scholarly journals In Vivo Imaging Biomarkers in Mouse Models of Alzheimer's Disease: Are We Lost in Translation or Breaking Through?

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Benoît Delatour ◽  
Stéphane Epelbaum ◽  
Alexandra Petiet ◽  
Marc Dhenain
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Imaging Biomarkers ◽  
Preclinical Research ◽  
Disease Modifier ◽  
Fundamental Research ◽  
Neuroimaging Biomarkers ◽  
Lost In Translation

Identification of biomarkers of Alzheimer's Disease (AD) is a critical priority to efficiently diagnose the patients, to stage the progression of neurodegeneration in living subjects, and to assess the effects of disease-modifier treatments. This paper addresses the development and usefulness of preclinical neuroimaging biomarkers of AD. It is today possible to image in vivo the brain of small rodents at high resolution and to detect the occurrence of macroscopic/microscopic lesions in these species, as well as of functional alterations reminiscent of AD pathology. We will outline three different types of imaging biomarkers that can be used in AD mouse models: biomarkers with clear translational potential, biomarkers that can serve as in vivo readouts (in particular in the context of drug discovery) exclusively for preclinical research, and finally biomarkers that constitute new tools for fundamental research on AD physiopathogeny.

Structural, Functional, and Molecular Neuroimaging Biomarkers for Alzheimer’s Disease

2013 ◽  
pp. 821-825
Author(s):  
James B. Brewer ◽  
Jorge Sepulcre ◽  
Keith A. Johnson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Neurodegenerative Disorders ◽  
Brain Dysfunction ◽  
Imaging Biomarkers ◽  
Neurocognitive Evaluation ◽  
Neuroimaging Biomarkers

Advances in quantitative structural, functional, and molecular neuroimaging have provided new tools for objective, in vivo, assessment of critical aspects of Alzheimer’s disease and other neurodegenerative disorders. Measures of brain atrophy or brain dysfunction, coupled with measures of disease-linked pathology, might complement the history, physical and neurocognitive evaluation of patients and thereby improve predictive prognosis, especially at early stages of cognitive impairment where neurodegenerative etiology is less certain. Such imaging biomarkers are currently used in nearly all clinical trials of therapeutic agents for Alzheimer’s disease and are increasingly incorporated into clinical practice. In this chapter, imaging biomarkers are introduced and discussed to familiarize the reader with their potential research and clinical uses.

scholarly journals Metabolic, Phenotypic, and Neuropathological Characterization of the Tg4-42 Mouse Model for Alzheimer’s Disease

2021 ◽  
Vol 80 (3) ◽  
pp. 1151-1168
Author(s):  
Barbara Hinteregger ◽  
Tina Loeffler ◽  
Stefanie Flunkert ◽  
Joerg Neddens ◽  
Thomas A. Bayer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Mouse Models ◽  
Neuronal Degeneration ◽  
Integrated Approach ◽  
In Vivo Model ◽  
Preclinical Research

Background: Preclinical Alzheimer’s disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression. Objective: We thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model. Methods: Therefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses. Results: Our in vivo experiments demonstrate a loss of body weight increase in homozygous Tg4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice. Conclusion: Our study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development.

[18F]-florbetaben PET/CT Imaging in the Alzheimer’s Disease Mouse Model APPswe/PS1dE9

2018 ◽  
Vol 16 (1) ◽  
pp. 49-55 ◽  
Author(s):  
J. Stenzel ◽  
C. Rühlmann ◽  
T. Lindner ◽  
S. Polei ◽  
S. Teipel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
New Drugs ◽  
Imaging Data ◽  
Wild Type ◽  
Preclinical Research ◽  
Standardized Uptake Values ◽  
Pet Ct

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [<sup>18</sup>F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [<sup>18</sup>F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [<sup>18</sup>F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [<sup>18</sup>F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [<sup>18</sup>F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [<sup>18</sup>F]-florbetaben in the APPswe/PS1dE9 mouse model.

scholarly journals Imaging and Molecular Mechanisms of Alzheimer’s Disease: A Review

2018 ◽  
Vol 19 (12) ◽  
pp. 3702 ◽  
Author(s):  
Grazia Femminella ◽  
Tony Thayanandan ◽  
Valeria Calsolaro ◽  
Klara Komici ◽  
Giuseppe Rengo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Multimodal Imaging ◽  
Molecular Mechanisms ◽  
Imaging Techniques ◽  
Structural Mri ◽  
Imaging Biomarkers ◽  
Significant Burden ◽  
Made In

Alzheimer’s disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer’s, as they provide an in vivo window to the pathological processes occurring in Alzheimer’s brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer’s disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer’s research and clinical practice.

In vivo neuronal gene editing via CRISPR–Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer’s disease

2019 ◽  
Vol 22 (4) ◽  
pp. 524-528 ◽  
Author(s):  
Hanseul Park ◽  
Jungju Oh ◽  
Gayong Shim ◽  
Byounggook Cho ◽  
Yujung Chang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Gene Editing ◽  
Neuronal Gene

scholarly journals Monitoring protein aggregation and toxicity in Alzheimer’s disease mouse models using in vivo imaging

Methods ◽  
2011 ◽  
Vol 53 (3) ◽  
pp. 201-207 ◽  
Author(s):  
Tara L. Spires-Jones ◽  
Alix de Calignon ◽  
Melanie Meyer-Luehmann ◽  
Brian J. Bacskai ◽  
Bradley T. Hyman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Mouse Models ◽  
In Vivo Imaging

scholarly journals At a Glance: An Update on Neuroimaging and Retinal Imaging in Alzheimer’s Disease and Related Research

2022 ◽  
pp. 1-10
Author(s):  
J. Ford ◽  
D. Kafetsouli ◽  
H. Wilson ◽  
C. Udeh-Momoh ◽  
M. Politis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Complex Disease ◽  
Historical Context ◽  
Imaging Biomarkers ◽  
Molecular Architecture ◽  
Complex Processes ◽  
Short Commentary ◽  
Recent Developments

Neuroimaging serves a variety of purposes in Alzheimer’s disease (AD) and related dementias (ADRD) research - from measuring microscale neural activity at the subcellular level, to broad topological patterns seen across macroscale-brain networks, and everything in between. In vivo imaging provides insight into the brain’s structure, function, and molecular architecture across numerous scales of resolution; allowing examination of the morphological, functional, and pathological changes that occurs in patients across different AD stages (1). AD is a complex and potentially heterogenous disease, with no proven cure and no single risk factor to isolate and measure, whilst known risk factors do not fully account for the risk of developing this disease (2). Since the 1990’s, technological advancements in neuroimaging have allowed us to visualise the wide organisational structure of the brain (3) and later developments led to capturing information of brain ‘functionality’, as well as the visualisation and measurement of the aggregation and accumulation of AD-related pathology. Thus, in vivo brain imaging has and will continue to be an instrumental tool in clinical research, mainly in the pre-clinical disease stages, aimed at elucidating the biological complex processes and interactions underpinning the onset and progression of cognitive decline and dementia. The growing societal burden of AD/ADRD means that there has never been a greater need, nor a better time, to use such powerful and sensitive tools to aid our understanding of this undoubtedly complex disease. It is by consolidating and reflecting on these imaging advancements and developing long-term strategies across different disciplines, that we can move closer to our goal of dementia prevention. This short commentary will outline recent developments in neuroimaging in the field of AD and dementia by first describing the historical context of AD classification and the introduction of AD imaging biomarkers, followed by some examples of significant recent developments in neuroimaging methods and technologies.

scholarly journals Imaging biomarkers for amyloid: a new generation of probes and what lies ahead

2014 ◽  
Vol 26 (5) ◽  
pp. 703-707 ◽  
Author(s):  
Antoine Leuzy ◽  
Eduardo Rigon Zimmer ◽  
Venkat Bhat ◽  
Pedro Rosa-Neto ◽  
Serge Gauthier
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Work Group ◽  
Imaging Biomarkers ◽  
Amyloid A ◽  
Positron Emission ◽  
Communicative Disorders ◽  
Physiologic Parameters ◽  
New Generation

Since the original 1984 criteria for Alzheimer's disease (AD), put forth by a work group jointly established by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA) (McKhann et al., 1984), important advances have occurred in our ability to detect AD pathophysiology, with the incorporation of biomarkers – defined as anatomic, biochemical, or physiologic parameters that provide in vivo evidence of AD neuropathology (Cummings, 2011) – that can improve the certainty of AD diagnosis. Use of imaging biomarkers such as positron emission tomography (PET) with amyloid ligands, particularly in asymptomatic and pre-dementia stages of AD, however, has been the subject of debate (Dubois et al., 2013), with arguments both for and against the biomarker driven diagnosis of AD.

scholarly journals Detection of Active Caspase-3 in Mouse Models of Stroke and Alzheimer’s Disease with a Novel Dual Positron Emission Tomography/Fluorescent Tracer [68Ga]Ga-TC3-OGDOTA

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Valeriy G. Ostapchenko ◽  
Jonatan Snir ◽  
Mojmir Suchy ◽  
Jue Fan ◽  
M. Rebecca Cobb ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Caspase 3 ◽  
Single Cells ◽  
Glucose Deprivation ◽  
Apoptotic Cells ◽  
The Brain

Apoptosis is a feature of stroke and Alzheimer’s disease (AD), yet there is no accepted method to detect or follow apoptosis in the brain in vivo. We developed a bifunctional tracer [68Ga]Ga-TC3-OGDOTA containing a cell-penetrating peptide separated from fluorescent Oregon Green and 68Ga-bound labels by the caspase-3 recognition peptide DEVD. We hypothesized that this design would allow [68Ga]Ga-TC3-OGDOTA to accumulate in apoptotic cells. In vitro, Ga-TC3-OGDOTA labeled apoptotic neurons following exposure to camptothecin, oxygen-glucose deprivation, and β-amyloid oligomers. In vivo, PET showed accumulation of [68Ga]Ga-TC3-OGDOTA in the brain of mouse models of stroke or AD. Optical clearing revealed colocalization of [68Ga]Ga-TC3-OGDOTA and cleaved caspase-3 in brain cells. In stroke, [68Ga]Ga-TC3-OGDOTA accumulated in neurons in the penumbra area, whereas in AD mice [68Ga]Ga-TC3-OGDOTA was found in single cells in the forebrain and diffusely around amyloid plaques. In summary, this bifunctional tracer is selectively associated with apoptotic cells in vitro and in vivo in brain disease models and represents a novel tool for apoptosis detection that can be used in neurodegenerative diseases.

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