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Tissue Is the Issue, Even During a Pandemic.
Shah KS, Moslehi JJ, Fang JC
(2020) Circulation 142: 423-425
MeSH Terms: Autopsy, COVID-19, Humans, Pneumonia, Risk, Tissue and Organ Procurement
Added September 29, 2020
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6 MeSH Terms
Total RNA Sequencing of Rett Syndrome Autopsy Samples Identifies the M Muscarinic Receptor as a Novel Therapeutic Target.
Gogliotti RG, Fisher NM, Stansley BJ, Jones CK, Lindsley CW, Conn PJ, Niswender CM
(2018) J Pharmacol Exp Ther 365: 291-300
MeSH Terms: Animals, Autopsy, Cerebellum, Humans, Mice, Molecular Targeted Therapy, Motor Cortex, Receptor, Muscarinic M4, Rett Syndrome, Sequence Analysis, RNA
Show Abstract · Added March 3, 2020
Mutations in the gene are responsible for the neurodevelopmental disorder Rett syndrome (RTT). MeCP2 is a DNA-binding protein whose abundance and ability to complex with histone deacetylase 3 is linked to the regulation of chromatin structure. Consequently, loss-of-function mutations in MeCP2 are predicted to have broad effects on gene expression. However, to date, studies in mouse models of RTT have identified a limited number of gene or pathway-level disruptions, and even fewer genes have been identified that could be considered amenable to classic drug discovery approaches. Here, we performed RNA sequencing (RNA-seq) on nine motor cortex and six cerebellar autopsy samples from RTT patients and controls. This approach identified 1887 significantly affected genes in the motor cortex and 2110 genes in the cerebellum, with a global trend toward increased expression. Pathway-level analysis identified enrichment in genes associated with mitogen-activated protein kinase signaling, long-term potentiation, and axon guidance. A survey of our RNA-seq results also identified a significant decrease in expression of the gene, which encodes a receptor [muscarinic acetylcholine receptor 4 (M)] that is the subject of multiple large drug discovery efforts for schizophrenia and Alzheimer's disease. We confirmed that expression was decreased in RTT patients, and, excitingly, we demonstrated that M potentiation normalizes social and cognitive phenotypes in mice. This work provides an experimental paradigm in which translationally relevant targets can be identified using transcriptomics in RTT autopsy samples, back-modeled in mice, and assessed for preclinical efficacy using existing pharmacological tool compounds.
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
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MeSH Terms
mGlu potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome.
Gogliotti RG, Senter RK, Fisher NM, Adams J, Zamorano R, Walker AG, Blobaum AL, Engers DW, Hopkins CR, Daniels JS, Jones CK, Lindsley CW, Xiang Z, Conn PJ, Niswender CM
(2017) Sci Transl Med 9:
MeSH Terms: Animals, Apnea, Autopsy, CA1 Region, Hippocampal, Cognition, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Humans, Long-Term Potentiation, Male, Memory, Methyl-CpG-Binding Protein 2, Mice, Motor Cortex, Neuronal Plasticity, Phenotype, Picolinic Acids, RNA, Messenger, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Respiration, Rett Syndrome, Social Behavior, Transcription, Genetic
Show Abstract · Added March 3, 2020
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the () gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)-CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in reduce mGlu protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu positive allosteric modulation decreases apneas in mice, suggesting that mGlu may be a potential therapeutic target for multiple aspects of the RTT phenotype.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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MeSH Terms
mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome.
Gogliotti RG, Senter RK, Rook JM, Ghoshal A, Zamorano R, Malosh C, Stauffer SR, Bridges TM, Bartolome JM, Daniels JS, Jones CK, Lindsley CW, Conn PJ, Niswender CM
(2016) Hum Mol Genet 25: 1990-2004
MeSH Terms: Adult, Allosteric Regulation, Animals, Autistic Disorder, Autopsy, Disease Models, Animal, Female, Gene Expression Regulation, Hippocampus, Humans, Male, Methyl-CpG-Binding Protein 2, Mice, Mice, Knockout, Motor Cortex, Neuronal Plasticity, Pyrazoles, Pyrimidinones, Receptor, Metabotropic Glutamate 5, Rett Syndrome, Seizures, Signal Transduction, Young Adult
Show Abstract · Added April 6, 2017
Rett syndrome (RS) is a neurodevelopmental disorder that shares many symptomatic and pathological commonalities with idiopathic autism. Alterations in protein synthesis-dependent synaptic plasticity (PSDSP) are a hallmark of a number of syndromic forms of autism; in the present work, we explore the consequences of disruption and rescue of PSDSP in a mouse model of RS. We report that expression of a key regulator of synaptic protein synthesis, the metabotropic glutamate receptor 5 (mGlu) protein, is significantly reduced in both the brains of RS model mice and in the motor cortex of human RS autopsy samples. Furthermore, we demonstrate that reduced mGlu expression correlates with attenuated DHPG-induced long-term depression in the hippocampus of RS model mice, and that administration of a novel mGlu positive allosteric modulator (PAM), termed VU0462807, can rescue synaptic plasticity defects. Additionally, treatment of Mecp2-deficient mice with VU0462807 improves motor performance (open-field behavior and gait dynamics), corrects repetitive clasping behavior, as well as normalizes cued fear-conditioning defects. Importantly, due to the rationale drug discovery approach used in its development, our novel mGlu PAM improves RS phenotypes and synaptic plasticity defects without evoking the overt adverse effects commonly associated with potentiation of mGlu signaling (i.e. seizures), or affecting cardiorespiratory defects in RS model mice. These findings provide strong support for the continued development of mGlu PAMs as potential therapeutic agents for use in RS, and, more broadly, for utility in idiopathic autism.
© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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23 MeSH Terms
A Mutual Self- and Informant-Report of Cognitive Complaint Correlates with Neuropathological Outcomes in Mild Cognitive Impairment.
Gifford KA, Liu D, Hohman TJ, Xu M, Han X, Romano RR, Fritzsche LR, Abel T, Jefferson AL
(2015) PLoS One 10: e0141831
MeSH Terms: Aged, Aged, 80 and over, Aging, Alzheimer Disease, Apolipoprotein E4, Autopsy, Brain, Cognition, Cognitive Dysfunction, Female, Humans, Male, Nervous System Diseases, Neurofibrillary Tangles, Neuropsychological Tests, Plaque, Amyloid
Show Abstract · Added February 22, 2016
BACKGROUND - This study examines whether different sources of cognitive complaint (i.e., self and informant) predict Alzheimer's disease (AD) neuropathology in elders with mild cognitive impairment (MCI).
METHODS - Data were drawn from the National Alzheimer's Coordinating Center Uniform and Neuropathology Datasets (observational studies) for participants with a clinical diagnosis of MCI and postmortem examination (n = 1843, 74±8 years, 52% female). Cognitive complaint (0.9±0.5 years prior to autopsy) was classified into four mutually exclusive groups: no complaint, self-only, informant-only, or mutual (both self and informant) complaint. Postmortem neuropathological outcomes included amyloid plaques and neurofibrillary tangles. Proportional odds regression related complaint to neuropathology, adjusting for age, sex, race, education, depressed mood, cognition, APOE4 status, and last clinical visit to death interval.
RESULTS - Mutual complaint related to increased likelihood of meeting NIA/Reagan Institute (OR = 6.58, p = 0.004) and Consortium to Establish a Registry for Alzheimer's Disease criteria (OR = 5.82, p = 0.03), and increased neurofibrillary tangles (OR = 3.70, p = 0.03), neuritic plaques (OR = 3.52, p = 0.03), and diffuse plaques (OR = 4.35, p = 0.02). Informant-only and self-only complaint was not associated with any neuropathological outcome (all p-values>0.12).
CONCLUSIONS - In MCI, mutual cognitive complaint relates to AD pathology whereas self-only or informant-only complaint shows no relation to pathology. Findings support cognitive complaint as a marker of unhealthy brain aging and highlight the importance of obtaining informant corroboration to increase confidence of underlying pathological processes.
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16 MeSH Terms
Pathological changes long after liver transplantation in a familial amyloidotic polyneuropathy patient.
Obayashi K, Ueda M, Oshima T, Kawahara S, Misumi Y, Yamashita T, Jono H, Yazaki M, Kametani F, Ikeda S, Ohya Y, Asonuma K, Inomata Y, Ando Y
(2012) BMJ Case Rep 2012:
MeSH Terms: Adult, Amyloid Neuropathies, Familial, Autopsy, Brain Chemistry, Fatal Outcome, Gastrointestinal Tract, Heart Ventricles, Humans, Kidney, Liver, Liver Transplantation, Lung, Male, Pancreas, Peripheral Nerves, Prealbumin, Thyroid Gland, Tongue
Show Abstract · Added February 11, 2015
Liver transplantation (LT) reportedly prolongs the survival of patients with familial amyloidotic polyneuropathy (FAP), a fatal hereditary systemic amyloidosis caused by mutant transthyretin (TTR). However, what happens in systemic tissue sites long after LT is poorly understood. In the present study, we report pathological and biochemical findings for an FAP patient who underwent LT and died from refractory ventricular fibrillation more than 16 years after FAP onset. Our autopsy study revealed that the distributions of amyloid deposits after LT were quite different from those in FAP amyloidogenic TTR V30M patients not having had LT and seemed to be similar to those observed in senile systemic amyloidosis (SSA), a sporadic systemic amyloidosis derived from wild-type (WT) TTR. Our biochemical examination also revealed that this patient's cardiac and tongue amyloid deposits derived mostly from WT TTR. We propose that FAP patients after LT may suffer from SSA-like WT TTR amyloidosis in systemic organs.
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18 MeSH Terms
Are respiratory complications common causes of death in inflammatory myopathies? An autopsy study.
Maldonado F, Patel RR, Iyer VN, Yi ES, Ryu JH
(2012) Respirology 17: 455-60
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Autopsy, Cardiovascular Diseases, Cause of Death, Dermatomyositis, Disease Progression, Female, Humans, Male, Middle Aged, Polymyositis, Respiratory Tract Diseases, Retrospective Studies, Young Adult
Show Abstract · Added February 1, 2016
BACKGROUND AND OBJECTIVE - Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory myopathies that are associated with a variety of clinical manifestations including pulmonary complications. The objective of the present study was to determine the causes of deaths in this complex patient population.
METHODS - A computer-assisted search of medical and autopsy records identified a total of 39 patients with either PM or DM who underwent an autopsy at the Mayo Clinic (Rochester, MN, USA) over a 29-year period from 1 January 1981 to 31 December 2009. The immediate causes of death along with contributing causes were determined by reviewing all available clinical data and autopsy findings. We also analysed the discordance between ante-mortem clinical diagnoses provided by clinicians and the final diagnosis by the post-mortem analysis.
RESULTS - Respiratory (33%), infectious (28%) and cardiovascular diseases (26%) accounted for the majority of immediate causes of death. Acute exacerbation of chronic interstitial lung disease (15%) and bronchopneumonia (15%) were the most common specific causes. Immediate cause of death was not suspected in nearly one third of cases and included bronchopneumonia, sepsis, acute myocardial infarction, aspiration pneumonia, pulmonary embolism, aortic stenosis, mycotic aneurysm rupture and acute haemoperitoneum.
CONCLUSIONS - We conclude that pulmonary injury is the immediate cause of death in one third of patients with PM/DM; acute exacerbation of chronic interstitial lung disease and bronchopneumonia were the most common specific causes. Immediate cause of death was not established ante-mortem in nearly one third of cases, and some of these causes were treatable.
© 2011 The Authors. Respirology © 2011 Asian Pacific Society of Respirology.
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17 MeSH Terms
Bipolar disorder type 1 and schizophrenia are accompanied by decreased density of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region.
Wang AY, Lohmann KM, Yang CK, Zimmerman EI, Pantazopoulos H, Herring N, Berretta S, Heckers S, Konradi C
(2011) Acta Neuropathol 122: 615-26
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Autopsy, Bipolar Disorder, Calbindins, Case-Control Studies, Cell Count, Entorhinal Cortex, Female, Hippocampus, Humans, Interneurons, Male, Middle Aged, Nerve Net, Parahippocampal Gyrus, Parvalbumins, S100 Calcium Binding Protein G, Schizophrenia, Somatostatin, Young Adult
Show Abstract · Added May 27, 2014
GABAergic interneurons synchronize network activities and monitor information flow. Post-mortem studies have reported decreased densities of cortical interneurons in schizophrenia (SZ) and bipolar disorder (BPD). The entorhinal cortex (EC) and the adjacent subicular regions are a hub for integration of hippocampal and cortical information, a process that is disrupted in SZ. Here we contrast and compare the density of interneuron populations in the caudal EC and subicular regions in BPD type I (BPD-I), SZ, and normal control (NC) subjects. Post-mortem human parahippocampal specimens of 13 BPD-I, 11 SZ and 17 NC subjects were used to examine the numerical density of parvalbumin-, somatostatin- or calbindin-positive interneurons. We observed a reduction in the numerical density of parvalbumin- and somatostatin-positive interneurons in the caudal EC and parasubiculum in BPD-I and SZ, but no change in the subiculum. Calbindin-positive interneuron densities were normal in all brain areas examined. The profile of decreased density was strikingly similar in BPD-I and SZ. Our results demonstrate a specific reduction of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region in BPD-I and SZ, likely disrupting synchronization and integration of cortico-hippocampal circuits.
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23 MeSH Terms
Analyzing schizophrenia by DNA microarrays.
Horváth S, Janka Z, Mirnics K
(2011) Biol Psychiatry 69: 157-62
MeSH Terms: Autopsy, Brain, Brain Chemistry, Gene Expression Profiling, Humans, Nerve Tissue Proteins, Neuropsychiatry, Oligonucleotide Array Sequence Analysis, Postmortem Changes, Schizophrenia
Show Abstract · Added May 19, 2014
To understand the pathological processes of schizophrenia, we must embrace the analysis of the diseased human brain: we will never be able to recapitulate the pathology of uniquely human disorders in an animal model. Based on the outcome of the transcriptome profiling experiments performed to date, it appears that schizophrenia is associated with a global gene expression disturbance across many cortical regions. In addition, transcriptome changes are present in multiple cell types, including specific subclasses of principal neurons, interneurons, and oligodendrocytes. Furthermore, transcripts related to synaptic transmission, energy metabolism, and inhibitory neurotransmission are routinely found underexpressed in the postmortem brain tissue of subjects with schizophrenia. To put these transcriptome data in biological context, we must make our data publicly available and report our findings in a proper, expanded Minimum Information About a Microarray Experiment format. Cell-type specific expression profiling and sequencing-based transcript assessments should be expanded, with particular attention to understanding splice-variant changes in various mental disorders. Deciphering the pathophysiology of mental disorders depends on integrating data from across many research fields and techniques. Leads from postmortem transcriptome profiling will be essential to generate model animals, perform tissue culture experiments, and develop or evaluate novel drugs to treat this devastating disorder.
Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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10 MeSH Terms
Perceptions, knowledge, incentives, and barriers of brain donation among African American elders enrolled in an Alzheimer's research program.
Lambe S, Cantwell N, Islam F, Horvath K, Jefferson AL
(2011) Gerontologist 51: 28-38
MeSH Terms: African Americans, Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Biomedical Research, Boston, Brain, Educational Status, Female, Focus Groups, Health Knowledge, Attitudes, Practice, Humans, Male, Middle Aged, Qualitative Research, Surveys and Questionnaires, Tissue Donors
Show Abstract · Added March 26, 2019
PURPOSE - To learn about African American older adults' knowledge and perceptions of brain donation, factors that relate to participating or not participating in a brain donation research program, and methods to increase African American brain donation commitment rates in the context of an Alzheimer's disease (AD) research program.
DESIGN AND METHODS - African American older adults (n = 15) from the Boston University Alzheimer's Disease Core Center participant research registry enrolled in 1 of 2 focus groups of 90 min about brain donation. Seven participants were selected for a third follow-up focus group.
RESULTS - Focus group transcripts were analyzed using consensual qualitative research methods, and 8 overarching themes emerged: (a) perceptions of and misconceptions about brain donation procedures, (b) racial minorities in medical research, (c) racial disparities and discrimination in medical settings, (d) influence of religion and spirituality, (e) family perceptions of and involvement in donation, (f) family history of disease and desire to find a cure, (g) prior exposure to medical and research settings, and (h) culturally sensitive approaches to brain donation.
IMPLICATIONS - Culturally relevant educational protocols need to be created for use with African American older adults. These protocols should include information about brain donation procedures, rates of AD among Black elders, and potential benefits of donation to Black communities; inclusion of religious figures, family, and peers in donation education and decisions; and methods to address mistrust, including cultural competence trainings for staff.
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MeSH Terms