Search

Your search keyword '"Stephen J. Sawiak"' showing total 28 results
Start Over Author "Stephen J. Sawiak" Language english
28 results on '"Stephen J. Sawiak"'

1. Mapping the neuroanatomical abnormalities in a phenotype of male compulsive rats

Author

Elena Martín-González, Ángeles Prados-Pardo, Stephen J. Sawiak, Jeffrey W. Dalley, Daniel Padro, Pedro Ramos-Cabrer, Santiago Mora, and Margarita Moreno-Montoya

Subjects
Compulsive behavior, Schedule-Induced Polydipsia, Magnetic resonance imaging, Voxel-based morphometry, Cortico-striatal-thalamic-cortical circuit, White matter, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Compulsivity is considered a transdiagnostic dimension in obsessive–compulsive and related disorders, characterized by heterogeneous cognitive and behavioral phenotypes associated with abnormalities in cortico-striatal-thalamic-cortical circuitry. The present study investigated the structural morphology of white and gray matter in rats selected for low- (LD) and high- (HD) compulsive drinking behavior on a schedule-induced polydipsia (SIP) task. Regional brain morphology was assessed using ex-vivo high-resolution magnetic resonance imaging (MRI). Voxel-based morphometry of segmented MRI images revealed larger white matter volumes in anterior commissure and corpus callosum of HD rats compared with LD rats. HD rats also showed significantly larger regional volumes of dorsolateral orbitofrontal cortex, striatum, amygdala, hippocampus, midbrain, sub-thalamic nucleus, and cerebellum. By contrast, the medial prefrontal cortex was significantly smaller in HD rats compared with LD rats with no significant group differences in whole brain, ventricular, or cerebrospinal fluid volumes. These findings show that limbic cortico-basal ganglia structures implicated in impulse control disorders are distinct in rats that are vulnerable to develop compulsive behavior. Such abnormalities may be relevant to the etiology of compulsive disorders in humans.

Published
2023
Full Text
View/download PDF

2. Cortical glutamate and GABA are related to compulsive behaviour in individuals with obsessive compulsive disorder and healthy controls

Author

Marjan Biria, Paula Banca, Máiréad P. Healy, Engin Keser, Stephen J. Sawiak, Christopher T. Rodgers, Catarina Rua, Ana Maria Frota Lisbôa Pereira de Souza, Aleya A. Marzuki, Akeem Sule, Karen D. Ersche, and Trevor W. Robbins

Subjects
Science
Abstract

Abstract There has been little analysis of neurochemical correlates of compulsive behaviour to illuminate its underlying neural mechanisms. We use 7-Tesla proton magnetic resonance spectroscopy (1H-MRS) to assess the balance of excitatory and inhibitory neurotransmission by measuring glutamate and GABA levels in anterior cingulate cortex (ACC) and supplementary motor area (SMA) of healthy volunteers and participants with Obsessive-Compulsive Disorder (OCD). Within the SMA, trait and clinical measures of compulsive behaviour are related to glutamate levels, whereas a behavioural index of habitual control correlates with the glutamate:GABA ratio. Participants with OCD also show the latter relationship in the ACC while exhibiting elevated glutamate and lower GABA levels in that region. This study highlights SMA mechanisms of habitual control relevant to compulsive behaviour, common to the healthy sub-clinical and OCD populations. The results also demonstrate additional involvement of anterior cingulate in the balance between goal-directed and habitual responding in OCD.

Published
2023
Full Text
View/download PDF

3. In-vitro gadolinium retro-microdialysis in agarose gel—a human brain phantom study

Author

Chisomo Zimphango, Marius O. Mada, Stephen J. Sawiak, Susan Giorgi-Coll, T. Adrian Carpenter, Peter J. Hutchinson, Keri L. H. Carpenter, and Matthew G. Stovell

Subjects
gadolinium, diffusion, MRI, brain phantom, agar, microdialysis, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Rationale and objectivesCerebral microdialysis is a technique that enables monitoring of the neurochemistry of patients with significant acquired brain injury, such as traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH). Cerebral microdialysis can also be used to characterise the neuro-pharmacokinetics of small-molecule study substrates using retrodialysis/retromicrodialysis. However, challenges remain: (i) lack of a simple, stable, and inexpensive brain tissue model for the study of drug neuropharmacology; and (ii) it is unclear how far small study-molecules administered via retrodialysis diffuse within the human brain.Materials and methodsHere, we studied the radial diffusion distance of small-molecule gadolinium-DTPA from microdialysis catheters in a newly developed, simple, stable, inexpensive brain tissue model as a precursor for in-vivo studies. Brain tissue models consisting of 0.65% weight/volume agarose gel in two kinds of buffers were created. The distribution of a paramagnetic contrast agent gadolinium-DTPA (Gd-DTPA) perfusion from microdialysis catheters using magnetic resonance imaging (MRI) was characterized as a surrogate for other small-molecule study substrates.ResultsWe found the mean radial diffusion distance of Gd-DTPA to be 18.5 mm after 24 h (p

Published
2024
Full Text
View/download PDF

4. Early-life stress biases responding to negative feedback and increases amygdala volume and vulnerability to later-life stress

Author

Ethan G. Dutcher, Laura Lopez-Cruz, E. A. Claudia Pama, Mary-Ellen Lynall, Iris C. R. Bevers, Jolyon A. Jones, Shahid Khan, Stephen J. Sawiak, Amy L. Milton, Menna R. Clatworthy, Trevor W. Robbins, Edward T. Bullmore, and Jeffrey W. Dalley

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Early-life stress (ELS) or adversity, particularly in the form of childhood neglect and abuse, is associated with poor mental and physical health outcomes in adulthood. However, whether these relationships are mediated by the consequences of ELS itself or by other exposures that frequently co-occur with ELS is unclear. To address this question, we carried out a longitudinal study in rats to isolate the effects of ELS on regional brain volumes and behavioral phenotypes relevant to anxiety and depression. We used the repeated maternal separation (RMS) model of chronic ELS, and conducted behavioral measurements throughout adulthood, including of probabilistic reversal learning (PRL), responding on a progressive ratio task, sucrose preference, novelty preference, novelty reactivity, and putative anxiety-like behavior on the elevated plus maze. Our behavioral assessment was combined with magnetic resonance imaging (MRI) for quantitation of regional brain volumes at three time points: immediately following RMS, young adulthood without further stress, and late adulthood with further stress. We found that RMS caused long-lasting, sexually dimorphic biased responding to negative feedback on the PRL task. RMS also slowed response time on the PRL task, but without this directly impacting task performance. RMS animals were also uniquely sensitive to a second stressor, which disproportionately impaired their performance and slowed their responding on the PRL task. MRI at the time of the adult stress revealed a larger amygdala volume in RMS animals compared with controls. These behavioral and neurobiological effects persisted well into adulthood despite a lack of effects on conventional tests of ‘depression-like’ and ‘anxiety-like’ behavior, and a lack of any evidence of anhedonia. Our findings indicate that ELS has long-lasting cognitive and neurobehavioral effects that interact with stress in adulthood and may have relevance for understanding the etiology of anxiety and depression in humans.

Published
2023
Full Text
View/download PDF

5. Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral and neural responses to threat

Author

Laith Alexander, Christian M. Wood, Philip L. R. Gaskin, Stephen J. Sawiak, Tim D. Fryer, Young T. Hong, Lauren McIver, Hannah F. Clarke, and Angela C. Roberts

Subjects
Science
Abstract

Alexander et al. causally implicate over-activity in primate subgenual cingulate in affective and cardiovascular dysfunction relevant to anxiety and depression. Over-activation led to elevated activity in a stress-related network whilst decreasing activity in higher-order prefrontal cognitive regions.

Published
2020
Full Text
View/download PDF

6. Encephalopathy induced by Alzheimer brain inoculation in a non-human primate

Author

Charlotte Gary, Suzanne Lam, Anne-Sophie Hérard, James E. Koch, Fanny Petit, Pauline Gipchtein, Stephen J. Sawiak, Raphaëlle Caillierez, Sabiha Eddarkaoui, Morvane Colin, Fabienne Aujard, Jean-Philippe Deslys, French Neuropathology Network, Emmanuel Brouillet, Luc Buée, Emmanuel E. Comoy, Fabien Pifferi, Jean-Luc Picq, and Marc Dhenain

Subjects
Alzheimer’s disease, β-Amyloid pathology, Cerebral atrophy, Cognitive impairment, Microcebus murinus, Mouse, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Alzheimer’s disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated β-amyloid peptides (Aβ) and tau proteins. Iatrogenic induction of Aβ is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aβ. Induction of Aβ and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer’s disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express Aβ or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aβ depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer’s disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes.

Published
2019
Full Text
View/download PDF

7. Characterizing infarction and selective neuronal loss following temporary focal cerebral ischemia in the rat: A multi-modality imaging study

Author

Sohail Ejaz, David J. Williamson, Tahir Ahmed, Sergey Sitnikov, Young T. Hong, Stephen J. Sawiak, Tim D. Fryer, Franklin I. Aigbirhio, and Jean-Claude Baron

Subjects
Stroke, Cerebral ischemia, 11C-flumazenil, Cerebral infarction, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background and purpose: Current models dictate that, depending on occurrence of early reperfusion, the ischemic penumbra either undergoes or escapes infarction (i.e., “pan-necrosis”). However, tissue outcome following temporary middle-cerebral artery occlusion (tMCAo) in rodents can also include selective neuronal loss (SNL), which even if subtle may impede functional recovery. In order to explore the pathophysiology of ischemic stroke, determine potential therapeutic targets and monitor effects of therapy, in vivo imaging surrogates of these varied histopathological outcomes applicable in the clinical setting would be useful. Although hyperintense signal on T2-weighted MRI in the chronic post-stroke stage is considered a reliable surrogate of tissue infarction, SNL is not associated with T2W abnormal signal. In the clinical setting, the neuron-specific PET ligand 11C-flumazenil (FMZ) has been used to identify both pan-necrosis and peri-infarct SNL, but this inference has not been histopathological confirmed so far. Here we investigated the late tissue sequelae of tMCAo in the rodent using in vivo T2W MRI and FMZ-PET against post mortem immunohistochemistry as gold standard. Methods: Adult spontaneously hypertensive rats (SHRs) underwent 45 min distal-clip middle-cerebral artery occlusion and, 28 days later, FMZ-PET and T2W-MRI, immediately followed by immunohistochemistry for neuronal loss (NeuN), activated microglia and astrocytosis. Based on standard histopathological definitions, ischemic lesions were classified into pan-necrosis, partial infarction or SNL. NeuN changes and FMZ binding across the whole hemisphere were quantified in the same set of 44 regions-of-interest according to previously validated protocols; linear regressions between these two measures were carried out both within and across subjects. Results: Both cortical pan-necrosis/partial infarction and SNL were present in all rats except one, where SNL was isolated and extensive. Infarction/partial infarction, but not SNL, was associated with T2W hyperintense signals and cortical atrophy. In contrast, FMZ binding was decreased in all types of lesions including SNL, in proportion with NeuN staining intensity both within (p

Published
2013
Full Text
View/download PDF

8. Toward next-generation primate neuroscience: A collaboration-based strategic plan for integrative neuroimaging

Author

David C. Van Essen, Caspar M. Schwiedrzik, Takuro Ikeda, Shaomin Zhang, Marcello G. P. Rosa, Ning Liu, Aidan Murphy, Li Min Chen, Pinglei Bao, Julia Lehman, Yuki Hori, Pengcheng Li, Julien Vezoli, Peter H. Rudebeck, Yao Meng, Julian 'Bene' Ramirez, Pierre Pouget, Guillermo Gallardo, Rogier B. Mars, Charles E. Schroeder, Minqing Jiang, Steve Frey, Michael P. Milham, Mohammad Hadi Aarabi, Pascal Belin, Patrick Friedrich, Bichan Wu, Hector Figueroa, Ye He, Charles L. Wilson, Melanie Wilke, Eunha Baeg, Fadila Hadj-Bouziane, Danny Garside, Marco Pagani, Ting-Yat Wong, Igor Kagan, Abdelhadi Essamlali, Bharat B. Biswal, Wasana Ediri Arachchi, Julio Villalon, Zheng Wang, Kacie Dougherty, Neo Sunhang Shi, Luciano Simone, Roberto Toro, Benjamin Jung, Masaki Fukunaga, Zhanguang Zuo, Loïc Magrou, Xiaowei Song, Kadharbatcha S. Saleem, Michele A. Basso, Eduardo A. Garza-Villarreal, Chihiro Yokoyama, Aaron Tanenbaum, Brian E. Russ, Alexandre Rosa Franco, Alison R. Weiss, Isabel Restrepo, Alan C. Evans, Lixia Gao, Nobuyuki Kimura, Augix Guohua Xu, Piotr Majka, Colline Poirier, Justine Cléry, Bassem Hiba, Alessandro Gozzi, Xiaojie Wang, Nick Upright, Stan Colcombe, Yang Gao, Won Mok Shim, Eduardo Rojas Hortelano, Takuya Hayashi, Anna S. Mitchell, Andrew F. Rossi, Itamar Kahn, Jorge Jaramillo, Henry C. Evrard, Xin Yumeng, Gregory Kiar, Sean Froudist-Walsh, Elise Roger, Roberto A. Gulli, Yufan Wang, Damien A. Fair, Yuguang Zhao, Stephen J. Sawiak, Boris C. Bernhardt, Ulysse Klatzmann, Ashkan Alvand, Kep Kee Loh, David Schaeffer, Virginie Sivan, Daniel S. Margulies, Carly M. Drzewiecki, Tomoko Sakai, Ting Xu, Cirong Liu, Essa Yacoub, Theresa M. Desrochers, Seok-Jun Hong, Sethu Boopathy, Reza Azadi, Lu Yuheng, Aarit Ahuja, Zhifeng Liang, Elena Borra, Fernanda Ponce, Robert Dahnke, Julien Sein, Li Deying, Jitendra Sharma, A.J. Mitchell, Roger Little, Luqi Cheng, Du Xiao, Choong-Wan Woo, Xinhui Li, Chris Petkov, Ruiliang Bai, D Zaldivar, Sheyla Mejia, Haidong D. Lu, Nikoloz Sirmpilatze, Diego Emanuel Ortuzar Martinez, Suzanne N. Haber, Catherine Elorette, Yue Cui, Michael Hawrylycz, Jerome Sallet, Wim Vanduffel, Daniel R. Glen, Ralph Adolphs, Dongrong Xu, Simon Clavagnier, Rakshit Dadarwal, Marzio Gerbella, Hannah Doyle, Ningrong Ye, Xiaojin Liu, Xinyu Liu, Quansheng He, Christopher R. Madan, Vikas Pareek, James Cavanaugh, Sze Chai Kwok, Zhang Ying, Sam Vickery, Xiaoguang Tian, Zhou Xufeng, Bevil R. Conway, Mark Postans, Wei-an Sheng, Gianfranco Chavez, Rober Boshra, Yuki Kikuchi, Michael Ortiz-Rios, Céline Amiez, Felix Hoffstaedter, Elizabeth A. Buffalo, Amy Howard, Hsin-Yi Lai, Marianne Duyck, Samy Rima, Froesel Mathilda, Towela Mvula, Guilherme Freches, Alfonso Fajardo, Maria de la Iglesia-Vaya, Ana Rita Ribeiro Gomes, Xiongjie Yu, Afonso C. Silva, Andrew S. Fox, Long Cao, Anna W. Roe, Meizhen Qian, David Meunier, Erika Raven, Nicola Palomero-Gallagher, Jordy Tasserie, Joonas A. Autio, Francois Chouinard-Decorte, Hank P. Jedema, Shasha Yue, Xinjian Li, Xiaodong Chen, Kathleen Rockland, Satoka Hashimoto Fujimoto, Amiez Celine, Melina Cordeau, Olivier Coulon, Ravi S. Menon, Sandra Gonzalez Torrecilla, Bjørg Elisabeth Kilavik, Adam Messinger, Hecheng Jin, Steven Giavasis, Pierce Perkins, Conor Liston, Yujie Hou, Jakob Seidlitz, Kelly Shen, Yvonne Bennett, Franck Lamberton, Maxime Gaudet-Trafit, Suliann Ben Hamed, Chris Klink, Sabine Kastner, Lucas R. Trambaiolli, Lucija Jankovic-Rapan, Atsushi Fujimoto, Nadira Yusif Rodriguez, Maeva Gacoin, Amir Shmuel, Katja Heuer, Austin K. Behel, Susann Boretius, Paul A. Taylor, Child Mind Institute, Institute of Neurosciences and Psychology [Glasgow], University of Glasgow, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Tübingen, Oregon Health and Science University [Portland] (OHSU), New York University [New York] (NYU), NYU System (NYU), Princeton Neuroscience Institute [Princeton], Consortium, PRIMatE Data and Resource Exchange (PRIME-DRE) Global Collaboration Workshop and, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Nathan S. Kline Institute for Psychiatric Research (NKI), New York State Office of Mental Health, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Nencki Institute of Experimental Biology, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Monash University [Clayton], Wellcome Trust Centre for Integrative Neuroimaging (WIN - FMRIB), University of Oxford, Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], National Institute of Mental Health (NIMH), Newcastle University [Newcastle], McConnell Brain Imaging Centre (MNI), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Laboratorium voor Neuro- en Psychofysiologie, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), and Washington University in Saint Louis (WUSTL)

Subjects
Strategic planning, 0303 health sciences, Open science, biology, Action, intention, and motor control, Resource exchange, [SCCO.NEUR]Cognitive science/Neuroscience, Neuroscience(all), General Neuroscience, Nonhuman primate, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, biology.animal, Primate, Beacon - Precision Imaging, ddc:610, Psychology, Neuroscience, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Contains fulltext : 239574.pdf (Publisher’s version ) (Closed access) Open science initiatives are creating opportunities to increase research coordination and impact in nonhuman primate (NHP) imaging. The PRIMatE Data and Resource Exchange community recently developed a collaboration-based strategic plan to advance NHP imaging as an integrative approach for multiscale neuroscience. 5 p.

Published
2022
Full Text
View/download PDF

9. A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension

Author

Robert C. Glen, Anthony P. Davenport, Duuamene Nyimanu, Alexi Crosby, Janet J. Maguire, Guido Buonincontri, Cai Read, Mark Southwood, Thomas L Williams, Nicholas W. Morrell, Peiran Yang, Rhoda E. Kuc, Stephen J. Sawiak, Maguire, Janet J [0000-0002-9254-7040], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Agonist, Male, medicine.drug_class, RIGHT-VENTRICULAR FUNCTION, Vasodilation, Pharmacology, Endothelial NOS, MECHANISMS, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, medicine.artery, medicine, Animals, Pharmacology & Pharmacy, ANTAGONIST, Apelin receptor, Apelin Receptors, Pulmonary Arterial Hypertension, Science & Technology, Ejection fraction, Monocrotaline, PLASMA, business.industry, CONCISE GUIDE, Research Papers, 3. Good health, Apelin, Rats, Disease Models, Animal, 030104 developmental biology, DISCOVERY, APJ, Pulmonary artery, Ventricular pressure, LIGAND, 1115 Pharmacology and Pharmaceutical Sciences, business, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Research Paper
Abstract

© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. Background and Purpose: Apelin is an endogenous vasodilatory and inotropic peptide that is down-regulated in human pulmonary arterial hypertension, although the density of the apelin receptor is not significantly attenuated. We hypothesised that a G protein-biased apelin analogue MM07, which is more stable than the endogenous apelin peptide, may be beneficial in this condition with the advantage of reduced β-arrestin-mediated receptor internalisation with chronic use. Experimental Approach: Male Sprague–Dawley rats received either monocrotaline to induce pulmonary arterial hypertension or saline and then daily i.p. injections of either MM07 or saline for 21 days. The extent of disease was assessed by right ventricular catheterisation, cardiac MRI, and histological analysis of the pulmonary vasculature. The effect of MM07 on signalling, proliferation, and apoptosis of human pulmonary artery endothelial cells was investigated. Key Results: MM07 significantly reduced the elevation of right ventricular systolic pressure and hypertrophy induced by monocrotaline. Monocrotaline-induced changes in cardiac structure and function, including right ventricular end-systolic and end-diastolic volumes, ejection fraction, and left ventricular end-diastolic volume, were attenuated by MM07. MM07 also significantly reduced monocrotaline-induced muscularisation of small pulmonary blood vessels. MM07 stimulated endothelial NOS phosphorylation and expression, promoted proliferation, and attenuated apoptosis of human pulmonary arterial endothelial cells in vitro. Conclusion and Implications: Our findings suggest that chronic treatment with MM07 is beneficial in this animal model of pulmonary arterial hypertension by addressing disease aetiology. These data support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.

Published
2019

10. Accelerating the Evolution of Nonhuman Primate Neuroimaging

Author

Olivier Coulon, Michael P. Milham, Patrik Lindenfors, Karl-Heinz Nenning, Xiaojin Liu, Ravi S. Menon, Stephanie J. Forkel, Adam Messinger, Zheng Wang, Alexander Thiele, Luciano Simone, Benjamin Jung, Chika Sato, Jamie Nagy, Sean Froudist-Walsh, Kelvin Mok, Renée Hartig, Julien Sein, Alessandro Gozzi, Julien Vezoli, Tomoko Sakai, Lynn Uhrig, Martine Meunier, Christienne G. Damatac, Bonhwang Koo, Roberto Toro, Rogier B. Mars, Henrietta Howells, Lea Roumazeilles, Ming Zhan, Ann-Marie Mallon, Román Rossi-Pool, Elinor L. Sullivan, Yannick Becker, Doris Y. Tsao, Antoine Grigis, Lei Ai, Céline Amiez, Sara Wells, Reza Rajimehr, Aki Nikolaidis, Anna S. Mitchell, Simon M. Reader, Michele A. Basso, Béchir Jarraya, Amir Raz, Wim Vanduffel, Charles R.E. Wilson, Brian E. Russ, Christopher R. Madan, Orlin S. Todorov, Wasana Madushanka, Carole Guedj, Mark A. Pinsk, Clémentine Bodin, Hugo Merchant, Jennifer Nacef, Damien A. Fair, Anna W. Roe, Sze Chai Kwok, Stephen J. Sawiak, Essa Yacoub, Bastien Cagna, Kevin N. Laland, Wilbert Zarco, Charles E. Schroeder, Ting Xu, P. Christiaan Klink, Stanislas Dehaene, Takuya Hayashi, Matthew F. S. Rushworth, Amir Shmuel, Fadila Hadj-Bouziane, Katja Heuer, Ioana-Sabina Rautu, Andrew S. Fox, Austin Benn, Sabine Kastner, Thomas Brochier, Emmanuel Procyk, Marco Pagani, David C. Van Essen, Frank Q. Ye, Dirk Jan Ardesch, Régis Trapeau, Jakob Seidlitz, Marike Schiffer, Bassem Hiba, John H. Morrison, David A. Rudko, Paula L. Croxson, Patrick Friedrich, Augix Guohua Xu, Lazar Fleysher, Piotr Majka, Jonathan Smallwood, Aihua Chen, Timothy D. Griffiths, Fabien Balezeau, Stefan Everling, Michael C. Schmid, Robert Leech, Leslie G. Ungerleider, Mark G. Baxter, Afonso C. Silva, Clare Kelly, Zhi-ming Shen, Daniel S. Margulies, Mark J. Prescott, Pascal Belin, Erwin L. A. Blezer, Igor Kagan, Suliann Ben Hamed, David A. Leopold, Adrien Meguerditchian, Wendy Jarrett, Michel Thiebaut de Schotten, Nikoloz Sirmpilatze, Julia Sliwa, Henry Kennedy, Vikas Pareek, Yong-di Zhou, Michael Ortiz-Rios, Sherif Hamdy El-Gohary, Susann Boretius, Christopher I. Petkov, Pamela Garcia-Saldivar, Bella Williams, Jordy Tasserie, Hank P. Jedema, Jerome Sallet, Pieter R. Roelfsema, Winrich A. Freiwald, Eduardo A. Garza-Villarreal, Noam Harel, Caspar M. Schwiedrzik, Kevin Marche, Colline Poirier, Yang Gao, Henry C. Evrard, Ashkan Alvand, ANS - Cellular & Molecular Mechanisms, Laboratoire des Sciences de l'Information et des Systèmes (LSIS), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Centre National de la Recherche Scientifique (CNRS), Institut cellule souche et cerveau (SBRI), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Psychologie cognitive expérimentale, Collège de France (CdF (institution)), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Consortium, PRIMatE Data Exchange Global Collaboration Workshop and, Nathan S. Kline Institute for Psychiatric Research (NKI), New York State Office of Mental Health, Newcastle University [Newcastle], Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, Medical Oncology, Department of Internal Medicine, Università Cattolica del Sacro Cuore [Roma] (Unicatt), Voice Neurocognition Laboratory, University of Glasgow, Oregon Health and Science University [Portland] (OHSU), Manchester Royal Infirmary, University of Manchester [Manchester], Princeton Neuroscience Institute [Princeton], University of Pennsylvania [Philadelphia], National Institute of Mental Health (NIMH), Harvard Medical School [Boston] (HMS), Washington University in St Louis, Laboratoire de psychologie cognitive (LPC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, New York University [New York] (NYU), NYU System (NYU), State Key Laboratory of Novel Software Technology, University of Nanjing, Center for Nanotechnology Innovation, @NEST (CNI), National Enterprise for nanoScience and nanoTechnology (NEST), Scuola Normale Superiore di Pisa (SNS)-Scuola Universitaria Superiore Sant'Anna [Pisa] (SSSUP)-Istituto Italiano di Tecnologia (IIT)-Consiglio Nazionale delle Ricerche [Pisa] (CNR PISA)-Scuola Normale Superiore di Pisa (SNS)-Scuola Universitaria Superiore Sant'Anna [Pisa] (SSSUP)-Istituto Italiano di Tecnologia (IIT)-Consiglio Nazionale delle Ricerche [Pisa] (CNR PISA), Unité Analyse et Traitement de l'Information (UNATI), Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Neuroimagerie cognitive - Psychologie cognitive expérimentale (UNICOG-U992), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Saclay (COmUE), Institut cellule souche et cerveau (U846 Inserm - UCBL1), Royal Netherlands Academy of Arts and Sciences (KNAW), East China Normal University [Shangaï] (ECNU), The Computational, Cognitive and Clinical Neuroimaging Lab, Imperial College London, Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Medical Research Counc, Station de primatologie (SP), Centre National de la Recherche Scientifique (CNRS), Institute of Language, Communication and the Brain (ILCB), The University of Western Ontario, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Institute of integrative biology (Liverpool), University of Liverpool, McGovern Institute for Brain Research [Cambridge], Massachusetts Institute of Technology (MIT), University of Cambridge [UK] (CAM), Rockefeller University [New York], McConnell Brain Imaging Centre (MNI), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Laboratory for Neuro- and Psychofysiology, katho, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of York [York, UK], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Tianjin University of Science and Technology (TUST), Child Mind Institute, Center for Magnetic Resonance Research [Minneapolis] (CMRR), University of Minnesota Medical School, University of Minnesota System-University of Minnesota System, Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (U1208 Inserm - UCBL1 / SBRI), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University Medical Center [Utrecht], Radboud university [Nijmegen], Chaire Psychologie cognitive expérimentale, Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of St Andrews [Scotland], Stockholm University, Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Princeton University, Utrecht University [Utrecht], Netherlands Institute for Neuroscience, Wellcome Trust Centre for Integrative Neuroimaging (WIN - FMRIB), University of Oxford [Oxford], National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH), Oregon National Primate Research Center (ONPRC), California Institute of Technology (CALTECH), Johns Hopkins University (JHU), The PRIMatE Data Exchange (PRIME-DE) Global Collaboration Workshop and Consortium, ANR-16-CONV-0002,ILCB,ILCB: Institute of Language Communication and the Brain(2016), Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Complex Trait Genetics, Centre National de la Recherche Scientifique (CNRS)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Université de Toulon (UTLN)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA), and Vanduffel, Wim

Subjects
Primates, 0301 basic medicine, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, education, Neuroimaging, Article, [SPI]Engineering Sciences [physics], 03 medical and health sciences, 0302 clinical medicine, London, Psychology, Animals, Humans, Sociology, ComputingMilieux_MISCELLANEOUS, Cognitive science, Science & Technology, Human Connectome Project, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Action, intention, and motor control, Information Dissemination, General Neuroscience, Neurosciences, Brain, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Congresses as Topic, Nonhuman primate, 030104 developmental biology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurosciences & Neurology, Life Sciences & Biomedicine, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 217200.pdf (Publisher’s version ) (Closed access) Nonhuman primate neuroimaging is on the cusp of a transformation, much in the same way its human counterpart was in 2010, when the Human Connectome Project was launched to accelerate progress. Inspired by an open data-sharing initiative, the global community recently met and, in this article, breaks through obstacles to define its ambitions. 4 p.

Published
2020
Full Text
View/download PDF

11. Encephalopathy induced by Alzheimer brain inoculation in a non-human primate

Author

Emmanuel Brouillet, Jean-Luc Picq, Luc Buée, Charlotte Gary, Morvane Colin, Fabienne Aujard, Anne-Sophie Hérard, Raphaëlle Caillierez, Emmanuel Comoy, Marc Dhenain, Stephen J. Sawiak, James E. Koch, Suzanne Lam, Fanny Petit, Fabien Pifferi, Jean-Philippe Deslys, Sabiha Eddarkaoui, Pauline Gipchtein, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Fonctionnement, évolution et mécanismes régulateurs des écosystèmes forestiers (ECOTROP), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CEA [Fontenay-aux-Roses] (UGRA / SETA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Mécanismes Adaptatifs et Evolution (MECADEV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Mécanismes adaptatifs : des organismes aux communautés (MECADEV), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Mécanismes adaptatifs : des organismes aux communautés (MAOAC), Muséum national d'Histoire naturelle (MNHN)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Dhenain, Marc [0000-0001-8804-4101], Apollo - University of Cambridge Repository, Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, and Dhenain, Marc

Subjects
0301 basic medicine, Male, Pathology, Neurology, Tau pathology, Mouse, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Microcebus murinus, Cerebral atrophy, Electroencephalography, Neurodegenerative disease, lcsh:RC346-429, Mice, 0302 clinical medicine, Premovement neuronal activity, ComputingMilieux_MISCELLANEOUS, Brain Diseases, medicine.diagnostic_test, Brain, Human brain, Alzheimer's disease, Magnetic Resonance Imaging, 3. Good health, medicine.anatomical_structure, Cognitive impairment, β-Amyloid pathology, Prion, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cheirogaleidae, Alzheimer’s disease, Primates, medicine.medical_specialty, Encephalopathy, Mice, Transgenic, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Species Specificity, Alzheimer Disease, medicine, Animals, Humans, lcsh:Neurology. Diseases of the nervous system, business.industry, Research, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Entorhinal cortex, 030104 developmental biology, Neurology (clinical), business, 030217 neurology & neurosurgery, Neuronal function
Abstract

Alzheimer’s disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated β-amyloid peptides (Aβ) and tau proteins. Iatrogenic induction of Aβ is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aβ. Induction of Aβ and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer’s disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express Aβ or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aβ depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer’s disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes. Electronic supplementary material The online version of this article (10.1186/s40478-019-0771-x) contains supplementary material, which is available to authorized users.

Published
2019
Full Text
View/download PDF

12. MR fingerprinting with simultaneous B1 estimation

Author

Stephen J. Sawiak, Guido Buonincontri, Buonincontri, Guido [0000-0002-8386-639X], and Apollo - University of Cambridge Repository

Subjects
Computer science, relaxometry, In Vitro Techniques, computer.software_genre, Sensitivity and Specificity, 030218 nuclear medicine & medical imaging, Pattern Recognition, Automated, 03 medical and health sciences, Acceleration, 0302 clinical medicine, Redundancy (information theory), Imaging, Three-Dimensional, Sampling (signal processing), Flip angle, Image Interpretation, Computer-Assisted, Animals, Radiology, Nuclear Medicine and imaging, Sensitivity (control systems), Imaging Methodology—Full Papers, T2, Full Paper, T1, Brain, Signal Processing, Computer-Assisted, Image Enhancement, Magnetic Resonance Imaging, Rats, fingerprinting, Undersampling, Spin echo, Trajectory, Data mining, MRF, Algorithm, computer, B1, 030217 neurology & neurosurgery, Algorithms, 3D
Abstract

PURPOSE: MR fingerprinting (MRF) can be used for quantitative estimation of physical parameters in MRI. Here, we extend the method to incorporate B1 estimation. METHODS: The acquisition is based on steady state free precession MR fingerprinting with a Cartesian trajectory. To increase the sensitivity to the B1 profile, abrupt changes in flip angle were introduced in the sequence. Slice profile and B1 effects were included in the dictionary and the results from two- and three-dimensional (3D) acquisitions were compared. Acceleration was demonstrated using retrospective undersampling in the phase encode directions of 3D data exploiting redundancy between MRF frames at the edges of k-space. RESULTS: Without B1 estimation, T2 and B1 were inaccurate by more than 20%. Abrupt changes in flip angle improved B1 maps. T1 and T2 values obtained with the new MRF methods agree with classical spin echo measurements and are independent of the B1 field profile. When using view sharing reconstruction, results remained accurate (error

Published
2015

13. Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids

Author

Kim B. Jensen, Nicholas R.F. Hannan, Johannes Bargehr, Olivia C. Tysoe, William Gelson, Ludovic Vallier, Edmund Godfrey, María J Gómez-Vázquez, Susan E. Davies, Sanjay Sinha, Negar Pirmadjid, Casey A. Rimland, Mariëlle C. F. Zonneveld, Marianne Terndrup Pedersen, Kirsten E. Snijders, Athina E. Markaki, N.L. Berntsen, Ingrid Simonic, Kourosh Saeb-Parsy, Laura Valestrand, Nikitas Georgakopoulos, Stephanie Brown, Richard L. Gieseck, Thomas A. Wynn, Pedro Madrigal, Graeme J.M. Alexander, Daniel Ortmann, Matthias Zilbauer, Fotios Sampaziotis, Alessandro Bertero, Tom H. Karlsen, Miguel Cardoso de Brito, Stephen J. Sawiak, Wenmiao Shu, Sara Upponi, Paulina M. Materek, Alexander W. Justin, Espen Melum, Alexander Ross, Loukia Yiangou, Matthias Pawlowski, Gregor Skeldon, and John Casey

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Cell Transplantation, Cystic Fibrosis Transmembrane Conductance Regulator, In Vitro Techniques, Regenerative medicine, General Biochemistry, Genetics and Molecular Biology, Cholangiocyte, 03 medical and health sciences, Mice, Cholestasis, Secretin, Biliary atresia, Bile Ducts, Extrahepatic, TA164, medicine, Journal Article, Animals, Humans, Regeneration, Video-Audio Media, Biliary Tract, Keratin-19, Common bile duct, Tissue Engineering, Tissue Scaffolds, business.industry, Gallbladder, Keratin-7, Epithelial Cells, General Medicine, gamma-Glutamyltransferase, medicine.disease, Transplantation, Organoids, 030104 developmental biology, medicine.anatomical_structure, Biliary tract, business, Somatostatin
Abstract

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids $\textit{in vivo}$ and demonstrate that ECOs self-organize into bile duct–like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded $\textit{in vitro}$.

Published
2017
Full Text
View/download PDF

14. Replacement of the murine common bile duct with a bioengineered conduit incorporating primary human cholangiocyte organoids

Author

William Gelson, Olivia C. Tysoe, Casey A. Rimland, F. Sampaziotis, Stephen J. Sawiak, N. Pirmadjid, N.L. Berntsen, Stephanie Brown, Richard L. Gieseck, Kim B. Jensen, Paulina M. Materek, Alexander W. Justin, Tom H. Karlsen, M.C. de Brito, Daniel Ortmann, Nikitas Georgakopoulos, Marianne Terndrup Pedersen, Ludovic Vallier, Athina E. Markaki, Mariëlle C. F. Zonneveld, Alessandro Bertero, Kirsten E. Snijders, Ingrid Simonic, Sanjay Sinha, Graeme J.M. Alexander, Espen Melum, Thomas A. Wynn, Wenmiao Shu, Nicholas R.F. Hannan, Johannes Bargehr, Susan E. Davies, Kourosh Saeb-Parsy, Loukia Yiangou, Matthias Pawlowski, Edmund Godfrey, M.J. Gomez-Vazquez, and Gregor Skeldon

Subjects
Pathology, medicine.medical_specialty, medicine.anatomical_structure, Electrical conduit, Hepatology, Common bile duct, business.industry, medicine, Organoid, business, Cholangiocyte
Published
2017

15. Evolution of structural abnormalities in the rat brain following in utero exposure to maternal immune activation: A longitudinal in vivo MRI study

Author

Steven Williams, Stephen J. Sawiak, William R. Crum, Anthony C. Vernon, Winfred Chege, and Jonathan D. Cooper

Subjects
Male, Pathology, NEURODEVELOPMENTAL MODEL, Striatum, Hippocampus, Rats, Sprague-Dawley, Lateral ventricles, Behavioral Neuroscience, 0302 clinical medicine, RODENT MODEL, ANIMAL-MODEL, Image Processing, Computer-Assisted, Longitudinal Studies, skin and connective tissue diseases, medicine.diagnostic_test, Mental Disorders, Brain, MOUSE MODEL, Amygdala, medicine.anatomical_structure, PREGNANCY, VOXEL-BASED MORPHOMETRY, 1107 Immunology, Prenatal Exposure Delayed Effects, ADOLESCENCE, Cortex, REGISTRATION, Female, Psychology, Life Sciences & Biomedicine, medicine.medical_specialty, Special Issue on Perinatal Inflammation, Poly(I:C), Thalamus, Immunology, Nucleus accumbens, White matter, 03 medical and health sciences, Magnetic resonance imaging, C) [Poly(I], medicine, Maternal immune activation, Animals, Science & Technology, Neurology & Neurosurgery, Endocrine and Autonomic Systems, Volume, Neurosciences, Voxel-based morphometry, 030227 psychiatry, Rats, schizophrenia, Disease Models, Animal, Poly I-C, 1701 Psychology, Schizophrenia, sense organs, Neurosciences & Neurology, 1109 Neurosciences, Neuroscience, CORTICAL THICKNESS, 030217 neurology & neurosurgery
Abstract

Highlights • Maternal immune activation leads to brain structural changes. • Cortical volume decreases between post-natal day 50 and 100 and is static thereafter. • Hippocampus volume decreases early and is maintained into adulthood. • TBM reveals previously unappreciated changes in grey and white matter., Genetic and environmental risk factors for psychiatric disorders are suggested to disrupt the trajectory of brain maturation during adolescence, leading to the development of psychopathology in adulthood. Rodent models are powerful tools to dissect the specific effects of such risk factors on brain maturational profiles, particularly when combined with Magnetic Resonance Imaging (MRI; clinically comparable technology). We therefore investigated the effect of maternal immune activation (MIA), an epidemiological risk factor for adult-onset psychiatric disorders, on rat brain maturation using atlas and tensor-based morphometry analysis of longitudinal in vivo MR images. Exposure to MIA resulted in decreases in the volume of several cortical regions, the hippocampus, amygdala, striatum, nucleus accumbens and unexpectedly, the lateral ventricles, relative to controls. In contrast, the volumes of the thalamus, ventral mesencephalon, brain stem and major white matter tracts were larger, relative to controls. These volumetric changes were maximal between post-natal day 50 and 100 with no differences between the groups thereafter. These data are consistent with and extend prior studies of brain structure in MIA-exposed rodents. Apart from the ventricular findings, these data have robust face validity to clinical imaging findings reported in studies of individuals at high clinical risk for a psychiatric disorder. Further work is now required to address the relationship of these MRI changes to behavioral dysfunction and to establish thier cellular correlates.

Published
2016
Full Text
View/download PDF

16. From impulses to maladaptive actions: the insula is a neurobiological gate for the development of compulsive behavior

Author

Morgane Besson, David Belin, D Howett, Jeffrey W. Dalley, Mickaël Puaud, Bianca Jupp, Trevor W. Robbins, Aude Belin-Rauscent, Stephen J. Sawiak, Daniele Caprioli, M-L Daniel, Colin McKenzie, Barry J. Everitt, University of Cambridge [UK] (CAM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), National National Institute on Drug Abuse Intramural Research Program, National Institute of Health, Neurobiologie intégrative des Systèmes cholinergiques (NISC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), It was supported by an INSERM AVENIR grant and a FYSSEN foundation grant to DB. MLD was supported by a PhD fellowship from the Fondation pour la Recherche Médicale (FRM) and ABR was supported by a post-doctoral fellowship from the INSERM. BJE was supported by the United Kingdom Medical Research Council (MRC) Grant 9536855, This research was carried out within the Department of Psychology and the Department of Pharmacology of the University of Cambridge, as well as the INSERM AVENIR team Psychobiology of Compulsive Disorders of the University of Poitiers., Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Belin, D [0000-0002-7383-372X], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, Serial reaction time, Obsessive-Compulsive Disorder, Neural substrate, [SDV]Life Sciences [q-bio], Neuropsychological Tests, Choice Behavior, Developmental psychology, [SCCO]Cognitive science, 0302 clinical medicine, 5 - Choice serial reaction time task, MESH: Animals, Insular cortex, Cerebral Cortex, MESH: Neuropsychological Tests, Compulsivity, 3. Good health, Psychiatry and Mental health, Schizophrenia, Compulsive behavior, animals, behavior, addictive, cerebral cortex, choice behavior, compulsive behavior, impulsive behavior, male, neuropsychological tests, obsessive-compulsive disorder, rats, reaction time, molecular biology, psychiatry and mental health, cellular and molecular neuroscience, Compulsive Behavior, MESH: Compulsive Behavior, MESH: Impulsive Behavior, medicine.symptom, Psychology, Impulsivity, Schedule induced polydipsia, MESH: Rats, MESH: Choice Behavior, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Behavior, Addictive, Reaction Time, medicine, Animals, Molecular Biology, MESH: Obsessive-Compulsive Disorder, behavior, [SCCO.NEUR]Cognitive science/Neuroscience, addictive, medicine.disease, MESH: Cerebral Cortex, MESH: Male, Rats, MESH: Reaction Time, Behavior, Addictive, 030104 developmental biology, Endophenotype, Impulsive Behavior, Neuroscience, Insula, 030217 neurology & neurosurgery
Abstract

International audience; Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situ hybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to individual vulnerability to impulsive-compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders.

Published
2016
Full Text
View/download PDF

17. Generation of Bioengineered Biliary Tissue Using Primary in Vitro Propagated Extra-Hepatic Cholangiocytes and Biodegradable Scaffolds

Author

William Gelson, F. Sampaziotis, Daniel Ortmann, Sara Upponi, Alessandro Bertero, Ludovic Vallier, Kourosh Saeb-Parsy, Stephen J. Sawiak, M.C. de Brito, Graeme J.M. Alexander, Nikitas Georgakopoulos, Nicholas R.F. Hannan, Johannes Bargehr, Edmund Godfrey, and Matthias Pawlowski

Subjects
Primary (chemistry), Hepatology, Chemistry, Biodegradable scaffold, Anatomy, In vitro, Cell biology
Published
2016

18. Combining MRI with PET for partial volume correction improves image-derived input functions in mice

Author

Stephen J. Sawiak, R. C. Hawkes, Guido Buonincontri, Thomas Krieg, Eleanor Evans, David Izquierdo, Richard E. Ansorge, Carmen Methner, T. Adrian Carpenter, Ansorge, Richard [0000-0002-5064-3640], Krieg, Thomas [0000-0002-5192-580X], Carpenter, Adrian [0000-0002-2939-8222], Sawiak, Stephen [0000-0003-4210-9816], and Apollo - University of Cambridge Repository

Subjects
Point spread function, Nuclear and High Energy Physics, Partial volume correction, Partial volume, Biomedical Engineering, Article, Medicine, Radiology, Nuclear Medicine and imaging, Arterial input function, small animal PET, Electrical and Electronic Engineering, Instrumentation, Mouse Heart, Image resolution, Physics, Radiation, medicine.diagnostic_test, business.industry, Image (category theory), Geometric transfer matrix, medicine.anatomical_structure, Nuclear Energy and Engineering, Positron emission tomography, Ventricle, partial volume correction, Meeting Abstract, Mr images, business, Nuclear medicine, Biomedical engineering, Blood sampling, MRI
Abstract

Kinetic modelling in PET requires the arterial input function (AIF), defined as the time-activity curve (TAC) in plasma. This measure is challenging to obtain in mice due to low blood volumes, resulting in a reliance on image-based methods for AIF derivation. We present a comparison of PET- and MR-based region-of-interest (ROI) analysis to obtain image-derived AIFs from the left ventricle (LV) of a mouse model. ROI-based partial volume correction (PVC) was performed to improve quantification. MRI and dynamic PET images were obtained from a recent study investigating treatment effects in 12 mice following myocardial infarction [1], where half the mice received a new treatment and half did not. Prospectively gated MRI (4.7T Bruker BioSpec, FLASH TR/TE 400/3ms, spatial resolution 140μm in 1mm slices) were acquired prior to PET acquisition (approx. 25MBq 18F-FDG bolus, 45 minute emission listmode acquisition reconstructed with 3DRP in four cardiac frames) on a split-magnet PET camera [2]. Images were co-registered using SPMMouse [3] (see Figure ​Figure11). Figure 1 Mouse heart MR (left) and fused with 18F-FDG static PET (right). Arrow indicates infarcted region. AIF extraction AIFs were obtained by taking mean time courses from LV Lumen ROIs, shown in Figure ​Figure2.2. The regional geometric transfer matrix (GTM) method was applied for PVC [4], using ROIs drawn on either the co-registered MR images or directly onto the last dynamic frame PET images. ROIs covered LV lumen, myocardium, lungs/body and background. Patlak [5] analysis was performed to evaluate glucose metabolism. Figure 2 AIFs and TACs derived for single subject using (A) MR ROIs, (B) PET ROIs with PVC and (C) MR ROIs with PVC. Insets detail first 500s Uncorrected AIFs and myocardial TACs produced by manual ROI delineation displayed contamination with myocardial signal. AIFs and myocardial curves became distinguishable if GTM PVC was applied. Only MR-based PVC produced significant differences (p

Published
2015

19. Direct evaluation of MR-derived attenuation correction maps for PET/MR of the mouse myocardium

Author

Stephen J. Sawiak, Richard E. Ansorge, R. C. Hawkes, T. Adrian Carpenter, Guido Buonincontri, and Eleanor Evans

Subjects
Nuclear and High Energy Physics, Materials science, Biomedical Engineering, Standardized uptake value, Iterative reconstruction, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Nuclear magnetic resonance, medicine, Radiology, Nuclear Medicine and imaging, Pet tracer, Direct evaluation, Electrical and Electronic Engineering, Instrumentation, Physics, Radiation, medicine.diagnostic_test, Attenuation, Gold standard (test), Nuclear Energy and Engineering, Positron emission tomography, 030220 oncology & carcinogenesis, Attenuation coefficient, Meeting Abstract, Body region, Correction for attenuation, Biomedical engineering, Radiofrequency coil
Abstract

Attenuation correction (AC) must be applied to provide accurate measurements of PET tracer activity concentrations. Due to the limited space available in PET/MR scanners, MR-derived AC (MRAC) is used as a substitute for transmission source scanning. In preclinical PET/MR, there has been limited exploration of MRAC, as the magnitude of AC in murine imaging is much smaller than that required in clinical scans. We investigated if a simple 2 class (air and tissue) segmentation-based MRAC approach could provide adequate AC for mouse PET imaging. To construct the default MRAC ${\mu }$ maps, MR images were thresholded and segmented using ASIPRO software (Siemens Molecular Imaging), which defined the mouse body region as tissue with a uniform linear attenuation coefficient ( ${\mu }$ ) of $0.095~\hbox{cm}^{ - 1}$ , and the background and lungs as air, with a ${\mu }$ value of $0~\hbox{cm}^{ - 1}$ . To correct for the misassignment of the lungs as air, two further MRAC ${\mu }$ maps were tested: 1) MRAC (tissue) approach, which changed the lung region designation from air to tissue ( ${\mu } = 0.095~\hbox{cm}^{ - 1}$ ) and 2) MRAC (lung) approach, which treated the lungs as an additional tissue class, with a ${\mu }$ value of $0.032~\hbox{cm}^{ - 1}$ . All ${\mu }$ maps were then forward projected to create attenuation sinograms for image reconstruction. Standard uptake value (SUV) maps of the myocardium were derived for 10 mice with and without AC applied using gold standard transmission scans (TXAC), the 3 MRAC methods and PET emission scans (EmAC). All AC methods produced significantly different myocardial SUVs to those produced without AC when compared across the mouse group ( ${\rm p} ). Similar ( $ ) SUV were derived with all AC methods, with the best agreement to TXAC achieved using the MRAC (tissue) method, giving a mean difference of $0.9{\pm }2.4\% $ in myocardial SUV when compared across all mice. SUV differences of up to 40%, however, were seen in areas adjacent to the RF coil in images produced using all AC methods, except for TXAC. A 2 class MRAC approach can therefore provide acceptable AC for myocardial imaging in mice, although additional CT templates of coils and animals beds would be recommended to further improve image quantification.

Published
2014

20. Voxel-based morphometry analyses of in vivo MRI in the aging mouse lemur primate

Author

Jean-Luc Picq, Marc Dhenain, and Stephen J. Sawiak

Subjects
Pathology, medicine.medical_specialty, Microcebus murinus, Cognitive Neuroscience, SPMMouse, Corpus callosum, Nucleus basalis, primate, lcsh:RC321-571, Atrophy, atrophy, medicine, Original Research Article, VBM, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Cerebral atrophy, biology, Mouse lemur, mouse lemur, aging, Subiculum, Voxel-based morphometry, biology.organism_classification, medicine.disease, Psychology, Neuroscience, MRI
Abstract

Cerebral atrophy is one of the most widely brain alterations associated to aging. A clear relationship has been established between age-associated cognitive impairments and cerebral atrophy. The mouse lemur (Microcebus murinus) is a small primate used as a model of age-related neurodegenerative processes. It is the first non-human primate in which cerebral atrophy has been correlated with cognitive deficits. Previous studies of cerebral atrophy in this model were based on time consuming manual delineation or measurement of selected brain regions from magnetic resonance images (MRI). These measures could not be used to analyse regions that cannot be easily outlined such as the nucleus basalis of Meynert or the subiculum. In humans, morphometric assessment of structural changes with age is generally performed with automated procedures such as voxel-based morphometry (VBM). The objective of our work was to perform user-independent assessment of age-related morphological changes in the whole brain of large mouse lemur populations thanks to VBM. The study was based on the SPMMouse toolbox of SPM 8 and involved thirty mouse lemurs aged from 1.9 to 11.3 years. The automatic method revealed for the first time atrophy in regions where manual delineation is prohibitive (nucleus basalis of Meynert, subiculum, prepiriform cortex, Brodmann areas 13-16, hypothalamus, putamen, thalamus, corpus callosum). Some of these regions are described as particularly sensitive to age-associated alterations in humans. The method revealed also age-associated atrophy in cortical regions (cingulate, occipital, parietal), nucleus septalis, and the caudate. Manual measures performed in some of these regions were in good agreement with results from automatic measures. The templates generated in this study as well as the toolbox for SPM8 can be downloaded. These tools will be valuable for future evaluation of various treatments that are tested to modulate cerebral aging in lemurs.

Published
2014
Full Text
View/download PDF

21. Comparison of first pass bolus AIFs extracted from sequential 18F-FDG PET and DSC-MRI of mice

Author

T. Adrian Carpenter, Guido Buonincontri, Stephen J. Sawiak, Eleanor Evans, R. C. Hawkes, Alexander O. Ward, Sawiak, Stephen [0000-0003-4210-9816], Carpenter, Adrian [0000-0002-2939-8222], and Apollo - University of Cambridge Repository

Subjects
Nuclear and High Energy Physics, medicine.medical_specialty, Partial volume, computer.software_genre, Article, Mice, Bolus (medicine), Voxel, medicine, Medical physics, cardiovascular diseases, Instrumentation, Physics, Reproducibility, Arterial input function, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, PET/MR, PET, Contrast agent, Positron emission tomography, Temporal resolution, biological phenomena, cell phenomena, and immunity, Nuclear medicine, business, computer, Blood sampling, MRI
Abstract

Accurate kinetic modelling of in vivo physiological function using positron emission tomography (PET) requires determination of the tracer time–activity curve in plasma, known as the arterial input function (AIF). The AIF is usually determined by invasive blood sampling methods, which are prohibitive in murine studies due to low total blood volumes. Extracting AIFs from PET images is also challenging due to large partial volume effects (PVE). We hypothesise that in combined PET with magnetic resonance imaging (PET/MR), a co-injected bolus of MR contrast agent and PET ligand can be tracked using fast MR acquisitions. This protocol would allow extraction of a MR AIF from MR contrast agent concentration–time curves, at higher spatial and temporal resolution than an image-derived PET AIF. A conversion factor could then be applied to the MR AIF for use in PET kinetic analysis. This work has compared AIFs obtained from sequential DSC-MRI and PET with separate injections of gadolinium contrast agent and 18F-FDG respectively to ascertain the technique′s validity. An automated voxel selection algorithm was employed to improve MR AIF reproducibility. We found that MR and PET AIFs displayed similar character in the first pass, confirmed by gamma variate fits (p

Published
2014

22. PET/MRI assessment of the infarcted mouse heart

Author

Thomas Krieg, R. C. Hawkes, Guido Buonincontri, Stephen J. Sawiak, Carmen Methner, and T. Adrian Carpenter

Subjects
Physics, Nuclear and High Energy Physics, medicine.medical_specialty, medicine.diagnostic_test, Ischemia, Magnetic resonance imaging, medicine.disease, Article, Positron emission tomography, In vivo, Internal medicine, Heart failure, medicine, Cardiology, Myocardial infarction, Instrumentation, Reperfusion injury, Perfusion
Abstract

Heart failure originating from myocardial infarction (MI) is a leading cause of death worldwide. Mouse models of ischaemia and reperfusion injury (I/R) are used to study the effects of novel treatment strategies targeting MI, however staging disease and treatment efficacy is a challenge. Damage and recovery can be assessed on the cellular, tissue or whole-organ scale but these are rarely measured in concert. Here, for the first time, we present data showing measures of injury in infarcted mice using complementary techniques for multi-modal characterisation of the heart. We use in vivo magnetic resonance imaging (MRI) to assess heart function with cine-MRI, hindered perfusion with late gadolinium enhancement imaging and muscular function with displacement encoded with stimulated echoes (DENSE) MRI. These measures are followed by positron emission tomography (PET) with 18-F-fluorodeoxyglucose to assess cellular metabolism. We demonstrate a protocol combining each of these measures for the same animal in the same imaging session and compare how the different markers can be used to quantify cardiac recovery on different scales following injury.

Published
2014

23. Early and progressive circadian abnormalities in Huntington's disease sheep are unmasked by social environment

Author

Nigel I. Wood, Timothy R. Kuchel, Richard L.M. Faull, Greg Brown, Clive J. McLaughlan, A. Jennifer Morton, Stephen J. Sawiak, Russell G. Snell, C. Simon Bawden, Skye R. Rudiger, Morton, A Jennifer, Rudiger, Skye R, Wood, Nigel I, Sawiak, Stephen J, Brown, Gregory C, Mclaughlan, Clive J, Kuchel, Timothy R, Snell, Russell G, Faull, Richard LM, and Bawden, C Simon

Subjects
medicine.medical_specialty, sheep, Disease, Biology, Irritability, Social Environment, social environment, Huntington's disease, Internal medicine, Genetics, medicine, Huntingtin Protein, Dementia, Animals, Circadian rhythm, biochemistry & molecular biology, Molecular Biology, Genetics (clinical), Depression (differential diagnoses), Sheep, Sundowning, General Medicine, Huntington disease, medicine.disease, Circadian Rhythm, Endocrinology, Huntington Disease, genetics & heredity, medicine.symptom
Abstract

Insidious changes in behaviour herald the onset of progressive neurodegenerative disorders such as Huntington's disease (HD), sometimes years before overt symptoms are seen. Sleep and circadian disturbances are particularly disruptive symptoms in patients with neurological disorders, but they are difficult to measure in humans. Here we studied circadian behaviour in transgenic HD sheep expressing the full-length human huntingtin protein with an expanded CAG repeat mutation in the juvenile range. Young HD sheep with no other symptoms exhibited circadian behavioural abnormalities that worsened with age. The most obvious change was a disturbed evening behaviour reminiscent of 'sundowning' that is seen in some patients with dementia. There were no structural abnormalities seen with magnetic resonance imaging, even in 5-year-old HD sheep. Interestingly, detection of the circadian abnormalities depended upon their social grouping. Abnormalities emerged in sheep kept in an 'HD-only' flock, whereas the behaviour of HD sheep kept mixed with normal sheep was relatively normal. Sleep-wake abnormalities in HD patients are also likely to be hidden, and may precede overt symptoms by many years. Sleep disruption has deleterious effects, even in normal people. The knock-on effects of sleep-wake disturbance may exacerbate, or even cause symptoms such as irritability and depression that are common in early stage HD patients. HD sheep will be useful models for probing the mechanisms underlying circadian behavioural disorder in HD. Refereed/Peer-reviewed

Published
2014

24. Effects of hyperoxia on 18F-fluoro-misonidazole brain uptake and tissue oxygen tension following middle cerebral artery occlusion in rodents: Pilot studies.

Author

Tim D Fryer, Sohail Ejaz, Ulf Jensen-Kondering, David J Williamson, Sergey Sitnikov, Stephen J Sawiak, Franklin I Aigbirhio, Young T Hong, and Jean-Claude Baron

Subjects
Medicine, Science
Abstract

PURPOSE:Mapping brain hypoxia is a major goal for stroke diagnosis, pathophysiology and treatment monitoring. 18F-fluoro-misonidazole (FMISO) positron emission tomography (PET) is the gold standard hypoxia imaging method. Normobaric hyperoxia (NBO) is a promising therapy in acute stroke. In this pilot study, we tested the straightforward hypothesis that NBO would markedly reduce FMISO uptake in ischemic brain in Wistar and spontaneously hypertensive rats (SHRs), two rat strains with distinct vulnerability to brain ischemia, mimicking clinical heterogeneity. METHODS:Thirteen adult male rats were randomized to distal middle cerebral artery occlusion under either 30% O2 or 100% O2. FMISO was administered intravenously and PET data acquired dynamically for 3hrs, after which magnetic resonance imaging (MRI) and tetrazolium chloride (TTC) staining were carried out to map the ischemic lesion. Both FMISO tissue uptake at 2-3hrs and FMISO kinetic rate constants, determined based on previously published kinetic modelling, were obtained for the hypoxic area. In a separate group (n = 9), tissue oxygen partial pressure (PtO2) was measured in the ischemic tissue during both control and NBO conditions. RESULTS:As expected, the FMISO PET, MRI and TTC lesion volumes were much larger in SHRs than Wistar rats in both the control and NBO conditions. NBO did not appear to substantially reduce FMISO lesion size, nor affect the FMISO kinetic rate constants in either strain. Likewise, MRI and TTC lesion volumes were unaffected. The parallel study showed the expected increases in ischemic cortex PtO2 under NBO, although these were small in some SHRs with very low baseline PtO2. CONCLUSIONS:Despite small samples, the apparent lack of marked effects of NBO on FMISO uptake suggests that in permanent ischemia the cellular mechanisms underlying FMISO trapping in hypoxic cells may be disjointed from PtO2. Better understanding of FMISO trapping processes will be important for future applications of FMISO imaging.

Published
2017
Full Text
View/download PDF

25. Rapid and Progressive Regional Brain Atrophy in CLN6 Batten Disease Affected Sheep Measured with Longitudinal Magnetic Resonance Imaging.

Author

Stephen J Sawiak, Sunthara Rajan Perumal, Skye R Rudiger, Loren Matthews, Nadia L Mitchell, Clive J McLaughlan, C Simon Bawden, David N Palmer, Timothy Kuchel, and A Jennifer Morton

Subjects
Medicine, Science
Abstract

Variant late-infantile Batten disease is a neuronal ceroid lipofuscinosis caused by mutations in CLN6. It is a recessive genetic lysosomal storage disease characterised by progressive neurodegeneration. It starts insidiously and leads to blindness, epilepsy and dementia in affected children. Sheep that are homozygous for a natural mutation in CLN6 have an ovine form of Batten disease Here, we used in vivo magnetic resonance imaging to track brain changes in 4 unaffected carriers and 6 affected Batten disease sheep. We scanned each sheep 4 times, between 17 and 22 months of age. Cortical atrophy in all sheep was pronounced at the baseline scan in all affected Batten disease sheep. Significant atrophy was also present in other brain regions (caudate, putamen and amygdala). Atrophy continued measurably in all of these regions during the study. Longitudinal MRI in sheep was sensitive enough to measure significant volume changes over the relatively short study period, even in the cortex, where nearly 40% of volume was already lost at the start of the study. Thus longitudinal MRI could be used to study the dynamics of progression of neurodegenerative changes in sheep models of Batten disease, as well as to assess therapeutic efficacy.

Published
2015
Full Text
View/download PDF

26. Complex I deficiency due to selective loss of Ndufs4 in the mouse heart results in severe hypertrophic cardiomyopathy.

Author

Edward T Chouchani, Carmen Methner, Guido Buonincontri, Chou-Hui Hu, Angela Logan, Stephen J Sawiak, Michael P Murphy, and Thomas Krieg

Subjects
Medicine, Science
Abstract

Mitochondrial complex I, the primary entry point for electrons into the mitochondrial respiratory chain, is both critical for aerobic respiration and a major source of reactive oxygen species. In the heart, chronic dysfunction driving cardiomyopathy is frequently associated with decreased complex I activity, from both genetic and environmental causes. To examine the functional relationship between complex I disruption and cardiac dysfunction we used an established mouse model of mild and chronic complex I inhibition through heart-specific Ndufs4 gene ablation. Heart-specific Ndufs4-null mice had a decrease of ∼ 50% in complex I activity within the heart, and developed severe hypertrophic cardiomyopathy as assessed by magnetic resonance imaging. The decrease in complex I activity, and associated cardiac dysfunction, occurred absent an increase in mitochondrial hydrogen peroxide levels in vivo, accumulation of markers of oxidative damage, induction of apoptosis, or tissue fibrosis. Taken together, these results indicate that diminished complex I activity in the heart alone is sufficient to drive hypertrophic cardiomyopathy independently of alterations in levels of mitochondrial hydrogen peroxide or oxidative damage.

Published
2014
Full Text
View/download PDF

27. Huntington's disease mouse models online: high-resolution MRI images with stereotaxic templates for computational neuroanatomy.

Author

Stephen J Sawiak, Nigel I Wood, T Adrian Carpenter, and A Jennifer Morton

Subjects
Medicine, Science
Abstract

Magnetic resonance imaging (MRI) has proved to be an ideal modality for non-destructive and highly detailed assessment of structural morphology in biological tissues. Here we used MRI to make a dataset of ex vivo brains from two different rodent models of Huntington's disease (HD), the R6/2 line and the YAC 128 mouse. We are making the whole dataset (399 transgenic HD and wildtype (WT) brains, from mice aged 9-80 weeks) publicly available. These data will be useful, not only to investigators interested in the study of HD, but also to researchers of computational neuroanatomy who may not have access to such large datasets from mouse models. Here we demonstrate a number of uses of such data, for example to produce maps of grey and white matter and cortical thickness. As an example of how the library might provide insights in mouse models of HD, we calculated whole brain grey matter volumes across different age groups with different numbers of cytosine-adenine-guanine (CAG) repeats in a fragment of the gene responsible for HD in humans. (The R6/2 dataset was obtained from an allelic series of R6/2 mice carrying a range of CAG repeat lengths between 109 and 464.) This analysis revealed different trajectories for each fragment length. In particular there was a gradient of decreasing pathology with longer CAG repeat lengths, reflecting our previous findings with behavioural and histological studies. There will be no constraints placed on the use of the datasets included here. The original data will be easily and permanently accessible via the University of Cambridge data repository (http://www.dspace.cam.ac.uk/handle/1810/243361).

Published
2012
Full Text
View/download PDF

28. Tensor-based morphometry and stereology reveal brain pathology in the complexin1 knockout mouse.

Author

Catherine Kielar, Stephen J Sawiak, Paloma Navarro Negredo, Desmond H Y Tse, and A Jennifer Morton

Subjects
Medicine, Science
Abstract

Complexins (Cplxs) are small, soluble, regulatory proteins that bind reversibly to the SNARE complex and modulate synaptic vesicle release. Cplx1 knockout mice (Cplx1(-/-)) have the earliest known onset of ataxia seen in a mouse model, although hitherto no histopathology has been described in these mice. Nevertheless, the profound neurological phenotype displayed by Cplx1(-/-) mutants suggests that significant functional abnormalities must be present in these animals. In this study, MRI was used to automatically detect regions where structural differences were not obvious when using a traditional histological approach. Tensor-based morphometry of Cplx1(-/-) mouse brains showed selective volume loss from the thalamus and cerebellum. Stereological analysis of Cplx1(-/-) and Cplx1(+/+) mice brain slices confirmed the volume loss in the thalamus as well as loss in some lobules of the cerebellum. Finally, stereology was used to show that there was loss of cerebellar granule cells in Cplx1(-/-) mice when compared to Cplx1(+/+) animals. Our study is the first to describe pathological changes in Cplx1(-/-) mouse brain. We suggest that the ataxia in Cplx1(-/-) mice is likely to be due to pathological changes in both cerebellum and thalamus. Reduced levels of Cplx proteins have been reported in brains of patients with neurodegenerative diseases. Therefore, understanding the effects of Cplx depletion in brains from Cplx1(-/-) mice may also shed light on the mechanisms underlying pathophysiology in disorders in which loss of Cplx1 occurs.

Published
2012
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results