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      The App NL- G- F mouse retina is a site for preclinical Alzheimer’s disease diagnosis and research

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          Abstract

          In this study, we report the results of a comprehensive phenotyping of the retina of the App NL- G- F mouse. We demonstrate that soluble Aβ accumulation is present in the retina of these mice early in life and progresses to Aβ plaque formation by midlife. This rising Aβ burden coincides with local microglia reactivity, astrogliosis, and abnormalities in retinal vein morphology. Electrophysiological recordings revealed signs of neuronal dysfunction yet no overt neurodegeneration was observed and visual performance outcomes were unaffected in the App NL- G- F mouse. Furthermore, we show that hyperspectral imaging can be used to quantify retinal Aβ, underscoring its potential as a biomarker for AD diagnosis and monitoring. These findings suggest that the App NL- G- F retina mimics the early, preclinical stages of AD, and, together with retinal imaging techniques, offers unique opportunities for drug discovery and fundamental research into preclinical AD.

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          The online version of this article (10.1186/s40478-020-01102-5) contains supplementary material, which is available to authorized users.

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          Most cited references58

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          Fiji: an open-source platform for biological-image analysis.

          Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.
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            NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

            In 2011, the National Institute on Aging and Alzheimer’s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer’s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.
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              Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

              The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious. Copyright © 2011. Published by Elsevier Inc.
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                Author and article information

                Contributors
                Lies.Degroef@kuleuven.be
                Journal
                Acta Neuropathol Commun
                Acta Neuropathol Commun
                Acta Neuropathologica Communications
                BioMed Central (London )
                2051-5960
                6 January 2021
                6 January 2021
                2021
                : 9
                : 6
                Affiliations
                [1 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Neural Circuit Development and Regeneration Research Group, Department of Biology, , University of Leuven (KU Leuven), ; Naamsestraat 61, Box 2464, 3000 Leuven, Belgium
                [2 ]Leuven Brain Institute, Leuven, Belgium
                [3 ]GRID grid.410569.f, ISNI 0000 0004 0626 3338, Department of Ophthalmology, , University Hospitals Leuven, ; Leuven, Belgium
                [4 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Research Group Ophthalmology, Department of Neurosciences, , KU Leuven, ; Leuven, Belgium
                [5 ]GRID grid.410670.4, ISNI 0000 0004 0625 8539, Centre for Eye Research Australia, , Royal Victorian Eye and Ear Hospital, ; East Melbourne, Australia
                [6 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Ophthalmology, Department of Surgery, , University of Melbourne, ; Parkville, Australia
                [7 ]GRID grid.11486.3a, ISNI 0000000104788040, Center for Brain and Disease Research, , Flemish Institute for Biotechnology (VIB), ; Leuven, Belgium
                [8 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, , KU Leuven, ; Leuven, Belgium
                [9 ]GRID grid.6717.7, ISNI 0000000120341548, Health Unit, , Flemish Institute for Technological Research (VITO), ; Mol, Belgium
                [10 ]GRID grid.474690.8, Laboratory for Proteolytic Neuroscience, , RIKEN Center for Brain Science, ; Saitama, Japan
                [11 ]GRID grid.260433.0, ISNI 0000 0001 0728 1069, Department of Neurocognitive Science, Institute of Brain Science, , Nagoya City University Graduate School of Medical Sciences, ; Nagoya, Japan
                [12 ]GRID grid.15762.37, ISNI 0000 0001 2215 0390, Interuniversity Microelectronics Centre (Imec), ; Leuven, Belgium
                [13 ]GRID grid.12155.32, ISNI 0000 0001 0604 5662, Center of Environmental Sciences, Hasselt University, ; Diepenbeek, Belgium
                [14 ]GRID grid.5284.b, ISNI 0000 0001 0790 3681, Department of Biology, , University of Antwerp, ; Wilrijk, Belgium
                Author information
                http://orcid.org/0000-0002-3329-3474
                Article
                1102
                10.1186/s40478-020-01102-5
                7788955
                33407903
                cb2bb519-8e86-46ab-a032-c6d4cf786714
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 15 October 2020
                : 13 December 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003130, Fonds Wetenschappelijk Onderzoek;
                Award ID: PhD fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003130, Fonds Wetenschappelijk Onderzoek;
                Award ID: PhD fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003130, Fonds Wetenschappelijk Onderzoek;
                Award ID: PhD fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003130, Fonds Wetenschappelijk Onderzoek;
                Award ID: senior postdoctoral fellowship
                Award Recipient :
                Funded by: Alzheimer's Research Foundation (BE)
                Funded by: FundRef http://dx.doi.org/10.13039/501100007601, Horizon 2020;
                Funded by: FundRef http://dx.doi.org/10.13039/501100004752, State Government of Victoria;
                Funded by: H & L Hecht Trust
                Funded by: Yulgilbar Alzheimer’s Research Program
                Categories
                Research
                Custom metadata
                © The Author(s) 2021

                alzheimer’s disease,mouse model,retina,retinal imaging,electroretinogram,hyperspectral imaging

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