Extended post-mortem delay times should not be viewed as a deterrent to the scientific investigation of human brain tissue: a study from the Brains for Dementia Research Network Neuropathology Study Group, UK

Robinson, Andrew C; Palmer, Laura; Love, Seth; Hamard, Marie; Esiri, Margaret M.; Ansorge, Olaf; Lett, Debbie; Attems, Johannes; Morris, Christopher M.; Troakes, Claire; Selvackadunco, Sashika; King, Andrew; Al‐Sarraj, Safa; Mann, David

doi:10.1007/s00401-016-1617-2

Cited by 18 publications

(26 citation statements)

References 2 publications

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“…We found that the sensitivity of different tissues to PMI-associated mRNA degradation shows distinct gene to gene differences, and in a given tissue, numbers of PMI-associated genes vary dramatically from none to 2,763. For example, mRNAs in the central nervous system show more stability than those in the digestive tract tissues (e.g., esophageal mucosa), which is consistent with previous studies 11, 25 . Of particular interest, we found that even different regions in the same tissue may have significantly different sensitivities to postmortem mRNA degradation, and differing numbers of PMI-associated genes may be identified.…”

Section: Discussionsupporting

confidence: 91%

Systematic analysis of gene expression patterns associated with postmortem interval in human tissues

Zhu

Wang

Yin

et al. 2017

Sci Rep

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Postmortem mRNA degradation is considered to be the major concern in gene expression research utilizing human postmortem tissues. A key factor in this process is the postmortem interval (PMI), which is defined as the interval between death and sample collection. However, global patterns of postmortem mRNA degradation at individual gene levels across diverse human tissues remain largely unknown. In this study, we performed a systematic analysis of alteration of gene expression associated with PMI in human tissues. From the Genotype-Tissue Expression (GTEx) database, we evaluated gene expression levels of 2,016 high-quality postmortem samples from 316 donors of European descent, with PMI ranging from 1 to 27 hours. We found that PMI-related mRNA degradation is tissue-specific, gene-specific, and even genotype-dependent, thus drawing a more comprehensive picture of PMI-associated gene expression across diverse human tissues. Additionally, we also identified 266 differentially variable (DV) genes, such as DEFB4B and IFNG, whose expression is significantly dispersed between short PMI (S-PMI) and long PMI (L-PMI) groups. In summary, our analyses provide a comprehensive profile of PMI-associated gene expression, which will help interpret gene expression patterns in the evaluation of postmortem tissues.

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Section: Discussionsupporting

confidence: 91%

Systematic analysis of gene expression patterns associated with postmortem interval in human tissues

Zhu

Wang

Yin

et al. 2017

Sci Rep

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“…Although there are no studies that have analyzed the influence of the post-mortem delay on DNA methylation, previous reports did not find any effect on pH, RNA quality [ 43 ], or protein concentration (post-synaptic proteins [ 44 ] and primary microglia [ 45 ]) in brain. Therefore, we considered that the difference in post-mortem delay between both groups, healthy controls, and PD cases would not affect our results.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Study in Parkinson’s Disease: A Pilot Analysis of DNA Methylation in Candidate Genes in Brain

Navarro-Sánchez

Águeda-Gómez

Aparicio

et al. 2018

Cells

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Efforts have been made to understand the pathophysiology of Parkinson’s disease (PD). A significant number of studies have focused on genetics, despite the fact that the described pathogenic mutations have been observed only in around 10% of patients; this observation supports the fact that PD is a multifactorial disorder. Lately, differences in miRNA expression, histone modification, and DNA methylation levels have been described, highlighting the importance of epigenetic factors in PD etiology. Taking all this into consideration, we hypothesized that an alteration in the level of methylation in PD-related genes could be related to disease pathogenesis, possibly due to alterations in gene expression. After analysing promoter regions of five PD-related genes in three brain regions by pyrosequencing, we observed some differences in DNA methylation levels (hypo and hypermethylation) in substantia nigra in some CpG dinucleotides that, possibly through an alteration in Sp1 binding, could alter their expression.

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“…Previous research showed conflicting results on how PMD affects the stability of RNA in brain tissue. In some studies, total RNA was shown to be well‐preserved in postmortem brain tissue, and RNA degradation did not correlate with PMD (Cummings, Strum, Yoon, Szymanski, & Hulette, 2001; Ervin et al, 2007; Johnson, Morgan, & Finch, 1986; Kobayashi et al, 1990; Robinson et al, 2016), but rather with other factors such as tissue handling, brain pH (homogenate) and agonal state (Durrenberger et al, 2010; Harrison et al, 1995; Preece & Cairns, 2003; Robinson et al, 2016). In addition, degradation of selective gene transcripts was monitored from brain tissues with different postmortem intervals by PCR, and no correlation between degradation of specific mRNAs and postmortem interval were detected for the PMDs investigated (Heinrich, Matt, Lutz‐Bonengel, & Schmidt, 2007; Kobayashi et al, 1990; Koppelkamm, Vennemann, Lutz‐Bonengel, Fracasso, & Vennemann, 2011).…”

Section: Introductionmentioning

confidence: 99%

The effects of postmortem delay on mouse and human microglia gene expression

Heng

Dubbelaar

Marie

et al. 2020

Glia

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Microglia are specialized macrophages of the central nervous system (CNS) and first to react to pathogens or injury. Over the last decade, transcriptional profiling of microglia significantly contributed to our understanding of their functions. In the case of human CNS samples, either potential CNS pathology in the case of surgery samples, or a postmortem delay (PMD) due to the time needed for tissue access and collection, are potential factors that affect gene expression profiles. To determine the effect of PMD on the microglia transcriptome, we first analyzed mouse microglia, where genotype, antemortem conditions and PMD can be controlled. Microglia were isolated from mice after different PMDs (0, 4, 6, 12, and 24 hr) using fluorescence‐activated cell sorting (FACS). The number of viable microglia significantly decreased with increasing PMD, but even after a 12 hr PMD, high‐quality RNA could be obtained. PMD had very limited effect on mouse microglia gene expression, only 50 genes were differentially expressed between different PMDs. These genes were related to mitochondrial, ribosomal, and protein binding functions. In human microglia transcriptomes we previously generated, 31 of the 50 PMD‐associated mouse genes had human homologs, and their relative expression was also affected by PMD. This study provides a set of genes that shows relative expression changes in relation to PMD, both in mouse and human microglia. Although the gene expression changes detected are subtle, these genes need to be accounted for when analyzing microglia transcriptomes generated from samples with variable PMDs.

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Extended post-mortem delay times should not be viewed as a deterrent to the scientific investigation of human brain tissue: a study from the Brains for Dementia Research Network Neuropathology Study Group, UK

Cited by 18 publications

References 2 publications

Systematic analysis of gene expression patterns associated with postmortem interval in human tissues

Systematic analysis of gene expression patterns associated with postmortem interval in human tissues

Epigenetic Study in Parkinson’s Disease: A Pilot Analysis of DNA Methylation in Candidate Genes in Brain

The effects of postmortem delay on mouse and human microglia gene expression

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