as well as the methodological limitations and the specific requirements of these technologies. We furthermore outline future directions of transgene-imaging research. Transgene imaging is an emerging area of translational research that implies strong multi- and interdisciplinary collaborations. It will become ever more valuable with the introduction of new diagnostic standards and novel treatment approaches which will require valid and reliable biological markers to improve the diagnosis and early treatment of AD patients.

Highlights

► Ultrahighfield MRI of transgenic models allows detection of amyloid pathology in vivo. ► Neurochemical profiles of amyloid pathology show discrepancies between human disease and animal models. ► PET and SPECT with radiolabelled compounds are the most promising translational markers of amyloid pathology in animal and human studies. ► Imaging features of transgenic models of amyloid pathology reveal the underlying substrate of signal changes in imaging studies in humans.

Introduction

Imaging-derived biomarkers are currently being implemented as a defining criterion for the diagnosis of AD according to currently discussed revised research criteria (Dubois et al., 2007, Dubois et al., 2009). The revision of the NINCDS-ADRDA criteria of AD (McKhann et al., 1984) suggests several new diagnostic entities (http://www.alz.org/research/diagnostic_criteria): the presence of positive biomarkers including imaging and CSF markers together with clinically probable AD defines the entity of “highly probable AD”; together with positive biomarkers the clinical syndrome of amnestic mild cognitive impairment (MCI) becomes “MCI of the Alzheimer type” or even “prodromal AD”. Moreover, a new entity of “preclinical AD” will solely be defined by CSF and imaging biomarkers in the absence of any cognitive decline. These new entities are intended to enable the early diagnosis in clinical diagnostic studies and the enrichment and stratification of samples for testing the effects of potential disease modification in clinical trials of AD (Hampel et al., 2010, Hampel et al., 2011).

With regard to current discussions about diagnostic criteria, the question remains, what the evidence might be that imaging markers of atrophy or neurochemical and functional abnormalities represent essential features of (preclinical) AD pathology? The validity of biomarkers regarding their supposed neurobiological substrate is crucial for the evaluation of disease-modifying treatment strategies. Several lines of research support the use of imaging biomarkers for the early diagnosis or the detection of intervention effects, including the clinical validity of a marker to predict a clinically relevant endpoint, such as cognitive decline (Teipel et al., 2008), the pathological validity of an atrophy marker to represent regional neuronal density (Bobinski et al., 2000) or the neurochemical validity of a marker to specifically bind to Aβ-containing amyloid plaques in the brain (Lockhart et al., 2007). One important line of evidence that is gaining increasing relevance for the validation of in vivo markers of AD are studies in transgenic animal models with amyloid pathology or other AD-related pathological features. Studies in transgenic animals serve a double function: Firstly, they provide independent evidence for potential pathological processes underlying specific imaging changes. Secondly, they represent a testing field for the development of new imaging technologies and sequences. Below we will give an overview of widely used transgenic models of amyloid pathology and discuss the findings on changes of cerebral anatomy, neurochemistry and neuronal function using in vivo imaging techniques in these models.

Section snippets

Transgene models of cerebral β-amyloidosis

The nosological models of AD keep shifting as a consequence of the lack of more precise knowledge about its etiology. This makes it difficult to design animal models precisely according to the human disease context and always requires an adaptation of mouse models to the changing concepts of human AD. Mutations in the amyloid precursor protein (APP) or one of the presenilins are sufficient to cause the complete AD phenotype of plaques, tangles, neuronal loss, and clinically progressive

In vivo imaging of transgenic models of AD

In vivo imaging techniques in transgenic models focus on (i) structural changes, (ii) biochemical changes, and (iii) in vivo amyloid-plaque load, employing technologies of high-field MRI, MR spectroscopy and PET. A summary of the methodological aspects is given in Table 2, while details are discussed in the following section.

Summary

A number of transgenic models replicate essential features of AD histopathology and molecular mechanisms. However, there is no single model that comprehensively resembles human AD pathophysiology. Most likely, there will never be a transgenic model which completely and fully replicates the converging mechanistic and pathological spectrum of sporadic AD, because the chronic decade-long time frame and progression of disease development as well as the complexity of the underlying neuronal

Acknowledgements

Part of this work was supported by grants of from the Interdisciplinary Faculty, Department “Aging Science and Humanities”, University of Rostock to S.J.T. and J.P., the Alzheimer Forschung Initiative e.V. and the Exzellenz Initiative Mecklenburg-Vorpommern to J.P., and of the Hirnliga e.V. (Nürmbrecht, Germany) to S.J.T. The work was further supported by the Science Foundation Ireland (SFI) investigator program award 08/IN.1/B1846 to H.H. Partly supported by the “Landesoffensive zur

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Development of Alzheimer-disease neuroimaging-biomarkers using mouse models with amyloid-precursor protein-transgene expression

Abstract

Highlights

Introduction

Section snippets

Transgene models of cerebral β-amyloidosis

In vivo imaging of transgenic models of AD

Summary

Acknowledgements

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The pinhole: gateway to ultra-high-resolution three-dimensional radionuclide imaging

Eur. J. Nucl. Med. Mol. Imaging

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Proc. Natl. Acad. Sci. U.S.A.

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Ann. N.Y. Acad. Sci.

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Neuroscience

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