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1. Brain Fluid Clearance After Traumatic Brain Injury Measured Using Dynamic Positron Emission Tomography

Author

Tracy Butler, Julia Schubert, Nikolaos A. Karakatsanis, Xiuyuan Hugh Wang, Ke Xi, Yeona Kang, Kewei Chen, Liangdong Zhou, Edward K. Fung, Abigail Patchell, Abhishek Jaywant, Yi Li, Gloria Chiang, Lidia Glodzik, Henry Rusinek, Mony de Leon, Federico Turkheimer, and Sudhin A. Shah

Subjects
adult brain injury, cerebrospinal fluid, clearance, glymphatic system, PET scanning, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Brain fluid clearance by pathways including the recently described paravascular glymphatic system is a critical homeostatic mechanism by which metabolic products, toxins, and other wastes are removed from the brain. Brain fluid clearance may be especially important after traumatic brain injury (TBI), when blood, neuronal debris, inflammatory cells, and other substances can be released and/or deposited. Using a non-invasive dynamic positron emission tomography (PET) method that models the rate at which an intravenously injected radiolabeled molecule (in this case 11C-flumazenil) is cleared from ventricular cerebrospinal fluid (CSF), we estimated the overall efficiency of brain fluid clearance in humans who had experienced complicated-mild or moderate TBI 3?6 months before neuroimaging (n?=?7) as compared to healthy controls (n?=?9). While there was no significant difference in ventricular clearance between TBI subjects and controls, there was a significant group difference in dependence of ventricular clearance upon tracer delivery/blood flow to the ventricles. Specifically, in controls, ventricular clearance was highly, linearly dependent upon blood flow to the ventricle, but this relation was disrupted in TBI subjects. When accounting for blood flow and group-specific alterations in blood flow, ventricular clearance was slightly (non-significantly) increased in TBI subjects as compared to controls. Current results contrast with past studies showing reduced glymphatic function after TBI and are consistent with possible differential effects of TBI on glymphatic versus non-glymphatic clearance mechanisms. Further study using multi-modal methods capable of assessing and disentangling blood flow and different aspects of fluid clearance is needed to clarify clearance alterations after TBI.

Published
2024
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2. Choroid plexus enlargement is associated with neuroinflammation and reduction of blood brain barrier permeability in depression

Author

Noha Althubaity, Julia Schubert, Daniel Martins, Tayyabah Yousaf, Maria A. Nettis, Valeria Mondelli, Carmine Pariante, Neil A. Harrison, Edward T. Bullmore, Danai Dima, Federico E. Turkheimer, and Mattia Veronese

Subjects
Choroid Plexus, Neuroinflammation, Depression, Blood brain barrier, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Recent studies have shown that choroid plexuses (CP) may be involved in the neuro-immune axes, playing a role in the interaction between the central and peripheral inflammation. Here we aimed to investigate CP volume alterations in depression and their associations with inflammation. Methods: 51 depressed participants (HDRS score > 13) and 25 age- and sex-matched healthy controls (HCs) from the Wellcome Trust NIMA consortium were re-analysed for the study. All the participants underwent full peripheral cytokine profiling and simultaneous [11C]PK11195 PET/structural MRI imaging for measuring neuroinflammation and CP volume respectively. Results: We found a significantly greater CP volume in depressed subjects compared to HCs (t(76) = +2.17) that was positively correlated with [11C]PK11195 PET binding in the anterior cingulate cortex (r = 0.28, p = 0.02), prefrontal cortex (r = 0.24, p = 0.04), and insular cortex (r = 0.24, p = 0.04), but not with the peripheral inflammatory markers: CRP levels (r = 0.07, p = 0.53), IL-6 (r = -0.08, p = 0.61), and TNF-α (r = -0.06, p = 0.70). The CP volume correlated with the [11C]PK11195 PET binding in CP (r = 0.34, p = 0.005). Integration of transcriptomic data from the Allen Human Brain Atlas with the brain map depicting the correlations between CP volume and PET imaging found significant gene enrichment for several pathways involved in neuroinflammatory response. Conclusion: This result supports the hypothesis that changes in brain barriers may cause reduction in solute exchanges between blood and CSF, disturbing the brain homeostasis and ultimately contributing to inflammation in depression. Given that CP anomalies have been recently detected in other brain disorders, these results may not be specific to depression and might extend to other conditions with a peripheral inflammatory component.

Published
2022
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3. Risk Factors for Maternal Body Mass Index and Gestational Weight Gain in Twin Pregnancies

Author

Julia, Schubert, Nina, Timmesfeld, Kathrin, Noever, Susann, Behnam, Angela, Vinturache, and Birgit, Arabin

Subjects
Maternity and Midwifery, Obstetrics and Gynecology
Abstract

Objective This retrospective cohort study analyzes risk factors for abnormal pre-pregnancy body mass index and abnormal gestational weight gain in twin pregnancies. Methods Data from 10 603/13 682 twin pregnancies were analyzed using uni- and multivariable logistic regression models to determine risk factors for abnormal body mass index and weight gain in pregnancy. Results Multiparity was associated with pre-existing obesity in twin pregnancies (aOR: 3.78, 95% CI: 2.71 – 5.27). Working in academic or leadership positions (aOR: 0.57, 95% CI: 0.45 – 0.72) and advanced maternal age (aOR: 0.96, 95% CI: 0.95 – 0.98) were negatively associated with maternal obesity. Advanced maternal age was associated with a lower risk for maternal underweight (aOR: 0.95, 95% CI: 0.92 – 0.99). Unexpectedly, advanced maternal age (aOR: 0.98, 95% CI: 0.96 – 0.99) and multiparity (aOR: 0.6, 95% CI: 0.41 – 0.88) were also associated with lower risks for high gestational weight gain. Pre-existing maternal underweight (aOR: 1.55, 95% CI: 1.07 – 2.24), overweight (aOR: 1.61, 95% CI: 1.39 – 1.86), obesity (aOR: 3.09, 95% CI: 2.62 – 3.65) and multiparity (aOR: 1.64, 95% CI: 1.23 – 2.18) were all associated with low weight gain. Women working as employees (aOR: 0.85, 95% CI: 0.73 – 0.98) or in academic or leadership positions were less likely to have a low gestational weight gain (aOR: 0.77, 95% CI: 0.64 – 0.93). Conclusion Risk factors for abnormal body mass index and gestational weight gain specified for twin pregnancies are relevant to identify pregnancies with increased risks for poor maternal or neonatal outcome and to improve their counselling. Only then, targeted interventional studies in twin pregnancies which are desperately needed can be performed.

Published
2022

4. Investigations on physico-chemical properties of TSPCU nonwoven for application as prosthetic venous valve

Author

Julia Schubert, Daniela Arbeiter, Andreas Götz, Kerstin Lebahn, Wolfram Schmidt, Niels Grabow, and Sabine Illner

Subjects
mechanical testing, nanofibers, Biomedical Engineering, technology, industry, and agriculture, prosthetic venous valve, Medicine, electrospinning, nonwoven
Abstract

Electrospinning is used for producing nonwovens for medical polymer-based implants, such as prosthetic valves or covered scaffolds. In this study, nonwovens for prosthetic venous valves are investigated regarding their morphology and mechanics in physiological medium. Spinning molds were developed based on previous venous valve leaflet designs, 3D printed in different sizes and covered with electrospun nonwovens. Samples were stored in a physiological 0.9% saline at 37°C to investigate the influence of fiber rearrangement and swelling in medium for several weeks. Two different nonwovens of thermoplastic silicone-based polycarbonaturethane (TSPCU) were compared. Tensile test results show that storage in medium has a relevant influence on the mechanical properties. SEM images of TSPCU show substantially increased fiber diameters after 8 days stored in medium. After detaching the valve leaflet nonwovens from the molds, shrinkage of the material of approximately 12% was detected. A suitable valve size could be identified for joining with the stent structure into an interventional prosthetic venous valve. The results demonstrate the influence of storage conditions on the morphological and mechanical properties of electrospun TSPCU nonwovens. For development and dimensioning of venous valve leaflets, this change in mechanical behavior and possible shrinkage of the material has to be considered.

Published
2021

5. Impact of maternal body mass index and gestational weight gain on maternal and neonatal outcomes in twin pregnancies

Author

Julia Schubert, Nina Timmesfeld, Kathrin Noever, Susann Behnam, Angela Vinturache, and Birgit Arabin

Subjects
Obstetrics and Gynecology, General Medicine
Abstract

To date, there have only been provisional recommendations about the appropriate gestational weight gain in twin pregnancies. This study aimed to contribute evidence to this gap of knowledge.Using a cohort of 10 603 twin pregnancies delivered between 2000 and 2015 in the state of Hessen, Germany, the individual and combined impact of maternal body mass index and gestational weight gain on maternal and neonatal outcomes was analyzed using uni- and multivariable logistic regression models. The analysis used newly defined population-based quartiles of gestational weight gain in women carrying twin pregnancies (Q1:419.4 g/week [low weight gain], Q2-Q3: 419.4-692.3 g/week [optimal weight gain], Q4:692.3 g/week [high weight gain]) and the World Health Organization body mass index classification.Pre-pregnancy body mass index ≥25 kg/mIn twin pregnancies, nonoptimal weekly maternal weight gain seems to be strongly associated with maternal and neonatal adverse outcomes. Since gestational weight gain is a modifiable risk factor, health care providers have the opportunity to counsel pregnant women with twins and target their care accordingly. Additional research to confirm the validity and generalizability of our findings in different populations is warranted.

Published
2022

6. Science‐state alliances and climate engineering: A ‘longue durée’ picture

Author

Julia Schubert

Subjects
Atmospheric Science, Global and Planetary Change, ddc:304.25, climate change, geoengineering, climate science, Geography, Planning and Development, climate engineering, weather modification, scientific expertise
Abstract

Since the early 2000s, proposals to deliberately modify the Earth's climate have gained political traction as a controversial last resort measure against dangerous global warming. The article provides a ‘longue durée’ picture of such climate engineering proposals. It traces their historical trajectory from the late 1950s to their most recent arrival on mainstream climate policy agendas. This perspective suggests that the history of climate engineering unfolds not only along historically specific modes of understanding climatic change. It also corresponds to changing alliances between climate science and the state. By bringing together historical scholarship with contributions from sociology and science policy studies, the article sheds new light on the rise of climate engineering proposals. It recontextualizes these proposals within the bigger history of the political cultivation of climate science. This perspective highlights how deeply entwined efforts to understand and efforts to govern climatic change have always been. This article is categorized under: Climate, History, Society, Culture > Ideas and Knowledge The Social Status of Climate Change Knowledge > Sociology/Anthropology of Climate Knowledge The Social Status of Climate Change Knowledge > Knowledge and Practice, A traveler at the end of the world peeks beyond the limits of the Earth, reaching for the unknown skies. Wood Carving by Unknown Artist in Flammarion, C. (1888). L'atmosphère: Météorologie Populaire. Hachette., German University of Administrative Sciences, Speyer (Germany)

Published
2022

7. A two-stage finite element based method for the study of stiffness and failure load of osteoporotic spines

Author

Heiner Martin, Guido Schröder, Julia Schubert, Anne Ringel, Jorid Paulsen, Sylvia Pfensig, Andreas Götz, Hans-Christof Schober, and Niels Grabow

Subjects
musculoskeletal diseases, animal structures, Biomedical Engineering, Medicine, finite element modeling, equipment and supplies, musculoskeletal system, spine, osteoporosis, biomechanics
Abstract

A two-step method for investigating the stiffnesses and failure loads of vertebral bodies is presented. It is based on the representation of the spine in a global finite element model of structural elements. A detailed model of two interconnected vertebrae and an intervertebral disc was implemented. Calculations on this model are shown which illustrate the dependencies of structural stiffnesses on vertebral body properties. These structural stiffnesses can then be used to represent the spine in the global model.

Published
2021

8. Increased serum peripheral C-reactive protein is associated with reduced brain barriers permeability of TSPO radioligands in healthy volunteers and depressed patients: implications for inflammation and depression

Author

Oliver Cousins, Federico Turkheimer, Mattia Veronese, Valeria Mondelli, Noha Althubaity, Carmine M. Pariante, Danai Dima, Edward T. Bullmore, Maria A. Nettis, and Julia Schubert

Subjects
0301 basic medicine, medicine.medical_specialty, Tracer percolation, Immunology, BF, Choroid plexus, CSF, Inflammation, Permeability, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Immune system, Receptors, GABA, Immunity, Internal medicine, medicine, Translocator protein, Humans, BBB permeability, Neuroinflammation, biology, Depression, Endocrine and Autonomic Systems, business.industry, C-reactive protein, Brain, Healthy Volunteers, Peripheral, C-Reactive Protein, Cross-Sectional Studies, PET, 030104 developmental biology, Endocrinology, Blood-Brain Barrier, Positron-Emission Tomography, RC0321, biology.protein, Radiopharmaceuticals, medicine.symptom, business, Perfusion, 030217 neurology & neurosurgery, RC
Abstract

The relationship between peripheral and central immunity and how these ultimately may cause depressed behaviour has been the focus of a number of imaging studies conducted with Positron Emission Tomography (PET). These studies aimed at testing the immune-mediated model of depression that proposes a direct effect of peripheral cytokines and immune cells on the brain to elicit a neuroinflammatory response via a leaky blood–brain barrier and ultimately depressive behaviour. However, studies conducted so far using PET radioligands targeting the neuroinflammatory marker 18 kDa translocator protein (TSPO) in patient cohorts with depression have demonstrated mild inflammatory brain status but no correlation between central and peripheral immunity. To gain a better insight into the relationship between heightened peripheral immunity and neuroinflammation, we estimated blood-to-brain and blood-to-CSF perfusion rates for two TSPO radiotracers collected in two separate studies, one large cross-sectional study of neuroinflammation in normal and depressed cohorts (N = 51 patients and N = 25 controls) and a second study where peripheral inflammation in N = 7 healthy controls was induced via subcutaneous injection of interferon (IFN)-α. In both studies we observed a consistent negative association between peripheral inflammation, measured with c-reactive protein P (CRP), and radiotracer perfusion into and from the brain parenchyma and CSF. Importantly, there was no association of this effect with the marker of BBB leakage S100β, that was unchanged. These results suggest a different model of peripheral-to-central immunity interaction whereas peripheral inflammation may cause a reduction in BBB permeability. This effect, on the long term, is likely to disrupt brain homeostasis and induce depressive behavioural symptoms.

Published
2021

9. The blood-CSF-brain route of neurological disease: The indirect pathway into the brain

Author

Oliver Cousins, Angela Hodges, Julia Schubert, Mattia Veronese, Federico Turkheimer, Jaleel Miyan, Britta Engelhardt, and Federico Roncaroli

Subjects
Central Nervous System, Histology, Neurology, Blood-Brain Barrier, Physiology (medical), Choroid Plexus, Brain, 610 Medicine & health, Biological Transport, Neurology (clinical), Pathology and Forensic Medicine
Abstract

The brain is protected by the endothelial blood-brain-barrier (BBB) that limits the access of micro-organisms, tumour cells, immune cells and autoantibodies to the parenchyma. However, the classic model of disease spread across a disrupted BBB does not explain the focal distribution of lesions seen in a variety of neurological diseases and why lesions are frequently adjacent to the cerebrospinal fluid (CSF) spaces. We have critically reviewed the possible role of a blood-CSF-brain route as a disease entry pathway into the brain parenchyma. The initial step of this pathway is the transfer of pathogens or immune components from the blood into the CSF at the choroid plexuses, where the blood-CSF-barrier (BCSFB) is located. The flow of CSF results in disease dissemination throughout the CSF spaces. Access to the brain parenchyma from the CSF, can then occur across the ependymal layer at the ventricular surface, or across the pial-glial barrier of the subarachnoid space and the Virchow-Robin spaces. We have reviewed the anatomy and physiology of the blood-CSF-brain pathway and the brain barriers controlling this process. We then summarised the evidence supporting this brain entry route in a cross-section of neurological diseases including neuromyelitis optica, multiple sclerosis, neurosarcoidosis, neuropsychiatric lupus, cryptococcal infection, and both solid and haematological tumours. This summary highlights the conditions that share the blood-CSF-brain pathway as a pathogenetic mechanism. These include the characteristic proximity of lesions to CSF, evidence of disruption of the brain barriers, and the identification of significant pathology within the CSF. An improved understanding of pathological transfer through the CSF and across all brain barriers will inform on more effective and targeted treatments of primary and secondary disease of the central nervous system.

Published
2021

10. Engineering the Climate

Author

Julia Schubert

Subjects
Politics, Vision, Political science, Control (management), Environmental ethics, Climate science
Abstract

Notions of the impending climate crisis have pushed a set of highly contested techno-scientific measures onto policy agendas around the world. Suggestions to deliberately alter, to engineer, the Earth’s climate have gained political currency in recent years not as a positive vision of techno-scientific innovation, but as a daunting measure of last resort. The controversial status of various so-called climate engineering proposals raises a simple, yet pressing question: How has it has come to this? And, more specifically, how did such contested measures earn their place on policy agendas, despite enormous scientific complexities and fierce political contestation? Global societal problems, such as climate change, financial crises, or pandemics have brought the political relevance of scientific expertise to the foreground. This book speaks to scholarship in sociology and science studies, seeking to illuminate the essential entanglements between efforts to understand and efforts to govern such problems. By giving climate engineering a life of its own and following its dynamic trajectory as a contested object of expert work, this book sheds light on the reflexive and historically contingent interplay of science and politics as two distinct, yet increasingly interdependent, realms of society.

Published
2021

11. Choroid plexus enlargement is associated with neuroinflammation and reduction of blood brain barrier permeability in depression

Author

Mondelli, Yousaf T, Edward T. Bullmore, Neil A. Harrison, Danai Dima, Maria A. Nettis, Federico Turkheimer, Daniel Martins, Julia Schubert, Noha Althubaity, Carmine M. Pariante, and Mattia Veronese

Subjects
medicine.medical_specialty, business.industry, Inflammation, Human brain, Insular cortex, Brain mapping, medicine.anatomical_structure, Endocrinology, Internal medicine, medicine, Choroid plexus, medicine.symptom, business, Prefrontal cortex, Anterior cingulate cortex, Neuroinflammation
Abstract

BackgroundRecent studies have shown that choroid plexuses (CP) may be involved in the neuro-immune axes, playing a role in the interaction between the central and peripheral inflammation. Here we aimed to investigate CP volume alterations in depression and their associations with inflammation.Methods51 depressed participants (HDRS score >13) and 25 age- and sex-matched healthy controls (HCs) from the Wellcome Trust NIMA consortium were re-analysed for the study. All the participants underwent full peripheral cytokine profiling and simultaneous [11C]PK11195 PET/structural MRI imaging for measuring neuroinflammation and CP volume respectively.ResultsWe found a significantly greater CP volume in depressed subjects compared to HCs (t(76) = +2.17) that was positively correlated with [11C]PK11195 PET binding in the anterior cingulate cortex (r=0.28, p=0.02), prefrontal cortex (r=0.24, p=0.04), and insular cortex (r=0.24, p=0.04), but not with the peripheral inflammatory markers: CRP levels (r=0.07, p=0.53), IL-6 (r=-0.08, p=0.61), and TNF-α (r=-0.06, p=0.70). The CP volume correlated with the [11C]PK11195 PET binding in CP (r=0.34, p=0.005). Integration of transcriptomic data from the Allen Human Brain Atlas with the brain map depicting the correlations between CP volume and PET imaging found significant gene enrichment for several pathways involved in neuroinflammatory response.ConclusionThis result supports the hypothesis that changes in brain barriers may cause reduction in solute exchanges between blood and CSF, disturbing the brain homeostasis and ultimately contributing to inflammation in depression. Given that CP anomalies have been recently detected in other brain disorders, these results may not be specific to depression and might extend to other conditions with a peripheral inflammatory component.

Published
2021

12. Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Author

Alison Halliday, Richard Bulbulia, Leo H Bonati, Johanna Chester, Andrea Cradduck-Bamford, Richard Peto, Hongchao Pan, John Potter, Hans Henning Eckstein, Barbara Farrell, Marcus Flather, Averil Mansfield, Boby Mihaylova, Kazim Rahimi, David Simpson, Dafydd Thomas, Peter Sandercock, Richard Gray, Andrew Molyneux, Cliff P Shearman, Peter Rothwell, Anna Belli, Will Herrington, Parminder Judge, Peter Leopold, Marion Mafham, Michael Gough, Piergiorgio Cao, Sumaira MacDonald, Vasha Bari, Clive Berry, S Bradshaw, Wojciech Brudlo, Alison Clarke, Robin Cox, Susan Fathers, Kamran Gaba, Mo Gray, Elizabeth Hayter, Constance Holliday, Rijo Kurien, Michael Lay, Steffi le Conte, Jessica McManus, Zahra Madgwick, Dylan Morris, Andrew Munday, Sandra Pickworth, Wiktor Ostasz, Michiel Poorthuis, Sue Richards, Louisa Teixeira, Sergey Tochlin, Lynda Tully, Carol Wallis, Monique Willet, Alan Young, Renato Casana, Chiara Malloggi, Andrea Odero Jr, Vincenzo Silani, Gianfranco Parati, Giuseppe Malchiodi, Giovanni Malferrari, Francesco Strozzi, Nicola Tusini, Enrico Vecchiati, Gioacchino Coppi, Antonio Lauricella, Roberto Moratto, Roberto Silingardi, Jessica Veronesi, Andrea Zini, Emanuele Ferrero, Michelangelo Ferri, Andrea Gaggiano, Carmelo Labate, Franco Nessi, Daniele Psacharopulo, Andrea Viazzo, Giovanni Malacrida, Daniela Mazzaccaro, Giovanni Meola, Alfredo Modafferi, Giovanni Nano, Maria Teresa Occhiuto, Paolo Righini, Silvia Stegher, Stefano Chiarandini, Filippo Griselli, Sandro Lepidi, Fabio Pozzi Mucelli, Marcello Naccarato, Mario D'Oria, Barbara Ziani, Andrea Stella, Mortalla Dieng, Gianluca Faggioli, Mauro Gargiulo, Sergio Palermo, Rodolfo Pini, Giovanni Maria Puddu, Andrea Vacirca, Domenico Angiletta, Claudio Desantis, Davide Marinazzo, Giovanni Mastrangelo, Guido Regina, Raffaele Pulli, Paolo Bianchi, Lea Cireni, Elisabetta Coppi, Rocco Pizzirusso, Filippo Scalise, Giovanni Sorropago, Valerio Tolva, Valeria Caso, Enrico Cieri, Paola DeRango, Luca Farchioni, Giacomo Isernia, Massimo Lenti, Gian Battista Parlani, Guglielmo Pupo, Grazia Pula, Gioele Simonte, Fabio Verzini, Federico Carimati, Maria Luisa Delodovici, Federico Fontana, Gabriele Piffaretti, Matteo Tozzi, Efrem Civilini, Giorgio Poletto, Bernhard Reimers, Barbara Praquin, Sonia Ronchey, Laura Capoccia, Wassim Mansour, Enrico Sbarigia, Francesco Speziale, Pasqualino Sirignano, Danilo Toni, Roberto Galeotti, Vincenzo Gasbarro, Francesco Mascoli, Tiberio Rocca, Elpiniki Tsolaki, Giulia Bernardini, Ester DeMarco, Alessia Giaquinta, Francesco Patti, Massimiliano Veroux, Pierfrancesco Veroux, Carla Virgilio, Nicola Mangialardi, Matteo Orrico, Vincenzo Di Lazzaro, Nunzio Montelione, Francesco Spinelli, Francesco Stilo, Carlo Cernetti, Sandro Irsara, Giuseppe Maccarrone, Diego Tonello, Adriana Visonà, Beniamino Zalunardo, Emiliano Chisci, Stefano Michelagnoli, Nicola Troisi, Maela Masato, Massimo Dei Negri, Andrea Pacchioni, Salvatore Saccà, Giovanni Amatucci, Alfredo Cannizzaro, Federico Accrocca, Cesare Ambrogi, Renzo Barbazza, Giustino Marcucci, Andrea Siani, Guido Bajardi, Giovanni Savettieri, Angelo Argentieri, Riccardo Corbetta, Attilio Odero, Pietro Quaretti, Federico Z Thyrion, Alessandro Cappelli, Domenico Benevento, Gianmarco De Donato, Maria Agnese Mele, Giancarlo Palasciano, Daniela Pieragalli, Alessandro Rossi, Carlo Setacci, Francesco Setacci, Domenico Palombo, Maria Cecilia Perfumo, Edoardo Martelli, Aldo Paolucci, Santi Trimarchi, Viviana Grassi, Luigi Grimaldi, Giuliana La Rosa, Domenico Mirabella, Matteo Scialabba, Leonildo Sichel, Costantino L D'Angelo, Gian Franco Fadda, Holta Kasemi, Mario Marino, Francesco Burzotta, Francesco Alberto Codispoti, Angela Ferrante, Giovanni Tinelli, Yamume Tshomba, Claudio Vincenzoni, Deborah Amis, Dawn Anderson, Martin Catterson, Mike Clarke, Michelle Davis, Anand Dixit, Alexander Dyker, Gary Ford, Ralph Jackson, Sreevalsan Kappadath, David Lambert, Tim Lees, Stephen Louw, James McCaslin, Noala Parr, Rebecca Robson, Gerard Stansby, Lucy Wales, Vera Wealleans, Lesley Wilson, Michael Wyatt, Hardeep Baht, Ibrahim Balogun, Ilse Burger, Tracy Cosier, Linda Cowie, Gunaratnam Gunathilagan, David Hargroves, Robert Insall, Sally Jones, Hannah Rudenko, Natasha Schumacher, Jawaharlal Senaratne, George Thomas, Audrey Thomson, Tom Webb, Ellen Brown, Bernard Esisi, Ali Mehrzad, Shane MacSweeney, Norman McConachie, Alison Southam, Wayne Sunman, Ahmed Abdul-Hamiq, Jenny Bryce, Ian Chetter, Duncan Ettles, Raghuram Lakshminarayan, Kim Mitchelson, Christopher Rhymes, Graham Robinson, Paul Scott, Alison Vickers, Ray Ashleigh, Stephen Butterfield, Ed Gamble, Jonathan Ghosh, Charles N McCollum, Mark Welch, Sarah Welsh, Leszek Wolowczyk, Mary Donnelly, Stephen D'Souza, Anselm A Egun, Bindu Gregary, Thomas Joseph, Christine Kelly, Shuja Punekar, M Asad Rahi, Sonia Raj, Dare Seriki, George Thomson, James Brown, Ragunath Durairajan, Iris Grunwald, Paul Guyler, Paula Harman, Matthew Jakeways, Christopher Khuoge, Ashish Kundu, Thayalini Loganathan, Nisha Menon, Raji O Prabakaran, Devesh Sinha, Vicky Thompson, Sharon Tysoe, Dennis Briley, Chris Darby, Linda Hands, Dominic Howard, Wilhelm Kuker, Ursula Schulz, Rachel Teal, David Barer, Andrew Brown, Susan Crawford, Paul Dunlop, Ramesh Krishnamurthy, Nikhil Majmudar, Duncan Mitchell, Min P Myint, Richard O'Brien, Janice O'Connell, Naweed Sattar, Shanmugam Vetrivel, Jonathan Beard, Trevor Cleveland, Peter Gaines, John Humphreys, Alison Jenkins, Craig King, Daniel Kusuma, Ralph Lindert, Robbie Lonsdale, Raj Nair, Shah Nawaz, Faith Okhuoya, Douglas Turner, Graham Venables, Paul Dorman, Andrea Hughes, Deborah Jones, David Mendelow, Helen Rodgers, Aidas Raudoniitis, Peter Enevoldson, Hans Nahser, Imelda O'Brien, Francesco Torella, Dave Watling, Richard White, Pauline Brown, Dipankar Dutta, Lorraine Emerson, Paula Hilltout, Sachin Kulkarni, Jackie Morrison, Keith Poskitt, Fiona Slim, Sarah Smith, Amanda Tyler, Joanne Waldron, Mark Whyman, Milda Bajoriene, Lucy Baker, Amanda Colston, Bekky Eliot-Jones, Gita Gramizadeh, Catherine Lewis-Clarke, Laura McCafferty, Deborah Oliver, Debbie Palmer, Abhijeet Patil, Suzannah Pegler, Gopi Ramadurai, Aisling Roberts, Tracey Sargent, Shivaprasad Siddegowda, Ravi Singh-Ranger, Akintunde Williams, Lucy Williams, Steve Windebank, Tadas Zuromskis, Lanka Alwis, Jane Angus, Asaipillai Asokanathan, Caroline Fornolles, Diana Hardy, Sophy Hunte, Frances Justin, Duke Phiri, Marie Mitabouana-Kibou, Lakshmanan Sekaran, Sakthivel Sethuraman, Margaret L Tate, Joyce Akyea-Mensah, Stephen Ball, Angela Chrisopoulou, Elizabeth Keene, Alison Phair, Steven Rogers, John V Smyth, Colin Bicknell, Jeremy Chataway, Nicholas Cheshire, Andrew Clifton, Caroline Eley, Richard Gibbs, Mohammad Hamady, Beth Hazel, Alex James, Michael Jenkins, Nyma Khanom, Austin Lacey, Maz Mireskandari, Joanna O'Reilly, Antony Pereira, Tina Sachs, John Wolfe, Philip Davey, Gill Rogers, Gemma Smith, Gareth Tervit, Ian Nichol, Andrew Parry, Gavin Young, Simon Ashley, James Barwell, Francis Dix, Azlisham M Nor, Chris Parry, Angela Birt, Paul Davies, Jim George, Anne Graham, Leon Jonker, Nicci Kelsall, Caroline Potts, Toni Wilson, Jamie Crinnion, Larissa Cuenoud, Nikola Aleksic, Srdan Babic, Nenad Ilijevski, Đorde Radak, Dragan Sagic, Slobodan Tanaskovic, Momcilo Colic, Vladimir Cvetic, Lazar Davidovic, Dejana R Jovanovic, Igor Koncar, Perica Mutavdžic, Miloš Sladojevic, Ivan Tomic, Eike S Debus, Ulrich Grzyska, Dagmar Otto, Götz Thomalla, Jessica Barlinn, Johannes Gerber, Kathrin Haase, Christian Hartmann, Stefan Ludwig, Volker Pütz, Christian Reeps, Christine Schmidt, Norbert Weiss, Sebastian Werth, Simon Winzer, Janine Gemper, Albrecht Günther, Bianka Heiling, Elisabeth Jochmann, Panagiota Karvouniari, Carsten Klingner, Thomas Mayer, Julia Schubert, Friederike Schulze-Hartung, Jürgen Zanow, Yvonne Bausback, Franka Borger, Spiridon Botsios, Daniela Branzan, Sven Bräunlich, Henryk Hölzer, Janin Lenzer, Christopher Piorkowski, Nadine Richter, Johannes Schuster, Dierk Scheinert, Andrej Schmidt, Holger Staab, Matthias Ulrich, Martin Werner, Hermann Berger, Gábor Biró, Hans-Henning Eckstein, Michael Kallmayer, Kornelia Kreiser, Alexander Zimmermann, Bärbel Berekoven, Klaus Frerker, Vera Gordon, Giovanni Torsello, Sebastian Arnold, Cora Dienel, Martin Storck, Bernhard Biermaier, Hans Martin Gissler, Christof Klötzsch, Tomas Pfeiffer, Ralph Schneider, Leander Söhl, Michael Wennrich, Angelika Alonso, Michael Keese, Christoph Groden, Andreas Cöster, Andreas Engelhardt, Christoph-Maria Ratusinski, Bengt Berg, Martin Delle, Johan Formgren, Peter Gillgren, Lotta Jarl, Torbjörn B Kall, Peter Konrad, Niklas Nyman, Claes Skiöldebrand, Johnny Steuer, Rabbe Takolander, Jonas Malmstedt, Stefan Acosta, Katarina Björses, Kerstin Brandt, Nuno Dias, Anders Gottsäter, Jan Holst, Thorarinn Kristmundsson, Tobias Kühme, Tilo Kölbel, Bengt Lindblad, Mats Lindh, Martin Malina, Tomas Ohrlander, Tim Resch, Viola Rönnle, Björn Sonesson, 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Crawford S., Dunlop P., Krishnamurthy R., Majmudar N., Mitchell D., Myint M.P., O'Brien R., O'Connell J., Sattar N., Vetrivel S., Beard J., Cleveland T., Gaines P., Humphreys J., Jenkins A., King C., Kusuma D., Lindert R., Lonsdale R., Nair R., Nawaz S., Okhuoya F., Turner D., Venables G., Dorman P., Hughes A., Jones D., Mendelow D., Rodgers H., Raudoniitis A., Enevoldson P., Nahser H., O'Brien I., Torella F., Watling D., White R., Brown P., Dutta D., Emerson L., Hilltout P., Kulkarni S., Morrison J., Poskitt K., Slim F., Smith S., Tyler A., Waldron J., Whyman M., Bajoriene M., Baker L., Colston A., Eliot-Jones B., Gramizadeh G., Lewis-Clarke C., McCafferty L., Oliver D., Palmer D., Patil A., Pegler S., Ramadurai G., Roberts A., Sargent T., Siddegowda S., Singh-Ranger R., Williams A., Williams L., Windebank S., Zuromskis T., Alwis L., Angus J., Asokanathan A., Fornolles C., Hardy D., Hunte S., Justin F., Phiri D., Mitabouana-Kibou M., Sekaran L., Sethuraman S., Tate M.L., Akyea-Mensah 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S., Branzan D., Braunlich S., Holzer H., Lenzer J., Piorkowski C., Richter N., Schuster J., Scheinert D., Schmidt A., Staab H., Ulrich M., Werner M., Berger H., Biro G., Eckstein H.-H., Kallmayer M., Kreiser K., Zimmermann A., Berekoven B., Frerker K., Gordon V., Torsello G., Arnold S., Dienel C., Storck M., Biermaier B., Gissler H.M., Klotzsch C., Pfeiffer T., Schneider R., Sohl L., Wennrich M., Alonso A., Keese M., Groden C., Coster A., Engelhardt A., Ratusinski C.-M., Berg B., Delle M., Formgren J., Gillgren P., Jarl L., Kall T.B., Konrad P., Nyman N., Skioldebrand C., Steuer J., Takolander R., Malmstedt J., Acosta S., Bjorses K., Brandt K., Dias N., Gottsater A., Holst J., Kristmundsson T., Kuhme T., Kolbel T., Lindblad B., Lindh M., Malina M., Ohrlander T., Resch T., Ronnle V., Sonesson B., Warvsten M., Zdanowski Z., Campbell E., Kjellin P., Lindgren H., Nyberg J., Petersen B., Plate G., Parsson H., Qvarfordt P., Ignatenko P., Karpenko A., Starodubtsev V., Chernyavsky M.A., Golovkova M.S., Komakha B.B., Zherdev N.N., Belyasnik A., Chechulov P., Kandyba D., Stepanishchev I., Csobay-Novak C., Dosa E., Entz L., Nemes B., Szeberin Z., Barzo P., Bodosi M., Fako E., Fulop B., Nemeth T., Pazdernyik S., Skoba K., Voros E., Chatzinikou E., Giannoukas A., Karathanos C., Koutsias S., Kouvelos G., Matsagkas M., Ralli S., Rountas C., Rousas N., Spanos K., Brountzos E., Kakisis J.D., Lazaris A., Moulakakis K.G., Stefanis L., Tsivgoulis G., Vasdekis S., Antonopoulos C.N., Bellenis I., Maras D., Polydorou A., Polydorou V., Tavernarakis A., Ioannou N., Terzoudi M., Lazarides M., Mantatzis M., Vadikolias K., Dzieciuchowicz L., Gabriel M., Krasinski Z., Oszkinis G., Pukacki F., Slowinski M., Stanisic M.-G., Staniszewski R., Tomczak J., Zielinski M., Myrcha P., Rozanski D., Drelichowski S., Iwanowski W., Koncewicz K., Bialek P., Biejat Z., Czepel W., Czlonkowska A., Dowzenko A., Jedrzejewska J., Kobayashi A., Leszczynski J., Malek A., Polanski J., Proczka R., Skorski M., Szostek M., Andziak P., Dratwicki M., Gil R., Nowicki M., Pniewski J., Rzezak J., Seweryniak P., Dabek P., Juszynski M., Madycki G., Pacewski B., Raciborski W., Slowinski P., Staszkiewicz W., Bombic M., Chlouba V., Fiedler J., Hes K., Kostal P., Sova J., Kriz Z., Privara M., Reif M., Staffa R., Vlachovsky R., Vojtisek B., Hrbac T., Kuliha M., Prochazka V., Roubec M., Skoloudik D., Netuka D., Steklacova A., Benes III V., Buchvald P., Endrych L., Sercl M., Campos W., Casella I.B., de Luccia N., Estenssoro A.E.V., Presti C., Puech-Leao P., Neves C.R.B., da Silva E.S., Sitrangulo C.J., Monteiro J.A.T., Tinone G., Bellini Dalio M., Joviliano E.E., Pontes Neto O.M., Serra Ribeiro M., Cras P., Hendriks J.M.H., Hoppenbrouwers M., Lauwers P., Loos C., Yperzeele L., Geenens M., Hemelsoet D., van Herzeele I., Vermassen F., Astarci P., Hammer F., Lacroix V., Peeters A., Verhelst R., Cirelli S., Dormal P., Grimonprez A., Lambrecht B., Lerut P., Thues E., De Koster G., Desiron Q., Maertens de Noordhout A., Malmendier D., Massoz M., Saad G., Bosiers M., Callaert J., Deloose K., Blanco Canibano E., Garcia Fresnillo B., Guerra Requena M., Morata Barrado P.C., Muela Mendez M., Yusta Izquierdo A., Aparici Robles F., Blanes Orti P., Garcia Dominguez L., Martinez Lopez R., Miralles Hernandez M., Tembl Ferrairo J.I., Chamorro A., Macho J., Obach V., Riambau V., San Roman L., Ahlhelm F.J., Blackham K., Engelter S., Eugster T., Gensicke H., Gurke L., Lyrer P., Mariani L., Maurer M., Mujagic E., Muller M., Psychogios M., Stierli P., Stippich C., Traenka C., Wolff T., Wagner B., Wiegert M.M., Clarke S., Diepers M., Grochenig E., Gruber P., Isaak A., Kahles T., Marti R., Nedeltchev K., Remonda L., Tissira N., Valenca Falcao M., de Borst G.J., Lo R.H., Moll F.L., Toorop R., van der Worp B.H., Vonken E.J., Kappelle J.L., Jahrome O., Vos F., Schuiling W., van Overhagen H., Keunen R.W.M., Knippenberg B., Wever J.J., Lardenoije J.W., Reijnen M., Smeets L., van Sterkenburg S., Fraedrich G., Gizewski E., Gruber I., Knoflach M., Kiechl S., Rantner B., Abdulamit T., Bergeron P., Padovani R., Trastour J.-C., Cardon J.-M., Le Gallou-Wittenberg A., Allaire E., Becquemin J.-P., Cochennec-Paliwoda F., Desgranges P., Hosseini H., Kobeiter H., Marzelle J., Almekhlafi M.A., Bal S., Barber P.A., Coutts S.B., Demchuk A.M., Eesa M., Gillies M., Goyal M., Hill M.D., Hudon M.E., Jambula A., Kenney C., Klein G., McClelland M., Mitha A., Menon B.K., Morrish W.F., Peters S., Ryckborst K.J., Samis G., Save S., Smith E.E., Stys P., Subramaniam S., Sutherland G.R., Watson T., Wong J.H., Zimmel L., Flis V., Matela J., Miksic K., Milotic F., Mrdja B., Stirn B., Tetickovic E., Gasparini M., Grad A., Kompara I., Milosevic Z., Palmiste V., Toomsoo T., Aidashova B., Kospanov N., Lyssenko R., Mussagaliev D., Beyar R., Hoffman A., Karram T., Kerner A., Nikolsky E., Nitecki S., Andonova S., Bachvarov C., Petrov V., Cvjetko I., Vidjak V., Haluzan D., Petrunic M., Liu B., Liu C.-W., Bartko D., Beno P., Rusnak F., Zelenak K., Ezura M., Inoue T., Kimura N., Kondo R., Matsumoto Y., Shimizu H., Endo H., Furui E., Bakke S., Krohg-Sorensen K., Nome T., Skjelland M., Tennoe B., Albuquerque e Castro J., Alves G., Bastos Goncalves F., de Aragao Morais J., Garcia A.C., Valentim H., Vasconcelos L., Belcastro F., Cura F., Zaefferer P., Abd-Allah F., Eldessoki M.H., Heshmat Kassem H., Soliman Gharieb H., Colgan M.P., Haider S.N., Harbison J., Madhavan P., Moore D., Shanik G., Kazan V., Nazzal M., Ramsey-Williams V., and Gargiulo M

Subjects
Male, medicine.medical_specialty, Time Factors, Time Factor, medicine.medical_treatment, Carotid Stenosi, MEDLINE, Carotid endarterectomy, Rate ratio, Risk Assessment, Asymptomatic, law.invention, Randomized controlled trial, law, Risk Factors, carotid artery stenting (CAS), carotid endarterectomy (CEA), Stent, medicine, Humans, Carotid Stenosis, Stroke, Endarterectomy, Aged, Endarterectomy, Carotid, business.industry, carotid artery, Risk Factor, Articles, General Medicine, trial, medicine.disease, Settore MED/22 - CHIRURGIA VASCOLARE, Surgery, Stenosis, Treatment Outcome, Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Female, Stents, Human medicine, medicine.symptom, business, Human
Abstract

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

Published
2021

13. Supervised clustering for TSPO PET imaging

Author

Paolo Zanotti-Fregonara, Julia Schubert, Federico Turkheimer, Mattia Veronese, and Matteo Tonietto

Subjects
Computer science, PET, Pseudo-reference region, Supervised clustering, TSPO, Context (language use), Review Article, Computational biology, Receptors, GABA, Translocator protein, Cluster Analysis, Humans, Radiology, Nuclear Medicine and imaging, Pet tracer, biology, Technical note, General Medicine, Pet imaging, Pyrimidines, Positron-Emission Tomography, biology.protein, Imaging technique, Tomography, X-Ray Computed, Blood sampling
Abstract

Purpose This technical note seeks to act as a practical guide for implementing a supervised clustering algorithm (SVCA) reference region approach and to explain the main strengths and limitations of the technique in the context of 18-kilodalton translocator protein (TSPO) positron emission tomography (PET) studies in experimental medicine. Background TSPO PET is the most widely used imaging technique for studying neuroinflammation in vivo in humans. Quantifying neuroinflammation with PET can be a challenging and invasive procedure, especially in frail patients, because it often requires blood sampling from an arterial catheter. A widely used alternative to arterial sampling is SVCA, which identifies the voxels with minimal specific binding in the PET images, thus extracting a pseudo-reference region for non-invasive quantification. Unlike other reference region approaches, SVCA does not require specification of an anatomical reference region a priori, which alleviates the limitation of TSPO contamination in anatomically-defined reference regions in individuals with underlying inflammatory processes. Furthermore, SVCA can be applied to any TSPO PET tracer across different neurological and neuropsychiatric conditions, providing noninvasivequantification of TSPO expression. Methods We provide an overview of the development of SVCA as well as step-by-step instructions for implementing SVCA with suggestions for specific settings. We review the literature on SVCAapplications using first- and second- generation TSPO PET tracers and discuss potential clinically relevant limitations and applications. Conclusions The correct implementation of SVCA can provide robust and reproducible estimates of brain TSPO expression. This review encourages the standardisation of SVCA methodology in TSPO PET analysis, ultimately aiming to improve replicability and comparability across study sites.

Published
2021

14. A Modest Increase in 11C-PK11195-Positron Emission Tomography TSPO Binding in Depression Is Not Associated With Serum C-Reactive Protein or Body Mass Index

Author

Julia J. Schubert, Mattia Veronese, Tim D. Fryer, Roido Manavaki, Manfred G. Kitzbichler, Maria A. Nettis, Valeria Mondelli, Carmine M. Pariante, Edward T. Bullmore, Federico E. Turkheimer, Dominika Wlazly, Amber Dickinson, Andy Foster, Clare Knight, Claire Leckey, Paul Morgan, Angharad Morgan, Caroline O'Hagan, Samuel Touchard, Shahid Khan, Phil Murphy, Christine Parker, Jai Patel, Jill Richardson, Paul Acton, Nigel Austin, Anindya Bhattacharya, Nick Carruthers, Peter de Boer, Wayne Drevets, John Isaac, Declan Jones, John Kemp, Hartmuth Kolb, Jeff Nye, Gayle Wittenberg, Gareth Barker, Anna Bogdanova, Heidi Byrom, Diana Cash, Annamaria Cattaneo, Daniela Enache, Tony Gee, Caitlin Hastings, Melisa Kose, Giulia Lombardo, Nicole Mariani, Anna McLaughlin, Maria Nettis, Naghmeh Nikkheslat, Carmine Pariante, Karen Randall, Julia Schubert, Luca Sforzini, Hannah Sheridan, Camilla Simmons, Nisha Singh, Federico Turkheimer, Vicky Van Loo, Marta Vicente Rodriguez, Toby Wood, Courtney Worrell, Zuzanna Zajkowska, Brian Campbell, Jan Egebjerg, Hans Eriksson, Francois Gastambide, Karen Husted Adams, Ross Jeggo, Thomas Moeller, Bob Nelson, Niels Plath, Christian Thomsen, Jan Torleif Pederson, Stevin Zorn, Catherine Deith, Scott Farmer, John McClean, Andrew McPherson, Nagore Penandes, Paul Scouller, Murray Sutherland, Mary Jane Attenburrow, Jithen Benjamin, Helen Jones, Fran Mada, Akintayo Oladejo, Katy Smith, Rita Balice-Gordon, Brendon Binneman, James Duerr, Terence Fullerton, Veeru Goli, Zoe Hughes, Justin Piro, Tarek Samad, Jonathan Sporn, Liz Hoskins, Charmaine Kohn, Lauren Wilcock, Franklin Aigbirhio, Junaid Bhatti, Ed Bullmore, Sam Chamberlain, Marta Correia, Anna Crofts, Tim Fryer, Martin Graves, Alex Hatton, Manfred Kitzbichler, Mary-Ellen Lynall, Christina Maurice, Ciara O'Donnell, Linda Pointon, Peter St George Hyslop, Lorinda Turner, Petra Vertes, Barry Widmer, Guy Williams, Jonathan Cavanagh, Alison McColl, Robin Shaw, Erik Boddeke, Alison Baird, Stuart Clare, Phil Cowen, I-Shu (Dante) Huang, Sam Hurley, Simon Lovestone, Alejo Nevado-Holgado, Elena Ribe, Anviti Vyas, Laura Winchester, Madeleine Cleal, Diego Gomez-Nicola, Renzo Mancuso, Hugh Perry, Mara Cercignani, Charlotte Clarke, Alessandro Colasanti, Neil Harrison, Rosemary Murray, Jason O'Connor, and Howard Mount

Subjects
medicine.medical_specialty, Cognitive Neuroscience, 050105 experimental psychology, Body Mass Index, C-reactive protein, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Receptors, GABA, Interquartile range, Internal medicine, medicine, Translocator protein, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Prefrontal cortex, Biological Psychiatry, Anterior cingulate cortex, Inflammation, Depressive Disorder, Major, biology, business.industry, Depression, 05 social sciences, Microglia, PET, TSPO, medicine.disease, Isoquinolines, Archival Report, Endocrinology, medicine.anatomical_structure, Positron-Emission Tomography, biology.protein, Major depressive disorder, Neurology (clinical), business, Body mass index, 030217 neurology & neurosurgery
Abstract

Background: Immune mechanisms have been implicated in the pathogenesis of depression. Translocator protein (TSPO)–targeted positron emission tomography (PET) has been used to assess neuroinflammation in major depressive disorder. We aimed to 1) test the hypothesis of significant case-control differences in TSPO binding in the anterior cingulate cortex, prefrontal cortex, and insula regions; and 2) explore the relationship between cerebral TSPO binding and peripheral blood C-reactive protein (CRP) concentration. Methods: A total of 51 depressed subjects with Hamilton Depression Rating Scale score >13 (median 17; interquartile range, 16–22) and 25 healthy control subjects underwent dynamic brain 11C-PK11195 PET and peripheral blood immune marker characterization. Depressed subjects were divided into high CRP (>3 mg/L; n = 20) and low CRP (2 p = .09; F 1,71 = 6.97, p = .01), which was not influenced by body mass index. The case-control difference was greatest in the anterior cingulate cortex (d = 0.49; t 74 = 2.00, p = .03) and not significant in the prefrontal cortex or insula (d = 0.27 and d = 0.36, respectively). Following CRP stratification, significantly higher TSPO binding was observed in low-CRP depression compared with controls (d = 0.53; t 54 = 1.96, p = .03). These effect sizes are comparable to prior major depressive disorder case-control TSPO PET data. No significant correlations were observed between TSPO and CRP measures. Conclusions: Consistent with previous findings, there is a modest increase in TSPO binding in depressed patients compared with healthy control subjects. The lack of a significant correlation between brain TSPO binding and blood CRP concentration or body mass index poses questions about the interactions between central and peripheral immune responses in the pathogenesis of depression.

Published
2021

15. Increased serum peripheral C-reactive protein is associated with reduced small-molecule brain perfusion in healthy volunteers and subjects with major depressive disorder

Author

Maria A. Nettis, Oliver Cousins, Edward T. Bullmore, Federico Turkheimer, Noha Althubaity, Carmine M. Pariante, Danai Dima, Mattia Veronese, Valeria Mondelli, and Julia Schubert

Subjects
medicine.medical_specialty, biology, business.industry, C-reactive protein, Perfusion scanning, Inflammation, medicine.disease, Peripheral, Endocrinology, Immune system, Internal medicine, Translocator protein, biology.protein, medicine, Major depressive disorder, medicine.symptom, business, Neuroinflammation
Abstract

The relationship between peripheral and central immunity and how these ultimately may cause depressed behaviour has been the focus of a number of imaging studies conducted with Positron Emission Tomography (PET). These studies aimed at testing the immune-mediated model of depression that proposes a direct effect of peripheral cytokines and immune cells on the brain to elicit a neuroinflammatory response via a leaky blood-brain barrier and ultimately depressive behaviour. However, studies conducted so far using PET radioligands targeting the neuroinflammatory marker 18 kDa translocator protein (TSPO) in patient cohorts with depression have demonstrated mild inflammatory brain status but no correlation between central and peripheral immunity.To gain a better insight into the relationship between heightened peripheral immunity and neuroinflammation, we estimated blood-to-brain and blood-to-CSF perfusion rates for two TSPO radiotracers collected in two separate studies, one large cross-sectional study of neuroinflammation in normal and depressed cohorts and a second study where peripheral inflammation in healthy controls was induced via subcutaneous injection of interferon (IFN)-α. In both studies we observed a consistent negative association between peripheral inflammation, measured with c-reactive protein P (CRP), and radiotracer perfusion into and from the brain parenchyma and CSF. Importantly, there was no association of this effect with the marker of BBB leakage S100β, that was unchanged, but there was an association between the reduction of tracer perfusion in volunteers injected with interferon (IFN)-α and VEGF, a potent vascular permeability factor.These results support a different model of peripheral-to-central immunity interaction whereas peripheral inflammation causes a “stiffening” of the healthy BBB with consequent reduction of small molecule trafficking to and from the blood into the brain and CSF. This effect, on the long term, is likely to disrupt brain homeostasis and induce depressive behavioural symptoms. Moreover, given the molecular similarity between the TSPO ligands and antidepressant, this phenomenon may underlie treatment resistance in depressive cohorts with heightened peripheral status.

Published
2020
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16. A modest increase in 11C-PK11195-PET TSPO binding in depression is not associated with serum C-reactive protein or body mass index

Author

Carmine M. Pariante, Valeria Mondelli, Roido Manavaki, Manfred G. Kitzbichler, Julia Schubert, Mattia Veronese, Edward T. Bullmore, Federico Turkheimer, Maria A. Nettis, and Tim D. Fryer

Subjects
medicine.medical_specialty, medicine.diagnostic_test, biology, business.industry, C-reactive protein, medicine.disease, Peripheral, Pathogenesis, Endocrinology, Immune system, Positron emission tomography, Internal medicine, biology.protein, Medicine, Major depressive disorder, business, Body mass index, Neuroinflammation
Abstract

BACKGROUNDImmune mechanisms have been implicated in the pathogenesis of depression, and translocator-protein (TSPO) targeted positron emission tomography (PET) has been used to assess neuroinflammation in major depressive disorder. We aimed to: (i) test the prior hypothesis of significant case-control differences in TSPO binding in anterior cingulate (ACC), prefrontal (PFC) and insular (INS) cortical regions; and (ii) explore the relationship between cerebral TSPO binding and peripheral blood concentration of C-reactive protein (CRP).METHODS51 depressed cases with Hamilton Depression Rating Scale score > 13 (median 17; IQR 16-22) and 25 healthy matched controls underwent dynamic brain 11C-PK11195 PET and peripheral blood immune marker characterisation. Depressed cases were divided into high CRP (>3mg/L;N=20) and low CRP (RESULTSAcross the three regions, TSPO binding was significantly increased in cases vs controls (; F(1,71)=6.97, P=0.01). which was not influenced by differences in body mass index (BMI). The case-control difference was greatest in ACC (d=0.49; t(74)=2.00, .P=0.03) and not significant in PFC or INS (d=0.27; d=0.36). Following CRP stratification, significantly higher TSPO binding was observed in low CRP depression compared to controls (d=0.53; t(54)=1.96, P=0.03). These effect sizes are comparable to prior MDD case-control TSPO PET data. No significant correlations were observed between TSPO and CRP measures.CONCLUSIONSConsistent with previous findings, there is a modest increase in TSPO binding in depressed cases compared to healthy controls. The lack of a significant correlation between brain TSPO binding and blood CRP concentration or BMI poses questions about the interactions between central and peripheral immune responses in the pathogenesis of depression.

Published
2020

17. Investigation of balloon dilation devices for treatment of Eustachian tube dysfunction

Author

Julia Schubert, Tamara Wilfling, Klaus-Peter Schmitz, Thomas Lenarz, Gerrit Paasche, Kerstin Schümann, Niels Grabow, and Wolfram Schmidt

Subjects
medicine.medical_specialty, business.industry, Biomedical Engineering, Eustachian tube dysfunction, eustachian tube dysfunction, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Cardiology, Balloon dilation, tube balloon dilation, Medicine, balloon dilation eustachian tuboplasty (bet), 030223 otorhinolaryngology, business
Abstract

The presented three different balloon dilation devices for treating Eustachian tube dysfunction were compared regarding their geometries and designs. The balloon dilation behaviour was investigated by an in vitro test setup consisting of a test chamber with 37 °C water, a 2-axis laser scanner and a pressure controller. All balloons could be properly dilated up to the given nominal pressure (NP) or to rated burst pressure (RBP). The balloons reached their expected balloon diameter and length. The compliance data were 1.07 %/atm (TubaVent short), 1.16 %/atm (Acclarent Aera) and 1.28 %/atm (XprESS LoProfile). The measured profile and compliance data can be used for development of new devices for balloon dilation Eustachian tuboplasty.

Published
2018

18. Magnetic resonance spectroscopy evidence for declining gliosis in MS patients treated with ocrelizumab versus interferon beta-1a

Author

Julia Schubert, Roger Tam, Hideki Garren, Erin L. MacMillan, Anthony Traboulsee, David Kb Li, Victoria Levesque, Alexander Rauscher, Irene M. Vavasour, Richard A. White, Carolyn Taylor, Shannon H. Kolind, and David Clayton

Subjects
Inflammation, 030218 nuclear medicine & medical imaging, Multiple sclerosis, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Nuclear magnetic resonance, medicine, Choline, relapsing/remitting, T-cell receptor, Interferon beta-1a, Nuclear magnetic resonance spectroscopy, medicine.disease, magnetic resonance spectroscopy, 3. Good health, Original Research Paper, nervous system, chemistry, Gliosis, Ocrelizumab, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, medicine.drug, MRI
Abstract

Background Magnetic resonance spectroscopy quantitatively monitors biomarkers of neuron-myelin coupling (N-acetylaspartate (NAA)), and inflammation (total creatine (tCr), total choline (tCho), myo-inositol (mI)) in the brain. Objective This study aims to investigate how ocrelizumab and interferon beta-1a differentially affects imaging biomarkers of neuronal-myelin coupling and inflammation in patients with relapsing multiple sclerosis (MS). Methods Forty patients with relapsing MS randomized to either treatment were scanned at 3T at baseline and weeks 24, 48, and 96 follow-up. Twenty-four healthy controls were scanned at weeks 0, 48, and 96. NAA, tCr, tCho, mI, and NAA/tCr were measured in a single large supra-ventricular voxel. Results There was a time × treatment interaction in NAA/tCr (p = 0.04), primarily driven by opposing tCr trends between treatment groups after 48 weeks of treatment. Patients treated with ocrelizumab showed a possible decline in mI after week 48 week, and stable tCr and tCho levels. Conversely, the interferon beta-1a treated group showed possible increases in mI, tCr, and tCho over 96 weeks. Conclusions Results from this exploratory study suggest that over 2 years, ocrelizumab reduces gliosis compared with interferon beta-1a, demonstrated by declining ml, and stable tCr and tCho. Ocrelizumab may improve the physiologic milieu by decreasing neurotoxic factors that are generated by inflammatory processes.

Published
2019

19. Dynamic 11C-PiB PET shows cerebrospinal fluid flow alterations in Alzheimer’s disease and multiple sclerosis

Author

Matteo Tonietto, Julia Schubert, Federico Turkheimer, Bruno Stankoff, Mattia Veronese, Paul Edison, Alessandra Bertoldo, Benedetta Bodini, David J. Brooks, Livia Marchitelli, and Medical Research Council (MRC)

Subjects
0301 basic medicine, medicine.medical_specialty, Cerebellum, Neurology, glymphatic system, Disease, multiple sclerosis, cerebrospinal fluid, 03 medical and health sciences, Lateral ventricles, 0302 clinical medicine, Cerebrospinal fluid, Internal medicine, medicine, Radiology, Nuclear Medicine and imaging, PiB PET, Pathological, 030304 developmental biology, 0303 health sciences, business.industry, Multiple sclerosis, Area under the curve, 1103 Clinical Sciences, Alzheimer's disease, medicine.disease, Molecular Imaging, Nuclear Medicine & Medical Imaging, 030104 developmental biology, PET, PET/MRI, medicine.anatomical_structure, Ventricle, Cardiology, Alzheimer disease, Glymphatic system, Analysis of variance, business, 030217 neurology & neurosurgery
Abstract

Cerebrospinal fluid (CSF) plays an important role in the clearance of solutes and maintenance of brain homeostasis. 11C-PiB PET was recently proposed as a tool for detection of CSF clearance alterations in Alzheimer’s disease. The current study seeks to investigate the magnitude of 11C-PiB PET signal in the lateral ventricles of an independent group of Alzheimer’s and mild cognitive impairment subjects. We have also evaluated multiple sclerosis as a model of disease with CSF clearance alterations without amyloid-beta tissue accumulation.MethodsA set of Alzheimer’s and mild cognitive impairment subjects and a set of multiple sclerosis subjects with matched healthy controls underwent MRI and dynamic 11C-PiB PET. Manual lateral ventricle regions of interest were generated from MRI data. PET data was analysed using a simplified reference tissue model with cerebellum or a supervised reference region, for the Alzheimer’s and multiple sclerosis datasets, respectively. Magnitude of 11C-PiB signal in the lateral ventricles was calculated as area under curve from 35 to 80 minutes and standard uptake value ratio (SUVR) from 50 to 70 minutes. Compartmental modelling analysis was performed on a separate dataset containing Alzheimer’s and matched healthy control data with an arterial input function to further understand the kinetics of the lateral ventricular 11C-PiB signal.ResultsAnalysis of variance revealed significant group differences in lateral ventricular SUVR across the Alzheimer’s, mild cognitive impairment, and healthy control groups (p=0.004). Additional pairwise comparisons revealed significantly lower lateral ventricular SUVR in Alzheimer’s compared to healthy controls (p11C-PiB signal from blood (p=0.005) and brain tissue (p=0.004) to the lateral ventricles in Alzheimer’s compared to healthy controls. This analysis also revealed significantly lower clearance of 11C-PiB signal out of the lateral ventricles in Alzheimer’s compared to healthy controls (p=0.002).ConclusionOverall, these results indicate that dynamic 11C-PiB PET can be used to observe pathological changes in cerebrospinal fluid dynamics and that cerebrospinal fluid-mediated clearance is reduced in Alzheimer’s disease and multiple sclerosis compared to healthy controls.

Published
2018

20. Autoimmune Enzephalitiden

Author

Albrecht Günther, Julia Schubert, Dirk Brämer, and Otto Witte

Subjects
General Medicine
Published
2016

21. Spontaneous Chloroplast Mutants Mostly Occur by Replication Slippage and Show a Biased Pattern in the Plastome of Oenothera

Author

Amid Massouh, Tommaso Pellizzer, Johanna Sobanski, Liliya Yaneva-Roder, Julia Schubert, Marc T. J. Johnson, Ralph Bock, Stephen I. Wright, Stephan Greiner, Arkadiusz Zupok, and Elena S. Ulbricht-Jones

Subjects
DNA Replication, 0301 basic medicine, Chloroplasts, food.ingredient, DNA, Plant, Mutant, Oenothera, Plant Science, Biology, theater, Genome, 03 medical and health sciences, Replication slippage, food, Plastids, Research Articles, Genetics, DNA replication, food and beverages, Cell Biology, Evening primrose, 030104 developmental biology, Chloroplast DNA, Mutation, theater.play, Nucleotide excision repair
Abstract

Spontaneous plastome mutants have been used as a research tool since the beginning of genetics. However, technical restrictions have severely limited their contributions to research in physiology and molecular biology. Here, we used full plastome sequencing to systematically characterize a collection of 51 spontaneous chloroplast mutants in Oenothera (evening primrose). Most mutants carry only a single mutation. Unexpectedly, the vast majority of mutations do not represent single nucleotide polymorphisms but are insertions/deletions originating from DNA replication slippage events. Only very few mutations appear to be caused by imprecise double-strand break repair, nucleotide misincorporation during replication, or incorrect nucleotide excision repair following oxidative damage. U-turn inversions were not detected. Replication slippage is induced at repetitive sequences that can be very small and tend to have high A/T content. Interestingly, the mutations are not distributed randomly in the genome. The underrepresentation of mutations caused by faulty double-strand break repair might explain the high structural conservation of seed plant plastomes throughout evolution. In addition to providing a fully characterized mutant collection for future research on plastid genetics, gene expression, and photosynthesis, our work identified the spectrum of spontaneous mutations in plastids and reveals that this spectrum is very different from that in the nucleus.

Published
2016

22. Management and prognostic markers in patients with autoimmune encephalitis requiring ICU treatment

Author

Christian Geis, Stefan T. Gerner, Hannah Fuhrer, Otto W. Witte, Harald Prüss, Aleksandra Juranek, Dirk Brämer, Franziska S. Thaler, Christian Urbanek, Julian Bösel, Marius Ringelstein, Andre Dik, Hagen B. Huttner, André Scherag, Julia Schubert, Andrea Kraft, Kurt-Wolfram Sühs, Christian Dohmen, Gunnar Nissen, Nico Melzer, Albrecht Günther, Frank Leypoldt, Ingo Schirotzek, Jan Lewerenz, Lam-Than Ly, and Kornelius Fuchs

Subjects
Adult, Male, medicine.medical_specialty, Critical Care, media_common.quotation_subject, medicine.medical_treatment, Hashimoto Disease, Article, law.invention, Sepsis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Interquartile range, law, Modified Rankin Scale, Internal medicine, Outcome Assessment, Health Care, medicine, Humans, Registries, 030212 general & internal medicine, Prospective cohort study, media_common, Autoimmune encephalitis, Mechanical ventilation, business.industry, Convalescence, Middle Aged, Prognosis, medicine.disease, Intensive care unit, Intensive Care Units, Neurology, Encephalitis, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

ObjectiveTo assess intensive care unit (ICU) complications, their management, and prognostic factors associated with outcomes in a cohort of patients with autoimmune encephalitis (AE).MethodsThis study was an observational multicenter registry of consecutively included patients diagnosed with AE requiring Neuro-ICU treatment between 2004 and 2016 from 18 tertiary hospitals. Logistic regression models explored the influence of complications, their management, and diagnostic findings on the dichotomized (0–3 vs 4–6) modified Rankin Scale score at hospital discharge.ResultsOf 120 patients with AE (median age 43 years [interquartile range 24–62]; 70 females), 101 developed disorders of consciousness, 54 autonomic disturbances, 42 status epilepticus, and 39 severe sepsis. Sixty-eight patients were mechanically ventilated, 85 patients had detectable neuronal autoantibodies, and 35 patients were seronegative. Worse neurologic outcome at hospital discharge was associated with necessity of mechanical ventilation (sex- and age-adjusted OR 6.28; 95% CI, 2.71–15.61) tracheostomy (adjusted OR 6.26; 95% CI, 2.68–15.73), tumor (adjusted OR 3.73; 95% CI, 1.35–11.57), sepsis (adjusted OR 4.54; 95% CI, 1.99–10.43), or autonomic dysfunction (adjusted OR 2.91; 95% CI, 1.24–7.3). No significant association was observed with autoantibody type, inflammatory changes in CSF, or pathologic MRI.ConclusionIn patients with AE, mechanical ventilation, sepsis, and autonomic dysregulation appear to indicate longer or incomplete convalescence. Classic ICU complications better serve as prognostic markers than the individual subtype of AE. Increased awareness and effective management of these AE-related complications are warranted, and further prospective studies are needed to confirm our findings and to develop specific strategies for outcome improvement.

Published
2018

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