news ts-eurotrain.eu inside... 1 st World Congress & TS-EUROTRAIN Training Workshop

Transcription

1 news 1 st World Congress & TS-EUROTRAIN Training Workshop ts-eurotrain.eu The TS-EUROTRAIN consortium training workshop "Neurotransmitters in Tourette Syndrome: From neurobiology to neuroimaging" is going to take place in Tower Hotel, London, UK on June 24, The TS-EUROTRAIN consortium invites you learn more about the neurobiology of Tourette Syndrome during a one day workshop held by leading experts in the field. The event takes place in conjunction with the 1st world Congress on TS and tic disorders. Registration is free and you can register at the World Congress website. Life as a PhD student 1 st World Congress on Tourette Syndrome inside... ts-eurotrain@googlegroups.com page 3 The European Society for the Study of Tourette Syndrome (ESSTS), Tourette Syndrome Association (TSA), Tourettes Action-UK (TA), along with other partners, join forces for the first time to organize the 1 st World Congress on Tourette Syndrome and Tic Disorders, which will be held June 24-26, 2015, at the Tower Hotel in London. The Congress programme features internationally renowned experts and speakers who will present the latest information on all aspects of TS, tic disorders and related conditions. Satellite events include a Global Summit for TS Support and Advocacy Groups, an international meeting for the Deep Brain Stimulation Registry and a TS-EUROTRAIN workshop on the Neurobiology of TS. More information available at page 7

2 ummer 2014 TS-EUROTRAIN Workshops and Conference held in 2014 ESSTS The 2014 Annual Meeting of the European Society for the Study of Tourette Syndrome and COST International Conference for Tourette Syndrome was a successful event took place in Paris on April 25-26, 2014, at the historic La Pitié salpêtrière Hospital in Paris, home to Jean-Martin Charcot and pedagogue to one of his most famous students, Georges Gilles de la Tourette himself. The meeting featured presentations from world renowned experts on Tourette Syndrome, who presented current advances in basic research as well as clinical practice. Please visit our website for more information: Twin and association studies of complex traits with a focus on obsessive compulsive disorder. D. Boomsma, VU University Amsterdam, Netherlands. Recurrent copy number variant phenotypes in a population sample - focus on Tourette. H. Stefansson, Decode Genetics, Iceland Role of environmental factors in the etiology of Tourette syndrome and related neurodevelopmental disorders. P.Hoekstra, Groningen University, Netherlands Epigenetic studies related to the etiology of Tourette syndrome and comorbid disorders. C. Barta, Semmelweis University, Hungary Pharmacological interventions in TS and the importance of the glutamatergic and GABAergic system for new treatment strategies. A. Ludolph, Ulm University, Germany The phenotype of tics, Gilles de la Tourette Syndrome, and obsessive compulsive disorder (including video practicing). D. Cath, Utrecht University, Netherlands; K. Mueller-Vahl, University of Hannover, Germany Complementary Skills workshop Hannover DeCODE Workshop The workshop conducted by one of our partners is about training ESRs in using statistical tools especially in R programming. The workshop took place on May at DeCODE genetics, Reykjavik, Iceland, one of the collaborators of TS-EUROTRAIN Initial Training Network (ITN). ESRs were trained to use statistical tool R for statistical analysis which will be carried out in their projects. The workshop also provided basic knowledge on statistics in different fields of research such as Phasing, Imputing and Association tests. ESRs were taken on tour in the institute to get a feel of Next Generation Sequencing machines. As a part of the TS-EUROTRAIN ESRs were given workshop on complementary skills like leadership, presentation, time-management and communication, at Medical School Hannover on October 20-24, The workshop was successful in making all the ESRs opening up and made the bonds stronger than before. Different activities of workshop helped each ESR realize their potential in complementary skills. At the end of the workshop, ESRs felt confidence facing the future either leader or as a good team player. International Workshop on Neurodevelopmental Disorders This workshop highlighted on talks from different areas of research from genetics to animal models on Tourette Syndrome by the experts. The talks in this workshop very rich in information. The workshop took place on July 12, 2015 at Hotel Grecotel-Egnatia Alexandroupoli, Greece. As this was an open for public many science enthusiasts along with many medical doctors participation made the workshop more interesting and exciting. The talks covered current research on Genetics, Neuroimaging, and Animal models of Tourette Syndrome. The workshop was a successful event where public along with ESRs had an influx of rich information on Tourette Syndrome. The talks are as follows: The genetic basis of Gilles de la Tourette Syndrome. P. Paschou, Democritus, University of Thrace, Greece. Page 2

3 One Year in a PhD Nataiie Forde Tell us about yourself. I m more than a year in. I think all of us (ESRs) in the network are over one year into this amazing adventure by now. We left the comfort of our respective homelands and moved into a whole new world of Tourette research. For me personally this meant leaving an economically crumbling country along with what seems like the rest of my peers to embark into the unknown and literally move somewhere they speak Dutch to me! So I think now s a good time to reflect on this journey to date and man it s been busy! Moving is always stressful and I guess it didn t help that I went bounding around Europe for a month right up to my moving day (and lets not talk about the party.). But I made it surrounded by IKEA furniture and unintelligible paper work - and so began life in Groningen. And that life, well it s pretty awesome. A recent map of the stereotypes of Dutch regions claimed the Groningen province is full of stoic farmers and the city too far away for any practical purposes, and I can t argue. Groningen is a small charming city isolated in the north of the Netherlands and full of students (and stoic farmers). It s isolation (and come on 2 hours and 10 minutes direct on a train to one of the biggest international airports in the world isn t exactly that isolated) means that Groningen has become the centre of the north, so while being small it kind of has everything just not so many of everything. It s lively and entertaining. The people are very Dutch; friendly but reserved and serious. And often so direct it s definitely rude (Irish perspective). Maybe my attitude to life is a little different to the average dutchie but we get on well, I even appreciate the directness - usually. So a year in I have my little adopted family of friends. In a word settled. But Dutch.dat is een ander verhaal. But now to work. Unfortunately, more than occasionally research can be amazingly frustrating. Dealing with administration seems to be a necessary evil that often requires waiting for the go ahead from this board or that. And during my first year I certainly had my share of it and I don t think that s too unusual. It s a story I hear repeatedly from PhD students globally. And it s just something we have to deal with, it s in the nature of research to some extent. It s quite amazing how you can feel like you ve achieved nothing in a year of work in research. But in reality the organising, setting up and getting approval for a study are huge undertakings. In my case add in the recruiting processes and you nearly hit the year mark. But all this I, with a little help from my friends, achieved within the first year and shortly after began scanning our participants with Tourette Syndrome. As for the forwarding of our understanding of TS, I m on it, you ll have to give me some more time though. Data collection is now underway for what will be a unique study comparing the brains (and genetics) of children with TS and those with ADHD (or both). And it s exciting! I get to scan and meet participants on a weekly basis, this is what I signed up for all those months ago! So that s work. That s why I m here and I do love it despite the frequent derailing of progress in the early days. My colleagues are amazing and it feels like we have our own little community for work, fun, and help and support when needed. But let s talk about this Network and all the travelling. Wow. Where to begin? Ulm. The ESR s first meeting. I still wonder how we almost instantly blended into this one comprehensive unit. But we did and the new additions and subsequent trips only compounded this feeling. Apart from the great friendships and epic moments (not sure I ll ever forget digging out the TS-Eurobus) we have all learned and grown over the last year or so. This is of course as well as the huge progress all of us are making with our projects. Time has flown by, generally too busy to notice the months tic by I m assured they are passing by the recent morning sunshine on the way to work and imminent end of the ice hockey season. There is still so much work to be done but finally it feels like progress is being made. Also we have many more meetings and travels to look forward to. And in my case way too many trains to catch but so far it s been a great ride not noticing time pass must be a good sign, right? Page 3

4 TS-EUROTRAIN Marie Curie ITN Newsletter ISSUE 3 Winter 2015 Recent Developments in TS research For over a century, basic and clinical research on Gilles de la Tourette syndrome (TS) remained stagnant. In the 1980's, a new era in TS research was ushered following the discovery of the effects of doapminergic drugs on the suppression of tics. Although the field has exhibited marked advancements over the last three decades, the etiology of TS remain elusive. Today, various groups around the world are attempting to uncover the neurobiological basis of TS using methods from molecular biology, biochemistry, immunology, pharmacology, psychology, statistics, computer science and neuroimaging. In this section, we aim to review recently published articles on TS in such a way that this knowledge is accessible to both scientists working in the field and the general public. GABA and Motor Excitability in Tourette Syndrome Francesca Rizo Based on: Increased GABA Contributes to Enhanced Control over Motor Excitability in TouretteSyndrome Authors: Draper et al. Journal: Current Biology (2014) What makes the basic mechanisms of Tourette syndrome (TS) hard to underpin are the developmental aspect of the disease. As known, TS often follows a developmental time course: onset of tics typically between ages 4-6with peak severity occuring between ages with a decline in severity during adolescence. What happens in the brain during adolescence is still not clear, but it seems that a process able to make tics increasingly more controlled takes place and adolescents show an enhanced control over their volitional movements. This is probably what led the majority of TS patients to experience diminished symptoms during adulthood, even if a small percentage of individuals will still suffer from a persistently severe or worsening tics. But what happens in the brain during development? TS is associated with alterations in the development of brain networks that result in neural circuits with imbalanced excitatory and inhibitory influences. What does it mean? Let s step back for a while and say that particular areas of the brain such as cortex, striatum, globus pallidus, substantia nigra and thalamus taken together form the cortico-striatal-thalamic-cortical (CSTC) circuit where different pathways originate. They are named after the presumed function of the region of the cortex where they start from, so they are called motor, oculomotor, executive/associative and emotion/motivation pathways. Talking about tics, deficiency in the motor circuit is involved. During tics particular subsets of striatal neurons are thought to become active within inappropriate contexts, resulting in the disinhibition of thalamocortical circuits and the hyperexcitability of motor regions of the brain that lead to the occurrence of tics. Due to the characteristic developmental time course of TS it has been proposed that during development individuals gain control over their tics through compensatory mechanisms based on an increased inhibition and ability to control motor outputs. The main role in neuronal inhibition is played by g-aminobutyrric acid (GABA) and its alterations have been linked with TS. Postmortem examinations indeed show a decreased number of GABA interneurons and GABA receptors in the striatum of patients with TS leading to the suggestion that the primary cause of tic generation is reduced GABAergic inhibition. In this paper, Draper et al. propose a novel hypothesis on how this increased control over tics can arise. They assume that a localized increased inhibition within neurons is due to extracellular GABA concentration that operates to decrease excitability in the sensorimotor area (SMA). To test this hypothesis they investigate GABA concentration within primary and secondary motor areas of 15 adolescents with a confirmed clinical diagnosis of TS and a control group matched by age and gender. They used 1H magnetic resonance spectroscopy (MRS) at ultra-high field (7 T), a technique that allows for non-invasive determination of tissue concentration and metabolic turn-over rates of various metabolites and compounds. It is a method commonly used for clinical diagnostics and also provides an important tool for physiological research. The target areas in the brain where easily localized thanks to the performance of a simple task by the participants: they were asked to continuously tap, with both hands, each finger sequentially against the thumb until instructed to stop. In this study they demonstrate that in adolescents with TS, concentrations of GABA are surprisingly significantly elevated within the SMA, but not in the other two regions. Also, they observed that GABA levels within the SMA do not correlate with the fmri BOLD response (a signal able to maps the neuronal activity in the brain measuring the change in blood flow in relation to the energy used by neurons) and cortical excitability (measured after transcranial magnetic stimulation, a non-invasive method used clinically to measure activity and function of specific brain circuits) in the same area. Most importantly, they report for the first time that GABA levels within the SMA are strongly correlated with both motor tic severity and a number of projections (linking SMA) within the striatum. These findings may help our understanding of how delimited changes in brain function occurring during development play a key role in the control of behavioral symptoms in neurodevelopmental disorders. References 1. American Psychiatric Association. (2013). American Psychiatric Association Board of Trustees Approves DSM-5. DSMfacts.org. Retrieved from 2. Eric Kandel, James Schwartz, Thomas Jessell, Steven Siegelbaum, A.J. Hudspeth, Principles of neuronal science - Fifth edition (2012) McGraw-Hill publication. Page 84

5 Genetic Association Signal Near NTN4 in Tourette Syndromez John Alexander Based on: Genetic Association Signal Near NTN4 in Tourette Syndrome. Authors: Paschou et al Journal: Annals of Neurology, 2014 The Gilles de la Tourette Syndrome (TS) Genome-Wide Association Study Replication Initiative (GGRI) is a collaboration of European and North American TS investigators through which TS cases and controls were recruited from Hungary, Germany, Austria, Italy, Greece and Canada in order to follow up on the results of the first Genomewide Association Study (GWAS) for TS (Scharf et. al., 2013) Investigating a panel of carefully selected 42 Single Nucleotide Polymorphisms (SNPs) among the top hits of the first TS (GWAS) [1], the authors aimed to test the significance of these SNPS in an independent cohort of 609 independent cases and 610 ancestry-matched controls. The studied SNPs included either top hits or SNPs known to be located near either eqtl/mqtls [JF1] (expression/methylation quantitative trait loci) or candidate genes for TS/other related neuropsychiatric disorders. The results yielded only one significant SNP (rs located on chromosome 12q22) associated with TS in the GGRI sample. The analysis was supplemented by conducting a meta-analysis (a method used to combine results, like p-values from different studies) combining data from the GGRI and the original TS study (1,285 TS cases and 4964 controls) resulting in the SNP having the strongest association to TS todate (p=5.8 x 10-7). This SNP lies distal to the NTN4 gene, which belongs to a family of extracellular proteins that direct axon outgrowth and guidance (netrins) in the developing nervous system. These netrins interact with other axon guidance molecules like WNT and SLIT family members, which also share similarity to the protein from the SLITRK1 gene, one of the most debated genes in the TS literature as it has been reported to be associated with TS in a number of studies but not through large family based investigation [2]. All these provide strong evidence that NTN4 is a strong candidate for a TS susceptibility gene. Although no other SNP was nominally found to be significant in the GGRI sample, 26 out of the 42 SNPs yielded the same direction of effect as the original GWAS through meta-analysis. Importantly, the aggregated risk score for all 42 SNPs was found to discriminate cases from controls. In conclusion, the results from this study strengthen the evidence for association relative to the original GWAS study and suggest that many of these variants are in fact true TS risk alleles. The authors emphasize the need for future collaborative efforts in larger TS samples so as to clarify the potential significance of all variants in the current analysis and for further identification of definitive TS susceptibility genes. References 1. American Psychiatric Association. (2013). American Psychiatric Association Board of Trustees Approves DSM-5. DSMfacts.org. Retrieved from 2. Eric Kandel, James Schwartz, Thomas Jessell, Steven Siegelbaum, A.J. Hudspeth, Principles of neuronal science - Fifth edition (2012) McGraw-Hill publication 3. Scharf, Jeremiah M., et al. "Genome-wide association study of Tourette's syndrome." Molecular psychiatry 18.6 (2013): Scharf JM, Moorjani P, Fagerness J, et al. Lack of association between SLITRK1var321 and Tourette syndrome in a large family- based sample. Neurology 2008;70: Genetic evidence suggesting a dysfunctional striatum in GTS Natalie Forde Based on: Transcriptome Analysis of the Human Striatum in Tourette Syndrome. Authors: J. B. Lennington et al., Journal: Biological Psychiatry, 2014 It s not just our DNA that determines who we are. This is also governed by our environment and a complex interplay between the two. Our genetic code is like an ingredients list but other factors, epigenetic, tells our code how much of each ingredient we need to get the perfect mix. In a recent study by Jessica Lennington and colleagues the transcriptome they analyse can be thought of as the measured out ingredients, or the gene expression. In this study they measure the gene expression in the striatum. The striatum is a subcortical brain structure that is involved in many functions including the planning and modulation of movements and executive function, like memory. Structural or functional abnormalities of the striatum have previously been implicated in Tourette syndrome as well as other conditions like Parkinson s Disease, Attention Deficit/Hyperactivity Disorder and Obsessive Compulsive Disorder. In this study segments from 9 brains of people who had TS and 9 matched controls were obtained for analysis. The striatum was dissected and sectioned, following this RNA was extracted and network techniques used to identify gene co-expression modules. Group comparison revealed 1131 genes differentially expressed between TS and controls. Of these 309 genes were downregulated (less expressed) and 822 were upregulated (more expressed). Many of these downregulated genes were associated with interneurons (cholinergic and GABAergic) within the striatum. Interneurons are short range connections important for the modulation of signals through the striatum. Many of the upregulated genes were related to inflammatory processes linked to activated brain microglia. Regional differences were seen within the striatum (caudate vs putamen) suggesting differential regional contribution to these changes while most findings were common across regions. Very little overlap with previous analyses that utilized blood suggests that the gene expression in the periphery is not consistent with that in the brain highlighting the importance of studies on the brain when possible. So what does it all mean? Well it has provided more evidence that the striatum is dysfunctional in TS and pointed at what systems underlie this dysfunction (neuronal signaling, immune and inflammatory processes). As the authors conclude more work will be needed to clarify the cause-effect mechanism underlying these phenomena and their role during development, but this paper has provided the first comprehensive characterization of gene expression in a the striatum of patients with TS. Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette s Syndrome and OCD Nuno Noguiera Page Page 9 5

6 Based on: Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette s Syndrome and OCD Authors: Dongmei Yu et al. Journal: American Journal of Psychiatry, 2014 A recent study from the Psychiatric & Neurodevelopmental Genetics Unit (PNGU) at the Massachusetts General Hospital, assessed the genetic relationship between Tourette Syndrome (TS) and Obsessive Compulsive Disorder (OCD) [1]. In this report, published in the American Journal of Psychiatry, Dongmei and colleagues provided some important clues into the joint genetic architecture of these two diseases. The recent emergence and development of the genetics of complex traits has definitely provided a major advance in the understanding and study of psychiatric disorders. This has been possible, mainly, by studying whole-genome genotype data revealing the nature of genetic factors contributing to these disorders. With it, new concepts and paradigms have also emerged. First, psychiatric disorders have been classified as complex trait disorders, due to the fact that their etiology results from a complex interplay between genetic and non-genetic factors; also, we use the term genetic architecture to characterize those genetic factors. These result, not from a single gene mutation with a clear inheritance pattern, but from a multiple variation across multiple genes, all with small effect, that collectively account for the variability observed in these traits. Second, the new genetic datasets available have enabled new research questions to be posed, for example, to what extent do common genetic factors underlie different and/or comorbid traits? This has been the case for OCD and TS. Both are neuropsychiatric disorders, highly familial, and with a known common genetic etiology estimated up to 90%. [2, 3]. This was then the rationale behind the current report. There is a scarcity of studies jointly analyzing the shared genetic background for these two disorders. This was a large international collaborative effort, the authors conducted a series of genetic association analyses in a total of 8680 individuals, including 1310 participants with OCD, 834 with TS, and 579 diagnosed with both. Some top signals were found within genes expressed in regions of the brain, although no statistical significant associations were found. More interesting, were the results regarding the polygenic analysis. The authors found that the polygenic component was significant for OCD but low and non-significant for TS. Surprisingly, however, the results showed a non-significant polygenic component across the two disorders. In other words, when considering the results together, this suggests that OCD and TS have distinct genetic backgrounds. Moreover, OCD analyzed by subgroups (with/without TS or tics) revealed different genetic architectures for both. This is a strong indicator that OCD segregates as different subtypes, associated or not with TS, with different genetic susceptibility and different genetic risk. In summary, we may be looking at two disorders more genetically different than previously thought. On the other hand, OCD seems to have different genetic background depending on weather it co-occurs with tics or not. Without a doubt, we witness yet again how genetics and medicine can in this era revolutionize the clinical diagnosis of important psychiatric disorders, and fill an important gap between psychiatry and biology. Page Page 106

7 Marie Curie TS-EUROTRAIN ITN Newsletter ISSUE 3 Summer ST WORLD CONGRESS ON TOURETTE SYNDROME & TIC DISORDERS New Frontiers in Research, Treatment and Global Collaboration JUNE 24 26, 2015 L O N D O N, U K The 1st World Congress on Tourette Syndrome and Tic Disorders is designed for clinicians, researchers, post-doctoral fellows, medical residents and allied healthcare professionals with an interest in current research, diagnosis and treatment of these and related conditions. SCIENTIFIC PROGRAM STEERING COMMITTEE Co-Chairs Members Carol Mathews, M.D. (USA) Peristera Paschou, Ph.D., DABMG (Greece) Jeremy Stern, M.D. (UK) Alan Apter, M.D. (Israel) Kevin Black, M.D. (USA) Nicole Calakos, M.D., Ph.D. (USA) Heather Cowley, Ph.D. (USA) Stanley Fahn, M.D. (USA) Tamara Hershey, Ph.D. (USA) Pieter Hoekstra, M.D., Ph.D. (The Netherlands) Joseph Jankovic, M.D. (USA) Davide Martino, M.D., Ph.D. (UK) Kevin McNaught, Ph.D. (USA) Jonathan Mink, M.D., Ph.D. (USA) Kirsten Müller-Vahl, M.D. (Germany) Tanya Murphy, M.D. (USA) Michael Okun, M.D. (USA) Renata Rizzo, M.D., Ph.D. (Italy) Paul Sandor, M.D. (Canada) Jeremiah Scharf, M.D., Ph.D. (USA) Zsanett Tarnok, Ph.D. (Hungary) Douglas Woods, Ph.D. (USA) For additional information and online registration, please visit touretteworldcongress.org us at touretteworldcongress@tsa-usa.org or call TOURET Share the event with your colleagues on Twitter: #touretteworldcongress Page 117

8 Training Workshop Neurotransmitters in Tourette Syndrome: From neurobiology to neuroimaging The Tower Hotel, London, UK Wednesday, June 24, am The TS-EUROTRAIN consortium invites you learn more about the neurobiology of Tourette Syndrome during a one day workshop held by leading experts in the field. The event takes place in conjunction with the 1st world Congress on TS and tic disorders. Registration is free at Please be advised that seating is limited. Registration Deadline: March TS-EUROTRAIN is a Marie Curie Initial Training Network focused on the study of Gilles de la Tourette Syndrome (TS) and related neurodevelopmental disorders. The network aims to disentangle the relative contribution of environment and genetics in TS etiology, elucidate the neurobiological underpinnings of TS and related disorders, investigate the mechanism of effect of existing drugs for TS, while also seeking to identify novel drug targets. More information available at Page 8

9 Marie Curie TS-EUROTRAIN ITN Newsletter ISSUE 3 Summer 2015 The TS-EUROTRAIN TEAM! Muhammad Sulaman Nawaz, Iceland Shanmukha Sampath, Greece Ester Nespoli, Germany Luca, Pagliaroli, Hungary John Alexander, Greece Natalie Forde, Netherlands Joanna Widomska, Netherlands Ahmad Seif Kanaan, Germany Nacho Rodríguez, Denmark Nuno Nogueira, Netherlands Sarah Fan, Netherlands Francesca Rizzo, Germany Page 129

10 Marie Curie TS-EUROTRAIN ITN Newsletter ISSUE 3 Summer 2015 Participating institutions Page 13