Brain Banking

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• Publisher: Elsevier
• Year: 2018
• Print ISBN: 9780444636393
• eBook ISBN: 9780444636423
• Topic: Medicine
• Subtopic: Neurology

Brain Banking, Volume 150, serves as the only book on the market offering comprehensive coverage of the functional realities of brain banking. It focuses on brain donor recruitment strategies, brain bank networks, ethical issues, brain dissection/tissue processing/tissue dissemination, neuropathological diagnosis, brain donor data, and techniques in brain tissue analysis. In accordance with massive initiatives, such as BRAIN and the EU Human Brain Project, abnormalities and potential therapeutic targets of neurological and psychiatric disorders need to be validated in human brain tissue, thus requiring substantial numbers of well characterized human brains of high tissue quality with neurological and psychiatric diseases.- Offers comprehensive coverage of the functional realities of brain banking, with a focus on brain donor recruitment strategies, brain bank networks, ethical issues, and more- Serves as a valuable resource for staff in existing brain banks by highlighting best practices- Enhances the sharing of expertise between existing banks and highlights a range of techniques applicable to banked tissue for neuroscience researchers- Authored by leaders from brain banks around the globe – the broadest, most expert coverage available

Section VII

Human brain tissue analyses: old and new techniques

Chapter 16

Considerations for optimal use of postmortem human brains for molecular psychiatry: lessons from schizophrenia

Cynthia Shannon Weickert^1,2,*; Debora A. Rothmond²; Tertia D. Purves-Tyson^{1,2 1} School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia
² Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, Australia
^* Correspondence to: Professor Cyndi Shannon Weickert, Neuroscience Research Australia, Randwick NSW 2031, Australia. Tel: + 61-02-9399-1600 email address: [email protected]

Abstract

Schizophrenia is a disabling disease impacting millions of people around the world, for which there is no known cure. Current antipsychotic treatments for schizophrenia mainly target psychotic symptoms, do little to ameliorate social or cognitive deficits, have side-effects that cause weight gain, and diabetes and 30% of people do not respond. Thus, better therapeutics for schizophrenia aimed at the route biologic changes are needed and discovering the underlying neurobiology is key to this quest. Postmortem brain studies provide the most direct and detailed way to determine the pathophysiology of schizophrenia. This chapter outlines steps that can be taken to ensure the best-quality molecular data from postmortem brain tissue are obtained. In this chapter, we also discuss targeted and high-throughput methods for examining gene and protein expression and some of the strengths and limitations of each method. We briefly consider why gene and protein expression changes may not always concur within brain tissue. We conclude that postmortem brain research that investigates gene and protein expression in well-characterized and matched brain cohorts provides an important foundation to be considered when interpreting data obtained from studies of living schizophrenia patients.

Keywords

postmortem brain; gene expression; mRNA; transcriptomics; qRT-PCR; protein expression; schizophrenia

Why use postmortem tissue for schizophrenia research?

Schizophrenia severely impairs the function of the human brain and is associated with molecular and cellular changes within cortical and subcortical areas. Individuals who suffer from schizophrenia can have difficulty distinguishing reality from nonreality, can use bizarre language to express themselves, are often socially anxious, and are unable to pay attention and remember things well. Certainly, it has been hypothesized for over 100 years that biologic changes should be identifiable in the brains of those who suffered from schizophrenia. Early attempts to find evidence of neuronal cell loss or obvious neuropathology in brain tissue from those who suffered from schizophrenia largely failed to identify any obvious neuronal loss. This is in contrast to other brain diseases, now in the realm of neurology, where dying cells and hallmark pathologic lesions could be found, and for which diagnostic certainty gained dependence on and an appreciation for neuropathology.

In contrast, psychiatry largely divorced itself from the microscopic evaluation of brain tissue for decades and instead tended to use neuropathologists to screen and remove cases from any brain collection of people with schizophrenia who have changes consistent with other neurologic or infectious agents. While this is a limited and brief historic context, it provides the basis for an important aspect of how brain banking is practiced today, in that even if an individual carried a clinical diagnosis of schizophrenia for decades and was medicated with antipsychotics for most of his or her life, if a neuropathologist identified changes consistent with another brain disease, say Alzheimer disease or encephalitis, the brain would typically be removed from further analysis.

The de-prioritization of histologic examination of schizophrenia brain tissue and an emphasis on more psychologic or psychosocial-based approaches to understanding schizophrenia meant that for decades (in the early to mid-1900s), there appeared to be little progress in identifying the biologic basis of schizophrenia. After the realization that the most efficacious drugs for blunting schizophrenia symptoms (antipsychotics) acted as antagonists at dopamine receptors, that are enriched in the basal ganglia, there was renewed interest in identifying the putative biologic or chemical changes in the human brain of those who suffered from schizophrenia. Currently the study of the human brain has gained some momentum, largely due to the fact that more modern tools have been developed to study biologic tissue on subcellular and molecular levels. Based on the research that we, and others, have done over the past few decades, it is clear that there are many biologic changes in the brains of people with schizophrenia. However, the optimal way to uncover these neurobiologic changes has evolved over time, and developing strategies to interpret the meaning of these neurobiologic changes remains challenging when conducting research on postmortem schizophrenia brains.

Postmortem studies bridge a gap between in vivo human imaging studies and in vivo animal models, providing answers to questions that neither of these two approaches alone can address. Postmortem human brain studies come with their own unique set of strengths and weaknesses and to ensure the best-quality data requires the strengths to be enhanced and the weaknesses to be limited. The quality of data depends on a well-characterized brain cohort, well controlled for confounding factors, and a good experimental design. The first steps to a well-characterized postmortem brain cohort are rigorous brain collection methods and careful assessment and documentation of clinical records. During brain collection and construction of cohorts, rigorous analysis of ante- and postmortem variables and comprehensive documentation of cohort demographics are also important.

How to insure the best data from postmortem brain research?

Cohort size

One of the most important design issues to have been overcome by the field is to study dozens of brains at the same time. In very early anatomic studies, perhaps due to logistical issues, only a few brains were studied in each experiment (at one time). Today, while it is not uncommon in neurologic diseases to have group sizes of fewer than 10 individuals, studies on schizophrenia brains have been increasing the numbers of subjects/group from ~ 10–15/group in the mid-1990s (Knable et al., 1996; Webster et al., 1999), to ~ 30/group in the mid to late 2000s (Lipska et al., 2006b; Fung et al., 2010; McFadden et al., 2016) to ~ 50/group or more currently (Kunii et al., 2015; Volk et al., 2016) and even up to over 250/group (Fromer et al., 2016). There are at least three reasons that the field has done this: (1) the biologic changes are often of a small magnitude (20–30% change from controls); (2) the inherent variability in many human brain measures is large (even within normal cases) and this requires at least 30 brains/group to have adequate statistical power to detect diagnostic differences at the molecular level (Weickert et al., 2010); and (3) it is widely accepted that schizophrenia is a heterogeneous disorder with many possible causes so that different changes may be found in different subsets of cases. This means that a larger sample size is needed in order to discover molecular changes in subpopulations of individuals (Catts and Shannon Weickert, 2012; Fillman et al., 2013).

Clinical characterization and antemortem considerations

The quality and standardization of the clinical data are critical to a well-characterized cohort. A drawback is relying on clinical notes that sometimes are not consistent across sites and may be missing information and this has to be balanced with the value of a brain donated to clinical research. In addition to well-characterized schizophrenia brains (in terms of symptoms, medications, duration of illness, and potential clinical subtype (DSM-IV)), it is critical to confir...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Handbook of Clinical Neurology 3rd Series
• Foreword
• Preface
• Contributors
• Section I: Brain donor recruitment strategies
• Section II: Brain bank networks
• Section III: Ethical aspects of brain banking and management of brain banks
• Section IV: Brain dissection, tissue processing, and tissue dissemination
• Section V: Neuropathologic diagnosis
• Section VI: Brain donor data: clinical, genetic, radiologic, and research data storage and mining
• Section VII: Human brain tissue analyses: old and new techniques
• Index