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      Perfusion fixation in brain banking: a systematic review

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          Abstract

          Background

          Perfusing fixatives through the cerebrovascular system is the gold standard approach in animals to prepare brain tissue for spatial biomolecular profiling, circuit tracing, and ultrastructural studies such as connectomics. Translating these discoveries to humans requires examination of postmortem autopsy brain tissue. Yet banked brain tissue is routinely prepared using immersion fixation, which is a significant barrier to optimal preservation of tissue architecture. The challenges involved in adopting perfusion fixation in brain banks and the extent to which it improves histology quality are not well defined.

          Methodology

          We searched four databases to identify studies that have performed perfusion fixation in human brain tissue and screened the references of the eligible studies to identify further studies. From the included studies, we extracted data about the methods that they used, as well as any data comparing perfusion fixation to immersion fixation. The protocol was preregistered at the Open Science Framework: https://osf.io/cv3ys/.

          Results

          We screened 4489 abstracts, 214 full-text publications, and identified 35 studies that met our inclusion criteria, which collectively reported on the perfusion fixation of 558 human brains. We identified a wide variety of approaches to perfusion fixation, including perfusion fixation of the brain in situ and ex situ, perfusion fixation through different sets of blood vessels, and perfusion fixation with different washout solutions, fixatives, perfusion pressures, and postfixation tissue processing methods. Through a qualitative synthesis of data comparing the outcomes of perfusion and immersion fixation, we found moderate confidence evidence showing that perfusion fixation results in equal or greater subjective histology quality compared to immersion fixation of relatively large volumes of brain tissue, in an equal or shorter amount of time.

          Conclusions

          This manuscript serves as a resource for investigators interested in building upon the methods and results of previous research in designing their own perfusion fixation studies in human brains or other large animal brains. We also suggest several future research directions, such as comparing the in situ and ex situ approaches to perfusion fixation, studying the efficacy of different washout solutions, and elucidating the types of brain donors in which perfusion fixation is likely to result in higher fixation quality than immersion fixation.

          Electronic supplementary material

          The online version of this article (10.1186/s40478-019-0799-y) contains supplementary material, which is available to authorized users.

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          Most cited references84

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          Collateral circulation.

          The collateral circulation plays a pivotal role in the pathophysiology of cerebral ischemia. Current knowledge of the collateral circulation remains sparse, largely because of prior limitations in methods for evaluation of these diminutive routes of cerebral blood flow. Anatomic descriptions of the collateral circulation often focus on more proximal anastomoses at the circle of Willis, neglecting secondary collateral pathways provided by leptomeningeal vessels. Pathophysiological recruitment of collateral vessels likely depends on the temporal course of numerous compensatory hemodynamic, metabolic, and neural mechanisms. Subsequent endurance of these protective vascular pathways may determine the severity of ischemic injury. Characterization of the collateral circulation with advanced neuroimaging modalities that provide angiographic information and perfusion data may elucidate critical determinants of collateral blood flow. Such information on the status of the collateral circulation may be used to guide therapeutic interventions. Prognostication and risk stratification may also be improved by routine evaluation of collateral blood flow. Contemporary understanding of the collateral circulation may be greatly enhanced through further refinement of neuroimaging modalities that correlate angiographic findings with perfusion status, providing the basis for future therapeutic and prognostic applications.
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            Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program.

            The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.
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              Chemical and physical basics of routine formaldehyde fixation

              Formaldehyde is the widely employed fixative that has been studied for decades. The chemistry of fixation has been studied widely since the early 20th century. However, very few studies have been focused on the actual physics/chemistry aspect of process of this fixation. This article attempts to explain the chemistry of formaldehyde fixation and also to study the physical aspects involved in the fixation. The factors involved in the fixation process are discussed using well documented mathematical and physical formulae. The deeper understanding of these factors will enable pathologist to optimize the factors and use them in their favor.
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                Author and article information

                Contributors
                wcmcfadden@gmail.com
                hadleyawalsh@gmail.com
                felix.richter@icahn.mssm.edu
                celine.soudant@mssm.edu
                clare.bryce@mountsinai.org
                patrick.hof@mssm.edu
                mary.fowkes@mountsinai.org
                john.crary@mountsinai.org
                andrew.mckenzie@icahn.mssm.edu
                Journal
                Acta Neuropathol Commun
                Acta Neuropathol Commun
                Acta Neuropathologica Communications
                BioMed Central (London )
                2051-5960
                5 September 2019
                5 September 2019
                2019
                : 7
                : 146
                Affiliations
                [1 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Psychiatry, , Icahn School of Medicine at Mount Sinai, ; One Gustave L. Levy Place, New York, NY 10029 USA
                [2 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Pathology, , Icahn School of Medicine at Mount Sinai, ; One Gustave L. Levy Place, New York, NY 10029 USA
                [3 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Graduate School of Biomedical Sciences, , Icahn School of Medicine at Mount Sinai, ; One Gustave L. Levy Place, New York, NY 10029 USA
                [4 ]ISNI 0000 0000 9963 6690, GRID grid.425214.4, Gustave L. and Janet W. Levy Library, , Mount Sinai Health System, ; One Gustave L. Levy Place, New York, NY 10029 USA
                [5 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Nash Family Department of Neuroscience, , Icahn School of Medicine at Mount Sinai, ; One Gustave L. Levy Place, New York, NY 10029 USA
                [6 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Friedman Brain Institute and Ronald M. Loeb Center for Alzheimer’s Disease, , Icahn School of Medicine at Mount Sinai, ; One Gustave L. Levy Place, New York, NY 10029 USA
                [7 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Neuropathology Brain Bank and Research Core, , Icahn School of Medicine at Mount Sinai, ; One Gustave L. Levy Place, New York, NY 10029 USA
                Author information
                https://orcid.org/0000-0002-1394-2131
                http://orcid.org/0000-0003-3429-9621
                https://orcid.org/0000-0003-2562-8585
                https://orcid.org/0000-0002-3208-1154
                https://orcid.org/0000-0001-7462-4340
                Article
                799
                10.1186/s40478-019-0799-y
                6728946
                31488214
                005920dd-d9a4-43f0-80d8-5fe22fe86a92
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

                History
                : 25 July 2019
                : 26 August 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;
                Award ID: P50 AG005138
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                brain banking,perfusion fixation,immersion fixation,brain perfusion,histology quality

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