Individual Case Analysis of Postmortem Interval Time on Brain Tissue Preservation

Blair, John D.; Wang, Chunyu; Hernandez, Damarys; Siedlak, Sandra L.; Rodgers, M. T.; Achar, Rojan K.; Fahmy, Lara M.; Torres, Sandy; Petersen, Robert B.; Zhu, Xiongwei; Casadesús, Gemma; Lee, Hyoung Gon

doi:10.1371/journal.pone.0151615

Cited by 86 publications

(95 citation statements)

References 21 publications

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“…While there are some differences between the patient and control groups in terms of cause of death and post-mortem delay (see Table 1), the present findings are unlikely to be due to these factors (Blair et al, 2016). The basal ganglia were also examined in these same brains and there was no neuronal loss in this structure (Karlsen and Pakkenberg, 2011), confirming the specificity of the current findings.…”

Section: Discussionsupporting

confidence: 77%

Striking reduction in neurons and glial cells in anterior thalamic nuclei of older patients with Down’s syndrome

Perry¹,

Pakkenberg²,

Vann³

2018

Preprint

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The anterior thalamic nuclei are important for spatial and episodic memory; however, there is surprisingly little information about how these nuclei are affected in many conditions that present with memory impairments, including Down's syndrome. To assess the status of the anterior thalamic nuclei in Down's syndrome we quantified neurons and glial cells in the brains from four older patients with this condition. There was a striking reduction in the volume of the anterior thalamic nuclei and this appeared to reflect the loss of approximately 70% of neurons. The number of glial cells was also reduced but to a lesser degree than neurons. The anterior thalamic nuclei appear to be particularly sensitive to effects of aging in Down's syndrome and the pathology in this region likely contributes to the memory impairments observed. These findings re-affirm the importance of assessing the status of the anterior thalamic nuclei in conditions where memory impairments have been principally assigned to pathology in the medial temporal lobe.

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Section: Discussionsupporting

confidence: 77%

Striking reduction in neurons and glial cells in anterior thalamic nuclei of older patients with Down’s syndrome

Perry¹,

Pakkenberg²,

Vann³

2018

Preprint

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“…The majority of our tissues (68%) had a PMI of less than 12 hours, and nearly all (97%) had a PMI of less than 24 hours. Several studies document the integrity of biochemical assessments done within these time frames (27)(28)(29)(30)(31)(32)(33), and formal statistical consideration of PMI in our study indicated that it did not significantly affect outcomes. The importance of establishing SMN levels in relevant human tissues has become particularly urgent in SMA, as breakthrough SMN-inducing therapeutics have now advanced to clinical trials or commercial use (11).…”

Section: Discussionmentioning

confidence: 50%

Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment

Ramos¹,

d’Ydewalle²,

Gabbeta³

et al. 2019

Journal of Clinical Investigation

124

114

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BACKGROUND. Spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein. New SMN-enhancing therapeutics are associated with variable clinical benefits. Limited knowledge of baseline and druginduced SMN levels in disease-relevant tissues hinders efforts to optimize these treatments. METHODS. SMN mRNA and protein levels were quantified in human tissues isolated during expedited autopsies. RESULTS. SMN protein expression varied broadly among prenatal control spinal cord samples, but was restricted at relatively low levels in controls and SMA patients after 3 months of life. A 2.3-fold perinatal decrease in median SMN protein levels was not paralleled by comparable changes in SMN mRNA. In tissues isolated from nusinersen-treated SMA patients, antisense oligonucleotide (ASO) concentration and full-length (exon 7 including) SMN2 (SMN2-FL) mRNA level increases were highest in lumbar and thoracic spinal cord. An increased number of cells showed SMN immunolabeling in spinal cord of treated patients, but was not associated with an increase in whole-tissue SMN protein levels. CONCLUSIONS. A normally occurring perinatal decrease in whole-tissue SMN protein levels supports efforts to initiate SMN-inducing therapies as soon after birth as possible. Limited ASO distribution to rostral spinal and brain regions in some patients likely limits clinical response of motor units in these regions for those patients. These results have important implications for optimizing treatment of SMA patients and warrant further investigations to enhance bioavailability of intrathecally administered ASOs.

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“…Similar to previous studies involving human tissue for western blotting (Blair et al, 2016), we performed denatured SDS-PAGE and Coomassie blue staining using the human samples, prior to examining the expression of proteins of interest. The sample preparations that exhibited the absence of smear (little or no degradation) and sharp resolution of protein bands were used for experiments.…”

Section: Methods Detailsmentioning

confidence: 99%

OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome

Brawner

et al. 2018

Preprint

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16 17 18 2 SUMMARY 1 2 Down syndrome (DS) is a common neurodevelopmental disorder, and cognitive defects in DS patients 3 may arise form imbalances in excitatory and inhibitory neurotransmission. Understanding the 4 mechanisms underlying such imbalances may provide opportunities for therapeutic intervention. Here, 5 we show that human induced pluripotent stem cells (hiPSCs) derived from DS patients overproduce 6 OLIG2 + ventral forebrain neural progenitors. As a result, DS hiPSC-derived cerebral organoids 7 excessively produce specific subclasses of GABAergic interneurons and cause impaired recognition 8 memory in neuronal chimeric mice. Increased OLIG2 expression in DS cells directly upregulates 9 interneuron lineage-determining transcription factors. shRNA-mediated knockdown of OLIG2 largely 10 reverses abnormal gene expression in early-stage DS neural progenitors, reduces interneuron 11 production in DS organoids and chimeric mouse brains, and improves behavioral deficits in DS 12 chimeric mice. Thus, altered OLIG2 expression may underlie neurodevelopmental abnormalities and 13 cognitive defects in DS patients. 2Down syndrome (DS), caused by human chromosome 21 (HSA21) trisomy, is the leading genetic 3 cause of intellectual disability (Parker et al., 2010). An imbalance in excitatory and inhibitory 4 neurotransmission is one of the underlying causes of cognitive deficit of DS (Fernandez et al., 2007; 5 Haydar and Reeves, 2012; Rissman and Mobley, 2011). The inhibitory GABAergic interneurons in the 6 cerebral cortex are derived from the neuroepithelium of the embryonic ventral forebrain (Butt et al., 7 2005; Kessaris et al., 2006; Marin, 2012; Wonders et al., 2008). Many of these neuroepithelial cells 8 express the HSA21 genes OLIG1 and OLIG2. In mice, both Olig1 and Olig2 are expressed in the 9 embryonic neuroepithelium of the ventral forebrain (Lu et al., 2000; Petryniak et al., 2007). In humans, 10 OLIG2, but not OLIG1, is abundantly expressed in the embryonic ventral forebrain (Jakovcevski and 11 Zecevic, 2005), as opposed to their overlapping expression pattern in mouse embryonic brain. Thus, 12 establishing the role of human OLIG genes, in regulating interneuron production, is critical for 13 understanding the mechanisms underlying cognitive deficit in DS and may help devise novel 14 therapeutic strategies. 15It is highly debatable how the production of GABAergic neurons is altered in DS and how OLIG 16 genes are involved as regulators of GABAergic neuron production under normal and DS disease 17 conditions. First, using mouse models, studies examining the functions of Olig genes in GABAergic 18 neuron production remain inconclusive. Loss-of-function studies showed that only Olig1 repressed the 19 production of GABAergic interneurons (Furusho et al., 2006; Ono et al., 2008; Petryniak et al., 2007; 20 Silbereis et al., 2014). Gain-of-function studies showed that overexpression of Olig2 promoted the 21 production of GABAergic neurons (Liu et al., 2015). However, this finding is confounded by the f...

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Individual Case Analysis of Postmortem Interval Time on Brain Tissue Preservation

Cited by 86 publications

References 21 publications

Striking reduction in neurons and glial cells in anterior thalamic nuclei of older patients with Down’s syndrome

Striking reduction in neurons and glial cells in anterior thalamic nuclei of older patients with Down’s syndrome

Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment

OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome

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