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      A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease

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          Abstract

          Cerebral small vessel disease (SVD) is a major health burden, yet the pathophysiology remains poorly understood with no effective treatment. Since much of SVD develops silently and insidiously, non-invasive neuroimaging such as MRI is fundamental to detecting and understanding SVD in humans. Several relevant SVD rodent models are established for which MRI can monitor in vivo changes over time prior to histological examination. Here, we critically review the MRI methods pertaining to salient rodent models and evaluate synergies with human SVD MRI methods. We found few relevant publications, but argue there is considerable scope for greater use of MRI in rodent models, and opportunities for harmonisation of the rodent-human methods to increase the translational potential of models to understand SVD in humans. We summarise current MR techniques used in SVD research, provide recommendations and examples and highlight practicalities for use of MRI SVD imaging protocols in pre-selected, relevant rodent models.

          Electronic supplementary material

          The online version of this article (10.1007/s12975-020-00843-8) contains supplementary material, which is available to authorised users.

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          Most cited references126

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          A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

          Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
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            MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging.

            The type, frequency, and extent of MR signal abnormalities in Alzheimer's disease and normal aging are a subject of controversy. With a 1.5-MR unit we studied 12 Alzheimer patients, four subjects suffering from multiinfarct dementia and nine age-matched controls. Punctate or early confluent high-signal abnormalities in the deep white matter, noted in 60% of both Alzheimer patients and controls, were unrelated to the presence of hypertension or other vascular risk factors. A significant number of Alzheimer patients exhibited a more extensive smooth "halo" of periventricular hyperintensity when compared with controls (p = .024). Widespread deep white-matter hyperintensity (two patients) and extensive, irregular periventricular hyperintensity (three patients) were seen in multiinfarct dementia. Areas of high signal intensity affecting hippocampal and sylvian cortex were also present in five Alzheimer and two multiinfarct dementia patients, but absent in controls. Discrete, small foci of deep white-matter hyperintensity are not characteristic of Alzheimer's disease nor do they appear to imply a vascular cause for the dementing illness. The frequently observed "halo" of periventricular hyperintensity in Alzheimer's disease may be of diagnostic importance. High-signal abnormalities in specific cortical regions are likely to reflect disease processes localized to those structures.
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              Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

              The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented.
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                Author and article information

                Contributors
                joanna.wardlaw@ed.ac.uk
                Journal
                Transl Stroke Res
                Transl Stroke Res
                Translational Stroke Research
                Springer US (New York )
                1868-4483
                1868-601X
                16 September 2020
                16 September 2020
                2021
                : 12
                : 1
                : 15-30
                Affiliations
                [1 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Brain Research Imaging Centre, Centre for Clinical Brain Sciences, , University of Edinburgh, ; Edinburgh, UK
                [2 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, UK Dementia Research Institute, Edinburgh Medical School, , University of Edinburgh, ; Edinburgh, UK
                [3 ]GRID grid.47100.32, ISNI 0000000419368710, Department of Anesthesiology, Yale School of Medicine, , Yale University, ; New Haven, CT USA
                [4 ]GRID grid.42505.36, ISNI 0000 0001 2156 6853, Zilkha Neurogenetic Institute, Keck School of Medicine, , University of Southern California, ; Los Angeles, CA USA
                [5 ]GRID grid.42505.36, ISNI 0000 0001 2156 6853, Department of Physiology and Neuroscience, Keck School of Medicine, , University of Southern California, ; Los Angeles, CA USA
                [6 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, , University of Toronto, ; Toronto, ON Canada
                [7 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Department of Medical Biophysics, , University of Toronto, ; Toronto, ON Canada
                [8 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Hurvitz Brain Sciences Research Program, , Sunnybrook Research Institute, ; Toronto, ON Canada
                [9 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Edinburgh Preclinical Imaging, Centre for Cardiovascular Science, , University of Edinburgh, ; Edinburgh, UK
                [10 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Department of Medicine (Neurology), , University of Toronto, ; Toronto, ON Canada
                Author information
                http://orcid.org/0000-0002-9812-6642
                Article
                843
                10.1007/s12975-020-00843-8
                7803876
                32936435
                598c1073-ad9d-45d1-bfa6-b86be35cd384
                © The Author(s) 2020

                Open Access This 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/.

                History
                : 1 June 2020
                : 16 August 2020
                : 19 August 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001674, Fondation Leducq;
                Award ID: 16 CVD 05
                Funded by: FundRef http://dx.doi.org/10.13039/501100007601, Horizon 2020;
                Award ID: PHC-03-15, project No 666881
                Funded by: MRC UK DRI at the University of Edinburgh
                Funded by: BHF Centre for Research Excellence, Edinburgh
                Funded by: SINAPSE
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01AG023084, R01NS090904, R01NS034467, R01AG039452, 1R01NS100459, 5P01AG052350
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000957, Alzheimer's Association;
                Award ID: 509279
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2021

                Cardiovascular Medicine
                small vessel disease,magnetic resonance imaging,systematic reviews,lacunar infarcts,dementia,brain imaging

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