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Elemental and Neurochemical Based Analysis of the Pathophysiological Mechanisms of Gilles De La Tourette Syndrome

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MEDIZINISCHE HOCHSCHULE HANNOVER Klinik für Psychiatrie, Sozialpsychiatrie und Psychotherapie Elemental and Neurochemical Based Analysis of the Pathophysiological Mechanisms of Gilles de la Tourette syndrome INAUGURALDISSERTATION zur Erlangung des Grades einer Doktorin oder eines Doktors der Naturwissenschaften Doctor rerum naturalium - Dr. rer. nat. vorgelegt von Ahmad Seif Kanaan B.Sc., M.Sc geb. am 17/05/1986, Amman, Jordanien Hannover, Deutschland (2017) Promotionsordnung der Medizinischen Hochschule Hannover für die Erlangung des Grades einer Doktorin/eines Doktors der Naturwissenschaften (Doctor rerum naturalium) Letzte Änderung in der 523. Sitzung Senatssitzung vom 15.07.2015 Wissenschaftliche Betreuung: Prof. Dr. med. Kirsten Müller-Vahl Wissenschaftliche Zweitbetreuung: Prof. Dr. rer. nat. Claudia Grothe 1. Erst-Gutachterin/Gutachter: Prof. Dr. med. Kirsten Müller-Vahl 2. Gutachterliche Stellungnahme durch: Prof. Dr. rer. nat. Claudia Grothe 3. Gutachterin/Gutachter: Prof Dr. Phil. Florian Beißner Tag der mündlichen Prüfung: 12.07.2017 Promotionsordnung der Medizinischen Hochschule Hannover für die Erlangung des Grades einer Doktorin/eines Doktors der Naturwissenschaften (Doctor rerum naturalium) Letzte Änderung in der 523. Sitzung Senatssitzung vom 15.07.2015 To Seif, Shireen, Farah & Mira . “How can a three-pound mass of jelly that you can hold in your palm imagine angels, contemplate the meaning of infinity, and even question its own place in the cosmos? Especially awe inspiring is the fact that any single brain, including yours, is made up of atoms that were forged in the hearts of countless, far-flung stars billions of years ago. These particles drifted for eons and light-years until gravity and change brought them together here, now. These atoms now form a conglomerate- your brain- that can not only ponder the very stars that gave it birth but can also think about its own ability to think and wonder about its own ability to wonder. With the arrival of humans, it has been said, the universe has suddenly become conscious of itself. This, truly, it the greatest mystery of all.” V.S. Ramachandran Acknowledgements I warmly thank that patients and their families for their selfless contribution of time and effort to further the understanding of their affliction — a disease that makes them lead difficult, stigmatized and action packed lives. I particularly admired the determination of many of the patients who had to travel vast distances across Germany to undergo multiple investigations. My most enduring acknowledgment goes to my supervisors Kirsten Müller-Vahl and Harald E. Möller who were the true pillars of this work. I sincerely thank them both for their excellent mentorship and guidance, and for giving me the opportunity to tackle absorbing ideas while traveling between Leipzig and Hannover. My deep gratitude also goes to Alfred Anwander for teaching me how to think like an image scientist and for always keeping the door open for discussion. I sincerely thank Sarah Gerasch for her significant contribution in recruiting the patients and acquiring the clinical data. I am also grateful to Daniel Margulies for giving me the opportunity to discover image analysis in his laboratory in the initial stages of my PhD. My deep admiration and gratitude go to Isabel Garcia-Garcia who provided ample ideas and reviewed multiple drafts of initial works. Thank you for crossing my path, for teaching me how to conduct statistical analyses with a smile and for being there when it counted. For their tremendous support in image and clinical data acquisition, I sincerely thank Saskia Czerwonatis, Claudia Pelke, Leonie Lampe, Tomas Goucha, Sieglinde Remane, Nicole Pampus, Christiane, Driedger-Garbe and Cornelia Gerbothe. I especially thank Andre Pampel and Torsten Schlumm for their support in developing the imaging se- quences. To Jamie Near, Berkin Bilgic and Andreas Schäfer, thank you for your openness to collaborate and for providing technical support in finding solutions to challenging imaging problems. I would also like to thank my colleagues in the NMR group: Ricardo Metere, Tobias Lenich, Miguel Martinez Maestro, Henrick Marschner, Maria Guidi, Jakob Georgi and all other members for sharing this experience with me. To the TS-EUROTRAIN community: Nacho Gonzalez, Francesca Rizzo, Ester Nespoli, Muhammad Sulaman Nawaz, Sam Padmanabhuni, John Alexander, Nuno Nogueira, Natalie Forde, Luca Pagliaroli, Sarah Fan, Joanna Widomska, Rayan Houssari, Peristera Paschou, Andrea Ludolph, Danielle Cathe, Pieter Hoekstra, Zeynep Tümer, Csaba Barta, Jeffrey Glennon, Bastian Hengerer, Hrienn Steffanson, Jeremiah Scharf, I thank you all for making this journey so cheerful and all the more worthwhile. I also warmly thank Professor Mary Robertson for our illuminating discussions and for inspiring me to keep going forward. To Jim Leckman, I thank you for appreciating my work and bestowing me with the honor of the 2016 Professor Mary Robertson Award. To my family Seif, Shireen, Mira, Farah and Hussam, I deeply thank you for your love, understanding and everlasting encouragement. Abstract Elemental and neurochemical based analysis of the pathophysiological mechanisms of Gilles de le Tourette syndrome. Ahmad Seif Kanaan Gilles de la Tourette syndrome is a developmental neuropsychiatric movement disorder characterized by the presence of tics and associated comorbid conditions. As current treatment strategies are often unsatisfactory and associated with significant adverse ef- fects, there is an urgent need in further elucidating the nature of GTS pathophysiology to accelerate the drug discovery and development process. Neurochemically, previous work has indicated that the clinical manifestations of GTS are primarily driven by putative ab- normalities in dopamine and γ-Aminobutyric-acid (GABA). Given the spatio-temporal and metabolic interdependence exhibit by the neurotransmitter glutamate with dopamine and GABA, respectively, we hypothesized the glutamatergic signalling is related to the pathophysiology of GTS. On a finer scale, considering the critical role exhibited by the el- ement iron in varied biochemical processes sustaining typical neurochemical synthesis and trafficking throughout the lifespan, we additionally postulated that GTS patients exhibit abnormalities in iron metabolism. Utilizing a multi-parametric, quantitative Magnetic Resonance Imaging approach in vivo, we investigated the role of glutamate and iron using 1H-Magnetic Resonance Spectroscopy and Quantitative Susceptibility Mapping, respectively, for the first time. To achieve these aims, two methodological investigations were initially conducted to obtain quantitative neurochemical and magnetic susceptibil- ity measurements of sufficient precision to identify rather subtle changes. Imaging, spec- troscopic and clinical data were acquired from a relatively large and well-characterized sample of adult patients with GTS and age/gender matched healthy controls. To in- terrogate the influence of treatment on neurochemical and clinical characteristics of the study sample, we employed a longitudinal study design in which the patients were in- vited to undergo treatment with the commonly used antipsychotic aripiprazole. At the neurochemical level, we report significant reductions in the concentrations of spec- troscopic glutamatergic signalling markers in the striatum and the thalamus in GTS. These reductions correlated with tic severity and were normalized with aripiprazole treat- ment. At the elemental level, we report significant reductions in subcortical magnetic susceptibility which is regarded as surrogate index for iron content. Reductions were specific to subcortical nuclei key in coordinating mechanisms of motor and non-motor habit formation, and were mirrored by decreases in serum ferritin levels. Importantly, significant associations were observed between striatal susceptibility and glutamatergic neurotransmission as indexed by the glutamine:glutamate ratio. Clinically, treatment with aripiprazole led to significant reductions of tic severity in the patient sample, and additionally led to an approximate 50% reduction in OCD diagnosis. Our results indi- cate that patients with GTS exhibit an abnormality in the flux of metabolites in the GABA-glutamate-glutamine cycle, thus implying perturbations in astrocytic-neuronal coupling systems that maintain the subtle balance between excitatory and inhibitory neurotransmission within subcortical nuclei. These abnormalities may be driven or fur- ther compounded by the observed abnormalities in iron metabolism. Chronic pertur- bations in the subcortical GABA-glutamate-glutamine cycle flux could lead to spatially focalized alterations in excitatory, inhibitory and modulatory subcortical neurochemical ratios that would have a profound influence on the neuroplastic mechanisms involved ii in reinforcement learning and habit formation systems, which are governed by striatal neurons that code the serial order of syntactic natural behaviour. This work sheds a new light on the neurobiological basis of GTS and provides novel clues that may prove critical in the future development of functionally selective pharmacological modulators that target multiple neurochemical systems. Zusammenfassung Elemental and neurochemical based analysis of the pathophysiological mechanisms of Gilles de le Tourette syndrome. Ahmad Seif Kanaan Das Gilles de la Tourette-Syndrom (GTS) ist eine neuropsychiatrische Entwicklungsstör- ung, die durch das Bestehen von Tics und psychiatrischen Komorbiditäten
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