SNC’23 SNC’ SiNAPSA NEUROSCIENCE CONFERENCE ‘23 28-30 September 2023 LJUBLJANA, SLOVENIA Image by ikatod on Freepik SiNAPSA Neuroscience Conference ‘23 Ljubljana, 28–30 September 2023 Organised by SiNAPSA, Slovenian Neuroscience Association in partnership with Faculty of Medicine, University of Ljubljana Regional ALS Meeting is co-organized by Slovenian Society of Clinical Neurophysiology SNC’23 Programme Committee Boris Rogelj (Chair), Pavle Andjus, Lana Blinc, Jure Bon, Mara Bresjanac, Emanuele Buratti, Blaž Koritnik, Ivana Munitić, Matej Perovnik, Grega Repovš, Veronika Stoka, Robert Zorec SNC’23 Organising Committee Blaž Koritnik (Chair), Lana Blinc, Maša Čater, Urša Čerček, Matjaž Deželak, Katarina Kouter, Karmen Krejan, Ana Kuder, Andraž Matkovič, Helena Motaln, Jerneja Nimac, Nina Omejc, Matej Perovnik, Iris Šalamon, Veronika Stoka Conference was supported by International Brain Research Organization (IBRO) SiNAPSA is a proud recipient of the IBRO PERC Conference Sponsorships Program Award 2023 which aims to support the organization of events in partnership between IBRO and its regional societies. SiNAPSA is also honored to receive IBRO PERC Meetings Support Grant 2023 for the Educational Workshop on Pain which is accompanying the SNC’23 core programme. International Centre for Genetic Engineering and Biotechnology (ICGEB) SiNAPSA is a proud recipient of the ICGEB Meetings and Courses Programme Sponsorship which supports the participation of young scientists from ICGEB Member States. Roche, Genesis Pharma, Medison, Novartis, Biogen, Pfizer, Krka, Lek Sandoz, Medis, Medistar, Octapharma, Sobi, Avantor VWR Editors Maša Čater, Blaž Koritnik Design Maša Čater Publisher SiNAPSA, Slovenian Neuroscience Association www.sinapsa.org Ljubljana, 2023 1st online edition Publication is available free of charge. www.sinapsa.org/SNC23/media/files/SNC23_Book_of_Abstracts.pdf CIP – Kataložni zapis o publikaciji Narodna in univerzitetna knjižnica, Ljubljana Kataložni zapis o publikaciji (CIP) pripravili v Narodni in univerzitetni knjižnici v Ljubljani COBISS.SI-ID 165546755 ISBN 978-961-95519-1-2 (PDF) SNC’23 SNC’ SiNAPSA NEUROSCIENCE CONFERENCE ‘23 BOOK OF AB O S OK OF AB TR S A TR C A T C S T www.sinapsa.org/SNC23 Ljubljana, Slovenia 28-30 September 2023 Contents Schedule at a Glance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Scientific Programme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 SiNAPSA Neuroscience Conference ‘23 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 Educational Workshop on Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Ljubljana Clinical Neurophysiology Symposium 2023. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Abstracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Plenary and Special Lectures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Thematic Symposia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Posters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Educational Workshop on Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Sponsors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 [4] Schedule at a Glance SiNAPSA Neuroscience Conference ‘23 Schedule at a Glance Thursday, September 28 Friday, September 29 Saturday, September 30 8:30–10:00, Hal 3 9:00–10:45, Hall 2 Educational Workshop Short Oral Presentations 9:00–11:00, Hal 2 ALS on Pain I 11:10–12:00, Hal 1 Symposium III 10:00–10:30 Faganel Memorial Lecture: Martin Turner Coffee by the Posters 11:15–12:00, Hal 1 10:30–12:00, Hall 3 12:45–13:00, Hal 1 12:00–13:00 12:00–13:00, Hal 2 Plenary Lecture: Jasna Križ Educational Workshop SNC’23 Opening Lunch Satel ite Symposium on Pain II 12:00–13:00 12:00–13:00, Hal 2 13:00–13:45, Hall 1 13:00–14:00 13:00–14:00, Hal 2 Lunch Satel ite Symposium Plenary Lecture: Daniela Perani Poster Session Satel ite Symposium 13:00–14:00 13:00–14:00, Hall 2 13:45–15:45, Hall 1 13:45–15:45, Hal 2 Poster Session Satel ite Symposium 14:00–16:00, Hall 1 14:00–16:00, Hall 2 Brain Connectivity in Neuroimmunology Neuroendocrine Plasticity ALS Neurodegeneration Symposium Symposium Symposium I Symposium 14:00–16:00, Hall 1 14:00–16:00, Hal 2 14:00–16:00, Hal 3 TMS and Depression ALS Educational Symposium Symposium IV Workshop on Pain III 15:45–16:15 Coffee by the Posters 16:00–16:30 Coffee by the Posters 16:00–16:30 Coffee by the Posters 16:15–18:15, Hall 1 16:15–18:15, Hal 2 16:30–18:30, Hal 1 16:30–18:30, Hal 2 Mobile Brain and Neurodegeneration and Brain Health ALS Body Imaging Protein Aggregation Symposium Symposium II 16:30–18:30, Hal 1 16:30–18:30, Hal 3 Symposium Symposium Biology of Schizoaffective Educational Workshop Continuum Symposium Lightning Q&A Round 18:15–19:00, Hall 2 18:30–19:15, Hal 1 ICGEB Sponsored Symposium AOŽ Memorial Lecture: Apkar V. Apkarian 18:30–19:15, Hal 1 Plenary Lecture: Alexej Verkhratsky 19:00–20:30, Hal 1 20:30, Ljubljana Castle 19:15–19:30, Hal 1 Neuroscience & Society Dialogue Social Event Best Poster Award & SNC’23 Closing SNC’23 SNC’ SiNAPSA NEUROSCIENCE CONFERENCE ‘23 SiNAP SiNA S P A N S euro eur s o cienc s e C cienc onf e C e onf r e enc r e ‘ enc 23 Programme www.sinapsa.org/SNC23 Ljubljana, Slovenia 28-30 September 2023 SiNAPSA Neuroscience Conference ’23 Programme Thursday, 28 September 2023 12:45—13:00 SNC’23 Opening | Hall 1 13:00—13:45 Plenary Talk | Hall 1 Molecular neuroimaging, brain connectivity, neurodegenerative conditions: a challenging interplay Daniela Perani 13:45—15:45 Symposium | Hall 1 Tracking brain connections in neurodegenerative brain disorders Chairs: Matej Perovnik, Maja Trošt The concept of molecular connectivity Igor Yakushev Methods in molecular connectivity: getting at the single-subject level Arianna Sala Dynamic reconfiguration of metabolic brain connectivity during progression from MCI to Alzheimer’s disease dementia Silvia Caminiti Metabolic brain networks in neurodegenerative parkinsonisms Tomaž Rus Metabolic brain networks in neurodegenerative dementias Matej Perovnik 13:45—15:45 Symposium | Hall 2 Neuroimmune disorders Chair: Ivana Munitić Suppressing NLRP3 inflammasome Iva Hafner-Bratkovič Fluid biomarkers of neurodegeneration in neuroinflammatory diseases Uroš Rot Immune imbalance during ageing Ivana Munitić, Nikolina Mohović Stress-induced lipid droplet accumulation in astrocytes Anemari Horvat Genetic polymorphisms in oxidative stress and inflammatory pathways as potential biomarkers in Alzheimer’s disease and dementia David Vogrinc Microbiome in Parkinson’s disease Eliša Papić [7] 16:15—18:15 Symposium | Hall 1 Mobile Brain/Body Imaging (MoBI) – understanding brain oscillations and movement in natural and extreme environments Chairs: Uroš Marušič, Klaus Gramann Linking human behavior with brain responses using Mobile Brain/Body Imaging Klaus Gramann Neurophysiological bases of embodiment during physical manoeuvring of a virtual robot in VR Federica Nenna Detecting early signs of Parkinson’s disease using Mobile Brain/Body Imaging Manca Peskar Brain mapping during increased gravity gradients Uroš Marušič 16:15—18:15 Symposium | Hall 2 Neurodegeneration and protein aggregation; are aggregates protective or harmful; what comes first protein aggregation or oxidative stress? Chair: Eva Žerovnik Introduction to the topic of protein aggregation Eva Žerovnik Additional features of the mechanism of amyloid formation by human stefin B as revealed by infrared spectroscopy Eva Žerovnik Structural aspects of oligomerization processes of the Abeta peptides under interaction with nanoparticles utilized by NMR spectroscopy Igor Zhukov Modulation of the stability of cystatin C by intra- and extramolecular factors Aneta Szymańska FUS phosphorylation in FTLD Helena Motaln Alzheimer’s disease and canine cognitive dysfunction – two faces of the same disease? Gregor Majdič 18:15—19:00 ICGEB Lecture | Hall 2 NOS1AP and RGNEF as novel RNA-binding protein modifiers of TDP-43 pathology in Amyotrophic Lateral Sclerosis Emanuele Buratti 19:00—20:30 Neuroscience & Society Dialogue | Hall 1 Exploring the psychological, neurophysiological, and cognitive effects of COVID-19 Moderator: Tina Bregant Darja Kobal Grum, Peter Kapš, Žan Lep, Lina Savšek [8] Friday, 29 September 2023 9:00—10:45 Short Oral Presentations | Hall 2 9.00-9.05 Introduction by session chairs MOLECULAR: 9.05-9.15 Examining the impact of TDP-43 mislocalization on its protein network Jerneja Nimac 9.15-9.25 Exosomal miRNA alterations in rotenone models of Parkinson’s Disease Jason Cannon 9.25-9.35 Expression of disease-associated mRNAs in platelets: a potential new biomarkers of ALS pathology? Sara Cappelli CELLULAR: 9.35-9.45 Impaired octopamine-mediated calcium signaling and glucose metabolism in Drosophila aging brain Urška Černe 9.45-9.55 Neurotoxicity of cumyl-PINACA synthetic cannabinoid: involvement of multiple cannabinoid receptors Klara Bulc Rozman CLINICAL: 9.55-10.05 Nucleus accumbens valence processing during offset analgesia Andrew Vigotsky COGNITIVE: 10.05-10.15 Brain-derived neurotrophic factor and cognitive decline in patients diagnosed with mild cognitive impairment and Alzheimer’s disease Tina Miloš 10.15-10.25 Assessing cognitive sequelae of COVID-19 using telepsychological testing Ana Kuder COMPUTATIONAL: 10.25-10.35 Inferring coupling functions of brain regions from synthetic EEG data by using graph neural networks Nina Omejc 11:10—12:00 Dr. Janez Faganel Memorial Lecture | Hall 1 Biomarker development in ALS: from muscle to brain to blood Martin Turner 12:00—13:00 Roche Satellite Symposium | Hall 2 Experience with the oral drug Evrysdi in adult patients with SMA in Slovenia Blaž Koritnik 13:00—14:00 Medison Satellite Symposium | Hall 2 Myasthenia gravis – A look forward Efgartigimod: The significance of a new treatment option for generalized myasthenia gravis Filippo Rocca Challenges, limitations, and new opportunities for patients with generalized myasthenia gravis Mateja Baruca Grad [9] 14:00—16:00 Symposium | Hall 1 Neuroendocrine plasticity of the brain: from biology to therapy Chairs: Klementina Fon Tacer, Tomaž Bratkovič Prader-Willi Syndrome-associated MAGEL2 in the regulation of stress and endocrine function of the hypothalamus Klementina Fon Tacer Noradrenergic regulation of astrocytes allows metabolic and morphological plasticity of astrocytes and therapeutic opportunity Anemari Horvat Selective butyrylcholinesterase inhibitor for alleviating symptoms of canine cognitive dysfunction Urban Košak Endocrinology of precocious/delayed puberty Magdalena Avbelj Stefanija Neuroplastin in normal brain physiology and disease Svjetlana Kalanj Bognar Impact of oxidation on SOD-1 aggregation and interaction with lipid membranes Ana-Marija Vučković 16:30—18:30 Symposium | Hall 1 Brain health: public interest, assessment tools, effects of modifying lifestyle factors Chair: Mara Bresjanac Public awareness and active care for brain health in Slovenia Mara Bresjanac Public interest in brain health testing - Insights from the Global Brain Health Survey Nanna Alida Grit Fredheim Multi-dimensional McCance Brain Care Score - an accessible tool to maintain and improve brain health Sanjula Dhillon Singh Validation of the LIBRA Index in assessing modifiable risk factors and helping identify people who could benefit from primary prevention interventions Stephanie J. B. Vos Can a city prevent dementia? Jeremy Isaacs 18:30—19:15 Prof. Andrej O. Župančič Memorial Lecture | Hall 1 Predicting chronic pain Apkar Vania Apkarian [10] Saturday, 30 September 2023 11:15—12:00 Plenary Talk | Hall 1 Deregulation of immunity in injured brain: exploring novel regulatory mechanisms and targets Jasna Križ 12:00—13:00 Genesis Pharma Satellite Symposium | Hall 2 The evolving treatment landscape in ATTRv Amyloidosis Diagnostic challenges and importance of early intervention in ATTRv amyloidosis Janez Zidar Optimising management of ATTRv amyloidosis in clinical practice – from patisiran to vutrisiran Eleni Zamba-Papanicolaou 13:00—14:00 Novartis Satellite Symposium | Hall 2 Analysis of brain MRI images using artificial intelligence technologies Žiga Špiclin 14:00—16:00 Symposium | Hall 1 Novel approaches in treatment of depression with transcranial magnetic stimulation Chairs: Jurij Bon, Grega Repovš Advances in the use of resting state data for clinical application Grega Repovš Development of treatment protocols and methodological procedures for resting state networks based neuronavigation Nina Purg, Andraž Matkovič Accelerated and neuronavigated TMS therapy of depression Jurij Bon Electroencephalograhy for early prediction of TMS treatment success Aleš Oblak 16:30—18:30 Symposium | Hall 1 Biology of schizoaffective contiuum Chair: Milica Velimirović Bogosavljević Redox dysregulation in schizoaffective disorders continuum Tihomir Stojković Underlying inflammation in schizoaffective disorders continuum Milica Velimirović Bipolar spectrum disorders - neurobiology and treatment Maja Pantović Stefanović The price of becoming human: schizophrenia in the light of evolutionary neuroscience Milica Nešić 18:30—19:15 Plenary talk | Hall 1 Astroglia in ageing and neurodegeneration Alexej Verkhratsky [11] Poster sessions Friday, 29 September 2023 13:00—14:00 Cellular Neuroscience A CEL.01 FUS phosphorylation in FTLD Helena Motaln CEL.03 Neural agrin has an age-dependent stimulatory effect on the proliferation of cultured human myoblasts Sergej Pirkmajer CEL.05 Innervation of cultured human myotubes by α-motor neurons has divergent and time-dependent effects on the mRNA expression of Na+,K+-ATPase and myokines Sergej Pirkmajer CEL.07 Remote post-conditioning reduced inflammation markers and infarct size after focal ischemia associated with hyperinflammatory reaction (simulation of COVID-19) Jana Končeková CEL.09 The role of tenascin-C on the structural plasticity of perineuronal nets and synaptic expression in the hippocampus Ana Jakovljević CEL.11 Effects of elevated extracellular K+ on astrocyte metabolism and morphology Ena Begić Clinical Neuroscience A CLIN.01 Nucleus accumbens valence processing during offset analgesia Andrew D. Vigotsky Cognitive Neuroscience A COG.01 Assessing cognitive sequelae of COVID-19 using telepsychological testing Ana Kuder COG.03 Cortical changes during the learning of sequences of simultaneous finger presses Benjamín Garzón Molecular Neuroscience A MOL.01 Switch of rat dorsal root ganglia macrophages to M2 phenotype after cyto skeleton alteration reduces SNLinduced neuropathic pain Roxana-Olimpia Gheorghe MOL.03 Axonal and myelin recovery after traumatic spinal cord compression mediated via AT2 receptor stimulation Jana Fedorova MOL.05 Circular RNAs in association with amyotrophic lateral sclerosis Metka Ravnik Glavač MOL.07 Exosomal miRNA alterations in rotenone models of Parkinson’s Disease Jason Cannon MOL.09 hnRNPH localizes to G4C2 nuclear foci and cytoplasmic stress granules of C9orf72 amyotrophic lateral sclerosis Nives Škorja Milić MOL.11 Molecular factors that implicate involvement of human retrotransposon LINE1 in neurodegeneration Klementina Polanec MOL.13 Potential therapeutic effects of dehydroepiandrosterone and its sulfate in mouse models of Alzheimerś disease Barbara Vuić [12] MOL.15 The role of insulin and glucose in regulation of neuropathy target esterase-related esterase in primary human myotubes Katarina Miš MOL.17 The involvement of Angiotensin II receptors in posttraumatic recovery of severe injured spinal cord Jaroslav Pavel Neuroscience Methods MET.01 Smart probes for ex vivo assessment of Alzheimer disease conformational pathology Lana Blinc Systems Neuroscience A SYS.01 Behavioral sensitization and tolerance induced by ketamine enantiomers in male Wistar rats Kristian Elersič SYS.03 Effects of prayer on heart rate variability in resting sitting position in adults Breda Žunkovič Saturday, 30 September 2023 13:00—14:00 Cellular Neuroscience B CEL.02 Impaired octopamine-mediated calcium signaling and glucose metabolism in Drosophila aging brain Urška Černe CEL.04 Astroglial P2X7R and Cx-43 expression pattern in the vicinity of autoreactive immune cells in EAE model Katarina D. Miličević CEL.06 Neurotoxicity of cumyl-PINACA synthetic cannabinoid: involvement of multiple cannabinoid receptors Klara Bulc Rozman CEL.08 The role of glial potassium channel in Amyotrophic Lateral Sclerosis Danijela Bataveljić CEL.10 Transcriptomic screen of MASC-derived neurons from Niemann Pick C patients, reveals a feedback loop mechanism between TDP-43 and two novel TDP-43 potential second modifiers: ITPR1, and EPDR1 Francesca Paron CEL.12 Paclitaxel-induced peripheral neuropathy: in vitro and in vivo study Zuzana Michalová Clinical Neuroscience B CLIN.02 Challenging the search for neuromarkers of mental disorders Manca Kok Cognitive Neuroscience B COG.02 Brain-derived neurotrophic factor and cognitive decline in patients diagnosed with mild cognitive impairment and Alzheimer’s disease Tina Miloš COG.04 Survival and self-expression values in Slovenia and North Macedonia: exploring moderators in the relationship between cognitive reserve and cognitive performance Mia Micevska Computational Neuroscience COM.02 Inferring coupling functions of brain regions from synthetic EEG data by using graph neural networks Nina Omejc [13] Molecular Neuroscience B MOL.02 ALS/FTD-associated C9orf72 C4G2 repeat RNA binds to FARS protein and affect the rate of phenylalanine-tRNA aminoacylation Urša Čerček MOL.04 Muscle-specific microRNAs as spinal muscular atrophy biomarkers Maruša Barbo MOL.06 Examining the impact of TDP-43 mislocalization on its protein network Jerneja Nimac MOL.08 Expression of disease-associated mRNAs in platelets: a potential new biomarkers of ALS pathology? Sara Cappelli MOL.10 Hyperglycemic zebrafish exposed to chronic unpredictable mild stress display oxidative damage in the brain: mitigation by chlorogenic acid Rhea Subba MOL.12 Expression patterns of secretory pathway kinase FAM20C and its regulator FAM20A vary with differentiation stage in cultured skeletal muscle cells Katja Fink MOL.14 Crosstalk of Optineurin and TDP-43 in ALS and FTD Nikolina Prtenjaća Mohović MOL.16 Toxic potential of midazolam on rat cortical astrocytes Dan Faganeli Other B OTH.02 What has (not) been learnt from the COVID pandemics Tina Bregant Systems Neuroscience B SYS.02 Gut microbiota perturbations disrupts hippocampal serotonin bioavailability and anxiety behavior Jazib Shafiq SYS.04 The individual differences in response to ketamine enantiomers: an exploratory preclinical approach Anamarija Banja [14] SNC’23 SNC’ SiNAPSA NEUROSCIENCE CONFERENCE ‘23 Educ E ationa duc l Wor ationa ks l Wor hop on P ks ain hop on P Pr P ogramme r www.sinapsa.org/SNC23/workshop/programme Ljubljana, Slovenia 28-30 September 2023 Friday, 29 September 2023 18:30—19:15 AOŽ Memorial Lecture | Hall 1 Predicting chronic pain Apkar Vania Apkarian Saturday, 30 September 2023 8:30—9:30 Lecture | Hall 3 The search for pain biomarkers Giandomenico Iannetti 9:30—10:00 Lecture | Hall 3 Peripheral and spinal circuits Carole Torsney 10:30—11:00 Lecture | Hall 3 Pain and memory Jelena Radulović 11:00—11:30 Lecture | Hall 3 Pain modulation and emotion Volker Neugebauer 11:30—12:00 Lecture | Hall 3 Early anti-inflammatory treatment of pain: beneficial or detrimental? Massimo Allegri 14:00—14:20 Lecture | Hall 3 Pharmacogenetics of pain treatment Vita Dolžan 14:20—15:00 Lecture | Hall 3 Pharmaco-interventional treatment of non-oncological pain Gorazd Požlep 15:00—15:30 Lecture | Hall 3 Pharmaco-interventional treatment of oncological pain Iztok Potočnik, Branka Stražišar 15:30—16:00 Lecture | Hall 3 Non-pharmacological treatment of pain Jasmina Markovič Božič, Alenka Spindler Vesel 16:30—18:30 Raffle-based lightning round Q&A in small groups | Hall 3 [16] SNC’23 SNC’ SiNAPSA NEUROSCIENCE CONFERENCE ‘23 Ljubljana Clinic Ljublj a ana Clinic l N a europh eur y oph s y iolog s y iolog Sympo S s ympo ium 20 s 23 - Re ium 20 giona 23 - Re l A giona L l A S M L eeting e eting Pr P ogramme r www.sinapsa.org/SNC23/simpozij Ljubljana, Slovenia 29-30 September 2023 Image by ikatod on Freepik Friday, 29 September 11:10-11:15 Opening | Hall 1 11:15-12:00 39th Dr Janez Faganel Memorial Lecture | Hall 1 Biomarker development in ALS: from muscle to brain to blood Martin Turner 12:00-13:00 Roche Satellite Symposium | Hall 2 Experience with the oral drug Evrysdi in adult patients with SMA in Slovenia Blaž Koritnik 13:00-14:00 Medison Satellite Symposium | Hall 2 Myasthenia gravis – A look forward Efgartigimod: The significance of a new treatment option for generalized myasthenia gravis Filippo Rocca Challenges, limitations, and new opportunities for patients with generalized myasthenia gravis Mateja Baruca Grad 14:00-16:00 Symposium I | Hall 2 Update on genetics of ALS David Brenner Treatment of ALS patients with SOD1 mutations with tofersen - first results from the German Early Access Program Maximilian Wiesenfarth, Zeynep Elmas The effect of nutrition on prognosis of ALS - insights from clinical studies Johannes Dorst Ketogentic diet in ALS - a potential treatment option? Christine Herrmann Cognition in ALS - a transnational evaluation of the ECAS Dorothée Lulé 16:30-18:30 Symposium II | Hall 2 Novel approaches for gene hunting in ALS Ahmad Al Khleifat Epigenetic sex differences in ALS Olivia Grant Big data approaches for drug target validation in ALS Alfredo Iacoangeli Modelling and drug screening in ALS Jackie Mitchell [18] Saturday, 30 September 9:00-11:00 Symposium III | Hall 2 Integrative analyses of ALS patient tissue reveal pathogenic aberrant splicing events and hidden genetic risk factors Kevin Kenna MCH neurons in ALS: vulnerability and connectivity Jelena Scekic-Zahirovic The role of Sirt1 in C9ORF72-related ALS-FTD Hakan Cetin Protein homeostasis in C9orf72 Boris Rogelj Circular RNAs as potential peripheral blood biomarkers for amyotrophic lateral sclerosis Metka Ravnik Glavač 12:00-13:00 Genesis Pharma Satellite Symposium | Hall 2 The evolving treatment landscape in ATTRv Amyloidosis Diagnostic challenges and importance of early intervention in ATTRv amyloidosis Janez Zidar Optimising management of ATTRv amyloidosis in clinical practice – from patisiran to vutrisiran Elena Zamba-Papanicolaou 13:00-14:00 Novartis Satellite Symposium | Hall 2 Analysis of brain MRI images using artificial intelligence technologies Žiga Špiclin 14:00-16:00 Symposium IV | Hall 2 Genetics of ALS: a population-based study in Serbia Aleksa Palibrk ALS clinical practice in Croatia: current situation and future perspectives Hrvoje Bilić Three years of the home care ALS programme in Slovenia Janez Zidar Social cognition impairment in ALS Sara Kadenšek Gastrostomy and survival in ALS – benefits and risks Blaž Koritnik [19] SNC’23 SNC’ SiNAPSA NEUROSCIENCE CONFERENCE ‘23 Ab A s b tract s s tract SNC’23 P SNC’ lenar 23 P y and Specia y and Spe l L cia e l L ctur e e ctur s e www.sinapsa.org/SNC23 Ljubljana, Slovenia 28-30 September 2023 SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Thursday, September 28th, 13:00 clinical aspects of neurological and psychiatric diseases, hopefully pro- Molecular neuroimaging, brain con- viding information for early diagnosis programs, and for pharmacological and rehabilitative treatments. nectivity, neurodegenerative condi- tions: a challenging interplay Saturday, September 30th, 11:15 Deregulation of immunity in injured Daniela Perani brain: exploring novel regulatory Istituto Scientifico H.S. Raffaele, INB-CNR, Università mechanisms and targets di Milano, Italy Positron emission tomography (PET) allows in vivo measurements of Jasna Križ multiple parameters of regional cerebral physiology, such as glucose metabolism, and molecular biology, such as multiple neurotransmitter/ Department of Psychiatry and Neuroscience & CERVO neuroreceptor systems of the human brain. Brain Research Centre, Faculty of Medicine, Université Laval, Québec, QC, Canada FDG-PET data analyses are mostly based on univariate approaches, however, in the last decade the increasing interest in multivariate meth- Inflammation is a key component of the innate immune response. Pri-ods has paved the way to the assessment of unexplored cerebral fea- marily designed to remove noxious agents and limit their detrimental tures, from resting state brain networks to the whole-brain connectome effects, once prolonged and/or inappropriately scaled innate immune assessment. These potentialities are becoming more and more impor- response may be detrimental to the host and lead to disease. There is tant as the field of research that includes system and molecular levels increasing evidence that a deregulation of innate immunity may repre-of investigation. sent one of the key elements in the pathobiology of acute and chronic neurodegeneration. Microglia are the principal immune cells of the The combination of PET molecular neuroimaging techniques with mul- brain. Under physiological conditions microglial cells are essential for tivariate connectivity methods represents one of the most powerful, yet the maintenance of brain tissue homeostasis. It is becoming increas-still emerging, approach to achieve novel insights into the pathophysi- ingly clear that in the context of disease and/or injury, microglial cells ology of neurodegenerative diseases. In particular, the analytical tools have pivotal role in initiation and regulation of inflammatory responses for connectivity assessment of derangement due to neurodegenera- in the brain. The current consensus is that once activated, microglia can tion can characterize the abnormal neural circuitry that underlies brain acquire a wide repertoire of immune profiles ranging from the classical pathology. Neurodegenerative disorders are characterized by spread pro-inflammatory to alternative, anti-inflammatory polarization pheno-of pathology along discrete neural pathways and the identification and types. Yet, the molecular mechanisms involved in the control of micro-validation of disease-specific brain connectivity changes is expected to glia polarization profiles remain elusive. We recently described a novel broaden the application of connectivity approaches to large and diverse ribosome-based check-point mechanism involved in translation control patient populations. of innate immune genes and microglia activation. The mechanism is based on a selective translational repression of ribosome-bound im- In this lecture the most common methods for FDG-PET molecular con- mune mRNAs orchestrated by RNA binding protein SRSF3. Our initial nectivity assessment will be reviewed together with examples from evidence suggests that targeting SRSF3 mRNA translation may open the related literature. For example, in amyloidopathy, tauopathy and new avenues for therapeutic reprogramming of immune response in synucleopathy diseases specific derangement of whole brain con- acute and chronic CNS pathologies. nectivity and resting state networks has been reported, also revealing compensatory or maladaptive effects. According to these results, brain dysfunctions and cognitive impairment in neurodegenerative condi- Saturday, September 30th, 18:30 tions, depend on altered interactions between distributed brain regions operating in large-scale networks. Astroglia in ageing and neurodegen- eration Together with [18F]FDG–PET metabolic connectivity studies, the ap- plication of connectivity approaches has now been extended to other PET targets, including neurotransmission systems. So far, molecular Alexej Verkhratsky connectivity approaches have demonstrated novel network-level al- terations in a range of neurodegenerative diseases. Possible future Faculty of Biology, Medicine and Health, The University perspectives in the field, with reference to newly available PET tracers, of Manchester, United Kingdom will expand the application of molecular connectivity to new, exciting, unforeseen possibilities. Challenging inflammageing of the brain: glial paralysis, rather than re- A crucial issue concerns validation, reproducibility, and resolution of activity defines brain ageing and opens the gate for neurodegeneration the multiple statistical and mathematical approaches and data results. A possibility can be represented by an integrative approach whereby Ageing is associated with morphological and functional remodelling MRI-based, electrophysiological techniques, and PET molecular imag- of astrocytes with a prevalence of morphological atrophy and loss of ing together contribute to the brain connectome study. function, not of the widely popularised ‘inflammation’. In particular age- ing is associated with (i) decrease in astroglial synaptic coverage; (ii) These applied studies will increase the understanding of biological and deficits in glutamate and potassium clearance; (iii) reduced astroglial synthesis of synaptogenic factors such as cholesterol; (iv) decrease in [21] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 aquaporin 4 channels in astroglial endfeet with subsequent decline in rofilament level has matured as the leading prognostic marker in ALS, the glymphatic clearance; (v) decrease in astroglial metabolic support whose lowering in response to drugs has great potential to be used through the lactate shuttle; (vi) decreased adult neurogenesis resulting as an early confidence-building marker of likely human clinical benefit. from diminished proliferative capacity of radial stem astrocytes; (vii) de- cline in the astroglial-vascular coupling and deficient blood-brain barrier and (viii) decrease in astroglial ability to mount reactive astrogliosis. Thursday, September 28th, 18:15 Decrease in reactive capabilities of astroglia as well as degeneration off dystrophy of microglia are permissive for age-dependent neuro- ICGEB Lecture: NOS1AP and RGNEF degenerative diseases. Neuroglial morphology and function can be as novel RNA-binding protein modi-influenced and improved by lifestyle interventions such as intellectual fiers of TDP-43 pathology in Amyo-engagement, social interactions physical exercise, caloric restriction, and healthy diet. These modifications of lifestyle are paramount for cog- trophic Lateral Sclerosis nitive longevity. Yasmine Abbassi, Sara Cappelli, Cristiana Friday, September 29th, 18:30 Stuani, Luca Zangrando, Francesca Paron, Predicting chronic pain Emanuele Buratti International Centre for Genetic Engineering and Bio- Apkar Vania Apkarian technology (ICGEB), Trieste, Italy Feinberg School of Medicine, Chicago, IL, USA Pathological aggregation of TDP-43 is principally associated with Amyo- trophic Lateral Sclerosis (ALS) but is also present in approximately 50% Classically, chronic pain has been conceptualized as the persistent of all Frontotemporal dementia patients and is a co-pathology in ~40% nociceptive barrage invading the central nervous system. Yet even its of Alzheimer’s disease cases and in Chronic traumatic encephalopathy definition suggests this notion is not tenable. I will begin my lecture by (CTE). These observations suggest that TDP-43 pathological aggre-revisiting fundamental definitions of nociception, pain, and chronic pain. gation can occur in different brain areas/tissues and in many different I will then present human and rodent studies that complimentarily iden- pathological conditions, which can be differentially affected depending tify critical brain circuitry that seems causally engaged in the transition on the relative abundance and expression of other RNA binding pro-from acute to chronic pain. Multiple mesolimbic circuits are now rec- teins that are present in the local context. ognized, each suggesting distinct mechanistic concepts and providing venues for novel treatment options for chronic pain. If time allows I will To address this issue, several years ago we performed transcriptome also cover the topic of identifying pain from brain activity – reading the analysis of SH-SY5Y cells silenced for DAZAP1, hnRNP Q, hnRNP D, mind in pain, and discuss recent concepts of perceptual states existing hnRNP K and hnRNP U that were shown to affect TDP-43 pathology in everywhere in the brain. fly and human cell models of disease. After cross-comparing transcrip- tomic profiles of cells depleted by each of these factors, we identified seven commonly regulated transcripts: CHPF2, IGF2, IRAK2, RNF112, UBE2E3, C1orf226 and NOS1AP. Out of this list, NOS1AP (also known Friday, September 29th, 11:10 as CAPON) has recently emerged as an important player in brain phys- Biomarker development in ALS: from iology and pathophysiology for the formation of neuronal processes and probably in the onset of schizophrenia. Most importantly, we ob-muscle to brain to blood served a clear correlation between the reduction of NOS1AP and the inclusion of two previously characterized cryptic exons in different brain regions of patients with TDP-43 pathology. Then, using primary mouse Martin Turner neuronal cultures we demonstrated that decrease of TDP-43 induced a drop in NOS1AP expression and this correlated with a significant de- Nuffield Department of Clinical Neurosciences, Oxford, crease in several essential component of the synaptic network: PSD93, United Kingdom PSD95, SynGAP, and Synapsin-3. Finally, we observed that upregula- tion of NOS1AP in TDP-43 depleted SH-SY5Y cells can successfully The ability to objectively measure disease activity in amyotrophic lateral rescue of many of these genes in the absence of TDP-43. In addition, sclerosis (ALS) has been one of the greatest barriers to therapeutic downregulation of NOS1AP is also capable to rescue on its own the development. A focus on biomarker research for more than 20 years degenerative phenotype induced by TDP-43 overexpression in fly eyes. has coincided with the acceptance of a fundamental brain pathology More recently, we have started analyzing Rho guanine nucleotide ex-associated with ALS, which has clinical, histopathological and genetic change factor (RGNEF). RGNEF is a guanine nucleotide exchange overlap with frontotemporal dementia (FTD). The focus on downstream factor (GEF) mainly involved in regulating the activity of Rho-family markers of muscle denervation and has widened to include consid- GTPases. In neurodegenerative diseases, RGNEF is known to act as eration of cortical hyperexcitability as a hallmark through transcranial a destabilising factor of neurofilaments (NEFL) RNA in motor neurons magnetic stimulation and the application of advanced neuroimaging of ALS patients and it could potentially contribute to their sequestra-tools to study cortical function as well as structure. These have been tion in nuclear cytoplasmic inclusions. Most importantly, RGNEF inclu-increasingly applied to asymptomatic carriers of ALS-causing monoge- sions in the spinal motor neurons of ALS patients have been shown netic variants, unveiling the clinical syndrome as the common endpoint to colocalise with inclusions of TDP-43. To further characterise their of a long pathological process with many different starting points and relationship, we have compared the transcriptomic profiles of neuronal possibly neurodevelopmental underpinnings. Most recently, blood neu- cells depleted of TDP-43 and RGNEF and show that these two fac- [22] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 tors predominantly act in an antagonistic manner when regulating the expression of axon guidance genes. From a mechanistic point of view, our experiments show that the effect of these genes on the processivity of long introns can explain their mode of action. Taken together, our re- sults show that loss-of-function of factors co-aggregating with TDP-43 can potentially affect the expression of commonly regulated neuronal genes in a very significant manner. This finding further highlights that neurodegenerative processes at the RNA level are the result of combi- natorial interactions between different RNA binding factors that can be co-aggregating in neuronal cells. Taken together, our identification of NOS1AP and RGNEF as TDP-43 modifiers link these genes with modulating the neurological dysfunc- tions associated with ALS, allowing a better understanding of the vari- ability of patients affected by this disease, and making them a suitable candidate for the development of novel therapeutic strategies in the context of this pathology. [23] SNC’23 SNC’ SiNAPSA NEUROSCIENCE CONFERENCE ‘23 Ab A s b tract s s tract SNC’23 Thematic S SNC’ ympo 23 Thematic S s ympo ia s www.sinapsa.org/SNC23 Ljubljana, Slovenia 28-30 September 2023 SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Thursday, September 28th, 13:45 2. Methods in molecular connectivity: getting at the single-subject Tracking brain connections in neuro- level degenerative brain disorders Arianna Sala University of Liége, Belgium Matej Perovnik, Maja Trošt My talk will provide a practical overview of the different approaches and methods to estimate molecular connectivity, with a particular focus Department of Neurology, University Medical Centre on derivation of single-subject measures, i.e. with potential for appli-Ljubljana, Slovenia cation as clinical biomarkers. Advantages and disadvantages of each approach and method will be critically discussed. Neurodegenerative brain disorders are chronic proteinopathies that cause a major burden for the affected individual, caregiver, and the First, I will provide an overview of the main approaches available to society. Their prevalence is growing with the ageing population. Vari- derive molecular connectivity, based on the inter-subject vs. the intra-ous neuroimaging approaches are used in clinic and research settings subject estimation of molecular connectivity. to improve early diagnostic and differential diagnostic accuracy and help us better understand underlying pathophysiological processes Second, I will cover the main families of methods for the estimation of of neurodegenerative brain disorders. Molecular brain imaging using molecular connectivity, including: (1) seed correlation or interregional positron emission tomography (PET) and various radiopharmaceuticals correlation analysis (IRCA), (2) principal and independent component that show brain activity (glucose metabolism), blood flow, accumula- analysis (PCA and ICA) and (3) regional correlations. tion of abnormal proteins and neurotransmitter systems is a well-es- tablished research and clinical tool. Analytical advancements in recent Finally, I will explain which combinations of approaches and methods years have brought forth the field of molecular connectivity that enables allow to achieve either the single-subject estimation of molecular con-insight into molecular networks of healthy and diseased individuals. nectivity or the derivation of connectivity-based single-subject indices These advances are transforming the landscape of neurodegenerative that may likewise serve as potential clinical biomarkers. research by providing additional information on the development and progression of the disease process. Furthermore, as the changes in the Practical examples of application in the field of neurology will be pro-brain activity and accumulation of abnormal proteins begin early in the vided throughout the talk. disease process, we can follow these changes already in early or even pre-symptomatic disease stages. 3. Dynamic reconfiguration of metabolic brain connectivity during Keywords: neuroimaging, neurodegenerative brain disorders, network progression from MCI to Alzheimer’s disease dementia analysis Silvia Caminiti San Raffaele, Milano, Italy 1. The concept of molecular connectivity Introduction: longitudinal design to investigate FDG-PET brain connec- Igor Yakushev tivity reconfigurations along the progression from mild cognitive impair- Technical University of Munich, Germany ment (MCI) to Alzheimer’s disease (AD) dementia. Do you apply molecular imaging to study brain connectivity? My talk Methods: Patients classified according to ATN pipeline in MCI (AD-will encourage you to consider doing this. Why? The current knowledge MCI, N=31), mild dementia (mild-AD, N=31) and AD-dementia (AD-D, on how brain connectivity and networks underpin brain function (and N=20). A group of age/sex-matched healthy controls (HC) was longitu-dysfunction) disproportionately stems from the hemodynamic signal of dinally evaluated for comparison. Between-nodes pairwise correlation functional MRI (fMRI). In fact, this method has been dominating the analysis was applied to obtain adjacent matrices. The extent of connec-field of brain connectivity for decades, generating valuable knowledge tivity alterations was quantified by means of nodal summary indices. about functional brain organization. As compared to fMRI, molecular The obtained indices also served as input for k-means cluster-analysis imaging captures a broad range of biological processes such as neural (KM1 and KM2). function, neurotransmission, and proteinopathies. Thanks to its robust- ness, molecular imaging has been successfully utilized in the diagnosis Results: The AD-MCI showed less connectivity alterations than mild-of neurodegenerative brain disorders. In this talk I will introduce the AD and AD-D, specifically characterized by relatively higher numbers of concept of molecular connectivity, application of molecular imaging to gained than lost connections. KM1 identified two clusters: “altered clus-estimate brain connectivity. Herewith, I will explain the notion of ergo- ter” and “spared cluster”. In AD-MCI, altered cluster involved connec-dicity and compare glucose PET with fMRI as markers of neural func- tions of subcortical/limbic regions, occipito-parietal cortices/cerebellum. tion. Approaches to estimate molecular connectivity will be explained At mild-AD and AD-D stages, the altered cluster involved a large por-by Dr. Arianna Sala in the subsequent talk. In the end, I will discuss tion of connections within occipito-parietal cortices/cerebellum. KM2 outstanding questions and provide a vision of a future of molecular identified four clusters: Cluster1 included nodes with low-levels of lost/ connectivity by the Molecular Connectivity Working Group, a recently gained connections in frontal cortex, insula, and basal ganglia across established initiative of neuroimaging experts. Overall, we encourage the whole-disease course; Cluster2 grouped nodes with high levels the neuroscientific community to take an integrative approach whereby of gained connections in occipito-temporo-parietal regions; Cluster3 MRI-based, electrophysiological techniques, and molecular imaging grouped nodes with high-levels of lost connections in subcortical/limbic contribute to our understanding of the brain connectome. regions; in Cluster4 only the precuneus showed the highest levels of lost/gained connections, constant along the whole-disease. [25] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Conclusion: The initial prevalent hyperconnectivity might represent an metabolic networks have been identified for atypical parkinsonism, inearly response to neurodegeneration. As disease progresses, connec- cluding the multiple system atrophy-related pattern (MSARP), progres-tivity alteration was limited to the cortical-associative regions and cere- sive supranuclear palsy-related pattern (PSPRP), corticobasal degen-bellum. Moreover, our results shed light on the critical role of precuneus eration-related pattern (CBDRP), and other networks associated with in the dynamic connectivity reconfigurations of AD. rare movement disorders. Based on the expression of these networks, machine learning-based algorithms have been developed to accurately differentiate among different syndromes, particularly in the early clinical 4. Metabolic brain networks in neurodegenerative parkinsonisms stages when clinical differentiation is challenging. A recent real-world study has demonstrated that these algorithms can enhance the diag-Tomaž Rus nosis of PD and atypical parkinsonisms by 15-20% in the early stages Department of Neurology, University Medical Centre Ljubljana, Slove- of the disease. nia Beyond their role in differential diagnosis, metabolic brain networks also In the era of emerging disease-modifying therapies for neurodegenera- play an important role in assessing treatment responses in clinical trials. tive disorders, the importance of accurate and timely diagnosis of neu- Several research groups have shown that positive clinical responses to rodegenerative disorders – dementias, and parkinsonisms – is steadily symptomatic therapies, such as levodopa, deep brain stimulation, or increasing. While there has been a shift from syndromic to biology- therapeutic thalamotomy, are associated with a reduction in PDRP. Fur-based diagnoses in the case of Alzheimer’s disease, the diagnosis of thermore, these metabolic brain network-based approaches facilitate neurodegenerative parkinsonian disorders still predominantly relies on the examination of treatment impacts on network reconfiguration, which clinical criteria. However, in recent years, a range of biomarkers has be- involves the development of new functional connections. This capability come available to help distinguish among these conditions. In addition was showcased in two studies: one focused on STN AAV2-GAD gene to emerging cerebrospinal fluid and blood-based biomarkers, such as therapy, and the other on an oral supplement targeting mitochondrial alpha-synuclein, biomarkers based on brain connectivity are increas- respiratory function. Both treatments, considered disease-modifying, ingly accessible and ready for utilization in both research and clinical were associated with distinct treatment-induced network alterations. applications. The metabolic brain network approach for studying brain changes in Aberrant brain circuitry can be explored using various imaging tech- neurodegenerative parkinsonisms is a robust and reliable technique, niques, with FDG PET and functional MRI (fMRI) being the most read- valuable both in research and clinical practice. In conjunction with other ily accessible. Advanced analytical methods like the scaled subprofile emerging biomarkers, it is guiding us toward a deeper comprehension model based on principal component analysis (SSM-PCA), independ- of the disease mechanisms, enabling more accurate diagnoses, and ent component analysis (ICA), and graph theory approaches enable us facilitating advanced treatment options for parkinsonian syndromes. to investigate connectivity within resting-state metabolic activity maps (captured through FDG PET) or regional blood oxygenation signals (captured via fMRI). While the fMRI-based approach is emerging as 5. Metabolic brain networks in neurodegenerative dementias a cost-effective alternative, distinct disease-specific metabolic patterns based on FDG PET have been identified and validated across multiple Matej Perovnik centers in several neurodegenerative parkinsonian syndromes and are Department of Neurology, University Medical Centre Ljubljana, Slove-already being used in clinical settings. nia The Parkinson’s disease (PD) related pattern (PDRP) was first identi- Metabolic brain imaging with Fluorodeoxyglucose positron emission to-fied in the 1990s and has since been validated in diverse cohorts of PD mography (FDG PET) and a special form of network analysis, so called patients at various disease stages worldwide. This pattern is character- scaled subprofile model/principal component analysis (SSM/PCA) is ized by relative hypermetabolism in the putamen, pallidum, thalamus, used to detect specific disease-related brain networks. These networks pons, and cerebellum, alongside hypometabolism in the premotor and represent topographic patterns of neural activity in which interconnect-posterior parietal regions. The expression of this PD-specific network ed brain regions form discrete networks. They are identified by using correlates with the core signs of the disease, bradykinesia and rigidity, scans of diseased and healthy individuals and have been characterized underscoring the pattern’s biological significance. However, it’s worth for different neurodegenerative dementia disorders. After a successful noting that the expression of PDRP does not align with parkinsonian identification and validation of such network pattern, we can then cal-tremor, as a distinct network, known as the PD tremor pattern, is as- culate the expression levels/subject scores, which quantify the extent sociated with tremor and is primarily represented in the cerebello-thala- to which a given network is represented in an individual’s scan. This mo-cortical regions. forward application of the SSM/PCA procedure enables the clinicians to obtain valuable, quantifiable information from an individual’s FDG PET In addition to the PDRP and PD tremor patterns, researchers have image that can be then used alongside a more traditional visual report. identified a separate metabolic network associated with cognitive de- Using SSM/PCA and FDG PET scans from patients with dementia due cline in PD, so called PD cognitive pattern (PDCP). PDCP is character- to Alzheimer’s disease and healthy controls an Alzheimer’s disease re-ized by functional changes within the ventral default mode network and lated pattern (ADRP) has been identified in different sites across the other neocortical regions. PDCP becomes evident in PD patients with a world. The pattern’s topography has been well validated, and it consist-noticeable delay after PDRP. This difference between the expressions ently involves the hypometabolic changes in the precuneus and tempo-of PDRP and PDCP is a distinctive feature of PD and aligns with the roparietal cortices with relative hypermetabolic changes in the cerebel-progression of neuropathological changes from the Braak 3 to Braak lum, pons and primary sensorimotor cortex. Furthermore, it has been 4/5 stage. shown that ADRP subject scores can be used to separate patients with dementia or mild cognitive impairment (MCI) due to Alzheimer’s While the characteristic relationship between PDRP and PDCP can disease from patients with dementia or MCI due to other causes. The offer valuable insights for differential diagnosis, other disease-specific subject scores also correlate with the degree of cognitive impairment. [26] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Finally, in a recent longitudinal study we also showed that the subject molecules are present in autoinhibited form, while cleavage and rec-scores increased monotonically in patient’s with worsening cognition ognition of negatively charged phospholipids enable the N-terminal and that they can be used to predict conversion from normal cognition domain of Gasdermin D to form pores in the membranes and facilitate to MCI and from MCI to dementia. pyroptotic cell death. Similarly, to ADRP a metabolic brain network characteristic for demen- We investigate the regulation of the initial steps of NLRP3 inflamma-tia with Lewy bodies (DLBRP), frontotemporal dementia (FTDRP), and some assembly and downstream responses that are common to all most recently Creutzfeld-Jakob’s disease (CJDRP) have been identi- inflammasomes. We are exploring different ways to inhibit NLRP3 infied. In all three diseases the subject scores showed to bear excellent flammasome activation, using small molecules and designed peptides. diagnostic value and a differential diagnostic machine learning algo- We demonstrated that the peptide corresponding to H2-H3 segment rithm utilizing the expression of ADRP, FTDRP and DLBRP was shown of ASC pyrin domain selectively inhibited NLRP3 inflammasome by to be able to accurately distinguish between patients with AD, FTD, binding to NLRP3 pyrin domain in the micromolar range. The peptide DLB and healthy controls. had no effect on AIM2 and NLRC4 inflammasomes as well as NF-κB pathway. The peptide effectively dampened neutrophil infiltration in the silica-induced peritonitis and when equipped with Antennapedia or Thursday, September 28 Angiopep-2 motifs crossed the blood-brain barrier in a mouse model. th, 13:45 Our study demonstrates that peptides represent an important tool for Neuroimmune disorders targeting multiprotein inflammatory complexes and can serve as the basis for the development of novel anti-inflammatory strategies for neu- rodegeneration. Ivana Munitić Department of Biotechnology, University of Rijeka, 2. Fluid biomarkers of neurodegeneration in neuroinflammatory Croatia diseases This symposium will cover several hot topics in the neuroimmune Uroš Rot crosstalk: immune disbalance in neurodegenerative diseases, multiple Department of Neurology, University Medical Centre Ljubljana, Slove-sclerosis, viral meningoencephalitis, inflammageing, immunosurveil- nia lance in health and disease, immune biomarkers, and/or immunothera- peutic approaches in neurological diseases. Cerebrospinal fluid (CSF) and blood biomarkers of neurodegeneration could become useful in assessment of acute neuronal damage and Neuroimmunology is an increasingly prominent field since genetic and prediction of long-term outcomes in many central nervous system in-epigenetic analyses have implicated innate and adaptive immune path- flammatory diseases. Frequently studied biomarkes include amyloid ways as either initiators or accelerators of a broad spectrum of neu- beta measurements reflecting amyloid metabolism in the brain, neurological pathologies (autoimmune diseases of the CNS, neurodegen- rofilament light chain (NFL, axonal injury), tau (neuronal injury), phos-erative diseases, stroke and others). Some of them are also linked to phorylated tau (neurofibrillary pathology), glial fibrillary acidic protein exaggerated or failed responses to infection, as recently exemplified in (GFAP, astrogliosis) and YKL-40 (microglial activation). In multiple scle-the pandemic of SARS-Cov2. Importantly, experimental immunothera- rosis (MS) high CSF NFL associates with acute axonal injury and is peutic approaches for neurological disorders are on the rise because of in correlation with relapses and early MRI activity. It decreases after the greater plasticity and accessibility of the immune than the nervous immune treatment. NFL can also be measured in blood and its determi-system. nation has already entered clinical routine. CSF YKL-40 is on the other hand more often associated with silent progression which is especially Keywords: immunity, inflammation, neurodegeneration, inflammage- important in primary progressive MS. GFAP can also be determined in ing blood and is a promising biomarker of the immune treatment response in neuromyelitis optica spectrum disorder. In fulminant infections such as tick-borne meningoencephalitis high CSF NFL levels are found. CSF 1. Suppressing NLRP3 inflammasome NFL concentrations are somewhat lower in infections with more pro- tracted clinical course such us neuroborreliosis. Both of the diseases Iva Hafner-Bratkovič are associated with altered amyloid metabolism as reflected by low Department of Synthetic Biology and Immunology, National Institute of CSF amyloid beta concentrations. Neuroinflammation may also affect Chemistry, Ljubljana, Slovenia tau phosphorylation. Neuropathological studies report accumulation of EN-FIST Centre of Excellence, Ljubljana, Slovenia abnormally phosphorylated tau in primary and secondary progressive MS, suggesting possible contribution of tau pathology to disease pro- Multiprotein complexes inflammasomes are central components of the gression. Fluid biomarkers can provide insights into underlying patho-early inflammatory response to invading pathogens, however, particu- genetic processes and are therefore valuable in the diagnosis and larly NLRP3 inflammasome has been shown to support inflammation in prognosis of many degenerative but also inflammatory central nervous various sterile conditions, such as neurodegenerative diseases, where system diseases. amyloids activate NLRP3. Upon sensing disrupted tissue homeosta- sis, NLRP3 through oligomerization leads to the recruitment of adapter ASC and assembly of inflammasomes, followed by the activation of inflammatory caspase-1. Caspase-1 afterward proteolytically activates proinflammatory cytokines IL-1b and IL-18. Gasdermin D is another substrate of inflammatory caspases. In a dormant state, gasdermin D [27] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 3. Immune imbalance during ageing accumulation in astrocytes. This response may serve to support energy metabolism and/or provide neuroprotection against lipotoxicity, increas- Ivana Munitić, Nikolina Mohović ing the viability of stressed astrocytes and neighboring cells. Department of Biotechnology, Rijeka, Croatia The brain is a composite neuro-endocrine organ, influenced by intri- Immune functions are dramatically affected by ageing, a major trigger cate neuronal and peripheral hormonal signaling conveying information for adult-onset neurodegenerative diseases like amyotrophic lateral from internal and external environments. In turn, complex neuropeptide sclerosis (ALS) and frontotemporal dementia (FTD). In the adaptive networks enable efficient adaptation to an ever-changing environment immune system, the most prominent changes comprise a decreased and affect many bodily functions, such as metabolic status/ energy numbers and lower diversity of naive T and B cells, with an increase in consumption, fertility, and stress responses. Dysregulation in any of effector and memory populations. In the innate immune system, ageing the systems due to genetic or epigenetic changes can lead to neu-is linked to functional defects in phagocytosis, which lead to a lower rodevelopmental, reproductive, and cognitive disorders, or obesity, and capacity to cope with various exogenous and endogenous stressors, can have wide-ranging effects on behavior, mood, and overall health, ultimately leading to higher inflammatory responses and low-grade leading to different diseases, including Prader-Willi Syndrome and Alz-chronic inflammation (termed inflammageing). Numerous studies have heimer disease. This symposium will address, from an interdisciplinary found mutations in the genes directly regulating immune functions in and comparative point of view, the neuroendocrine plasticity of the ALS and FTD, including those in C9ORF72, TBK1, OPTN and CYLD. brain. The topics to be presented by confirmed speakers range from In this talk I will discuss the lessons that we learned by analysing the basic molecular biology and genetics to translational research at pre-effect of ageing on neuroimmune functions in a mouse model of OPTN clinical and clinical levels, applicable in human and veterinary medicine. insufficiency. 5. Genetic polymorphisms in oxidative stress and inflammatory 4. Stress-induced lipid droplet accumulation in astrocytes pathways as potential biomarkers in Alzheimer’s disease and de- mentia Anemari Horvat1,2, Tina Smolič1, Petra Tavčar1, Urška Černe1, Larisa Tratnjek3, Mateja Erdani Kreft3, Maja Matis4,5, Toni Petan6, Robert David Vogrinc1, Milica Gregorič Kramberger2,3,4, Andreja Emeršič2, Zorec1,2, Nina Vardjan1,2 Saša Čučnik2,5,6, Katja Goričar1, Vita Dolžan1 1 Laboratory of Neuroendocrinology-Molecular Cell Physiology, Insti- 1 Pharmacogenetics Laboratory, Institute of Biochemistry and Molecu-tute of Pathophysiology, Faculty of Medicine, University of Ljubljana, lar Genetics, Faculty of Medicine, University of Ljubljana, Slovenia Slovenia 2 Department of Neurology, University Medical Centre Ljubljana, Slo- 2 Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, Slove- venia nia 3 Faculty of Medicine, University of Ljubljana, Slovenia 3 Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, 4 Care Sciences and Society (NVS) Division of Clinical Geriatrics, De-Slovenia partment of Neurobiology, Karolinska Institutet, Huddinge, Sweden 4 Institute of Cell Biology, Medical Faculty, University of Münster, Ger- 5 Department of Rheumatology, University Medical Centre Ljubljana, many Slovenia 5 Cells in Motion Interfaculty Centre, University of Münster, Germany 6 Faculty of Pharmacy, University of Ljubljana, Slovenia 6 Department of Molecular and Biomedical Sciences, Jožef Stefan In- stitute, Ljubljana, Slovenia Background: Oxidative stress and neuroinflammation are important processes involved in Alzheimer’s disease (AD) and mild cognitive im- Lipid droplets (LDs) are cellular organelles involved in lipid turnover pairment (MCI). Numerous risk factors, including genetic background, and stress response and provide substrates for energy metabolism and can affect the complex interplay between those mechanisms in the ag-protection against lipotoxicity. In brain pathologies LD content increas- ing brain and can also affect typical AD hallmarks: amyloid plaques and es. This occurs mainly in neuroglial cells. The characteristics of LDs neurofibrillary tangles. Our aim was to evaluate the association of poly-and the mechanisms driving the accumulation of LDs in astrocytes, a morphisms in oxidative stress- and inflammation-related genes with subtype of neuroglial cells with key homeostatic functions, are poorly cerebrospinal fluid (CSF) biomarker levels and cognitive test results. understood. We studied the (sub)cellular localization and LD content Methods: The study included 54 AD patients, 14 MCI patients with path-using fluorescent and electron microscopy in isolated and brain tissue ological CSF biomarker levels, 20 MCI patients with normal CSF bio-rat astrocytes, and in Drosophila melanogaster brain, under various marker levels and 62 controls. Isolated DNA from blood was genotyped stress stimuli associated with brain pathologies. In resting astrocytes, for polymorphisms in SOD2, CAT, GPX1, IL1B, MIR146A, IL6, TNF, LDs were found to be ~450 nm in diameter and located close to mito- CARD8, NLRP3, GSTP1, NOS1, KEAP1 and NFE2L2 using competi-chondria and the endoplasmic reticulum. Following attenuation of de tive allele-specific PCR. Association of polymorphisms with CSF bio-novo LD biogenesis by inhibiting DGAT1 and DGAT2 enzymes, the marker levels and cognitive tests was evaluated using nonparametric astrocyte number decreased by ~40%, indicating the importance of LD tests. turnover for cell survival and/or proliferation. Exposure to metabolic and hypoxic stress significantly increased LD content in astrocytes, indicat- Results: Carriers of two polymorphic IL1B rs16944 alleles had higher ing LD accumulation. Increased LD accumulation was also observed in CSF Aβ1–42 levels (p = 0.025), while carriers of at least one poly-astrocytes exposed to a brain stress response system neuromodulator morphic NFE2L2 rs35652124 allele had lower CSF Aβ1–42 levels (p noradrenaline, upon β- and α2-adrenergic receptor activation that af- = 0.040). Association with IL1B rs16944 remained significant in the fects cAMP signaling. Finally, the accumulation of LDs was observed AD group (p = 0.029). Additionally, MIR146A rs2910164 was associ-also in Drosophila brain upon exposure of flies to 24 h-hypoxic and nu- ated with Aβ42/40 ratio (p = 0.043) in AD. Significant associations with trient stress. Thus noradrenergic activation and metabolic and hypoxic cognitive test scores were observed for CAT rs1001179 (p = 0.022), stress, which are associated with many brain pathologies, trigger LD GSTP1 rs1138272 (p = 0.005), KEAP1 rs1048290 and rs9676881 (both [28] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 p = 0.019), as well as NFE2L2 rs35652124 (p = 0.030). In the AD group, understand the complex interactions between the brain and body dur-IL1B rs1071676 (p = 0.004), KEAP1 rs1048290 and rs9676881 (both p ing real-world activities and to gain insights into how the brain controls = 0.035) remained associated with cognitive scores. movement and how movement affects brain function. MoBI has the po- tential to revolutionize our understanding of the brain-body relationship Conclusions: Polymorphisms in antioxidative and inflammation genes and has applications in areas such as rehabilitation, sports science, might be associated with CSF biomarkers and cognitive test scores and and human-computer interaction. could serve as additional biomarkers contributing to early diagnosis of dementia. In this symposium, we will introduce the expanding research field of MoBI, which includes the scientific background of MoBI and current ap- plications in studies assessing the behavioral and neural bases of spa- 6. Microbiome in Parkinson’s disease tial navigation in real and virtual spaces (Speaker #1); an overview of the behavioral and neurophysiological bases of embodiment and motor Eliša Papić, Valentino Rački, Vladimira Vuletić control in the field of telerobotics (Speaker #2); Clinical aspect of MoBI Clinic for Neurology, Clinical Hospital Center Rijeka, Croatia for early signs of Parkinson’s disease (Speaker #3); High-density EEG source imaging for mapping brain sources in extreme environments Parkinson’s disease (PD) is a neurodegenerative disease with a mul- while subjecting the human body to increased gravity in a short-arm tifactorial etiopathogenesis. The main pathophysiological mechanism human centrifuge (Speaker #4). involves the loss of dopaminergic neurons due to α-synuclein accumu- lation. Increasing evidence has identified microbiota as a potential fac- Keywords: Mobile EEG, embodied cognition, advanced brain mapping tor in the earliest, prodromal phases of the disease. Thus far, research has shown a significant difference between microbiota composition in PD patients as opposed to healthy controls. Furthermore, the rela- 1. Linking human behavior with brain responses using Mobile tive abundance of certain microbiota has been correlated with motor Brain/Body Imaging and non-motor symptom severity, with varied findings between differ- ent bacterial taxa. Besides microbiome composition, metabolic side- Klaus Gramann products of microbiota with potential effects on Parkinson’s disease Technische Universität Berlin, Germany have also been identified, with short-chain fatty acids (SCFA) being the most prominent ones. Various therapeutic approaches targeting Decades of human brain imaging studies have used methods that are gut microbiota have also been explored, such as antibiotics, prebiot- either to heavy to follow participants movements (e.g., MRI) or that re-ics, probiotics, specific diets as well as fecal microbiota transplantation quired participants to sit still to avoid movement-related artifacts that (FMT) and enema. At the Clinic for Neurology of the Clinical Hospital might impact the feeble signal of interest (e.g., M/EEG). As a conse-Center Rijeka, we are currently conducting a longitudinal study with quence to the restrictions of the imaging modality, embodied cognitive de-novo patients and are looking to add to the current knowledge of processes and their underlying neural correlates have not been inves-both symptom/abundance correlation and the effects of therapy on the tigated and the impressive capacities of the human brain to support composition and metabolic function of microbiota. flexible cognition during interaction with dynamic environments remains elusive. Further research into the field could offer a better and more individual- ized approach to Parkinson’s disease treatment. Recent technological advancements have provided brain imaging mo- dalities that are small and lightweight and allow for recording of human brain activity in actively moving participants. In combination with vir- Thursday, September 28th, 16:15 tual reality (VR), such systems enable controlled experiments beyond standard laboratory protocols offering new opportunities in cognitive Mobile Brain/Body Imaging (MoBI) – neuroscience research introducing hitherto unknown possibilities for understanding brain oscillations and mapping out human brain function in ecological valid scenarios. While movement in natural and extreme en- a combination of virtual reality, motion capture, and brain imaging can assess the most important aspects of embodied cognitive processes, it vironments further provides unprecedented opportunities for systematically manip- ulating the constituent factors of sensory-motor integration underlying natural cognitive processes with protocols that would not be possible Uroš Marušič1, Klaus Gramann2 without VR. 1 Science and Research Centre Koper, Slovenia I report results from MoBI experiments that reveal striking differences 2 Technische Universität Berlin, Germany in brain dynamics underlying active behavior as compared to stationary protocols. The results give new insights into human brain activity during Mobile Brain/Body Imaging (MoBI) is a neuroimaging technique that active behaviors and a critical perspective on problems arising from the allows researchers to investigate brain activity while a person is en- combination of new technologies. gaged in natural movements and behaviors, such as walking or reach- ing movements. Unlike traditional neuroimaging methods such as functional magnetic resonance imaging (fMRI) and electroencephalog- raphy (EEG), MoBI allows neural activity to be recorded outside the laboratory setting. MoBI uses portable EEG systems in combination with motion capture devices and other wearable sensors to record brain activity, muscle movements, and other physiological signals to better [29] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 2. Neurophysiological bases of embodiment during physical ma- 4. Brain mapping during increased gravity gradients noeuvring of a virtual robot in VR Uroš Marušič Federica Nenna Science and Research Centre Koper, Slovenia University of Padua, Italy The human brain’s remarkable ability to adapt and reorganize its Virtual Reality (VR) is increasingly being used to teleoperate or simu- function and structure, known as neuroplasticity, plays a critical role late robotic systems. Human-robot interfaces leveraging intuitive body in acquiring skills and adapting to a changing environment. In light of motion and gestures, such as body-machine interfaces, likely trigger future space missions to the Moon, Mars, and beyond, the impact of embodiment mechanisms, increasing the teleoperation’s transpar- changing gravity conditions on neuroplasticity is becoming a pressing ency, leading to higher telepresence and oftentimes even altered body concern. The human centrifuge, originally developed for high-g training ownership. In such cases, users might forget about the mediator (i.e., in aviators and astronauts, has gained new attention for its potential the interface itself) and act more naturally. All these mechanisms were as a medical device. High-g training on the centrifuge protects against proposed to improve human-robot teleoperation performance and par- acceleration-induced loss of consciousness (g- LOC), a condition in ticularly motor control, despite scarce empirical findings currently sup- which excessive g-forces displace blood from the brain and lead to porting this hypothesis in the telerobotics sector. unconsciousness. Incidents of g- LOC have tragically resulted in fa- tal accidents in high-performance aircraft capable of sustaining high g In our last research, we covered these aspects within a VR-based conditions for extended periods of time. In addition to its role in high-g industrial scenario, where our participants maneuvered a faithful re- training, the centrifuge has also shown promise as a tool for person-production of the robotic arm e-Series UR10e via their own physical alized gravity therapy (GT). GT has shown potential in the treatment movements. Given the abstraction and the psychological nature of the and rehabilitation of individuals with neuromuscular disorders, balance variables of interest, we relied upon a multimodal setup for measuring disorders, stroke and sports injuries. The precise tailoring of GT to indi-explicit and implicit metrics related to embodiment, presence, workload, vidual needs opens new avenues for therapeutic interventions that take and motor control. Specifically, in addition to a battery of self-report advantage of the body’s response to gravity gradients. In my talk, I will questionnaires, we tracked the users’ motor performance in combina- present the feasibility of measuring electroencephalography (EEG) in tion with a Mobile Brain/Body Imaging (MoBI) approach to additionally the presence of elevated g-values, as well as preliminary data on pos-measure brain dynamics (i.e., EEG) without constraints throughout the sible differences in sensorimotor processing in healthy adults. task execution. This allowed linking users’ perceptions, performance, and related brain activity, offering a broad overview of behavioral and neurophysiological bases of embodiment and motor control in the teler- Thursday, September 28th, 16:15 obotics sector. Neurodegeneration and protein aggre- 3. Detecting early signs of Parkinson’s disease using Mobile gation; are aggregates protective or Brain/Body Imaging harmful; what comes first protein ag- gregation or oxidative stress? Manca Peskar Science and Research Centre Koper, Slovenia Parkinson’s disease (PD) is the second most common neurodegenera- Eva Žerovnik tive disorder affecting approximately 3% of people aged 65 and over Department of Biochemistry and Molecular and Struc-10% of people above 80 years. Typically, the first symptoms manifest in the motor domain which remains the most severely affected domain tural Biology, Jožef Stefan Institute, Ljubljana, Slovenia throughout the disease. To compensate for the lack of automaticity in balance and/or movement control, PD patients typically employ atten- We will show evidence for various amyloid forming proteins causing tional strategies. However, this process is also impeded because the neurodegenerative disease, how their aggregates affect cells’ and neu-disease manifests in non-motor symptoms too. Already in the early rons’ fate. Can we trace smaller oligomeric species perforating mem-disease stages, approximately one-third of patients reported cognitive branes? What comes first protein aggregation or oxidative stress or we impairment. These cognitive changes are difficult to diagnose in PD have a vicious circle? We will argue that in aging and neurodegenera-because the patients retain their mental acuity and continue their daily tion, first, by UV radiation or H2O2 exposure proteins get oxidized then living activities. they produce toxic still soluble aggregates and increase mitochondrial ROS release, thus, other proteins aggregate even more. Examples of In pursuit of gaining a better understanding of the cortical underpin- the protein aggregates causing various neurodegenerative pathologies nings supporting natural behaviors in early PD patients, the aim of our will be described, such as SOD-1 aggregation, alpha- synuclein, amy-study was to manipulate the motor load across balancing and over- loid-beta, amylin (islet amyloid polypeptide - IIAP), cystatin C and stefin ground walking tasks, both with and without the addition of a secondary B. We will give hints for other diseases of the CNS, which may be linked cognitive task. Using the Mobile Brain/Body Imaging (MoBI) approach to protein aggregation, such as progressive myoclonus epilepsies and we were able to simultaneously record behavior and neurophysiology major mental illnesses. associated with both motor and cognitive tasks. We present one of the first MoBI protocols investigating cognitive-motor dual tasking in a fully Keywords: protein aggregation, amyloid formation, neurodegenera-mobile setting. For the balancing task, we report the preliminary results tion, aging, major mental diseases comparing 10 healthy and 12 PD patients on postural sway and event-related potentials, while for the walking task, we present a preliminary gait cycle-related spectral modulation analysis approach. [30] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 1. Introduction to the topic of protein aggregation shift perturbations makes it possible to identify a structural motif con- sisting of α-helices formed intersubunit interface, interacting with the Eva Žerovnik Aβ(1-40) peptide. Our finding corroborates with previous reports about Department of Biochemistry and Molecular and Structural Biology, complex S100B with Aβ(1-42), exhibiting the changes in the dynamics Jožef Stefan Institute, Ljubljana, Slovenia of the S100B backbone in the absence and presence of Aβ(1-40). Spe- cifically, the complex S100B with Aβ(1-40) characterized a reduction of molecular dynamic processes within the μs – ns time-frame compared 2. Additional features of the mechanism of amyloid formation by to the S100B protein. At the same time, the intensity of the dynamic mo-human stefin B as revealed by infrared spectroscopy tions increased for the residues located in the ‘hinge’ loop between two Ca-binding EF-hand motifs. The presence of CuO nanoparticles leads Eva Žerovnik1, Urban Novak2, Ajda Taler-Verčič3, Barbara Zupančič2, to dramatic changes in the 3D structure and dynamic processes for the Magda Tušek-Žnidarič4, Jože Grdadolnik2 S100B protein but not for the Aβ amyloid in S100B-Aβ(1-40) complex. Acknowledgments The research was supported by a grant 2021/41/B/ 1 Department of Biochemistry and Molecular and Structural Biology, ST4/03807 from National Science Commitee (Poland). Jožef Stefan Institute, Ljubljana, Slovenia 2 Theory Department, National Institute of Chemistry, Ljubljana, Slo- Keywords: S100B, Abeta amyloid, metal nanoparticles, NMR spec-venia troscopy 3 Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia 4 Department of Biotechnology and Systems Biology, National Institute 4. Modulation of the stability of cystatin C by intra- and extramo-of Biology, Ljubljana, Slovenia lecular factors Modulation of the model for the mechanism of amyloid fibril formation Justyna Żygowska1, Przemysław Jurczak1, Marta Orlikowska1, Igor by human stefin B was obtained by using FTIR/1/. The model differs Zhukov2, Aneta Szymańska1 slightly from the previously proposed one/2/ and is most in line with the proposal obtained by heteronuclear NMR/3/. Native state is made 1 Department of Biomedicinal Chemistry, Faculty of Chemistry, Univer-by four β-strands which form one β-sheet and one α-helix. The core of sity of Gdańsk, Poland amyloid fibrils is formed from β-strands 3 and 4, which form a cross-β- 2 Institute of Biochemistry and Biophysics, Polish Academy of Scienc-structure. Around the fibril core α-helixes are placed. However, some- es, Warsaw, Poland what decrease population of the α-helical structures were observed, which can be ascribed to partial unfolding of the ends of α-helices. In- Human cystatin C (hCC) is associated with physiological and patho-termediates with partially unfolded secondary elements were detected logical processes in human organism. It functions mainly as an inhibitor for the first time. of cysteine proteases, but also exhibits neurodegenerative and neuro- protective properties. The wild-type protein modulates the amyloid-β Keywords: mechanism of amyloid aggregation, human cystatin B, in- peptide oligomerization and toxicity, protecting at the same time neuron frared spectroscopy, secondary structures cells. The L68Q variant of hCC, on the other hand, is associated with severe state called hereditary cerebral amyloid angiopathy (HCAA), a disease resulting from the protein oligomerization, causing brain artery 3. Structural aspects of oligomerization processes of the Abeta damage. Oligomerization of hCC is a result of domain swapping. The peptides under interaction with nanoparticles utilized by NMR protein conformational stability and unfolding necessary for the process spectroscopy to occur is partially controlled by the sequence of the L1 loop and hy- drophobic interaction network, centered around leucine at position 68 Thomas Okoth1,2, Lesia Kolomiiets1, Karolina Rucińska3, Joanna Mak- located in the hydrophobic core of the protein. In certain conditions, sim3, Maciej Kozak3,4, Igor Zhukov1 the L1 loop can induce intermolecular self-association of two hCC molecules through a “steric zipper” motif. hCC oligomerization occurs 1 Laboratory of Biological NMR, Institute of Biochemistry and Biophys- spontaneously as a result of the above mentioned L68Q mutation or ics, Polish Academy of Sciences, Warsaw, Poland can be induced by external factors including temperature, pH changes 2 Department of Organic Chemistry, Faculty of Chemistry, Warsaw Uni- or denaturation agents. Redox-active metal ions and biological mem-versity of Technology, Warsaw, Poland branes also play a vital role in the process. Understanding the impact 3 Department of Biomedical Physics, Faculty of Physics, Adam Mickie- of intra- and intermolecular factors on hCC’s conformational stability wicz University, Poznań, Poland and propensity for oligomerization can provide insights into the mecha- 4 National Synchrotron Radiation Centre SOLARIS, Jagiellonian Uni- nisms underlying amyloidogenic protein folding. It may aid in prevent-versity, Kraków, Poland ing pathological processes resulting from its misfolding and become a starting point for a design of an effective treatment against HCAA. S100B proteins, a specific type of calcium-binding protein, are essential for regulating various processes associated with Alzheimer’s disease Keywords: cystatin C, protein aggregation, amyloid formation, neuro- (AD). Among these processes, the S100B protein plays a critical role in degeneration the modulation of the amyloid precursor protein (APP) processing, the regulation of Abeta peptides (Aβ), and Tau phosphorylation. The inter- action between S100B and Aβ amyloid suggests that S100B acts as a regulatory factor, controlling the levels of Aβ oligomers in the human brain. In our study, we utilized NMR spectroscopy to explore the struc- tural changes that occur during the interaction between human S100B in its calcium-loaded form and Aβ(1-40) peptide. Analysis of chemical [31] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 5. FUS phosphorylation in FTLD these tangles also exist in the brain cells of canine patients, but to a lesser extent than in human patients. Because the disease has been Helena Motaln1, Urša Čerček1, Anand Goswami2, Boris Rogelj1,3 poorly studied, it is also possible that the neurofibrillary tangles appear similar to humans, but we do not have the right tools to detect them in 1 Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slo- the brain tissue. venia 2 Institute for Neuropathology, University Hospital RWTH, Aachen, Ger- Disease in dogs is important from two points of view - since it is a fairly many common disease in dogs, it is estimated that the prevalence of the dis- 3 Faculty of Chemistry and Chemical Technology, University of Lju- ease is more than 60% in dogs over the age of 12, the disease is of bljana, Slovenia interest for the development of new drugs and treatment methods for use in veterinary medicine, as quality of life of dogs and their owners is Nuclear to cytoplasmic mislocalization and aggregation of RNA-bind- severely compromised of dogs have this disease. On the other hand, ing proteins (RBPs), including Fused in sarcoma (FUS), are the main dogs with this disease also represent an important model for better neuropathological features of amyotrophic lateral sclerosis (ALS) and understanding of Alzheimer’s disease and for the development of new frontotemporal lobular degeneration (FTLD). In ALS-FUS these ag- drugs, but this model has only begun to be recognized in recent years. gregates arise from disease-associated mutations in FUS, whereas Dogs are undoubtedly an extremely interesting model for understanding in FTLD-FUS the cytoplasmic inclusions do not contain mutant FUS, dementia in humans, not only because the pathophysiological changes suggesting different molecular mechanisms of FUS pathogenesis. We in humans and dogs are similar, but also because dogs share with us have shown that phosphorylation of the C-terminal Tyr526 of FUS re- their living environment, our daily habits (too little movement and asso-sults in increased cytoplasmic retention of FUS due to impaired bind- ciated obesity often occurs simultaneously with owners and their dogs) ing to Transportin 1. Here we developed a novel antibody against the and are exposed to similar environmental factors. These are certainly C-terminally phosphorylated Tyr526 FUS (FUSp-Y526) that is specifi- completely different from the environment to which laboratory rodents cally capable of recognizing phosphorylated cytoplasmic FUS, which are exposed in controlled breeding facilities, so studying dogs with cog-is poorly recognized by commercially available FUS antibodies. Using nitive impairment could offer us many answers to the unknowns in the this FUSp-Y526 antibody, we demonstrated a FUS phosphorylation- development of Alzheimer’s dementia. specific effect on the cytoplasmic distribution of soluble and insoluble FUSp-Y526 in various cells. We found that FUSp-Y526 expression pat- tern corelates with active pSrc/pAbl kinases in specific brain regions Friday, September 29th, 14:00 of mice, indicating preferential involvement of cAbl in the cytoplasmic mislocalization of FUSp-Y526 in cortical neurons. Finally, altered cyto- Neuroendocrine plasticity of the brain: plasmic distribution of FUSp-Y526 was observed in cortical neurons of from biology to therapy post-mortem frontal cortex tissue from FTLD patients compared with controls. Given the overlapping patterns of cAbl activity and FUSp- Y526 distribution in cortical neurons, and cAbl induced sequestration of FUSp-Y526 into G3BP1 positive granules in stressed cells, we propose Klementina Fon Tacer1, Tomaž Bratkovič2 that cAbl kinase is actively involved in mediating cytoplasmic mislocali- 1 School of Veterinary Medicine, Texas Tech Univerzation and promoting toxic aggregation of wild-type FUS in the brains of FTLD patients, as a novel putative underlying mechanism of FTLD- sity & Texas Center for Comparative Cancer Research FUS pathophysiology. (TC3R), Amarillo, TX, USA 2 Faculty of Pharmacy, University of Ljubljana, Slove- nia 6. Alzheimer’s disease and canine cognitive dysfunction – two faces of the same disease? The brain is a composite neuro-endocrine organ, influenced by intri- cate neuronal and peripheral hormonal signaling conveying information Gregor Majdič from internal and external environments. In turn, complex neuropeptide Veterinary Faculty, University of Ljubljana, Slovenia networks enable efficient adaptation to an ever-changing environment and affect many bodily functions, such as metabolic status/ energy Advances in Alzheimer’s research are among other reasons limited by consumption, fertility, and stress responses. Dysregulation in any of the lack of good animal models, as neurodegenerative diseases do not the systems due to genetic or epigenetic changes can lead to neu-occur spontaneously in laboratory rodents. Although there are some rodevelopmental, reproductive, and cognitive disorders, or obesity, and models of genetically engineered mice that develop certain pathologi- can have wide-ranging effects on behavior, mood, and overall health, cal processes in the brain, such as the loading of amyloid plaques, the leading to different diseases, including Prader-Willi Syndrome and Alz-relevance of such models is questionable, as disease is not occurring heimer disease. This symposium will address, from an interdisciplinary spontaneously. However, neurodegenerative diseases occur in some and comparative point of view, the neuroendocrine plasticity of the domestic animals. Cognitive impairment of dogs - canine cognitive brain. The topics to be presented by confirmed speakers range from dysfunction is disease of older dogs that is similar in many ways to basic molecular biology and genetics to translational research at pre-Alzheimer’s dementia in humans. Dogs have problems with memory, clinical and clinical levels, applicable in human and veterinary medicine. spatial orientation, problems with recognizing the owners, changes in day-night rhythm, changes in character etc. Pathophysiologically, simi- Keywords: brain endocrine functions, neuroplasticity, stress, cognitive lar changes occur in the brain as in human patients with Alzheimer’s dysfunction, precocious/delayed puberty dementia, with brain cells dying and amyloid plaques being deposited in the brain. There are fewer reports of neurofibrillary tangles in brain cells, and some studies suggest that neurofibrillary tangles do not oc- cur in dogs with cognitive impairment, while other studies show that [32] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 1. Prader-Willi Syndrome-associated MAGEL2 in the regulation of Neurons from the noradrenergic nucleus locus coeruleus (LC) play a stress and endocrine function of the hypothalamus key neuromodulator role in the brain. They project axons to the most brain areas and release noradrenaline from their numerous axonal vari- Klementina Fon Tacer1,2, Maria Camila Hoyos Sanchez1,2, Tara Bayat1,2, cosities triggering global excitation by volume transmission. Noradren-Farzana Popy1,2, Igor Ponomarev3, Isabel Castro-Piedras3 aline preferentially activates astrocytes, homeostatic neuroglial cells, enriched with adrenergic receptors. Noradrenergic activation triggers in 1 School of Veterinary Medicine, Texas Tech University, Amarillo, TX, astrocytes Ca2+ and cAMP elevations and augments aerobic glycolysis USA with production of lactate, an important energy fuel that supports neu- 2 Texas Center for Comparative Cancer Research (TC3R), Amarillo, ronal function, including learning and memory formation. In most neu-TX, USA rodegenerative diseases and aging one of the first areas undergoing 3 Department of Pharmacology and Neuroscience, Texas Tech Univer- degeneration is the LC, suggesting that this may be the cause of agesity Health Sciences Center, Lubbock, TX, USA related brain hypometabolism and disease progression. By measuring lipid and glucose metabolism in astrocytes using fluorescent sensors The hypothalamus regulates fundamental aspects of physiological and microscopy, we have recently demonstrated that adrenergic recep-homeostasis and behavior, including stress response, reproduction, tor expression and signaling as well as lipid and glucose metabolism growth, sleep, and feeding, several of which are affected in patients and lactate release are dysregulated in stressed astrocytes that form with Prader–Willi (PWS) and Schaaf-Yang syndrome (SYS). PWS is intracellular protein (TDP-43) inclusions. These may suggest that astro-caused by the loss of expression of a maternally imprinted region of glial capacity to homeostatically support neurons is impaired, contribut-chromosome 15 encompassing five noncoding RNAs and six protein- ing to disease progression. The morphology of astrocytes determines coding genes; MAGEL2 is one of the coding genes that is also mutated the structural association between astrocytes and the synapse, con-in SYS patients. Management of PWS and SYS is mostly symptomatic sequently modulating synaptic function. We will also discuss how no-and finding cures is one of the unmet medical needs. Research over radrenergic excitability in astrocytes regulates morphology. In vivo and several decades into the molecular and cellular roles of PWS genes in vitro imaging of astrocytes revealed that adrenaline reduces hypo-has uncovered that several impinge on the neuroendocrine system. tonicity and trauma-induced cellular edema in astrocytes. Adrenaline, Notably, studies using mouse models with Magel2 loss have implicated via modifying cAMP-signaling, reduces hypotonicity-induced cytosolic the requirement of this protein for regulated secretion in the hypothala- Ca2+ excitability, which may prevent astrocyte swelling. These findings mus. On a cellular level, MAGEL2 regulates retromer-dependent endo- reveal astrocytes as new targets for the treatment of neurodegenera-somal protein trafficking and recycling of membrane proteins. However, tion and cellular edema in the central nervous system. the specific reasons why MAGEL2 is crucial for the secretory process in the hypothalamus, and which other molecular pathways are regu- lated by MAGEL2 under different conditions, in particular stress, remain 3. Selective butyrylcholinesterase inhibitor for alleviating symp-poorly understood. To gain an unbiased understanding of Magel2’s role toms of canine cognitive dysfunction in the hypothalamus, wild-type, and Magel2m+/pΔ mice were subjected to 24-hour fasting and analyzed on a single-cell level by single-nuclei Urban Košak1, Damijan Knez1, Anže Meden1, Simon Žakelj1, Jurij Tron-RNA sequencing. The insights gained from our studies will be pre- telj1, Jure Stojan2, Maja Zakošek Pipan3, Kinga Sałat4, Florian Nachon5, sented, which may provide novel perspectives on the pathogenesis of Xavier Brazzolotto5, Gregor Majdič3, Stanislav Gobec1 Prader-Willi syndrome, potentially leading to the discovery of innovative therapeutic interventions for affected patients. 1 Faculty of Pharmacy, University of Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Slovenia Acknowledgments/Funding: This work was supported by the Founda- 3 Veterinary Faculty, University of Ljubljana, Slovenia tion for Prader–Willi Syndrome Research Grant 22-0321 and 23-0447 4 Faculty of Pharmacy, Jagiellonian University, Krakow, Poland (to K.F.T. and Z.K.), Texas Tech University start-up (to K.F.T.), and 5 Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, Cancer Prevention and Research Institute of Texas Scholar Award France RR200059 (to K.F.T.). Canine cognitive dysfunction (CCD) is an incurable neurodegenera- Keywords: retromer, protein recycling, hormone, neuropeptide secre- tive disease which effects 60% of older dogs and its most prominent tion, single-cell RNAseq, neurodevelopmental disease, rare disease sign is cholinergic hypofunction. (1) As long as this disease cannot be prevented or cured, symptomatic treatment is critical. The only FDA approved drug for treating symptoms CCD is selegiline. This monoam- ine B inhibitor has adverse effects which make tolerability a significant 2. Noradrenergic regulation of astrocytes allows metabolic and limitation. (2) However, this problem can be overcome by inhibiting a morphological plasticity of astrocytes and therapeutic opportunity different enzyme, butyrylcholinesterase (BChE). Anemari Horvat1,2, Ena Begić1, Urška Černe1, Jelena Velebit1,2, Marko We used virtual screening to discover our hit compound, a novel pi-Kreft1,2,3, Robert Zorec1,2, Nina Vardjan1,2 peridine-based nanomolar selective BChE inhibitor. (3) Using ligand- based and structure-based drug design for hit-to-lead optimization, 1 Laboratory of Neuroendocrinology-Molecular Cell Physiology, Insti- we produced and evaluated a huge number of various derivatives. (4) tute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Our most promising compound is the sulfonamide derivative which im-Slovenia proved memory, cognitive functions and learning abilities of dogs suf- 2 Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, Slove- fering from CCD with no adverse effects. All owners of treated dogs nia reported a drastic improvement in the quality of life and dog-owner 3 Department of Biology, Biotechnical Faculty, University of Ljubljana, interaction. (5) Our selective BChE inhibitor is a new drug for treating Slovenia CCD and is a drug candidate for treating other forms of dementia, like Alzheimer’s disease in humans. [33] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 References: 5. Neuroplastin in normal brain physiology and disease 1. Mihevc, S. P. and Majdič, G. Front. Neurosci. 2019, 13, 604 2. Campbell, S. et al. Vet. Ther. 2001, 2, 24–39 Katarina Ilić1, Rodrigo-Herrera Molina2, Kristina Mlinac Jerković3, Goran 3. Brus, B.; Košak, U. et al. J. Med. Chem. 2014, 57, 8167–8179 Sedmak3, Nataša Jovanov Milošević3, Goran Šimić3, Borna Puljko3, 4. Košak, U. et al. Sci. Rep. 2016, 6, 39495; Košak, U. et al. Bioorg. Mario Stojanović3, Ivana Rosenzweig4, Svjetlana Kalanj Bognar3 Med. Chem. 2017, 25, 633–645; Košak, U. et al. J. Med. Chem. 2018, 61, 119–139; Košak, U. et al. Eur.J. Med. Chem. 2020, 197, 112282; 1 BRAIN Centre, Department of Neuroimaging, Institute of Psychiatry, EP3256128B1; US10071964 Psychology and Neuroscience, King’s College London, United King- 5. Zakošek Pipan, M. et al. Sci. Rep. 2021, 11, 18098; WO2022063751A1 dom 2 Synaptic Signalling Laboratory, Combinatorial NeuroImaging, Leibniz Institute for Neurobiology, Magdeburg, Germany 4. Endocrinology of precocious/delayed puberty 3 Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Croatia Magdalena Avbelj Stefanija 4 Sleep and Brain Plasticity Centre, CNS, IoPPN, King’s College Lon- Faculty of Medicine, University of Ljubljana, Slovenia don, United Kingdom Dept. for Pediatric Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Centre Ljubljana, Slovenia Transmembrane glycoprotein neuroplastin (Np) is a member of the im- munoglobulin superfamily of cell adhesion molecules. In animal cells, Pubertal timing is regulated by a balance between inhibitory and excita- two Np isoforms are produced by alternative splicing of the same gene: tory signals acting upstream of gonadotropin releasing factor (GnRH), a Np55 isoform is expressed in many different tissues while Np65 is brain-key hypothalamic hormone that orchestrates puberty and reproduction. specific and abundant in synaptic membranes. Studying neuroplastin-Yet, what triggers puberty remains unanswered. deficient mice revealed variety of important physiological actions of neuroplastin, such as involvement of brain-specific Np65 in synaptic Monozygotic twin studies suggest that genetic factors majorly deter- plasticity and associative memory formation. Interestingly, some of minate pubertal timing; furthermore, around 400 genes are associated the phenotypic characteristics of neuroplastin-deficient mice include with age at menarche by genome-wide association studies. Precocious reduced life span, corticosterone elevation in blood, disregulation of and delayed puberty also commonly appear as familial traits. Neverthe- the hypothalamic-pituitary axis and male infertility, indicating potential less, monogenic causes are identified in a minority of pedigrees. roles of Np65 in neuroendocrine homeostasis maintenance. Recent evidence suggests that effects of neuroplastins are associated with cel- Major secular trends toward earlier pubertal timing occurred along with lular calcium transport and homeostasis through the established struc-improved nutrition in recent centuries, and in recent decades the age tural interaction of Np with plasma membrane calcium ATPases. Also, at the onset of puberty is further decreasing. Some factors that could it has been demonstrated that the specific lipid microenvironment influ-be responsible, are childhood obesity, exposure to hormone disrupt- ences greatly on the intramembrane position, distribution, and func-ing chemicals and epigenetic changes. Adoption as a specific stressor, tions of neuroplastin in brain tissue. In this lecture, we will review the significantly increases the risk for precocious puberty. present knowledge about neuroplastins in animal tissues and elaborate in more details the involvement of Np65 in human brain (patho)physiol- Stress, weight loss, or excessive exercise can cause reversible hypo- ogy. We suggest that neuroplastin acts as a housekeeper of neuroplas-gonadism (in females termed hypothalamic amenorrhea (HA)), which ticity and may be considered as one of the important cognition-related can delay or arrest puberty. Similar effect have various endocrine dis- molecules in humans. Several potential routes for future investigations orders and chronic illness. The commonest cause of delayed puberty will be discussed, which might add to broader understanding of neurois constitutional delay in growth and puberty (CDGP), which is a self- plastin actions in animal tissues. limited condition. Keywords: neuroplasticity, neuroendocrine homeostasis, neurodevel- At the other end congenital hypogonadism (CH) presents with incom- opment, neurodegeneration plete or absent puberty, needing therapy. Above 50 genes implicated in GnRH neuron development, action or homeostasis are causative in about 50% of CH patients. Genetic heterogeneity, various inheritance 6. Impact of oxidation on SOD-1 aggregation and interaction with patterns, oligogenicity, and incomplete penetrance, make genetic coun- lipid membranes seling difficult. Some genetic overlap is observed also with HA, CDGP and patients with hypopituitarism. Interestingly, 10-20% of CH patients Ana-Marija Vučković1,2, Jelena Budimir1, Guillaume Combes1,2, Boštjan achieve remission of hypogonadism, the common denominator being Kokot3, Lucija Krce4, Eva Žerovnik5, Iztok Urbančič3, Miroslav Rad-normal blood sex hormone level achieved by therapy. man1,2,6, Katarina Trajković1,2 While the current knowledge of puberty regulation is incomplete, it is evident that multiple developmental and neuroendocrine pathways are 1 Mediterranean Institute for Life Sciences (MedILS), Split, Croatia involved, likely to facilitate adaptation to diverse environmental pres- 2 Center of Excellence for Science and Technology-Integration of sures on reproductive capacity. Mediterranean Region (STIM), Faculty of Science, University of Split, Croatia Keywords: puberty, gonadotropin releasing hormone, sex hormones, 3 Laboratory of Biophysics, Jožef Stefan Institute, Ljubljana, Slovenia genetics 4 Faculty of Science, University of Split, Croatia 5 Department of Biochemistry, Jožef Stefan Institute, Ljubljana, Slo- venia 6 NAOS Institute for Life Sciences, Aix-en-Provence, France [34] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenera- The aim of our work has been to gain insight into Slovenian public intive disease characterized by the progressive loss of motor neurons terest and active engagement in care for brain health. We carried out that control voluntary movement. Genetic studies revealed the involve- online surveys in 2017 and 2022 with different samples of the adult ment of superoxide dismutase 1 enzyme (SOD1) in the pathophysiol- population in Slovenia. The surveys revealed that the majority of the ogy of the disease. Both wild-type and mutant forms of SOD1 can gain Slovenian public correctly recognised brain health as optimal brain toxic function, which is reflected in their aggregation and cytotoxicity functioning, and not a mere absence of an illness. In both surveys, in ALS patients. However, it remains unclear how aging contributes to a vast majority of respondents (> 84%) considered brain health to be this toxic gain-of-function in SOD1. Since oxidative damage to proteins important or very important for quality of life. Interestingly, large seg-accumulates with age, in this study we investigated how oxidation con- ments (39% in 2017 and 73% in 2022) considered their knowledge on tributes to SOD1 toxicity. Thus, we analyzed the impact of oxidation on maintaining brain health as sufficient relative to their needs. A majority SOD1 aggregation properties and cellular behaviour, with the focus on of respondents denied having been diagnosed with a neurological or its interactions with the lipid membranes. psychiatric disorder. More than half stated, however, that they have a close friend or a family member with such a diagnosis. Most respond- Keywords: ALS, SOD1, oxidation, protein carbonylation, aging ents successfully identified science-based lifestyle choices that favor brain health, but struggled to adhere to the same choices in daily life. Women and older respondents were more actively engaged in main- Friday, September 29th, 16:30 taining brain health. Personal diagnosis or diagnoses of brain disorders among family members and friends were not associated with higher Brain health: public interest, assess- frequency of healthy practices. Key listed obstacles to engagement in ment tools, effects of modifying life- healthy activities were lack of time (> 22%), motivation (> 19 %) and style factors information (> 17%). Information was obtained primarily from televi- sion (> 38%), followed by newspapers and magazines, the internet, and conversations with people (friends and experts) in different propor- tions. Importantly, 38% of respondents struggled with the veracity of Mara Bresjanac information sources. The highest-rated desired sources of information on brain and brain health were: direct communication by experts and Institute of Pathophysiology, Faculty of Medicine, formal education. Our findings can inform new strategies to improve University of Ljubljana, Slovenia public awareness and engagement, and design policies for improving SiNAPSA, Slovenian Neuroscience Association, active care for brain health in Slovenia. ZDZG, Ljubljana, Slovenia Supported by Slovenian Ministry of Health grant ZDZG (2020 - 2025); High prevalence and steadily increasing burden of neuropsychiatric Public Research Agency grant UM (2022); IBRO Global Engagement disorders worldwide demand new and effective prevention strategies. Seed Grant 2021. Successful prevention hinges on early identification of individuals at high risk for development of a disorder, and on effective and accessible prevention measures. For many brain disorders, no disease modifying 2. Public interest in brain health testing - Insights from the Global treatment is available, yet, so value of any predictive tools could be Brain Health Survey questioned. In some disorders, even those with a huge public health and economy impact, like dementia, scientific evidence points to the Rebecca B. Carver1, Nanna Alida Grit Fredheim2, Athanasia Monika role of modifiable risk factors. These factors are promising targets for Mowinckel3, Klaus P. Ebmeier4, Barbara Bodorkos Friedman3, Tor Atle prevention strategies. We propose a symposium to tackle public aware- Rosnes5, Christian A. Drevon6,7, Sana Suri4,8, William F. C. Baaré9, ness of brain health and the role of modifiable factors in brain health, Eniko Zsoldos4,8, Cristina Solé-Padullés10, David Bartrés-Faz10,11, San-public interest in brain health testing, recently developed tools for as- dra Düzel12, Kathrine Skak Madsen9,13, Anders M. Fjell3, Ulman Linden-sessment of risk for certain brain disorders (dementia and stroke), and berger14,15, Kristine B. Walhovd3, Isabelle Budin-Ljøsne16 the recent progress in determining the effects of lifestyle modification on incidence and course of dementia. 1 Department of Communication, Norwegian Institute of Public Health, Oslo, Norway Keywords: primary prevention, neuropsychiatric disorders 2 School of Communication, Leadership and Marketing, Kristiania Uni- versity College, Oslo, Norway 3 Department of Psychology, Center for Lifespan Changes in Brain and 1. Public awareness and active care for brain health in Slovenia Cognition, University of Oslo, Norway 4 Department of Psychiatry, University of Oxford, United Kingdom Mara Bresjanac 5 Reviews and Health Technology Assessments Cluster, Norwegian 1,2, Ida Muc1,2, Lana Blinc1,2, Matej Perovnik3, Tina Vovk Institute of Public Health, Oslo, Norway 4, Slavko Kurdija4 6 Department Nutrition, Faculty of Medicine, Institute Basic Medical 1 Institute of Pathophysiology, Faculty of Medicine, University of Lju- Sciences, University of Oslo, Norway bljana, Slovenia 7 Vitas AS, Oslo Science Park, Oslo, Norway 2 SiNAPSA, Slovenian Neuroscience Association, ZDZG, Ljubljana, 8 Wellcome Centre for Integrative Neuroimaging, University of Oxford, Slovenia United Kingdom 3 Deparment of Neurology, University Medical Centre Ljubljana, Slo- 9 Danish Research Centre for Magnetic Resonance, Centre for Func-venia tional and Diagnostic Imaging and Research, Copenhagen University 4 Public Opinion and Mass Communication Research Centre, Faculty Hospital Amager and Hvidovre, Copenhagen, Denmark of Social Sciencies, University of Ljubljana, Slovenia 10 Department of Medicine, Faculty of Medicine and Health Sciences & Institute of Neurosciences, University of Barcelona, Spain [35] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 11 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), brain care and contribute significantly to reducing the incidence of Barcelona, Spain stroke, dementia and late-life depression for populations across the 12 Center for Lifespan Psychology, Max Planck Institute for Human De- globe. velopment, Berlin, Germany 13 Radiography, Department of Technology, University College Copen- hagen, Denmark 4. Validation of the LIBRA Index in assessing modifiable risk fac- 14 Center for Lifespan Psychology, Max Planck Institute for Human De- tors and helping identify people who could benefit from primary velopment, Berlin, Germany prevention interventions 15 Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, Germany Stephanie J. B. Vos 16 Department of Food Safety, Norwegian Institute of Public Health, Maastricht University, Maastricht, The Netherlands Oslo, Norway Alzheimer’s disease can already be identified at early disease stages This study investigated people’s interest in learning about personal using biomarkers in cerebrospinal fluid or on brain PET scans. These brain health, understood as mental wellbeing and cognitive health in biomarkers can predict cognitive decline. In midlife and later life also the absence of brain disorders. Through a cross-sectional multilan- lifestyle and vascular problems play a role in brain health. For instance, guage survey, respondents were asked to estimate their willingness it is known that physical activity, smoking and diabetes can influence and reasons to—or not to—undertake a hypothetical brain health test brain health and cognition. However, it remains unclear how lifestyle to learn about personal risk of developing a brain disease. The sur- and vascular problems are related to Alzheimer’s disease and how vey was open to the public between June 2019 and August 2020, and these processes influence each other. Dr. Stephanie Vos will address formed part of the Global Brain Health Survey, hosted by the Lifebrain in her presentation the association of Alzheimer’s disease with lifestyle project. In total, 27,590 people aged 18 years or older responded to the and vascular problems. More specifically, she will show findings on the online survey. Respondents were largely recruited via European brain relation of individual lifestyle factors and an overall lifestyle for brain councils and research organizations, and were predominantly women health (LIBRA) index with Alzheimer’s disease biomarkers and cogni- (71%), middle-aged or older (>40 years; 83%), and highly educated tive decline. In addition, she will highlight findings regarding the asso- (69%). Responses were analyzed to explore the relationship between ciation of diabetes with Alzheimer’s disease biomarkers and cognitive demographic variables and responses. The study finds an overall high decline. interest in brain health testing. Over 91% of respondents would defi- nitely or probably take a brain health test and 86% would do so even if Keywords: dementia, biomarkers, diabetes, vascular health it gave information about a disease that cannot be treated or prevented. The main reason for taking a test was the ability to respond if one was found to be at risk of brain disease, such as changing lifestyle, seeking 5. Can a city prevent dementia? counseling or starting treatment. Higher interest in brain health testing was found in men, respondents with lower education levels and those Jeremy D. Isaacs with poor self-reported cognitive health. St George’s University Hospitals NHS Foundation Trust, St George’s University of London NHS England London Dementia Clinical Network, London, United 3. Multi-dimensional McCance Brain Care Score - an accessible Kingdom tool to maintain and improve brain health Individual risk of developing dementia is falling in the global North. Sanjula Dhillon Singh However, due to demographic ageing, the overall number of people McCance Center and Harvard Medical School, Boston, MA, USA living with dementia is predicted to increase significantly; by 42% in London between 2019 and 2030. We are not powerless in the face Dr. Sanjula Singh will introduce the McCance Center for Brain Health’s of this change. The Lancet Commission identified 12 modifiable risk mission and unveil the McCance Brain Care Score™, a novel, patient- factors which if optimally addressed could prevent or delay up to 40% informed tool that simplifies science-backed lifestyle choices to lower of dementia cases. In London we have started to formulate a compre-their risk of dementia, stroke, and late-life depression. Developed in hensive dementia prevention plan based on these 12 risk factors. The collaboration with patients throughout the Harvard system, the Mc- first step was a scoping exercise to identify existing health programmes Cance Brain Care Score™ empowers both patients and providers to that are addressing these factors even if dementia is not explicitly men-proactively manage and enhance brain health. tioned. The next step will require co-ordination between multiple agen- cies and system leadership. Air quality is a current area of contention Furthering the conversation around brain care, Dr. Singh will also touch because of the introduction of a road pricing system targeting the most on the REACH-ICH study, which represents an innovative initiative, polluting vehicles. However, air quality in London has improved signifi-focusing on the social determinants of health (SDOH) that influence cantly in response to such policies and it is likely that this has already participation in a state-of-the-art blood pressure program in intracer- prevented or delayed dementia in thousands of people. I will contrast ebral hemorrhage (ICH survivors from underrepresented communities these population-level interventions with individualised solutions such throughout the US. The REACH-ICH study aims to assess if particular as the FINGER study and “brain health clinics” and propose that the modifiable SDOH are associated with (i) vascular cognitive impairment latter approaches are less likely to be effective or scalable or produce and dementia and recurrent stroke (ii) increased blood pressure, and equitable health outcomes. (iii) patient engagement in a blood pressure program, after a primary ICH – in order to test interventions targeting those specific SDOH. The integration of the McCance Brain Care Score™ and the findings from the REACH-ICH study are expected to reshape perceptions of [36] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Saturday, September 30th, 14:00 structural and functional neuroimaging approaches will be discussed. Novel approaches in treatment of de- Additionally, advancements in the understanding of the role of resting-state networks in psychiatric disorders are explored as potential av- pression with transcranial magnetic enues for enhancing target localization. The integration of these meth-stimulation ods offers the potential to tailor TMS treatment to individual patients, ultimately improving the efficacy and therapeutic impact of TMS in the realm of psychiatric disorders. Jurij Bon1,2, Grega Repovš3 1 University Psychiatric Clinic Ljubljana, Slovenia 3. Accelerated and neuronavigated TMS therapy of depression 2 Department of Psychiatry, Faculty of Medicine, Uni- Jurij Bon versity of Ljubljana, Slovenia University Psychiatric Clinic Ljubljana, Slovenia 3 Department of Psychology, Faculty of Arts, Univer- Department of Psychiatry, Faculty of Medicine, University of Ljubljana, sity of Ljubljana, Slovenia Slovenia Symposium will present novel approaches in the treatment of depres- The Slovenian national guidelines for the treatment of depression have sion with transcranial magnetic stimulation of the brain. We will show recently been updated. Treatment of drug-resistant depression now how the field is moving towards individualized treatment plans in pa- includes non-invasive methods of brain stimulation. Newer forms of tients, where stimulation targets are selected based on their specific depression treatment are difficult to introduce as publicly funded health resting state brain network activity. The general usability of resting state services in Slovenia, in part because it is difficult to objectively meas-brain network activity for clinical applications will be discussed and local ure the success of depression treatment. On the other hand, Slove-work presented that aims to generate usable and robust treatment pro- nian health authorities are aware of the importance of introducing new tocols. We will also discuss recent improvements in accelerated theta treatments given the high social burden of depression. Recent TMS burst stimulation and individually localized deep TMS stimulation. treatment protocols for depression, such as the neuronavigated and accelerated theta burst protocol, show the possibility of a significant Keywords: TMS, neuronavigation, depression breakthrough in the clinical effectiveness of non-invasive brain stimula- tion. I will present current developments in this field and our own clinical experience with TMS treatment of depression at University Psychiatric 1. Advances in the use of resting state data for clinical application Clinic Ljubljana. Grega Repovš Department of Psychology, Faculty of Arts, University of Ljubljana, Slo- 4. Electroencephalograhy for early prediction of TMS treatment venia success The ease of acquisition and the wealth of information embedded in rest- Aleš Oblak ing-state functional connectivity have driven its use in recent decades, University Psychiatric Clinic Ljubljana, Slovenia bringing it to the forefront of neuroimaging research. As it requires no cognitive engagement on the part of the subject, it has had a particular- TMS has proven to be an efficient clinical intervention for treatment-ly profound impact on both basic and applied clinical research. This in- resistant depression. However, depending on the study, only 50-75% troductory talk will provide a brief introduction to the use of resting-state patients respond to TMS treatment. TMS treatment protocols are time data, methods of data analysis, and examples of empirical findings. It consuming, lasting in the order of a couple of weeks, and can thus rep-will outline its potential, when combined with Research Domain Crite- resent an additional burden for the patients if unsuccessful. It is there-ria approach to psychopathlogy, for targeted therapy development and fore imperative to discern early biomarkers that could predict treatment validation, and personalised treatment. Finally, it will highlight some of outcome. We discuss some behavioral and EEG biomarkers that may the challenges and possible future developments in the use of resting- serve as potential candidates. We focus particularly on the role of an-state data for basic research and clinical applications. hedonia, dysphoria, cognition, and rumination as potential modifiers of treatment outcomes. Finally, we focus on alpha and theta EEG bands, which have been previously shown to be predictive of TMS outcome. 2. Development of treatment protocols and methodological proce- We discuss theta cordance, an approximation of cerebral perfusion as dures for resting state networks based neuronavigation a golden-standard biomarker. Nina Purg, Andraž Matkovič Department of Psychology, Faculty of Arts, University of Ljubljana, Slo- venia Transcranial magnetic stimulation (TMS) has emerged as a promising therapeutic approach for psychiatric disorders, but achieving optimal outcomes necessitates precise targeting of specific brain regions. The general assumption is that the optimal TMS target varies from person to person due to individual differences in the structure and function of the brain. We provide an overview of the most prominent methods em- ployed to determine personalized target locations for TMS treatment in psychiatric disorders. Techniques such as neuronavigation based on [37] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Saturday, September 30th, 16:30 glutathione in certain brain regions, including medial prefrontal cortex, Biology of schizoaffective contiuum striatum and thalamus. There is evidence that this is associated with the reduction of GABAergic interneurons, white matter abnormalities and microglial activations, all of which are implicated in the pathogene- sis of schizophrenia spectrum disorders. In addition, abnormal function Milica Velimirović Bogosavljević of the NADPH oxidase family of enzymes that normally produces ROS School of Medicine, University of Belgrade, Serbia may contribute to the disease. These and other redox-related molecular species should be further investigated to elucidate their role as poten- tial biological markers to improve the diagnosis of schizoaffective and Schizoaffective contiuum is a group of mental health condition that other schizophrenia spectrum disorders but also as new therapeutic includes mental disorders ranging from schizophrenia to mood disor- targets for future treatment strategies. ders such as bipolar disorder or even depression. It is characterized by wide range of signs and symptoms that makes the targeted diagnostics Keywords: schizophrenia spectrum disorders, psychosis, redox state, often challenging. Mental disorders pertaining to the schizoaffective glutathione, NADPH oxidase contiuum disorders usually become evident in adolescence or young adulthood with variety of difficulties including psychotic and/or affetctive symptoms, cognitive impairment or even metabolic changes. People 2. Underlying inflammation in Schizoaffective disorders continu-with these disorders can have higher risk of substance abuse problems um and suicide than the general population. Milica Velimirović1, Maja Pantović Stefanović2, Bojana Dunjić The exact pathophysiology responsible for overlap of symptoms or Kostić2, Tihomir Stojković1, Tatjana Nikolić1, Milica Živković1, Nataša specific differences among the disorders pertaining to schizoaffective Petronijević1 contiuum is currently unknown. The potential causes may be laying in genetics, abnormalities of neurotransmitters (dopamine, norepineph- 1 Institute of Clinical and Medical Biochemistry, School of Medicine, rine, and serotonin), and disorders of white matter in multiple areas University of Belgrade, Serbia of the brain, reduced hippocampal volumes and distinct deformations 2 Clinic for Psychiatry, Clinical Centre of Serbia, Belgrade, Serbia in the medial and lateral thalamic regions. Moreover, due to overlap of symptoms between the disorders the analysis of neurobiological un- There is an increasing interest in the role of inflammation in the patho-derpinnings of the disorders is of additional importance. However, the physiology of various mental health disorders. Inflammation involves exact causes of disorders of schizoaffective continuum are still a matter the activation of the immune system in response to various stressors, of study. infections, or other factors. In some cases, excessive or chronic in- flammation may contribute to changes in brain function and structure, Since the treatment of these disorders is of great importance for their potentially contributing to the development or progression of mental course, staging and quality of life of the patients it is necessary to focus disorders. Pro-inflammatory cytokines, such as C reactive protein on novel diagbistic and treatment strategies in order provide timely and (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), inadequate treatment, prevent neurodegeneration and foster neuropro- terleukin-1 beta (IL-1β), vascular cell adhesion molecule-1 (VCAM-1), tection. intercellular adhesion molecule-1 (ICAM-1) and others are often al- tered during inflammatory responses. These cytokines can cross the Keywords: schizoaffective, dementia, bipolar, schizophrenia, mental blood-brain barrier and affect brain function through activation of the health hypothalamic-pituitary-adrenal (HPA) axis, induction of oxidative stress, interference with neurotransmitter systems, affecting mood, cognition, damaging neurons, impairing neural circuits and provoking psychosis. 1. Redox dysregulation in schizoaffective disorders continuum Findings suggest that mentioned cytokines could potentially serve as early indicators of psychiatric disorders offering insights into the risk of Tihomir Stojković, Milica Velimirović, Tatjana Nikolić, Nataša Petronijević developing a broad spectrum of symptoms, ranging from affective tem-Institute of Clinical and Medical Biochemistry, School of Medicine, Uni- peraments to full blown disorders. Also these molecules could serve as versity of Belgrade, Serbia indicators of immune system involvement in both affective and psychot- ic disorders reflecting the progression and offer insights into potential The neurobiological exploration of schizoaffective disorder mainly relies immune-related mechanisms underlying these disorders. Further, they on data from the studies of schizophrenia and psychotic mood disor- may be potential indicators of association between inflammation, dis-ders (bipolar disorder and depression), due to similar clinical features ease activity and symptom severity. Additionally, specific cytokine pat-and presumed similar etiology and pathological mechanisms of these terns may be associated with different, clinical subtypes (endopheno-diseases. Converging evidence indicates that redox dysregulation types) of major disorders of schizoaffective continuum. These markers plays an important role in the development of psychosis. Redox dys- could offer insights into the immunomodulatory aspects of medication regulation is the alteration of the physiological balance in the production and could potentially inform treatment strategies. However, the exact and elimination of reactive oxygen (ROS) and nitrogen (RNS) species nature of inflammation and psychiatric disorders relationship is com-that impair the cellular redox state and can even lead to oxidative dam- plex and still not fully understood, nonetheless it did draw the attention age of macromolecules, including lipids, proteins and nucleic acids. on developing novel treatment strategies. The brain is particularly susceptible to oxidative damage due to its high demand for oxygen and relatively low levels of antioxidative defenses. Keywords: schizoaffective disorders continuum, inflammation, cy-Redox dysregulation can be caused by a variety of genetic and environ- tokines, CNS mental factors. Results from clinical research and animal model stud- ies, including the phencyclidine (PCP) model of glutamatergic NMDA receptor hypofunction, have shown reduced levels of the antioxidant [38] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 3. Bipolar spectrum disorders - neurobiology and treatment Maja Pantović Stefanović1,2, Marta Gostiljac1, Emilija Erić1, Bojana Dunjić Kostić1,2, Milica Velimirović2,3 1 Clinic for Psychiatry, University Clinical Center of Serbia, Belgrade, Serbia 2 School of Medicine, University of Belgrade, Serbia 3 Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Serbia A continuum-based approach to psychopathology of mood disorders, embedded into a prospective long-term follow-up is a new paradigm of multidimensional patient assessment throughout their clinical journey. Novel diagnostic guidelines and contemporary view of affective disor- ders allows more focus on dimensional approach and staging of bipolar disorders. Bipolar disorders are now perceived to exist on a continuum of wide range of symptoms varying in their duration, severity, and pat- tern of appearance, often resulting in the delay of treatment and poor prognosis. Their biological underpinning is complex, involving multiple systems and external factors shaping the clinical presentation, course of illness and response to treatment. Moreover, the interplay of inherent and environmental factors can be responsible for the specific relation- ship of these disorders with other diseases, but primarily for their longi- tudinal development. The assessment of biological markers involved in both neurodegenerative, but also neuroprotective processes is of vital importance in evaluating the course of the disorders and particularly treatment response. Early detection of the disease and timely and con- tinuous treatment can significantly help to strengthen neuroprotection and lead to a better course of bipolar disorders. Keywords: bipolar disorders, treatment, biomarkers, continuum, stagin 4. The price of becoming human: schizophrenia in the light of evo- lutionary neuroscience Milica Nešić Clinic for Psychiatry, University Clinical Center of Serbia, Belgrade, Serbia School of Medicine, University of Belgrade, Serbia Schizophrenia is a debilitating and chronic psychiatric disorder. The etiology of schizophrenia is still poorly understood. Moreover, schizo- phrenia presents an intriguing evolutionary paradox – even though it is heritable and decreases fecundity, it is still maintained in the population at a disproportionally high rate. Several different theories aim to explain this paradox. For instance, some authors suggest that schizophrenia is the “price” mankind pays for human-specific faculties (such as lan- guage). According to others, certain schizophrenia risk variants may have benefits patients or their relatives (e.g., creativity). Recent ad- vances in comparative genomics (especially comparisons of the human genome and the genomes of related species, such as chimpanzees and extinct hominids), neuroimaging, and neuropsychology have finally put long standing evolutionary theories of schizophrenia to the test and here I present some of the most outstanding findings. The exploration of evolutionary background of schizophrenia is important not only to better understand the etiology of the disorder, but to also uncover the fundamental processes of becoming human. Keywords: psychosis, natural selection, cognition, adaptation [39] SNC’23 SNC’ SiNAPSA NEUROSCIENCE CONFERENCE ‘23 Ab A s b tract s s tract SNC’23 P SNC’ o 23 P s o t s e t rs e www.sinapsa.org/SNC23 Ljubljana, Slovenia 28-30 September 2023 SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 CEL.01 Friday, September 29th, 13:00 [Cellular Neuroscience A] cally excitable and secretory cells. While motor neurons signal to mus- FUS phosphorylation in FTLD cle via acetylcholine and agrin, muscle secretes neurotrophic factors and myokines that signal back to motor neurons as well as the brain. Myokines, such as interleukin-6 (IL-6), whose secretion is driven by skeletal muscle contractions are thought to provide an important link Helena Motaln1, Urša Čerček1, Anand Goswa- between regular physical activity and its beneficial effects on the nerv-mi2, Boris Rogelj1,3 ous system. The majority of extracellular proteins, including IL-6, which plays an important role in myogenesis, muscle regeneration, inflam- 1 Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slove- mation and metabolism, are thought to be phosphorylated by FAM20C nia kinase. However, its function in skeletal muscle and neurons has not 2 Institute for Neuropathology, University Hospital RWTH, Aachen, Ger- been characterized. many 3 Faculty of Chemistry and Chemical Technology, University of Lju- Using primary human skeletal muscle cells, we investigated the expres-bljana, Slovenia sion of FAM20C and FAM20A, a pseudokinase and an allosteric activa- tor of FAM20C, during proliferation of myoblasts and their differentiation Nuclear to cytoplasmic mislocalization and aggregation of RNA-bind- into multinucleated myotubes. FAM20A showed increased expression ing proteins (RBPs), including Fused in sarcoma (FUS), are the main in differentiated myotubes, while FAM20C expression declined during neuropathological features of amyotrophic lateral sclerosis (ALS) and differentiation. Gene silencing of FAM20A expression moderately in-frontotemporal lobular degeneration (FTLD). In ALS-FUS these ag- creased the expression of IL-6, its receptors (IL-6Rα and gp130), and gregates arise from disease-associated mutations in FUS, whereas the phosphorylation of its downstream effector STAT3, while gene si-in FTLD-FUS the cytoplasmic inclusions do not contain mutant FUS, lencing of FAM20C had no effect. suggesting different molecular mechanisms of FUS pathogenesis. We These findings suggest that FAM20C and FAM20A expression depends have shown that phosphorylation of the C-terminal Tyr526 of FUS re- on the differentiation stage of skeletal muscle cells, potentially affect-sults in increased cytoplasmic retention of FUS due to impaired bind- ing IL-6 signalling and the extracellular phosphoproteome during myo-ing to Transportin 1. Here we developed a novel antibody against the genesis. Elucidation of the interplay between FAM20C and IL-6 may C-terminally phosphorylated Tyr526 FUS (FUSp-Y526) that is specifi- provide valuable insights into the complex communication between cally capable of recognizing phosphorylated cytoplasmic FUS, which skeletal muscle and the nervous system. is poorly recognized by commercially available FUS antibodies. Using this FUSp-Y526 antibody, we demonstrated a FUS phosphorylation- Keywords: FAM20C, skeletal muscle cell, IL-6, physical activity, gene specific effect on the cytoplasmic distribution of soluble and insoluble expression FUSp-Y526 in various cells. We found that FUSp-Y526 expression pat- tern corelates with active pSrc/pAbl kinases in specific brain regions of mice, indicating preferential involvement of cAbl in the cytoplasmic CEL.05 Friday, September 29th, 13:00 [Cellular Neuroscience A] mislocalization of FUSp-Y526 in cortical neurons. Finally, altered cyto- plasmic distribution of FUSp-Y526 was observed in cortical neurons of Innervation of cultured human myo-post-mortem frontal cortex tissue from FTLD patients compared with tubes by α-motor neurons has diver-controls. Given the overlapping patterns of cAbl activity and FUSp- Y526 distribution in cortical neurons, and cAbl induced sequestration of gent and time-dependent effects on FUSp-Y526 into G3BP1 positive granules in stressed cells, we propose the mRNA expression of Na+,K+-AT-that cAbl kinase is actively involved in mediating cytoplasmic mislocali- Pase and myokines zation and promoting toxic aggregation of wild-type FUS in the brains of FTLD patients, as a novel putative underlying mechanism of FTLD- FUS pathophysiology. Vid Jan1, Katarina Miš1, Natasa Nikolic2, Kle- Keywords: FUS, phosphorylation, dementia men Dolinar1, Metka Petrič1, Andraž Bone1, G. Hege Thoresen2,3, Arild C. Rustan2, Tomaž Marš1, Alexander V. Chibalin4,5, Sergej Pirk- CEL.03 Friday, September 29th, 13:00 [Cellular Neuroscience A] majer1 Expression patterns of secretory path- 1 Institute of Pathophysiology, Faculty of Medicine, University of Lju-way kinase FAM20C and its regulator bljana, Slovenia FAM20A vary with differentiation stage 2 Section for Pharmacology and Pharmaceutical Biosciences, Depart-in cultured skeletal muscle cells ment of Pharmacy, University of Oslo, Norway 3 Department of Pharmacology, Institute of Clinical Medicine, Univer- sity of Oslo, Norway 4 National Research Tomsk State University, Tomsk, Russia Katja Fink, Katarina Miš, Marjeta Milostnik, 5 Department of Molecular Medicine and Surgery, Integrative Physiol-Sergej Pirkmajer ogy, Karolinska Institutet, Stockholm, Sweden Laboratory for Molecular Neurobiology, Institute of Pathophysiology, Na+,K+-ATPase (NKA), a heterodimeric (α/β) ion pump and P-type Faculty of Medicine, University of Ljubljana, Slovenia ATPase, maintains transmembrane ion gradients and is essential for skeletal muscle excitability and contractility. Under in vivo conditions, Skeletal muscle cells share more common ground with motor neurons denervation reduces the abundance of NKA in skeletal muscle, while than just the neuromuscular junction. They are, like neurons, electri- subsequent reinnervation increases it. Cultured human myotubes, [41] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 a widely used experimental model to study human skeletal muscle istration and ischemia induction. We observed lower hematocrit level in vitro, typically do not contract spontaneously unless innervated by about 30% after 3 hours of reperfusion in non-treated rats and two-fold α-motor neurons. Using the co-culture of primary human myotubes and increase in sedimentation rate. Animals with RIPC induction have hem-embryonic rat spinal cord explants, we determined whether innervation atocrit level in normal range, as well as sedimentation rate. On the base by α-motor neurons modulated mRNA levels of NKA subunits (α and of our results, we assumed that RIPC should influence inflammation, β). In addition, we determined the effect of innervation on mRNA lev- what predispose this approach as treatment and possible prevention of els of muscle-derived cytokines (myokines), whose expression in vivo COVID-19 positive patients. is also regulated by contractions. Innervated myotubes, which started to contract 7-10 days after establishment of co-culture, had higher Supported by APVV-21-0069, VEGA 2/0073/21 a VEGA 2/0096/22. mRNA levels of myokines, such as IL-6, IL-7, IL-8, and IL-15, after 10- 11 days of co-culture. In contrast, the mRNA levels of NKA subunits Keywords: Remote conditioning, Stroke, COVID-19, inflammation and myokines, such as musclin, cathepsin B, meteorin-like protein, or SPARC, remained similar between the innervated and non-innervated cultures. In 21-day-old co-cultures the mRNA levels of NKA subunits CEL.09 Friday, September 29th, 13:00 [Cellular Neuroscience A] and myokines did not differ from those in non-innervated cultures. The The role of tenascin-C on the structur-NKA mRNA levels were not affected by neuromuscular blocking agents α-bungarotoxin or tubocurarine. Taken together, this study shows that in al plasticity of perineuronal nets and vitro innervation of human myotubes exerts divergent, time-dependent synaptic expression in the hippocam-effects on the expression of NKA subunits and myokines. Importantly, NKA expression in cultured myotubes seems to be independent of in- pus nervation, which suggests that the expression pattern of NKA subunits is determined by an intrinsic myogenic program. Ana Jakovljević1, Vera Stamenković1,2, Milena Keywords: innervation, myotubes, Na+,K+-ATPase Tucić1, Igor Jakovcevski3, Pavle R. Andjus1 1 Center for Laser Microscopy, Institute for Physiology and Biochem- CEL.07 Friday, September 29th, 13:00 [Cellular Neuroscience A] istry “Jean Giaja”, Faculty of Biology, University of Belgrade, Serbia Remote post-conditioning reduced in- 2 Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, USA flammation markers and infarct size 3 Institut für Anatomie und Klinische Morphologie, Universität Witten/ after focal ischemia associated with Herdecke, Witten, Germany hyper-inflammatory reaction (simula- Neuronal plasticity is a fundamental property of a nervous system that tion of COVID-19) allows its change in response to the stimulus by reorganizing structure, functions, and connections. Among the main regulators of neuronal plasticity are perineuronal nets (PNNs), condensed forms of extracel- Jana Končeková, Miroslav Gottlieb, Klaudia lular matrix (ECM) that enwraps mostly parvalbumin (PV+) expressing Kotorová, Petra Bonová inhibitory interneurons. Next, a member of a family of ECM glycopro- teins, protein tenascin-C (TnC) was demonstrated to modulate synaptic Institute of Neurobiology, Biomedical Research Center, Slovak Acad- plasticity in the hippocampus. This study aims to show if TnC deficiency affects the number, intensity, and ultrastructure of PNNs around PV+ emy of Sciences, Košice, Slovak Republic and PV- cells and the expression of inhibitory and excitatory synaptic markers in the hippocampus. To enhance neuronal plasticity, TnC-defi- Statistical prognoses for stroke are changing worldwide after SARS- cient (TnC -/-) and wild-type mice were reared in an enriched environ-CoV-2 pandemic. Infection-induced release of pro-inflammatory ment (EE), and control standard environment (SE) for 8 weeks and cytokines and abnormal levels of coagulation factors are cause of 4 weeks. Results have shown that TnC deficiency caused regional-thrombus formation. The only one treatment in a clinic (tPA) has many specific changes in PNNs expression and ultrastructure, as well as the limitations in these patients. The increased demand for developing nov- expression of synaptic markers. el non-pharmacological therapies to elevate the tolerance to ischemia has been paying attention. Remote ischemic conditioning (RIPC) meets Keywords: neuronal plasticity, perineuronal nets, tenascin-C these conditions because of the ability to stimulate the endogenous protective mechanisms ensuring resistance to stroke. CEL.11 Friday, September 29th, 13:00 [Cellular Neuroscience A] COVID-19 was simulated by lipopolysaccharide (LPS) intratracheal administration. We induced focal ischemia after one day of LPS ad- Effects of elevated extracellular K+ on ministration (development of hyper-inflammatory reaction). RIPC was astrocyte metabolism and morphology applied after one hour of reperfusion in the form of hind limb ischemia. Efficiency of RIPC was evaluated by infarct size determination using TTC staining. Moreover, we investigated effect of this therapy on sedi- Ena Begić1, Bojana Lazović1, Anemari Hor-mentation rate and hematocrit. vat1,2, Urška Černe1, Robert Zorec1,2, Nina Var- Our results confirmed neuroprotective potential of RIPC even in rats djan1,2 with hyper-inflammatory reaction. We observed reduced infarct size 1 Laboratory of Neuroendocrinology – Molecular Cell Physiology, In-about 50% in RIPC treated animals, compared to non-treated. Moreo- stitute of Pathophysiology, Faculty of Medicine, University of Ljubljana, ver, RIPC affect the inflammatory markers associated with LPS admin- Slovenia [42] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 2 Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, stimulation (an invertebrate analogue of noradrenaline). Octopamine Slovenia triggered Ca2+ signals in neurons and glial cells in young, but not aged brains. Octopamine triggered intracellular cAMP signal and lactate in- Neurons are highly specialized cells in the brain that transmit informa- creases only in neurons, indicating that cAMP-mediated aerobic gly-tion by electrical impulses (action potentials), which requires a lot of en- colysis occurs primarily in neurons. The latter were not affected by ag-ergy. Astrocytes, homeostatic neuroglial cells, can sense the increased ing. Octopamine increased cytosolic glucose levels (glucose uptake) neuronal activity and energy demand via released neurotransmitters only in astrocytes, which was absent in aged brains. When exposed (e.g., glutamate, noradrenaline, ATP). They begin to degrade glucose to elevated glucose or lactate levels, both neurons and glial cells were to lactate, which is considered to be delivered to neurons as energy able to uptake nutrients, although in neurons the glucose uptake was fuel. This is crucial for learning and memory formation. Increased neu- reduced in aged brains. ronal activity is accompanied with an extracellular rise in K+, which is released from neurons. Here, we investigated in rat cortical astrocytes Our results suggest impaired octopaminergic Ca2+ signaling in brain (in vitro) and in astrocytes in Drosophila brains (ex vivo) by using fluo- cells and glucose uptake in astrocytes and reduced glucose delivery rescent sensors (Fluo-4 AM dye and GcaMP (Ca2+), Epac1-camps to neurons in aged Drosophila brains, which may contribute to the age- (cAMP), FLII12Pglu-700μδ6 (D-glucose), Laconic (L-lactate)) and real- related cognitive deficits. time confocal microscopy how rise in extracellular K+ concentration ([K+]out) affects intracellular glucose and lactate levels and Ca2+ and Keywords: glial cells, neurons, Drosophila, cell signaling, metabolism cAMP signals. The latter have previously been linked to the regulation of astrocytic lactate production. Elevated [K+]out (physiological (15 mM) and pathological (50 mM) [K+]out (epilepsy, migraine, brain injury)) CEL.04 Saturday, September 30th, 13:00 [Cellular Neuroscience B] increased intracellular Ca2+, cAMP, D-glucose and L-lactate levels in Astroglial P2X7R and Cx-43 expres-cortical astrocytes. This indicates that K+ is an important regulator of astrocytic metabolism during increased neuronal activity and may con- sion pattern in the vicinity of autoreac-tribute to astroglial metabolic support of neurons by L-lactate. Because tive immune cells in EAE model astrocytes swell in response to increased [K+]out, we also measured morphological changes in astrocytes. Elevated [K+]out resulted not only in astrocytic volume increase (15%), but also in processes length in- Katarina D. Miličević1, Danijela B. Bataveljić1, crease (40%), which may affect the diffusion of molecules, including metabolites, in the extracellular space and neurotransmission. Jelena J. Bogdanović Pristov2, Pavle R. And- jus1, Ljiljana M. Nikolić3 CEL.02 Saturday, September 30th, 13:00 [Cellular Neuroscience B] 1 Center for Laser Microscopy, Institute for Physiology and Biochemis- try “Jean Giaja”, Faculty of Biology, University of Belgrade, Serbia Impaired octopamine-mediated calci- 2 Department of Life Sciencies, Institute for Multidisciplinary Research, um signaling and glucose metabolism University of Belgrade, Serbia in Drosophila aging brain 3 Department of Neurophysiology, Institute for Biological Research Siniša Stanović, National Institute of Republic of Serbia, University of Belgrade, Serbia Urška Černe1, Anemari Horvat1,2, Nika Kozo- Multiple sclerosis (MS) is a neuroinflammatory disorder of the central derc1, Anne-Kristin Dahse3, Robert Zorec1,2, nervous system (CNS) characterized by immune cell infiltration, glial Nicole Scholz3, Nina Vardjan1,2 cell activation, demyelination, and neuronal loss. Astrocytic interac- tion with CNS-infiltrated immune cells (CNS-IICs) is an important con- 1 Laboratory of Neuroendocrinology-Molecular Cell Physiology, Insti- tributor to the pathology of MS. In our previous study on experimental tute of Pathophysiology, Faculty of Medicine, University of Ljubljana, autoimmune encephalomyelitis (EAE) model of MS, we showed that Slovenia CNS-IICs induce hemichannel-dependent ATP release and subsequent 2 Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, P2X7 receptor P2X7R-mediated cytosolic Ca2+ increase in astrocytes Slovenia in an in vitro experimental setup. The aim of this study was to further 3 Division of General Biochemistry, Rudolf Schönheimer Institute of investigate the coupling of astrocytic connexin-43 (Cx-43) and P2X7R Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany in EAE. Thus, we combined Western blot and immunohistochemistry to examine the P2X7R and Cx-43 protein expression in EAE and their Age-related decline in brain glucose utilization may be due to malfunc- expression pattern on astrocytes in the vicinity of CNS-IICs. We found tion of the noradrenergic system, which controls the brain metabolism. that P2X7R protein expression is decreased in the spinal cords of both This may contribute to the age-related cognitive decline. Noradrenaline EAE males and females, while the expression of Cx-43 remains undis-release from the noradrenergic neurons triggers in astrocytes, neurogli- turbed. Furthermore, colocalization analysis of immunolabeled P2X7R al cell, intracellular Ca2+ and cAMP signals, facilitating glucose uptake, and Cx-43 demonstrated decreased co-occurrence of these two pro-glycogen degradation and aerobic glycolysis with the end-product lac- teins in EAE. However, distribution analysis showed that P2X7R signal tate. During increased brain activity, lactate is shuttled from astrocytes intensity and its colocalization with astrocytic Cx-43 is increased at the to neurons to serve as a fuel. Whether noradrenergic regulation of brain border surface of CD4+ CNS-IIC. By defining determinants of direct cell metabolism is impaired in aged brains and contributes to cognitive astrocyte-immune cell interaction in the pathology of EAE, our findings decline is poorly understood. move forward our understanding of the CNS-immune system commu- nication in MS. We expressed fluorescent sensors for Ca2+, cAMP, glucose and lactate in brain cells in young and aged Drosophila brains to measure changes Acknowledgment: This work was supported by the Ministry of Science, of intracellular second messengers and metabolites upon octopamine Technological Development and Innovation of Republic of Serbia (Con- [43] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 tract no. 451-03-47/2023-01/200007, 451-03-47/2023- 01/200053 and CEL.08 Saturday, September 30th, 13:00 [Cellular Neuroscience B] 451-03-47/2023-01/200178). The role of glial potassium channel in Keywords: astrocyte, immune cell, P2X7 receptor, connexin-43 Amyotrophic Lateral Sclerosis CEL.06 Saturday, September 30th, 13:00 [Cellular Neuroscience B] Mina Perić1,3, Ljiljana Nikolić2, Pavle Andjus1, Neurotoxicity of cumyl-PINACA syn- Danijela Bataveljić1 thetic cannabinoid: involvement of 1 Institute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biol-multiple cannabinoid receptors ogy, University of Belgrade, Serbia 2 Department of Neurophysiology, Institute for Biological Research “Sinisa Stanković”, National Institute of Republic of Serbia, University Klara Bulc Rozman1, Metoda Lipnik-Štangelj2, of Belgrade, Serbia Dušan Šuput3, Miran Brvar3,4, Damijana Mojca 3 Institute of Molecular Genetics and Genetic Engineering, University Jurič of Belgrade, Serbia 2 1 Institute of Pathophysiology, Faculty of Medicine, University of Lju- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative dis-bljana, Ljubljana, Slovenia ease caused by the death of motor neurons in the spinal cord and the 2 Institute of Pharmacology and Experimental Toxicology, Faculty of brain. Glial cells surrounding motor neurons are strongly implicated Medicine, University of Ljubljana, Slovenia in the ALS onset and progression. They play an important role in the 3 Centre for Clinical Physiology, Faculty of Medicine, University of Lju- maintenance of K+ homeostasis through inwardly rectifying potassium bljana, Slovenia channel Kir4.1. By using SOD1G93A rat model of ALS, we here dem- 4 Centre for Clinical Toxicology and Pharmacology, University Medical onstrate a reduced expression of oligodendrocyte Kir4.1 channel in the Centre Ljubljana, Slovenia spinal cord and more specifically in the myelin fraction isolated from ALS spinal cord. Moreover, we show that the alteration in the Kir4.1 Synthetic cannabinoids, as potent recreational drugs, interfere with the expression was associated with impaired membrane properties and a endocannabinoid system in the brain and can cause severe mental and lower Kir current density in the SOD1G93A oligodendrocytes in culture. behavioral consequences. Cumyl-PINACA or SGT-24 is a synthetic Although the overall expression of Kir4.1 was reduced in ALS spinal agonist designed to bind cannabinoid receptor 1 (CB1) with very high cord, we could observe isolated regions, Kir4.1+ clusters, displaying affinity, but the molecular mechanisms underlying its central toxic ef- pronounced Kir4.1 immunoreactivity in SOD1G93A ventral horns. Infects are poorly understood. terestingly, Kir4.1+ clusters were enriched in the presence of Iba1+ mi- croglial cells. Our data show that Kir4.1+/Iba1+ clusters are formed at Here, we elucidated the response of rat cortical neurons and astrocytes the sites of prominent aggregation of mutant SOD1 (mSOD1) suggest-to SGT-24 at nanomolar concentrations (0.1 - 1000 nM). The effect ing the presence of degenerating motor neurons within Kir4.1+/Iba1+ of SGT-24 was dose- and time-dependent and cell-specific. In neu- clusters. Collectively, our findings on Kir4.1 provide the evidence of a rons, 10 nM SGT-24 caused immediate dysregulation of mitochondrial compromised K+ homeostasis in ALS and point out biomarker proper-membrane potential (ΔΨm), ATP depletion and activation of caspases, ties of this potassium channel. resulting in early apoptotic cell death with reduction and shortening of dendrites, cell shrinkage and chromatin condensation. The reduc- Keywords: oligodendrocytes, microglia, Kir4.1, ALS tion in neuronal viability and the initiation of apoptotic processes were prevented by selective antagonists of the CB1 and cannabinoid-like receptors peroxisome proliferator-activator receptor gama (PPAR-γ) and transient receptor potential cation channel subfamily V member CEL.10 Saturday, September 30th, 13:00 [Cellular Neuroscience B] 1 (TrpV1). In astrocytes, SGT-24 was effective at 10-fold higher con- centrations (100 nM) and induced a progressive dysregulation of ΔΨm Transcriptomic screen of MASC-de-and ATP depletion by activation of caspases and leakage of lactate rived neurons from Niemann Pick dehydrogenase, leading to early apoptosis and subsequent necrop- C patients, reveals a feedback loop tosis. CB1 and PPAR-γ antagonists protected astrocyte viability and prevented death of these cells. mechanism between TDP-43 and two novel TDP-43 potential second modi- SGT-24 is neurotoxic on acute exposure of neural brain cells and acts on both cannabinoid and non-cannabinoid receptors. A better under- fiers: ITPR1, and EPDR1 standing of the complexity of the action of synthetic cannabinoids would contribute to the development of multi-target treatment of intoxication. Francesca Paron, Filippo Favarato, Elisa Keywords: cumyl-PINACA, astrocytes, neurons, neurotoxicity, recep- Bregolin, Sara Cappelli, Stefania Zampieri, tors Andrea Dardis, Emanuele Buratti International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy Niemann-Pick disease is an autosomal recessive disorder due to NCP1 [44] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 (95%) and NPC2 (5%) gene mutations. It is characterized by choles- analgesia stimulus trains to their volar forearms. We then fit a circuit-terol abnormal accumulation with visceral and neurological symptoms, based model, which we call the “mesolimbic valence competition mod-especially cerebellar ataxia. The visceral signs can be explained by el”, to the participants’ pain ratings. Our model consists of two latent a defect in LDL-lysosomal pathway, while the molecular mechanisms competing states—reward and aversion, each representing the firing of causing neurodegeneration in NPC are unknown. In 2016, TDP-43 po- a distinct subpopulation of dopamine neurons. By assuming that aver-tential involvement was tested to explain the NPC neurological symp- sion is necessary for pain, our model captures offset analgesia’s salient tom. TDP-43 is a well-known RNA binding protein that plays an impor- dynamics: Decreasing nociception activates rewarding dopamine neu-tant role in many neurodegenerative disorders, like Amyotrophic Lateral rons, which silence aversive neurons to promote analgesia. We then Sclerosis and Frontotemporal Dementia. Also in different NPC disease used the latent reward and aversion time series in a voxelwise general models, TDP-43 was described to be shuttled from the nucleus to the linear model of NAc activity. Our preliminary results provide a concrete cytosol, and to be hyperphosphorylated. The aim of this work is to char- mechanistic hypothesis and complementary neuroimaging evidence of acterize TDP-43 disfunctions in NPC disease by studying potential sec- how positive and negative valence-related NAc activity may interact to ond modifiers derived from a transcriptomic analysis of MASC-derived produce complex pain dynamics. neurons from NPC patients. By this analysis, two potential modifiers have been described to modulate TDP-43 phenotype, such as ITPR1 and EPDR1. These two genes establish a feedback loop by which TDP- CLIN.02 Saturday, September 30th, 13:00 [Clinical Neuroscience B] 43 loss of function will lead to their downregulation, and when this mis- Challenging the search for neuromark-regulation occurs, it impairs TDP-43 pathological phenotype, especially related to its subcellular localization and phosphorylation. In this work, ers of mental disorders we studied in parallel the mechanism by which TDP-43 loss is driving to ITPR1 and EPDR1 downregulation, focusing on the presence of long introns in both genes. In addition, we evaluated how ITPR1 and EPDR1 Manca Kok, Henk Cremers downregulation was affecting TDP-43 pathological phenotype, involv- ing the Calcium metabolism. University of Amsterdam, Netherlands Keywords: TDP-43, NPC, ITPR1, EPDR1 Over the past two decades, researchers have been actively investigat- ing ways to objectively diagnose mental health conditions using bio- markers based on neural activity (for here on: neuromarkers). Despite CLIN.01 Friday, September 29th, 13:00 [Clinical Neuroscience A] some occasionally report high predictive accuracy, neuromarkers have Nucleus accumbens valence process- yet to demonstrate their clinical usefulness. While the lack of success can be attributed to various methodological challenges (including low ing during offset analgesia statistical power and selective reporting, which have resulted in a lack of reproducibility in this field of research), this study focuses on the theoretical issues with neuromarkers. Andrew D. Vigotsky1,2,3, Rami Jabakhanji2,3, Lejian Huang2,3, Paulo Branco3,4, Marwan N. The present study challenges the prevailing notion of biological reduc-Baliki3,5,6, A. Vania Apkarian2,3,4,5 tionism, which underlies the conviction that objective neuromarkers are both feasible and desirable. One of the challenges to this notion 1 Departments of Biomedical Engineering and Statistics, Northwestern is multiple realizability, proposing that mental states can be realized University, Evanston, IL, USA through various different physical states. Further, the study explores 2 Department of Neuroscience, Northwestern University, Chicago, IL, emergence, according to which mental states arise from the interac-USA tions of the individual parts, rather than the parts themselves. Addition- 3 Center of Translational Pain Research, Northwestern University, Chi- ally, we explore the influence of general and immediate environmental cago, IL, USA factors on the identification of these neuromarkers. 4 Department of Anesthesiology, Northwestern University, Chicago, IL, USA To illustrate the implications of these notions, we simulated data and 5 Department of Physical Medicine & Rehabilitation, Northwestern Uni- trained classifiers to shed light on how these concerns impact the ac-versity, Chicago, IL, USA curacy of neuromarkers. An important part of the research was the op- 6 Shirley Ryan AbilityLab, Chicago, IL, USA erationalization of the issues and conceptualization of the models. This process demonstrates a method for translating and comparing theo- Pain is not a static function of a noxious stimulus. Instead, it is a time- retical models in neuromarker research. The findings emphasize the evolving experience with a complex history dependence. This is espe- importance of critically evaluating the plausibility of neuromarkers and cially apparent in offset analgesia, a pain psychophysical phenomenon identifying the factors that limit their predictive power. characterized by disproportionately large decreases in pain following a small decrease in the intensity of a noxious stimulus. Efforts to under- Keywords: diagnostics, biomarkers, multiple realizability, emergence, stand the circuits governing offset analgesia have ruled out the roles theory modelling, mental health of opioidergic (e.g., descending inhibition) and NMDAergic (e.g., dif-fuse noxious inhibitory control) circuits. This work examines the novel hypothesis that offset analgesia arises from mesolimbic dopamine cir- cuits. We combined psychophysics, modeling, and functional magnetic resonance imaging (fMRI) to study how dopamine circuit dynamics (nucleus accumbens, NAc) relate to offset analgesia. We collected fMRI brain scans on 14 participants while applying offset [45] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 COG.01 Friday, September 29th, 13:00 [Cognitive Neuroscience A] 10 Department of Psychology, University of Gothenburg, Sweden Assessing cognitive sequelae of COV- The cortical alterations underpinning the acquisition of motor skills re-ID-19 using telepsychological testing main debated. In this longitudinal study in younger adults, we acquired performance and neuroimaging (7T MRI) measures weekly over the course of 6 weeks to investigate neural changes associated with learn- Ana Kuder, Maja Smrdu ing sequences of simultaneous finger presses executed with the non- dominant hand. Both the intervention group (n = 33) and the control Adult Mental Health Centre Koper group (n = 30) showed general performance improvements, but per- Faculty of Mathematics, Natural Sciences and Information Technolo- formance improved more and became more consistent for sequences gies, University of Primorska, Koper, Slovenia that were intensively trained by the intervention group, relative to those that were not. Brain activity for trained sequences decreased com- From the start of the COVID-19 pandemic, evidence about prolonged pared with untrained sequences in the bilateral parietal and premotor symptoms of COVID-19 has been accumulating, with some individuals cortices. No trainingrelated changes in the primary sensorimotor areas experiencing several symptoms for weeks or months after the acute were detected. The similarity of activation patterns between trained and infection has passed. Cognitive sequelae after COVID-19 are a com- untrained sequences decreased in secondary, but not primary, senso-mon complaint. Current findings about the impairment of individual do- rimotor areas, while the similarity of the activation patterns between mains in cognitive abilities are somewhat contradictory. Thus we stud- different trained sequences did not show reliable changes. Neither the ied the differences in perceived and evaluated cognitive abilities in the variability of activation patterns across trials, nor the estimates of brain COVID-19 recovered group, compared to a group, that has not had the structure displayed practice-related changes that reached statistical disease. We used telepsychological testing for the evaluation of cog- significance. Overall, the main correlate of learning configural sequenc-nitive abilities. We included 35 participants who have recovered from es was a reduction in brain activity in secondary motor areas. COVID-19 at least three months before testing and 19 controls. Lower abilities in semantic fluency, executive functions and attention, speed of Keywords: skill acquisition, motor learning, cortical changes, plasticity, information processing and visual working memory were observed in a activation patterns group of participants, who have recovered from COVID-19. We did not demonstrate a relationship between perceived and evaluated cognitive abilities. In this study, we find that some psychological tests can be COG.02 Saturday, September 30th, 13:00 [Cognitive Neuroscience B] adapted and used in the context of telepsychological testing. The find- ings represent an important starting point for further research into the Brain-derived neurotrophic factor and cognitive sequelae of COVID-19. We conclude that in the future, it will cognitive decline in patients diag-be necessary to monitor the cognitive functioning of people, who have nosed with mild cognitive impairment recovered from COVID-19 over a longer period of time. and Alzheimer’s disease Keywords: COVID-19, SARS-CoV-2, cognitive sequelae, telepsychol- ogy Tina Miloš1, Matea Nikolac Perković1, Fran Borovečki2,3, Igor Filipčić4, Barbara Vuić1, COG.03 Friday, September 29th, 13:00 [Cognitive Neuroscience A] Gordana Nedić Erjavec1, Marcela Konjevod1, Cortical changes during the learning Lucija Tudor1, Ninoslav Mimica3,5, Suzana of sequences of simultaneous finger Uzun3,5, Oliver Kozumplik5, Dubravka Švob presses Štrac1 1 Laboratory for Molecular Neuropsychiatry, Division of Molecular Med- icine, Ruđer Bošković Institute, Zagreb, Croatia Benjamín Garzón1,2, Gunther Helms3, Ham- 2 Department of Neurology, University Hospital Centre Zagreb, Croatia pus Olsson4, Claudio Brozzoli5, Fredrik Ul- 3 School of Medicine, University of Zagreb, Croatia lén6, Jörn Diedrichsen7,8,9, Martin Lövdén2,10 4 Psychiatric Hospital “Sveti Ivan”, Zagreb, Croatia 5 Department for Biological Psychiatry and Psychogeriatrics, University 1 Institute of Education, University of Zurich, Switzerland Psychiatric Hospital Vrapče, Zagreb, Croatia 2 Aging Research Center, Karolinska Institutet, Stockholm, Sweden 6 University of Applied Sciences Hrvatsko Zagorje Krapina, Croatia 3 Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Ger- many Brain derived neurotrophic factor (BDNF) is important in development 4 Department of Medical Radiation Physics, Lund University, Lund, and function of neurons and recently, there is increasing evidence that Sweden alterations in its expression might contribute to development of Alzhei- 5 INSERM, Lyon, France mer’s disease (AD). AD is progressive neurodegenerative disorder and 6 Max Planck Institute for Empirical Aesthetics, Frankfurt am Main, Ger- a leading cause of dementia in elderly people. Mild cognitive impair-many ment (MCI) is transitional sate between the normal cognitive changes 7 The Brain and Mind Institute, University of Western Ontario, Ontario, of aging and more severe cognitive decline associated with AD or Canada other types of dementia. It has been shown that people with MCI are 8 Department of Computer Science, University of Western Ontario, On- at higher risk of developing dementia compared to those without MCI. tario, Canada Various studies reported that changes in BDNF concentrations affect 9 Department of Statistical and Actuarial Sciences, University of West- cognition and memory in different cognitive disorders, including AD and ern Ontario, Ontario, Canada MCI. The aim of this study was to investigate relationships between [46] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 plasma BDNF levels and cognitive decline in AD and MCI patients. The COM.02 Saturday, September 30th, 13:00 [Computational Neuroscience] study included 295 patients with AD and 209 subjects with MCI and their cognitive performances were evaluated using a Mini-Mental State Inferring coupling functions of brain Examination (MMSE) and Clock Drawing test (CDT). To determine regions from synthetic EEG data by the concentration of BDNF in plasma, enzyme-linked immunosorbent assay (ELISA) was used. Our results showed significantly increased using graph neural networks plasma BDNF concentration in AD patients compared to MCI subjects. Furthermore, there is a significant negative correlation between cogni- tive functions and BDNF plasma concentration, indicating that patients Nina Omejc1,2, Boshko Koloski1,2, Tomislav with more pronounced cognitive decline have higher BDNF levels. To Stankovski3,4, Sašo Džeroski1 summarize, further investigations are required to fully understand the potential use of BDNF as a novel diagnostic biomarker in clinical prac- 1 Department of Knowledge Technologies, Jožef Stefan Institute, Lju-tice and enhance the treatment of patients with AD and MCI. bljana, Slovenia 2 Jožef Stefan International Postgraduate School, Ljubljana, Slovenia Keywords: BDNF, Alzheimer’s disease, Mild Cognitive Impairment, 3 Faculty of Medicine, Ss Cyril and Methodius University, Skopje, North cognitive decline Macedonia 4 Department of Physics, Lancaster University, Lancaster, United King- dom COG.04 Saturday, September 30th, 13:00 [Cognitive Neuroscience B] Survival and self-expression values Electroencephalographic (EEG) measurements are a valuable tool in Slovenia and North Macedonia: ex- for investigating the intricate dynamics of large-scale brain activity in ploring moderators in the relationship humans. The theoretical aspects of such dynamics, however, like explaining observed oscillations and their interactions, remain elusive. between cognitive reserve and cogni- Numerous large-scale brain models have been developed to address tive performance this, some of which focusing on explaining coupling functions by using coupled phase oscillators. Mia Micevska In our study, we first generate synthetic EEG data based on the Desi- kan-Killiany atlas. Each of the 68 cortical regions is represented by five Cognitive Neuroscience and Clinical Neuropsychology, Department of oscillators operating within distinct frequency brainwave bands. To cre-General Psychology, University of Padua, Italy ate a diverse dataset, we randomly phase-couple these oscillators, with only a small subset of oscillator pairs exhibiting strong coupling. Finally, Cognitive reserve is a mechanism that enables maintenance of ad- we sum the oscillatory activity of the relevant oscillators to obtain a equate cognitive abilities despite the presence of age or pathology single time series per region and project it to the EEG electrodes using induced brain changes. Knowing that cognitive reserve reflects the ac- a forward model and a template anatomical atlas. tivities of everyday life (e.g., education and work engagement), which altogether aggregate with age, it is important to consider the cultural At the conference, we will present the outcomes of our ongoing analy-value systems that contribute to shaping and prioritizing said activities. sis, which aims to infer the source regions exhibiting phase-coupled The present study examines a subset of cultural values, within two coun- dynamics within the scalp EEG data. Our analysis uses a graph neural tries, Slovenia and North Macedonia. Survival values place emphasis network (GNN) approach. Initially, we transform each multivariate time on economic/physical security and low outgroup trust (typically found in series into a graph representation using Markov modeling. The result-developing countries, like North Macedonia), while self-expression val- ing graphs serve as input to the GNN, which is used to obtain a repreues prioritize environmental protection, equality, well-being, and quality sentation of the connections between regions. With such analysis, we of life (characteristic of developed countries, like Slovenia). Taking the strive towards discerning and classifying the information flow between above into consideration, we aim to explore whether prioritization of the regions with respect to time, frequency, and phase. In the future, we certain values moderates the relationship between cognitive reserve plan to test the proposed approach on real EEG data. and cognitive performance in healthy older adults from Slovenia and North Macedonia. We hypothesize that the positive predictive value of Keywords: electroencephalography, coupling functions, phase cou-cognitive reserve on cognitive performance will be stronger when self- pling, graph neural networks expression values are higher (and survival values are lower). Similarly, referring to results from an open-source database where Slovenia has MET.01 Friday, September 29th, 13:00 [Neuroscience Methods] steadily high self-expression values (opposite is true for North Mac- edonia), we hypothesize that the positive predictive value of cognitive Smart probes for ex vivo assessment reserve on cognitive performance will be stronger in the Slovenian of Alzheimer disease conformational sample, compared to the North Macedonian sample. pathology Keywords: cognitive reserve, cross-cultural comparisons, cognitive performance, ageing, cultural values Lana Blinc1, Mateja Drolec Novak1, Jerneja Kladnik2, Matic Rogan2, Damijan Knez3, Jernej Mlakar4, Ross Jansen-van Vuuren2, Janez Košmrlj2, Maja Bresjanac1 [47] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 1 Institute of Pathophysiology, Faculty of Medicine, University of Lju- 5 days after the lesion. In this study we investigated whether the siR-bljana, Slovenia NA-induced analgesia is due to a switch in the activation phenotype of 2 Department of Organic Chemistry, Faculty of Chemistry and Chemi- macrophages from M1 pro-inflammatory to M2 anti-inflammatory accal Technology, University of Ljubljana, Slovenia companied by a reduced mobility of macrophages, and complemented 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Uni- by a pro-regenerative profile of DRG neurons with reduced excitability. versity of Ljubljana, Slovenia The results have shown that the analgesic effect of Iba1 silencing in 4 Institute of Pathology, Faculty of Medicine, University of Ljubljana, DRG macrophages is due to their functional switch towards an M2, Slovenia anti-inflammatory state accompanied by an increased secretion of anti- inflammatory cytokines and pro-regenerative mediators which, howev- Therapeutic interventions’ lackluster performance in Alzheimer demen- er, doesn’t seem to alter significantly the electrophysiological properties tia (AD) may in part be due to the irreversibly advanced stage of the of L5 DRG neurons. This data are in line with a reduced contribution pathological process underlying cognitive decline once the latter is of L5 DRG neurons to pain pathogenesis after SNL, and suggest an diagnosed. Currently, clinical diagnosis of AD is supported by in vivo extended influence of the immune mechanism to neighboring non-le-molecular imaging of disease-related Aβ and Tau aggregates in the sioned DRG neurons, possibly responsible for the Iba1 siRNA-induced brain, and analysis of cerebrospinal liquid. Positron Emission Tomog- analgesia. raphy, Single Photon Emission Computed Tomography, and Magnetic This research was funded by the Romanian Government via Execu-Resonance imaging are the most common methods used. They are tive Agency for Higher Education, Research, Development and Inno-costly, which limits their use in routine screening. We used fluorecent vation Funding (UEFISCDI), grant number 374/2020, PN-III-P2-2.1-microscopy to examine and compare the selectivity and optical proper- PED-2019-3103, and by the ICGEB (International Center for Genetic ties of four small fluorescent molecules, designed to translate subtle Engineering and Biotechnology), Grant CRP/ROU16-04 (2017-2020). changes in their environment to their optical properties upon binding to AD biomarkers including amyloid-beta and Tau protein. In addition, we investigated their affinity for other targets, including Lewy and Pick MOL.03 Friday, September 29th, 13:00 [Molecular Neuroscience A] bodies, using brain tissue samples obtained post mortem from patients Axonal and myelin recovery after trau-with confirmed AD, a familial tauopathy with Tau mutation, PD, and Pick disease, and cross-referenced our findings with immunofluorescence matic spinal cord compression medi-staining. We found that several probes, primarily designed to bind AD ated via AT2 receptor stimulation biomarkers, also exhibit affinity for intra- and extracellular Tau deposits, as well as Lewy and Pick bodies, and can be used to distinguish vari- ous types of pathology based on emission spectra. While our long-term Jana Fedorova, Erika Kellerova, Jaroslav goal is the development of reliable and cost-effective molecular probes to detect conformational pathology in blood samples, our presentation Pavel will focus on comparative characteristics of the four canditate probes in Institute of Neurobiology, Biomedical Research Center, Slovak Acad-fluorescent microscopy of post mortem brain tissue samples. emy of Sciences, Košice, Slovakia Keywords: fluorescent microscopy, biomarkers, neurodegeneration In the present study, we tested pharmacological AT2 receptor stimu- lation in an experimental model of severe spinal cord compres- MOL.01 Friday, September 29th, 13:00 [Molecular Neuroscience A] sion in adult female Wistar rats using selective AT2 receptor agonist CGP42112 (0.1 mg/kg per day) continuously administrated by osmotic Switch of rat dorsal root ganglia mac- minipumps (s.c.). On the 28th post-injury day, the RT-PCR and WB rophages to M2 phenotype after cyto analysis revealed the increased expression of axonal and myelin struc-skeleton alteration reduces SNL-in- tural markers such as neurofilaments, myelin basic protein and CN-Pase, and marker of axonal regeneration GAP43 after AT2 stimulation duced neuropathic pain compared to trauma. The histopathological changes were analysed by using a histological Luxol fast blue staining combined with Cresyl vio- let. A statistically significant amount of spared spinal cord tissue was Roxana-Olimpia Gheorghe1, Andreea Grosu1, observed after AT2 stimulation, especially in the injury epicentre. Be-Sorina Dinescu2, Gisela Gaina2, Mihail Gheng- sides, the AT2 stimulation also reduced the formation of microcysts and cystic cavities, predominantly in caudal regions. The acquired results hea1, Damir Sapunar3, Violeta Ristoiu1 correlated with functional recovery. During the 28-day posttraumatic 1 Department of Anatomy, Animal Physiology and Biophysics, Faculty period, the motor function recovered rapidly, and the improvement was of Biology, University of Bucharest, Romania more profound after AT2 receptor stimulation compared to spinal cord 2 Department of Biochemistry and Molecular Biology, Faculty of Biol- injury alone (BBB locomotor score: 10.4 points vs 9 points) and strongly ogy, University of Bucharest, Romania negatively correlated (Pearson r= -0.908) with evidently shorter latency 3 Department of Anatomy, Histology and Embryology, School of Medi- (7.03 ms vs 10.8 ms). Many of these positive effects were partially or cine, University of Split, Croatia completely prevented by the AT2 receptor blocking. Our results sug- gested that posttraumatic AT2 receptor stimulation promotes axonal Traumatic nerve injury such as SNL (spinal nerve ligations) is accom- recovery resulting in improved functional neurological outcomes; thus, panied by clustering of Iba1 (+) macrophages around DRG (dorsal root it could be considered promising therapeutic approach for spinal cord ganglia) neurons, presumably activating them and facilitating neuro- injury. pathic pain development. Previously we have shown that intra-gan- Supported by APVV-18-0163, APVV-22-0248 and VEGA No. 2/0123/23. glionic L5 injection of naked siRNA directed against Iba1 significantly inhibited spinal nerve ligation- induced mechanical and cold allodynia, Keywords: spinal cord injury, AT2 receptor, axonal regeneration [48] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 MOL.05 Friday, September 29th, 13:00 [Molecular Neuroscience A] and genetic risk factors have been explored. Rotenone is an organic Circular RNAs in association with pesticide that primarily acts though mitochondrial complex I inhibition. It has been identified as a PD risk factor and is widely used to study amyotrophic lateral sclerosis PD in models. The current study aimed to test the hypothesis that spe- cific exosomal miRNA changes can serve as biomarkers in in rotenone PD models. The importance of exosomal changes in PD has received Metka Ravnik Glavač1, Massimo Mezzavil- much attention, but there is much yet to learn. Exosomal content can la2, Ana Dolinar3, Blaž Koritnik4,5, Damjan potentially serve as both biomarkers and key mediators of pathogen-Glavač3,6 esis. Preliminary studies in primary cortical and midbrain neurons treat- ed with rotenone (60nM and 25nM, respectively) for 24h demonstrated 1 Institute of Biochemistry and Molecular Genetics, Faculty of Medi- that several specific exosomal miRNAs were differentially expressed. cine, University of Ljubljana, Slovenia Further, 3-month-old Sprague Dawley male rats were acutely dosed 2 Department of Biology, University of Padua, Italy with rotenone (3 mg/kg) for 8h and 24h, and serum and CSF were 3 Department of Molecular Genetics, Institute of Pathology, Faculty of extracted. Exosomal miRNAs were differentially expressed in both Medicine, University of Ljubljana, Slovenia serum and CSF, notably miR-181c-5p and miR-93-5p; these miRNAs 4 Institute of Clinical Neurophysiology, University Medical Centre Lju- are important in modulation of mitochondrial functions and inflamma-bljana, Slovenia tion respectively. Further, neuronal cultures treated with isolated serum 5 Department of Neurology, Faculty of Medicine, University of Ljublja- exosomes from rotenone treated rats showed selective dopaminergic na, Slovenia toxicity. Taken together, our findings show changes in exosomal miR- 6 Center for Human Genetics and Pharmacogenomics, Faculty of Med- NAs may be early diagnostic markers for PD and that show changes icine, University of Maribor, Slovenia could be important in. pathogenesis. Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal adult- Keywords: Parkinson’s disease; exosome; rotenone onset neurodegenerative disease affecting both upper and lower motor neurons. Here, we investigated the potential association of circRNAs MOL.09 Friday, September 29th, 13:00 [Molecular Neuroscience A] and ALS. CircRNAs represent a class of non-coding RNAs that are formed during precursor mRNA processing via back-splicing events. hnRNPH localizes to G4C2 nuclear foci Among the versatile functions of circRNAs are also miRNA sponging and RNA-binding protein (RBP) sequestration, both linked to gene and cytoplasmic stress granules of regulation. We first performed a microarray analysis of circRNAs on C9orf72 amyotrophic lateral sclerosis peripheral blood mononuclear cells of a subset of ALS patients and controls. For further analyses, we selected two approaches. In one ap- proach we collected only circRNA with a host gene that harbors any Nives Škorja Milić1, Sonja Prpar Mihevc1, evidence of genetic constraints, which could hypothetically have a sig- Valter Bergant1, Julija Mazej1, Urša Čerček1, nificant role in determining a trait or disease. In another approach, we used different clustering algorithms to find the smallest dataset of cir- Alfredo Castello3, Gregor Gunčar2, Vera cRNA which have the best True positive rate and True negative rate in Župunski2, Boris Rogelj1,2 identifying cases and controls. In both approaches, hsa_circ_0060762 1 Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slo-and its host gene CSE1L were detected. Further analysis in larger sets venia of patients and controls revealed significant differences in expression 2 Faculty of Chemistry and Chemical Technology, University of Lju-levels for both hsa_circ_0060762 and CSE1L and receiver operating bljana, Slovenia characteristics curve analysis showed diagnostic potential for CSE1L 3 University of Glasgow Centre for Virus Research, Institute of Infec-and hsa_circ_0060762. CSE1L is a member of the importin β family tion, Immunity and Inflammation, College of Medical, Veterinary and and mediates inhibition of TDP-43 aggregation, the central pathogenic- Life Sciences, University of Glasgow, United Kingdom ity in ALS, and hsa_circ_0060762 has binding sites for several miRNAs that have been connected to ALS. The most common genetic cause of ALS is hexanucleotide G4C2 re- peat expansion in the first intron of C9orf72. One of the hallmarks is Keywords: Amyotrophic lateral sclerosis the formation of RNA G4C2 foci in the nucleus, which contain aberrant repeat transcripts and various RNA-binding proteins (RBP). hnRNPH is MOL.07 Friday, September 29th, 13:00 [Molecular Neuroscience A] a member of a large RBP family involved in the regulation of alternative splicing, mRNA stabilization, transcription, and translation. In ALS brain Exosomal miRNA alterations in rote- tissue, hnRNPH colocalizes with nuclear G4C2 foci, whereas under none models of Parkinson’s Disease cellular stress conditions, it is localized in cytoplasmic stress granules. Sequestration of hnRNPH in insoluble RNA aggregates correlates with dysregulation of splicing and may contribute to neurodegeneration. Jason Cannon, Fatema Currim Our goal was to reveal the domains of hnRNPH that determine its lo- calization to G4C2 foci and stress granules. We designed a series of School of Health Sciences, Purdue University, West Lafayette, IN, USA hnRNPH1 protein constructs based on its domain structure and introduced mutations into individual qRRM domains to disable their RNA- Parkinson’s Disease (PD) is a debilitating, progressive neurodegen- binding activity. Quasi (q)RRM2 and qRRM3, but not qRRM1, were erative disease. The loss of dopaminergic neurons in the substantia sufficient for localization of hnRNPH to stress granules. Localization of nigra is a hallmark pathology responsible for many of the motor deficits. hnRNPH to G4C2 foci was independent of the RNA-binding activity of While the etiology of most cases is unknown, a variety of environmental any individual qRRM domain. Using RBDmap, we demonstrated that [49] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 the putative ZnF domain of hnRNPH may have RNA-binding activity. MOL.13 Friday, September 29th, 13:00 [Molecular Neuroscience A] Surprisingly, hnRNPH localized to G4C2 foci even after the removal of the RNA-binding activity of the qRRM and ZnF domains. This re- Potential therapeutic effects of dehy-sult suggest that RNA-binding activity may not be the only driving force droepiandrosterone and its sulfate in for the sequestration of hnRNPH into the G4C2 foci associated with C9orf72 ALS. mouse models of Alzheimerś disease Keywords: ALS, C9orf72, hnRNPH, G4C2 foci, stress granules Barbara Vuić, Tina Miloš, Matea Nikolac Perković, Gordana Nedić Erjavec, Lucija Tu- MOL.11 Friday, September 29th, 13:00 [Molecular Neuroscience A] dor, Marcela Konjevod, Dubravka Švob Štrac Molecular factors that implicate in- Laboratory of Molecular Neuropsychiatry, Division of Molecular Medi-volvement of human retrotransposon cine, Ruđer Bošković Institute, Zagreb, Croatia LINE1 in neurodegeneration Alzheimer’s disease (AD), the most common form of dementia, com- prises 60-70% of all dementia cases. This neurodegenerative disor- Klementina Polanec der involves the accumulation of amyloid beta (Aβ) peptide in amyloid 1, Anamarija Habič1,2, Bo- plaques and hyperphosphorylated tau protein in neurofibrillary tangles. ris Rogelj1,3, Vera Župunski1 These contribute to neuronal loss, brain atrophy and cognitive dete- rioration. Unfortunately, there is currently no effective therapy to treat 1 Faculty of Chemistry and Chemical Technology, University of Lju- AD or prevent its onset. Therefore, extensive research is underway to bljana, Slovenia explore the therapeutic potential of different compounds. 2 National Institute of Biology, Ljubljana, Slovenia 3 Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slo- Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), abundant venia steroids in human circulation, decline with age and in neuropsychiat- ric disorders like AD. They are produced in the adrenal gland, ovaries Neurodegenerative diseases present a growing problem for the age- and testes, crossing the blood-brain barrier. Engaging in neurogenesis, ing global population. By 2050 more than 2 billion people will be 60 neurite growth, survival, neurotransmission, synaptic plasticity and in-years or older. Therefore, it is crucial to develop a better understanding flammation, they play significant roles in various brain processes. of molecular mechanisms of neurodegeneration. A growing number of research links mobile genetic elements, namely retrotransposons, to Our study included both genetic and pharmacologically induced mouse Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis models of AD. In the genetic AD model, the 3xTg-AD and 3xTg (+/+) (ALS) and frontotemporal dementia (FTD). The human genome con- control mice were chronically treated with DHEAS using the subcutane-sists of many copies of retrotransposons, of which LINE1 is the most ously intrascapulary implanted osmotic pumps. In the pharmacological prevalent. It represents up to 17 % of the human genome and is still AD model, C57BL/6 mice were chronically intraperitoneally treated with active today. Full-length LINE1 element includes 3 open reading frames DHEA or the vehicle, after the stereotaxic intracerebroventricular ad-for ORF1p, ORF2p, and ORF0p. In our work we analysed the protein ministration of Aβ oligomers. interactome of ORF1p with biotin identification. Mass spectrometry re- sults revealed that potential ORF1p interaction partners, like ORF1p, The results suggest that a longer period of Aβ treatment or a higher localize in stress granules, cytoplasm, nucleus, and nucleoli. Potential dose of DHEA might be necessary to effectively induce and treat AD interactors are mainly RNA-binding proteins involved in various steps pharmacologically. However, the administration of DHEAS yielded only of RNA metabolism, translation and its regulation, and stress granule modest effects in the genetic AD model. Further investigation in this do-assembly. By immunodetection, we confirmed 5 ORF1p interactors main is warranted and it is crucial to replicate and validate these results (TDP-43, IGF2BP1, ELAVL1, FUS, and hnRNPK), all of which are in studies encompassing a larger sample size. distinct RNA-binding proteins. IGF2BP1 and ELAVL1 also colocalized with transiently expressed Flag-ORF1p in unstressed HEK293T cells. Keywords: Alzheimer’s disease, DHEA, DHEAS, 3xTg-AD, C57BL/6, Among confirmed ORF1p interactors, TDP-43 and FUS are already Aβ oligomers strongly implicated in different neurodegenerative diseases. Moreover, aberrant RNA metabolism is emerging as a significant mechanism in neurodegeneration. Our results provide insight into the ORF1p-protein MOL.15 Friday, September 29th, 13:00 [Molecular Neuroscience A] interaction network, which may help us understand the role of ORF1p in health and disease. The role of insulin and glucose in reg- ulation of neuropathy target esterase- Keywords: retrotransposon LINE1, ORF1p, BioID, neurodegeneration related esterase in primary human myotubes Katarina Miš1, Ana-Marija Lulić2, Tomaž Marš1, Sergej Pirkmajer1*, Maja Katalinić2* 1 Institute of Pathophysiology, Faculty of Medicine, University of Lju- bljana, Slovenia [50] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 2 Institute for Medical Research and Occupational Health, Zagreb, Supported by VEGA Grant No. 2/0123/23, APVV Grants No. APVV-18-Croatia 0163 and APVV-22-0248. *These authors contributed equally to this work and share senior au- thorship. Keywords: Angiotensin II, AT1 receptor, AT2 receptor, neuroprotection, spinal cord injury In murine skeletal muscle, expression of neuropathy target esterase- related esterase (NRE), also known as patatin-like phospholipase do- main containing protein 7 (PNPLA7), a lysophospholipase, is increased MOL.02 Saturday, September 30th, 13:00 [Molecular Neuroscience B] by fasting and decreased by feeding, indicating NRE is regulated by ALS/FTD-associated C9orf72 C4G2 re-metabolic hormones and/or nutrients. Consistent with this notion, in- sulin reduced NRE expression in cultured murine adipocytes. Here peat RNA binds to FARS protein and we examined whether NRE is functionally expressed in primary hu- affect the rate of phenylalanine-tRNA man skeletal muscle cells and whether its expression is modulated by insulin and/or glucose. Primary human myoblasts and myotubes ex- aminoacylation pressed NRE mRNA and protein. Gene silencing of NRE in myoblasts reduced the activity of the mTOR pathway as well as the abundance of α1-subunit of Na+,K+-ATPase and acetyl-CoA carboxylase, indirectly Urša Čerček1,2, Mirjana Malnar1,2, Xiaoke Yin3, suggesting a functional role for NRE in these cells. In myotubes, in- Manh Tin Ho4, Barbka Repič Lampret5, Ma-sulin reduced NRE mRNA levels at normal glucose concentration (1 nuela Neumann6,7, Andreas Hermann8,9, Guy g/L), but not at low (0.5 g/L) or high (4.5 g/L) glucose concentrations. Rouleau10,11, Beat Suter4, Manuel Mayr3, Boris The NRE protein levels were inversely correlated with the glucose concentrations. Conversely, treatment with dexamethasone, a synthetic Rogelj1,12 glucocorticoid, and forskolin, an activator of adenylyl cyclase, did not 1 Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slo-affect NRE expression regardless of glucose concentration. In conclu- venia sion, NRE expression in human myotubes was regulated by insulin in a 2 Graduate School of Biomedicine, Faculty of Medicine, University of glucose-dependent manner, implicating a role for NRE in skeletal mus- Ljubljana, Slovenia cle energy metabolism. 3 King’s BHF Centre, King’s College London, United Kingdom 4 Institute of Cell Biology, University of Bern, Switzerland Keywords: NRE, PNPLA7, insulin, glucose, cultured human myotubes 5 Clinical Institute of Special Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana, Slovenia 6 Molecular Neuropathology of Neurodegenerative Diseases, German MOL.17 Friday, September 29th, 13:00 [Molecular Neuroscience A] Center for Neurodegenerative Diseases, Tübingen, Germany The involvement of Angiotensin II re- 7 Department of Neuropathology, University Hospital of Tübingen, Ger-ceptors in posttraumatic recovery of many 8 Translational Neurodegeneration Section »Albrecht-Kossel«, De- severe injured spinal cord partment of Neurology and Center for Transdisciplinary Neuroscience Rostock (CTNR), University Medical Center Rostock, University of Ros- tock, Germany Jaroslav Pavel, Jana Fedorova, Erika Kel- 9 Deutsches Centrum für Neurodegenerative Erkrankungen (DZNE), lerova Rostock/Greifswald, Rostock, Germany 10 Department of Human Genetics, McGill University, Montreal, QC, Department of Neurodegeneration, Plasticity and Repair, Institute of Canada Neurobiology, Biomedical Research Center, Slovak Academy of Sci- 11 Department of Neurology and Neurosurgery, Montreal Neurological ences, Košice, Slovakia Institute, McGill University, Montreal, QC, Canada 12 Faculty of Chemistry and Chemical Engineering, University of Lju- Most of the known physiological as well as pathological effects of An- bljana, Slovenia giotensin II are mediated via AT1 receptors. The AT2 receptor was considered as “enigmatic” for very long time, but intensive research in The most common genetic cause of amyotrophic lateral sclerosis recent decades has determined it as potential therapeutic target. Many (ALS) and frontotemporal dementia (FTD) is the C9orf72 gene muta-scientific results in recent decades clearly demonstrated beneficial ef- tion, which results in expanded hexanuleotide repeat – GGGGCC. It fects of the AT1 receptor blockage and the AT2 receptor stimulation. transcribes in sense (G4C2)n and antisense (C4G2)n direction and The appropriate timing of receptor blockade or stimulation after specific leads to the formation of nuclear RNA foci. We have identified proteins lesion is a one of crucial factors affecting the efficiency of therapeu- that bind to antisense transcripts. These include proteins involved in tic approach. Based on measured physiological parameters and the protein synthesis, cytoskeleton stability and mRNA processing. For the time-dependent receptor expression analysis in injured spinal cord, we first time we observed the interaction with phenylalanine-tRNA syn-specified an appropriate timing of pharmacologic intervention for AT1 thetase (FARS). To determine the interactors, we performed RNA-pull receptor blockage and AT2 receptor stimulation. Neurological dysfunc- down assay from mouse and human brain lysates followed by mass tion, motor evoked potentials, bladder function, blood pressure and spectrometry. We validated the interaction using WB, FISH/ICC and heart rate, body weight changes, post-traumatic tissue sparing and developed modified RNA-protein proximity ligation assay to observe cystic cavitation, axonal structural proteins and vascular markers have cytoplasmic interactions of the repeats. To evaluate the impact of anti-been evaluated. Our experimental results suggested a promising ther- sense RNA-FARS interaction on tRNA aminoacylation, protein synthe-apeutic potential of pharmacologic intervention aimed to these major sis and cellular stress we used two aminoacylation assays, western blot Angiotensin II receptors after severe spinal cord injury. analysis and Click-chemistry.Antisense RNA-FARS interaction resulted in significant decrease in aminoacylation rate in in vitro assay and [51] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 lower charged tRNAphe levels in patient derived lymphoblasts com- MOL.06 Saturday, September 30th, 13:00 [Molecular Neuroscience B] pared to controls. Additionally, we observed a decreased expression of phenylalanine-containing proteins at the whole protein level and of five Examining the impact of TDP-43 mislo-individual proteins with high phenylalanine content. We also evaluated calization on its protein network the effect of the lower aminoacylation level on cellular stress and autophagy. In the presented study we investigated and confirmed protein interactions with the biologically relevant 32×C4G2 RNA repeats and Jerneja Nimac1,2, Sonja Prpar Mihevc1,3, Julija how this affects cellular processes. Our discovery highlights the role Mazej1, Helena Motaln1, Eva Ogorevc1, Boris of aminoacyl-tRNA synthetases in C9orf72 ALS/FTD where they may be important contributors to the development of these diseases. This is Rogelj1,4 important because studies have linked irregularities in aminoacyl-tRNA 1 Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slo-synthetases to other neurodegenerative disorders. venia 2 Graduate School of Biomedicine, Faculty of Medicine, University of Keywords: ALS C9orf72 FARSA Ljubljana, Slovenia 3 Veterinary Faculty, University of Ljubljana, Slovenia MOL.04 Saturday, September 30 4 Faculty of Chemistry and Chemical Technology, University of Lju- th, 13:00 [Molecular Neuroscience B] bljana, Slovenia Muscle-specific microRNAs as spinal muscular atrophy biomarkers TDP-43 is a DNA/RNA-binding protein located mainly in the nucleus. In amyotrophic lateral sclerosis and frontotemporal dementia, it becomes mislocalized and is the main component of cytoplasmic protein aggre- Maruša Barbo gates. In the present study, we investigated the interactome of wild-type 1, Gregor Jezernik2, Damjan TDP-43 and TDP-43dNLS that mimics a pathological condition. We es-Glavač2,3, Metka Ravnik-Glavač1 tablished inducible mammalian cell lines stably expressing the recom- binant fusion protein TDP-43wt or TDP-43dNLS with the biotin ligase 1 Institute of Biochemistry and Molecular Genetics, Faculty of Medi- BioID2. We performed the BioID method and isolated biotinylated pro-cine, University of Ljubljana, Slovenia teins from the cell lysates. The isolated proteins were detected by mass 2 Center for Human Genetics and Pharmacogenomics, Faculty of Med- spectrometry (MS), resulting in a list of unique TDP-43wt and TDP-icine, University of Maribor, Slovenia 43dNLS interactors that were further validated. The cellular localization 3 Department of Molecular Genetics, Institute of Pathology, Faculty of and function of the interactors were investigated using bioinformatics Medicine, University of Ljubljana, Slovenia analyses. It revealed that TDP-43wt interacts mainly with proteins of the ribonucleoprotein and spliceosome complexes and with paraspeckles, Introduction: Spinal muscular atrophy (SMA) is a debilitating neurode- whereas the mutant TDP-43dNLS interactors are components of cyto-generative disease characterized by the progressive degeneration of plasmic stress granules and P-bodies. Validation of selected interacting motor neurons, leading to muscle weakness and paralysis. The primary proteins (NONO, SFPQ, FUS, MAML1, PUM1, and ATXN2L) revealed cause of SMA is the survival motor neuron (SMN) protein deficiency, that MAML1 is unique TDP-43wt interactor, whereas NONO, SFPQ, which is attributed to homozygous deletions in the survival of motor and FUS are common interactors of TDP-43wt and TDP-43dNLS and neuron (SMN1) gene. To address this underlying gene deficiency, three are more abundant in the TDP-43wt fraction. ATXN2L and PUM1 are drugs (nusinersen, risdiplam, and onasemnogene abeparvovec) have unique interactors of mutant TDP-43. Our results suggest that the de-been approved that aim to increase SMN protein production in SMA velopment of ALS may involve impaired regulatory functions related to patients. However, accurately assessing the efficacy of SMA therapy transcription/paraspeckle function and a potential link to stress gran-presents challenges in identifying reliable measures. Recently, circulat- ules and P-bodies due to their increased association with mutant TDP-ing microRNAs (miRNAs) have emerged as potential biomarkers for 43. In addition, the newly identified interactors of TDP-43 in this study assessing disease progression and predicting and monitoring treat- may contribute to the understanding of the aggregation process. ment response in various diseases, including SMA. Keywords: TDP-43, interactome, BioID, ALS Results: To investigate miRNAs associated with the pathogenesis of SMA and their potential use as biomarkers, we conducted an exten- sive literature search. Among the miRNAs studied, four muscle-specific MOL.08 Saturday, September 30th, 13:00 [Molecular Neuroscience B] miRNAs (myomiRs) have shown promise as potential SMA biomarkers. These myomiRs include hsa-miR-1-3p, hsa-miR-133a-3p, hsa-miR- Expression of disease-associated mR-133b, and hsa-miR-206, and were found to be frequently elevated in NAs in platelets: a potential new bio-SMA patients compared with healthy controls, and their levels dem- onstrated a decrease following nusinersen treatment. Moreover, their markers of ALS pathology? target genes were found to be involved in neurological inflammatory processes, further highlighting their relevance to SMA. Sara Cappelli, Cristiana Stuani, Himanashi Conclusions: Further studies with larger cohorts of healthy individuals Choudary, Emanuele Buratti and SMA patients, both pre- and post-treatment, are needed to validate the use of myomiRs as biomarkers for SMA. Ultimately, the identifica- International Centre for Genetic Engineering and Biotechnology tion of reliable biomarkers will enable more effective clinical manage- (ICGEB), Trieste, Italy ment and personalized treatment strategies for SMA patients. Loss of nuclear TAR DNA-Binding Protein of 43 kDa (TDP-43) and Keywords: spinal muscular atrophy, microRNA, biomarkers cytoplasmic TDP-43 accumulation are widely recognized as major [52] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 neuropathologic features in Amyotrophic Lateral Sclerosis (ALS) and a path for neuroscience researchers to model metabolic diseases in the Frontotemporal lobar degeneration (FTLD) cases. Particularly, neuro- adult zebrafish to explore its neurobiological implications. pathologic forms of TDP-43 arise from disease-associated changes in splicing and post-translational modification. Although, all these aberrant Keywords: diabetes, hyperglycemia, chronic stress, NRF2, chloro-TDP-43 forms can be detected in post-mortem tissue of ALS and FTLD genic acid patients, few literatures are currently available regarding their quantifi- cation in biological fluids. Recently, it has been reported that more than 90% of plasma TDP-43 arises from platelets, as well as an increase of MOL.12 Saturday, September 30th, 13:00 [Molecular Neuroscience B] TDP-43 phosphorylated forms in platelets of ALS patients compared Neural agrin has an age-dependent to healthy donors. Moreover, platelets express a large number of neurotransmission-related proteins and although they are anucleate cells, stimulatory effect on the proliferation they contain mitochondria and all the machinery to carry on signal-de- of cultured human myoblasts pendent RNA processing and de novo protein synthesis. Therefore, the aim of this work is to establish new bioassays for detecting pathologi- cal TDP-43 species in ALS platelet samples, as well as to define their Katarina Gros1, Urška Matkovič1, Giulia Par-significance as potential biomarkers. Our preliminary results identified several neurodegenerative-related targets commonly regulated among ato2, Katarina Miš1, Elisa Luin2, Annalisa healthy control platelets and brain-derived cells depleted for TDP-43, Bernareggi2, Marina Sciancalepore2, Tomaž including PDGFRB, COL6A2, ANXA2, FOXO4 and CEND1. Overall, Marš1, Paola Lorenzon2*, Sergej Pirkmajer1* these results strongly support our hypothesis of similarity in RNA ex- pression pattern of platelets and neurons, and they may contribute to 1 Institute of Pathophysiology, Faculty of Medicine, University of Lju-set the stage for an early detection of TDP-43 neuropathology in ALS. bljana, Slovenia 2 Department of Life Sciences and BRAIN Center, University of Trieste, Keywords: Platelets, TDP-43, RNAseq Italy *These authors contributed equally to the work MOL.10 Saturday, September 30th, 13:00 [Molecular Neuroscience B] Neural agrin, a heparan-sulphate proteoglycan secreted by the α-motor Hyperglycemic zebrafish exposed to neurons, promotes formation and maintenance of the neuromuscular junction via Lrp4 and the muscle-specific kinase (MuSK). By enhancing chronic unpredictable mild stress dis- differentiation and maturation of myotubes neural agrin also promotes play oxidative damage in the brain: myogenesis. Here we determined whether and how neural agrin affects proliferating human myoblasts, which are often considered to be unre-mitigation by chlorogenic acid sponsive to agrin. In cultured human myoblasts, neural agrin induced transient dephosphorylation of ERK1/2, while c-Abl, STAT3, and focal adhesion kinase were unresponsive to agrin treatment. Gene silenc- Rhea Subba, Amal Chandra Mondal ing of Lrp4 and MuSK markedly reduced the BrdU incorporation, sug- gesting the Lrp4/MuSK complex is functionally important for myoblast Laboratory of Cellular and Molecular Neurobiology, School of Life Sci- proliferation. Acute and chronic treatments with neural agrin increased ences, Jawaharlal Nehru University, New Delhi, India the proliferation of myoblasts of old donors, but they did not affect the proliferation of myoblasts of young donors. The C-terminal fragment Hyperglycemia, a core feature of diabetes, is speculated to be injurious of agrin which lacks the Lrp4-binding site and cannot activate MuSK to brain health. Diabetes often involves chronic stress, termed diabetic had a similar age-dependent effect, indicating that the age-dependent distress. Chronic stress is explored with reference to psychiatric dis- signalling pathways activated by neural agrin involve the Lrp4/MuSK orders such as depression and anxiety. However, extensive literature receptor complex as well as a Lrp4/MuSK-independent pathway. Taken addressing concurrently occurring hyperglycemia and chronic stress together, our results highlight an age-dependent role for neural agrin in is unavailable. Diabetes-associated brain pathology studies are now regulation of myoblast proliferation. including the zebrafish (Danio rerio) as a disease model. It has been repeatedly demonstrated that oxidative stress is associated with the Keywords: neural agrin, Lrp4, MuSK, myoblasts, ageing pathophysiology of various chronic diseases. The nuclear factor eryth-roid 2-related factor 2 (NRF2) is a transcription factor that influences the expression of several cytoprotective antioxidant genes. Consequently, MOL.14 Saturday, September 30th, 13:00 [Molecular Neuroscience B] studies are exploring the therapeutic effects of NRF2-targeting com- Crosstalk of Optineurin and TDP-43 in pounds to mitigate disease progression. For instance, chlorogenic acid (CGA), a polyphenol, has shown promise against oxidative damage but ALS and FTD whether it works through NRF2 is undetermined. We performed an ex- ploratory study on adult zebrafish wherein they were exposed to simul- taneous chronic unpredictable mild stress and hyperglycemia (111mM Nikolina Prtenjaća Mohović, Ivana Munitić dextrose) for 14 days. This was followed by intraperitoneal injection with 50, 100, and 200 mg/kg of CGA on the 15th day. Fasting blood glucose Laboratory of Molecular Immunology, Department of Biotechnology, levels were measured and brain tissue was extracted. Blood glucose University of Rijeka, Croatia levels were dramatically elevated in stressed-hyperglycemic fish com- pared to control. Furthermore, there were alterations in NRF2 protein Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and gene levels and also of its downstream target genes. Therefore, are neurodegenerative diseases marked by neuronal loss, chronic in-CGA may operate via NRF2 signaling in this context. This study paves flammation, and protein aggregation. TAR DNA- binding protein 43 (TDP-43) is present in neuronal and glial aggregates in >95% of ALS [53] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 and >45% of FTD patients. Its aggregation is closely linked to its nucle- Results: Midazolam up to 1 μM concentration did not increase cell ar depletion and loss-of-function. Moreover, TDP-43 aggregates trigger death in cultured astrocytes. Cytotoxic effects were dose dependent chronic inflammation and vice versa, chronic inflammation further exac- and observed only at concentrations 400-times higher compared to erbates TDP-43 aggregation. The autopsies of ALS and FTD patients therapeutic (300 μM – 15-fold vs. control, p < 0,0001). Majority of cells carrying the mutations in the OPTN gene, encoding for optineurin, also died due to necrosis (300 μM - 90%), via apoptotic pathway. Necropto-show TDP-43 aggregates. As optineurin has been proposed to act as sis was not observed. the adaptor protein in autophagy and inflammatory signaling, here we tested if optineurin ALS-linked mutations lead to impaired TDP-43 pro- Conclusions: Midazolam in concentrations, attainable in plasma during teostasis and/or altered immune responses. To address this, we used general anaesthesia, does not express any cytotoxic effects on cultured (1) optineurin deficient microglial BV2 cells made using CRISPR/Cas9 astrocytes. Even though astrocytes are relatively resistant to apoptosis technology (BV2 KO) and (2) optineurin insufficiency mouse model it seems that midazolam at high concentrations triggers apoptotic and (Optn470T) that mimics loss-of-function Q398X truncation found in ALS not necroptotic pathway. patients. We found elevated basal TDP-43 protein levels in BV2 KO cells and Optn470T primary microglia but without differences in TDP- Keywords: midazolam, astrocytes, toxicity 43 mRNA levels at basal state, arguing that TDP-43 is post-transla-tionally regulated. Moreover, our results demonstrated that optineurin was dispensable as an adaptor in the process of TDP-43 turnover via OTH.02 Saturday, September 30th, 13:00 [Other B] autophagy. To test the role of inflammation on TDP-43 levels, we stimu- What has (not) been learnt from the lated BV2 microglia cells and primary microglia with lipopolysaccharide (LPS) to mimic bacterial infection and observed a significant increase in COVID pandemics TDP-43 protein levels in WT cells, which was absent in optineurin defi- cient and insufficient cells. In the latter, TDP-43 remained at the same elevated state as in the basal conditions. We did not detect a difference Tina Bregant in TDP-43 mRNA levels upon LPS in optineurin deficient BV2 KO cells, but RNASeq analyses showed increased expression of inflammatory CIRIUS-Centre for Education and Rehabilitation of Physically Handi-genes arguing that lack of functional optineurin could lead to chroni- capped Children and Adolescents, Kamnik, Slovenia cally activated cells that can consequently increase levels in TDP-43. However, in vivo experiments did not show TDP-43 aggregation and On March 11th 2020, World Health Organization (WHO) declared that ALS/FTD-like neuropathology in the Optn470T mice up to two years of the disease caused by a Coronavirus has the characteristics of pan-age, suggesting that ageing was insufficient to provoke the phenotype. demics. It was first identified as an outbreak of respiratory illness cases In conclusion, we observed elevated TDP-43 levels in optineurin insuf- in Wuhan, China, initially reported to WHO on December 31st, 2019. On ficient and deficient microglia, but additional stimuli are likely necessary January 30th, 2020, the WHO declared the COVID-19 outbreak a global to exacerbate the phenotype and to elucidate the role of optineurin in health emergency. disease pathogenesis. Due to mutations, we were facing ever-changing clinical pictures from severe first wave illness caused by alpha variant, then delta variant in MOL.16 Saturday, September 30th, 13:00 [Molecular Neuroscience B] winter 2020 and spring 2021. Then a more virulent but less danger- Toxic potential of midazolam on rat ous omicron variant emerged. Understanding of disease, diagnostics, and measures changed over the time, which caused confusion among cortical astrocytes people not used to the scientific process. WHO and CDC were reluc- tant to some measures e.g.: public use of masks, but then changed their recommendations. Rapid development of vaccines was seen as Dan Faganeli, Metoda Lipnik-Štangelj an achievement among scientific communities while the general public remained sceptic, even more prone to anti-vaxxer theories. Physical Institute of Pharmacology and Experimental Toxicology, Faculty of distance became very important as a preventative measure. Many gov-Medicine, University of Ljubljana, Slovenia ernments have restricted free movement and placed populations under lockdown to limit the spread of the pandemic. The delays of screening Objective: Midazolam is frequently used for initial induction into gen- programmes, diagnostics, elective surgeries and cut numbers of physi-eral anaesthesia. Recently, several reports have emerged reporting cians and nurses available to treat other diseases than Covid-19, were anaesthetics’ toxicity following their use. Data on their potential toxic not contributing to the notion that Covid-19 was at that time more seri-impact on brain is scarce and no mechanism explaining the observed ous threat to public health than cancer. Many people lost their relatives. toxicity is currently defined. Simultaneously, the role of astrocytes has Fear and anxiety which helped to comply with the rules and contain the been shown to be crucial in preserving brain homeostasis. The viability virus during the first wave was replaced by pandemic fatigue. A consist-of astrocytes directly affects the function of the entire central nervous ent decline in compliance with mitigation behaviors over time globally system. The objective of this study is to examine the cytotoxic effects led to oblivion even of simple mitigation tasks such as hand washing or of midazolam on primary rat cortical astrocytes using flow cytometry. staying at home when ill with infection. Method: Primary cultures of cortical astrocytes obtained from new-born Digitalization of all sectors (distant schooling, cross border data ana-rats were used as the basis for the experimental model. Cells were lytics), took place. Children who were home-schooled showed certain exposed for 24 hours to increasing concentrations of midazolam, in- behavioral problems; mental health problems which were on the rise for cluding clinically observed plasma concentrations during anaesthesia. decades now became more apparent. In addition, long COVID (post-Apoptosis, necrosis, and necroptosis as types of cell death were exam- acute sequelae) persist in approx. 10 % of those affected, however ined using flow cytometric analysis. most of the symptoms resolve within a year. Multiple organs (heart, vessels, lungs, immune system, pancreas, nervous system, kidneys, [54] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 GIT, reproductive system) are involved, pathologies are overlapping, SYS.03 Friday, September 29th, 13:00 [Systems Neuroscience A] which can exacerbate management challenges. Effects of prayer on heart rate variabil- Pandemics showed the importance of scientific literacy. As a society ity in resting sitting position in adults we should educate and empower people to be literate citizens who are able to evaluate the quality of scientific information on the basis of its source and the methods used to generate it. If this were the lessons Breda Žunkovič1,2, Nataša Kejžar3, Fajko F. learnt and additional action taken in place, then we could maybe say Bajrović4,5 that the toll, measured in lives and healthy-years lost, due to COVID were not completely wasted. With better scientific literacy we could face 1 Institute of Clinical Neurophysiology, University Medical Centre Lju-next pandemics efficiently and better equipped. bljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Slovenia Keywords: Covid, Corona virus, mitigation measures, fear, scientific 3 Institute for Biostatistics and Medical Informatics, Faculty of Medicine, literacy University of Ljubljana, Slovenia 4 Department of Vascular Neurology and Intensive Neurological Thera- py, University Medical Centre Ljubljana, Slovenia SYS.01 Friday, September 29th, 13:00 [Systems Neuroscience A] 5 Institute of Pathophysiology, Faculty of Medicine, University of Lju- Behavioral sensitization and tolerance bljana, Slovenia induced by ketamine enantiomers in Background: Prayer is a common practice worldwide, but its effects on male Wistar rats HRV (heart rate variability) are unclear. The aims of this study was were to examine the immediate and long term effects of prayer on HRV and to determine whether these effects differ from those of recitation. Kristian Elersič, Marko Živin, Maja Zorović Methods: In 78 subjects (49 females, age 37±11), who pray regularly Institute of Pathophysiology, Faculty of Medicine, University of Ljublja- and 50 controls (35 females, age 35±8) who do not pray at all, ECG na, Slovenia and respiratory rate were recorded continuously for 60 minutes in sit- ting position during five phases: resting, silent prayer, resting, silent Ketamine has gained significant attention for its therapeutic benefits recitation of song lyrics, and resting. For a subgroup of subjects, the or-as a fast-acting antidepressant. However, it is crucial to address its der of interventions was reversed. From the 5-minute intervals of each undesirable side effects. In our study, we aimed to explore the diver- protocol phase, HRV parameters, reflecting parasympathetic heart rate gent side effects of ketamine enantiomers, namely S-ketamine and R- modulation, RMSSD (root mean square of successive differences) and ketamine, at subanesthetic doses (15 mg/kg), with a particular focus HF (high frequency) were calculated. on their abuse and psychotomimetic potentials during prolonged treat- ment. Our hypothesis was that R-ketamine will exhibit fewer unwanted Results: During prayer, the mean of RMSSD decreased significantly effects compared to S-ketamine, because of its lower NMDA receptor (p=0.001), and mean of HF tended to decrease (p=0.038). The means binding affinity. of baseline HRV parameters and their decreases during the prayer did not differ significantly between prayers and controls. In males, the Male Wistar rats were treated with either R-ketamine, S-ketamine, or decrease in RMSSD tended to be greater during prayer than during saline every third day for a total of three weeks. We evaluated the en- recitation (p=0.022). antiomers’ abuse potential by investigating their capacity to stimulate locomotion and induce locomotor sensitization. Additionally, we evalu- Conclusions: Parasympathetic modulation of heart rate decreased dur-ated their psychotomimetic potential by measuring dissociative stereo- ing silent prayer in a resting sitting position, but was unaffected by his-typy, which is defined by ataxia-like abnormal behaviors, stereotypical tory of regular prayer. The trend of a greater decrease during prayer behaviors, and a decrease in natural behaviors. than during recitation suggests that this cannot be explained solely by language processing. Furthermore, the trend of a greater decrease in Our findings revealed that S-ketamine acutely induced concurrent lo- males than in females suggests sex differences in autonomic heart rate comotor stimulation and ataxia, and attenuated the expression of other regulation. natural behaviors, whereas R-ketamine did not. With repeated treat- ment, S-ketamine led to locomotor sensitization and tolerance to the Keywords: heart rate variability, prayer, autonomic nervous system, ataxic effects. Repeated treatment with R-ketamine also led to locomo- parasympathetic tor sensitization, resulting in post-treatment locomotor stimulation that was not observed prior to repeated treatment. SYS.02 Saturday, September 30th, 13:00 [Systems Neuroscience B] We conclude that S-ketamine has a higher abuse and psychotomimetic Gut microbiota perturbations disrupts potential than R-ketamine. However, their safety profiles in the prolonged treatment of depression remain to be determined. hippocampal serotonin bioavailability and anxiety behavior Keywords: ketamine, enantiomers, side-effects, rats Jazib Shafiq, Ayaz Ahmed International Center for Chemical and Biological Sciences, University of Karachi, Pakistan [55] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Gut Microbiome-Brain axis is a dynamic trans-kingdom communication izers. Following the 1st dose, those treated with S-ketamine displayed system linking the gut microbiome and host CNS through metabolites, a significantly higher number of vocalizations compared to the baseline. hormones, and immune mediators. The composition of gut microbiome The difference disappeared following the 3rd dose, equating high vocal-correlates with host behavior and its disruption is implicated in several izers treated with S-ketamine to low vocalizers. High vocalizers treated neurological disorders. Germ free (GF) mice model is extensively used with R-ketamine displayed a significantly lower number of vocalizations to study GMB axis, however, recent research reported the dysregu- compared to baseline, but only after 7 doses, also equating them to low lated serotonergic transmission in GF mice. To address this issue, we vocalizers. The results indicate the importance of individual differences developed antibiotics-induced gut dysbiosis mice model and employing and dose quantity in antidepressant response. However, extreme cau-multi-omics approach to dissect the role of gut microbiota in modulation tion should be applied to any further conclusions due to the exploratory of hippocampal serotonin (5-HT) bioavailability and anxiety behavior. nature of the analysis and a low sample size. SPF mice were given combination of non-absorbable antibiotics for 14 days to induce dysbiosis before assessing anxiety using elevated plus Keywords: rats, ultrasonic vocalizations, antidepressant, ketamine maize and open field. After behavioral study, mice were euthanized, and organs/tissues were collected. Neurotransmitters and targeted genes transcripts were quantified in mice hippocampus using HPLC CEL.12 Saturday, September 30th, 13:00 [Cellular Neuroscience B] and RT-qPCR. DNA was extracted from mice cecum and subjected to Paclitaxel-induced peripheral neurop-shotgun metagenomic sequencing. Data was processed with standard bioinformatics pipelines and visualized using R Studio. Behavioral re- athy: in vitro and in vivo study sults showed dysregulated anxiety behavior in dysbiosis mice, and their hippocampus exhibited low levels of 5-HT, Trp, and 5-HIAA. Transcrip- tion level of 5-HT transporter was down-regulated in dysbiosis group, Zuzana Michalová, Ivo Vanický while expression of glucocorticoid, 5-HT, and GABA receptors, and TPH2 remains unchanged. Taxonomic analysis depicted increase in Institute of Neurobiology, Biomedical Research Center, Slovak Acad-beta diversity between groups, and Shannon-Weaver index was sig- emy of Sciences, Košice, Slovakia nificantly lower in dysbiosis group. Functional dominance in dysbiosis mice shifted from Firmicutes and Bacteroidetes to Proteobacteria. The Paclitaxel induced peripheral neuropathy (PIPN) is a severe adverse dominant communities in control group were Muribaculum and Bacte- effect observed in most cancer patients receiving paclitaxel. Although roides, whereas Klebsiella and Enterobacter were dominant in dysbio- highly effective in blocking tumor progression, a major dose-limiting sis group. 5-HT is the key regulator of anxiety, and our data suggest side effect of paclitaxel can persist for up to two years after complet-that gut microbiome perturbations disrupt hippocampal 5-HT bioavail- ing treatment, greatly affecting both the course of chemotherapy and ability, leading to dysregulated host anxiety. We are further integrating patients’ quality of life. The main symptoms are numbness, paresthesia metabolomics data to study the host/bacterial metabolites involved in and burning pain in a glove-and-stocking distribution. In this study, dor-5-HT and anxiety regulation. sal root ganglion (DRG) dissociated primary cultures have been used as a neurotoxicity-screening model to evaluate the effect of paclitaxel Keywords: microbiome gut brain axis, tryptophan metabolism, anxiety- on the neurite elongation in vitro. The neurotoxic effect of this drug was like behavior analyzed by measuring the neurite length of post-mitotic, non-dividing cells, such as neurons. Moreover, in DRG primary cultures, the mor- phological features of paclitaxel-induced cellular death were studied SYS.04 Saturday, September 30th, 13:00 [Systems Neuroscience B] and the DRG neurons were observed to die by necrosis. In vivo, ax- The individual differences in response onal degeneration was observed in sections of dorsal roots as well as to ketamine enantiomers: an explora- caudal nerves in a rat model of PIPN. In adult rats, we have observed a dose-dependent large-fiber sensory neuropathy with no deleterious tory preclinical approach effects on overall health, using two intravenous injections of paclitaxel 2 days apart. Currently, there are no therapeutic options available for the prevention of PIPN and only few drugs are recommended for the Anamarija Banjac, Kristian Elersič, Marko treatment of existing neuropathies because the mechanisms of PIPN Živin, Maja Zorović remain unclear. Our findings demonstrate a dose and time dependent neurotoxic effect of paclitaxel in DRG derived sensory neuron culture Institute of Pathophysiology, Faculty of Medicine, University of Ljublja- system as well as in rat in vivo model. na, Slovenia Acknowledgments: This work was supported by the Grant Agency of Rodent ultrasonic vocalizations (USVs) in the 50-kHz range can be used the Ministry of Education, Science, Research and Sport of the Slovak as a measure of individual differences in positive hedonic response, Republic (No. VEGA 2/0120/23, VEGA 2/0109/21) and ITMS 2014+: hence bringing great value to preclinical antidepressant research. To 313011V344. test differential hedonic response to two enantiomers of ketamine, R- and S-ketamine, we performed an exploratory statistical analysis. 18 male Wistar rats received daily s.c. injections of either R-ketamine, S-ketamine or saline, for seven consecutive days. Their USVs were measured before treatment (baseline measures, dose 0) and after the 1st, 3rd, 5th, and 7th dose (10 minutes each measurement). After the experimental procedure, the animals were categorized as either high or low vocalizers based on the number of their baseline 50-kHz vocaliza- tions. An exploratory paired-samples t-tests on square root transformed data showed significant differences in vocalizations only for high vocal- [56] SNC’23 SNC’ SiNAPSA NEUROSCIENCE CONFERENCE ‘23 Ab A s b tract s s tract Educ E ationa duc l Wor ationa ks l Wor hop ks on Pain on P www.sinapsa.org/SNC23/workshop/programme Ljubljana, Slovenia 30 September 2023 SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Saturday, September 30th, 08:30 Saturday, September 30th, 10:30 The search for pain biomarkers Pain and memory Giandomenico Iannetti Jelena Radulović Neuroscience and Behaviour Laboratory, Italian Insti- Departments of Neuroscience and Psychiarty, Albert tute of Technology (IIT), Rome, Italy Einstein College of Medicine, New York, USA Department of Neuroscience, Physiology and Pharma- Department of Biomedicine, Aarhus University, Den-cology, University College London, United Kingdom mark Functional brain imaging techniques are being used more than ever Negative experiences, including pain, negative emotions, moods, and to investigate pain in health and disease, with the objective of finding memories, share a common feature in that they are all perceived as new means to alleviate clinical pain and improve patient wellbeing. The unpleasant, distressing, or aversive. Yet these experiences also have observation that several brain areas are activated by transient pain- features that segregate them in discrete phenomena. This lecture will ful stimuli, and that the magnitude of this activity is often graded with focus on the molecular and circuit mechanisms of the brain as the pain intensity, has generated excitement but also confusion. Indeed, interface between pain and other negatively valenced states. We will researchers devise approaches to extract features of brain activity that discuss in more detail evidence linking pain to negative mood (i.e., de-could serve as biomarkers to measure pain objectively. However, most pression), and negative memories (i.e., stress-related memories), while of the brain responses observed when pain is present can also be ob- emphasizing the difference between acute and chronic pain. From the served when pain is absent. For example, similar brain responses can molecular standpoint, we will highlight how pain-inducing, relative to be elicited by salient but non-painful auditory, tactile and visual stimuli, valence neutral stimuli shape the key intraneuronal signaling pathways and such responses can even be recorded in patients with congenital mediating short- and long-term adaptation and plasticity through gene analgesia. Thus, as I will show in my talk, there is still disagreement expression and epigenetic changes. At the circuit level, we will analyze on the degree to which current measures of brain activity specifically findings on various input integration models leading to the generation of relate to pain. Furthermore, whether more recent analysis techniques negative affective states. The lecture will conclude with the significance can be used to identify distributed patterns of brain activity selective for of the aforementioned analyses for devising novel pain therapeutics. pain can be only warranted using carefully designed control conditions. In general, the clinical utility of current pain biomarkers derived from human functional neuroimaging is overstated, and evidence for their ef- Saturday, September 30th, 11:00 ficacy in real-life clinical conditions is scarce. Rather than searching for Pain modulation and emotion biomarkers of pain perception, several researchers are developing biomarkers to achieve mechanism-based stratification of pain conditions, predict response to medication and offer personalized treatments. Ini- tial results with promising clinical perspectives need to be further tested Volker Neugebauer for replicability and generalizability. Texas Tech University Health Sciences Center, Lub- bock, TX, USA Saturday, September 30th, 09:30 Peripheral and spinal circuits The amygdala and related limbic circuits have emerged as important players in pain modulation and in the affective dimension of pain. While pain-related neuroplasticity in this region is now well- established, the contribution of non-neuronal factors and mechanisms of chronic neuro- Carole Torsney plasticity are not clear. Evidence will be discussed to suggest a change Centre for Discovery Brain Sciences, University of Ed- of synapse- and cell type-specific mechanisms of amygdala neuroplasticity and pain behaviors in the transition from acute to chronic neuro- inburgh, United Kingdom pathic pain. The focus will be on CRF neurons and neuro-immune sign- aling, their interactions, and mechanistic links to pain behaviors. Data The pain network provides an important warning system to avoid injury. from opto- and chemogenetic strategies combined with electrophysiol-However if tissue injury occurs the somatosensory system is dynami- ogy and behavior will be presented and the application of transcriptom-cally altered to increase sensitivity and ensure maximal protection to ics will be discussed for the identification of molecular mechanisms and promote recovery and repair. If this adaptive response persists beyond factors of neuropathic pain-related changes in the amygdala. tissue healing there is transition to chronic pain. This somatosensory plasticity that drives the symptoms of hyperalgesia (exaggerated pain) and allodynia (touch-evoked pain) will be reviewed with a focus on pe- ripheral and spinal circuits. The advances made using techniques to genetically target, ablate or manipulate molecularly defined neuronal subtypes that has expanded understanding of nociceptor sensitisation and spinal circuit plasticity will be highlighted. Recent novel insights in to the amplified relay of nociceptive signals by peripheral sensory neu- rons and the regulation and unmasking of spinal circuits that manifest as hyperalgesia and allodynia will be presented. [58] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Saturday, September 30th, 11:30 is highly polymorphic with many important single nucleotide polymor- Early anti-inflammatory treatment of phisms, haplotypes and copy number variants that may influence the capacity for drug metabolism. Carriers of two non-functional CYP2D6 pain: beneficial or detrimental? variants are poor metabolizers (PMs) and are at risk for reduced treat- ment efficacy due to lower systemic concentrations active metabolite. On the other hand, carriers of multiple gene copies are ultrarapid me- Massimo Allegri tabolizers (UMs) and may be at increased risk of toxicity at therapeutic doses of tramadol and codeine due to elevated concentrations of active Centre Lemanique d’antalgie et neuromodulation, En- metabolites. The current level of pharmacogenetic evidence enabled semble Hospitalier de la Cote, Morges, Switzerland the preparation of genotype-guided treatment recommendations that can support safer opioid prescribing and better outcomes for patients Pain is an intricate phenomenon with a complex neurophysiological receiving pain management. basis. Recently, the definition of pain has undergone revision, accom- panied by the proposal of a new classification to enhance its under- Saturday, September 30th, 14:20 standing, aiding in more accurate diagnosis. In fact, pain can manifest as a simple symptom of acute or chronic diseases, or it can evolve into Pharmaco-interventional treatment of a distinct disease itself with its own underlying pathophysiology. For non-oncological pain instance, the emergence of “nociplastic pain” as a new entity encom- passes various syndromes, including fibromyalgia, shedding light on how alterations in pain pathways can result in a distinct disease, where pain is a prominent symptom. Another significant concern lies in the Gorazd Požlep persistence of pain after surgery, which can linger for up to 3-6 months Clinical Department of Anaesthesiology and Surgical post-surgery, affecting up to 20% of individuals. Understanding how acute pain transforms into chronic pain is vital for efficient treatment. Intensive Therapy, University Medical Centre Ljubljana, Slovenia Recent research has unveiled the immune system’s newfound role in this transition from a symptom to a chronic disease, not only in post- Over the last few decades our knowledge about pain has altered drasti-surgery pain but also in chronic conditions like low back pain and cally. Traditionally pain has been understood as a consequence of a temporomandibular pain. Surprisingly, chronic pain is not an aberrant disease or an injury. The implication being that a proper treatment of the response to pain stimuli, as previously believed; instead, it represents underlying disease or healing of the injury would relieve pain. But this is the immune system’s “non-response.” This discovery underscores the not always the case. In the latest international classification of diseases intricate interaction between neurons and the immune system and how chronic pain has been described as an independent disease. an inadequate immune response can lead to modifications in the nerv- ous system, giving rise to chronic pain. There are many different methods for pain treatment. So the approach we take is case specific and depends on the several factors including These revelations open up new avenues for prevention and treatment, the underlying cause of the pain, its severity and patient’s individual with potential therapeutic targets that will be explored in the presenta- characteristics. Acute pain is normally treated with drugs such as broad tion. spectrum of analgesics e.g. paracetamol and metamizole, non-ste- roidal anti-inflammatory drugs, opioids and adjuvant analgesics e.g. antidepressants, anticonvulsants and muscle relaxants. Often we can Saturday, September 30th, 14:00 achieve better results with the combination of different drugs. Pharmacogenetics of pain treatment Interventional pain management involves the use of different pro- cedures to diagnose and treat various types of pain. It can be used Vita Dolžan when traditional pharmacological methods have proven inadequate or have significant side-effects. These procedures are often performed Pharmacogenetics Laboratory, Institute of Biochemis- by a pain management specialist with the aim to provide pain relief try and Molecular Genetics, Faculty of Medicine, Uni- by directly targeting the source of pain. Some of the common used interventional pain management techniques include peripheral nerve versity of Ljubljana, Slovenia blocks, epidural steroid injections, facet joint injections, radiofrequency ablation, spinal cord stimulation, intrathecal drug delivery, joint infiltra- Opioids are commonly used in the treatment of moderate to severe tions and trigger point injections. pain, particularly in oncology patients. Opioids such as codeine, oxy- codone and tramadol are a preferable option to morphine as they pro- Psychological and social factors can play a significant role in shaping vide a similar level of analgesia with a lower risk of side effects and how pain is perceived tolerated and managed by the patient. Emotional opioid dependence. Contrary to morphine, these drugs need to be state, cognitive factors e.g. , expectations, social support, social and metabolically activated in the liver to their active metabolites that ex- cultural factors are some of the important psychosocial factors which hibits their analgesic activity by binding to µ opioid receptor (MOR). can contribute to the experience of pain. However some patients experience insufficient pain relief or adverse Thus, often an interdisciplinary approach is needed for patients with inevents when using standard therapeutic doses. Genetic variability of tractable pain. It involves a team of healthcare professionals from vari-drug metabolizing enzymes, drug transporters as well as drug targets ous disciplines working together to address the physical psychological may influence the response to treatment. The most well studied gene and social aspects of pain. involved in the metabolic activation of opioids, codeine and tramadol in particular, is cytochrome P450 2D6 (CYP2D6). The CYP2D6 gene [59] SiNAPSA Neuroscience Conference ‘23, Ljubljana, 28-30 September 2023 Saturday, September 30th, 15:00 pate in their own recovery and commitment to self-care. Pharmaco-interventional treatment of There are effective non-pharmacological therapies, such as physi-oncological pain cal (sensory) interventions that inhibit pain perception or behavioural and environmental approaches that activate pain control mechanisms. Some common non-pharmacological treatments are heat, cold, mas- Iztok Potočnik, Branka Stražišar sage, positioning, acupuncture, transcutaneous electrical neurostimu- lation (TENS), physical therapy, and psychological support. University Medical Centre Ljubljana, Slovenia Institute of Oncology, Ljubljana, Slovenia There are directed or self-engaged movement therapies and meditative movement therapies, as in yoga and tai chi. Psychological approaches, Pain is very common in oncological patients. The intensity of the pain such as stress management, medical hypnosis, cognitive behavioural increases with the progression of the disease. At assessment, 60-90% therapy, musical therapy, meditation, mindfulness, are also recom-of patients have significant pain. The cause of pain is complex and may mended. Other lifestyle approaches, including diet and sleep hygiene, be the result of tumor growth, metastasizing, or treatment (surgical, have been shown to benefit health. These are low-risk, low-cost treat-systemic and radiation). Patients may also have pain due to associated ments that are well accepted by patients. They have different mecha-diseases (diabetes, peripheral arterial occlusive disease, degenerative nisms of action that involve endogenous pain modulation systems, neu-joint diseases). The nature of the pain is usually mixed (nociceptive, roplasticity, and nonspecific effects. We will give a review lecture on the neuropathic and nociplastic). Effective pain management is vital. Good topic and focus more on acupuncture and medical hypnosis. pain management improves the quality and quantity of the patient’s life. In the treatment of carcinoma pain, we use a multimodal approach, including both non-pharmacological and pharmacological measures (medication and intervention). Pharmacological treatment is based on the World Health Organization’s analgesic grading ladder with a multi- modal approach. History, examination and pain assessment are always required. Oncological pain is usually severe. Opioids are the basis of pain treatment. If there is a neuropathic component, adjuvant drugs are added (antiepileptics, antidepressants, local anesthetics, ketamine, corticosteroids). When the pain is very severe or additional symptoms are present, clonidine and dexmedetomidine are added. Radiation and bisphosphonates are most helpful in alleviating bone pain. Inter- ventional techniques are necessary in a small proportion of patients (2-10%) when conservative methods fail. Nerve blocks, central nerve blocks and catheters are used. In Slovenia, subcutaneous application of drugs is common, especially towards the end of life, as it allows treat- ment of several symptoms of advanced disease. We must always adapt the treatment to the individual patient and use a multimodal approach. Saturday, September 30th, 15:30 Non-pharmacological treatment of pain Jasmina Markovič Božič, Alenka Spindler Ve- sel Clinical Department of Anaesthesiology and Surgical Intensive Therapy, University Medical Centre Ljublja- na, Slovenia Department of Anaesthesiology and Reanimation, Faculty of Medicine, University of Ljubljana, Slovenia Non-pharmacological treatment of pain is used when patients refuse pharmacological or interventional treatments, when such treatments prove unsuccessful, or mostly as part of an integrated multimodal pain approach. They may help decrease pain, give more control over pain, and improve quality of life. Evidence-based non-pharmacologic thera- pies are safe and effective components of comprehensive pain care that can be opioid-sparing and have additional benefits. They reduce anxiety and depression, reduce nausea and vomiting, facilitate restful sleep, increase a sense of well-being, and motivate patients to partici- [60] SNC’23 SNC’ SiNAPSA NEUROSCIENCE CONFERENCE ‘23 Sponsors Spons www.sinapsa.org/SNC23/sponsors Ljubljana, Slovenia 28-30 September 2023 Conference sponsors Principal sponsor Roche Main sponsors Genesis pharma Medison Novartis Supporting sponsors Biogen Pfizer Supporting organizations International Brain Research Organization, IBRO International Centre for Genetic Engineering and Biotechnology (ICGEB) Sponsors Krka Lek Sandoz Medis Medistar Octapharma Sobi Avantor VWR [62] Roche v nevroznanosti Skrbimo za tisto, kar nas dela edinstvene. Roche s ponosom spodbuja pomembne inovacije v nevroznanosti, osredotočene na zgodnejše prepoznavanje bolezni, natančno spremljanje in razvoj učinkovitejših in posamezniku prilagojenih zdravil. Naša področja raziskovanja obsegajo multiplo sklerozo, spinalno mišično atrofijo, bolezni spektra neuromielitis optika, motnje avtističnega spektra, Alzheimerjevo, Parkinsonovo in Huntingtonovo bolezen. Dodatne informacije so na voljo pri: Roche farmacevtska družba d.o.o., Stegne 13g, Ljubljana. Datum priprave: marec 2023 M-SI-00000806 (v1.0) Zdravilo ONPATTRO® (patisiran) je indicirano za zdravljenje dedne transtiretinske amiloidoze (hATTR) pri odraslih bolnikih s polinevropatijo 1. ali 2. stopnje1 2 mg/ml koncentrat za raztopino za infundiranje patisiran Zdravilo ONPATTRO® spreminja vaša pričakovanja pri zdravljenju dedne transtiretinske amiloidoze (hATTR) s polinevropatijo Zdravilo ONPATTRO® v primerjavi s placebom: obrne proces napredovanja polinevropatije pri večini bolnikov,2 izboljša meritve strukture srca v podskupini bolnikov s polinevropatijo in prizadetostjo srca,3 izboljša kakovost življenja pri večini bolnikov.2 Skrajšan povzetek glavnih značilnosti zdravila glavnih značilnosti zdravila. Kontraindikacije: Huda preobčutljivost (npr. anafilaksa) na in vitamina A v serumu. Vendar pa lahko v odsotnosti vezavne beljakovine za retinol učinkovino ali katero koli pomožno snov. Posebna opozorila in previdnostni ukrepi: prenos in privzem vitamina A v tkivo potekata s pomočjo alternativnih mehanizmov. Onpattro 2 mg/ml koncentrat za raztopino za infundiranje Reakcije, povezane z infuzijo Pri bolnikih, zdravljenih z zdravilom Onpattro, so opazili Posledično laboratorijske preiskave ravni vitamina A v serumu med zdravljenjem z Sestava zdravila: En ml vsebuje natrijev patisiranat v količini, ki ustreza 2 mg patisirana. reakcije, povezane z infuzijo. Pri bolnikih, ki imajo reakcije, povezane z infuzijo, se prva zdravilom Onpattro ne kažejo celotne količine vitamina A v telesu, zato se ne smejo Ena viala vsebuje natrijev patisiranat v količini, ki ustreza 10 mg patisirana, v obliki lipidnih reakcija, povezana z infuzijo, običajno pojavi pri prvih 2 infuzijah. Najpogostejši simptomi uporabljati kot smernice za dodajanje vitamina A. Plodnost, nosečnost in dojenje: Ženske nanodelcev. Pomožne snovi z znanim učinkom: En ml koncentrata vsebuje 3,99 mg reakcij, povezanih z infuzijo, o katerih so poročali v vseh kliničnih študijah (pri ≥ 2 % v rodni dobi Zdravljenje z zdravilom Onpattro zmanjšuje ravni vitamina A v serumu. natrija. Terapevtske indikacije: Zdravljenje dedne transtiretinske amiloidoze pri odraslih bolnikov) so bili zardevanje, bolečina v hrbtu, navzea, bolečina v trebuhu, dispneja in Previsoke ali prenizke ravni vitamina A so lahko povezane s povečanim tveganjem bolnikih s polinevropatijo 1. ali 2 stopnje. Odmerjanje in način uporabe: Zdravljenje mora glavobol. Reakcije, povezane z infuzijo, lahko vključujejo tudi hipotenzijo in sinkopo. Za malformacije ploda. Zato je treba pred uvedbo zdravljenja izključiti nosečnost, ženske uvesti in nadzirati zdravnik z izkušnjami pri zdravljenju bolnikov z amiloidozo. Odmerjanje zmanjšanje tveganja reakcij, povezanih z infuzijo, je treba bolnike na dan infundiranja v rodni dobi pa morajo uporabljati učinkovito kontracepcijo. Če ženska namerava zanositi, Priporočeni odmerek zdravila Onpattro je 300 mikrogramov na kg telesne mase v obliki zdravila Onpattro vsaj 60 minut pred začetkom infundiranja premedicirati. Če se pojavi je treba dajanje zdravila Onpattro in nadomestka vitamina A prekiniti in spremljati ravni intravenske (i.v.) infuzije vsake 3 tedne. Odmerjanje mora temeljiti na dejanski telesni reakcija, povezana z infuzijo, je treba razmisliti o upočasnitvi ali prekinitvi infundiranja masi. Za bolnike, ki tehtajo ≥ 100 kg, je največji priporočeni odmerek 30 mg. Zdravljenje in uvedbi ustreznega zdravljenja (npr. s kortikosteroidi ali drugo simptomatsko vitamina A v serumu, ki se morajo vrniti na normalno raven, preden poskusi zanositi. se mora začeti čim prej po pojavu simptomov. Pri bolnikih, ki prejemajo zdravilo Onpattro, zdravljenje). Pri prekinitvi infundiranja se infundiranje lahko ponovno začne z nižjo Nosečnost Podatkov o uporabi zdravila Onpattro pri nosečnicah ni. Ni dovolj študij na se svetuje dodajanje vitamina A v odmerku približno 2500 i.e. na dan. Potrebna hitrostjo, ko simptomi izzvenijo. Infundiranje je treba prekiniti v primeru resnih ali smrtno živalih o vplivu zdravila na sposobnost razmnoževanja. Zaradi možnosti tveganja za premedikacija Vsi bolniki morajo pred infundiranjem zdravila Onpattro prejeti nevarnih reakcij, povezanih z infuzijo. Pri nekaterih bolnikih, ki imajo reakcije, povezane teratogenost, ki izhaja iz neuravnoteženih ravni vitamina A zdravila Onpattro ne smete premedikacijo za zmanjšanje tveganja reakcij, povezanih z infuzijo. Na dan infundiranja z infuzijo, lahko upočasnitev hitrosti infundiranja ali dodatni oz. večji odmerki enega ali uporabljati pri nosečnicah, razen če klinično stanje nosečnice zahteva zdravljenje. V zdravila Onpattro je treba bolniku vsaj 60 minut pred začetkom infundiranja dati vsako več zdravil za premedikacijo pri nadaljnjih infuzijah pomagajo zmanjšati tveganje reakcij, primeru nenačrtovane nosečnosti je treba skrbno spremljati plod, zlasti v prvem od naslednjih zdravil: intravenski kortikosteroid (deksametazon 10 mg ali enakovredno povezanih z infuzijo. Pomanjkanje vitamina A Zdravilo Onpattro z zmanjšanjem ravni trimesečju. Dojenje Ni znano, ali se zdravilo Onpattro izloča v materino mleko. Tveganja zdravilo), peroralni paracetamol (500 mg), intravenski zaviralec histaminskega receptorja beljakovine TTR v serumu povzroči zmanjšanje ravni vitamina A (retinol) v serumu. Ravni za dojenega novorojenca/dojenčka ne moremo izključiti. Odločiti se je treba med H1 (difenhidramin 50 mg ali enakovredno zdravilo), intravenski zaviralec histaminskega vitamina A v serumu, ki so pod spodnjo mejo normalnih vrednosti, je treba korigirati in prenehanjem dojenja in prenehanjem/prekinitvijo zdravljenja z zdravilom Onpattro, pri receptorja H2 (ranitidin 50 mg ali enakovredno zdravilo). Če zdravila za premedikacijo pred uvedbo zdravljenja oceniti kakršne koli očesne simptome ali znake zaradi čemer je treba pretehtati prednosti dojenja za otroka in prednosti zdravljenja za mater. niso na voljo ali jih bolnik po intravenski poti ne prenaša, lahko enakovredna zdravila pomanjkanja vitamina A. Bolniki, ki prejemajo zdravilo Onpattro, morajo za zmanjšanje Plodnost Podatkov o učinku zdravila Onpattro na plodnost pri človeku ni. Študije na prejme peroralno. Če je klinično indicirano, je možno odmerek kortikosteroida postopoma možnega tveganja toksičnosti za oči zaradi pomanjkanja vitamina A peroralno jemati živalih niso pokazale vpliva na plodnost samcev ali samic. Vpliv na sposobnost vožnje zmanjševati v korakih po največ 2,5 mg do najmanjšega odmerka 5 mg deksametazona nadomestek vitamina A v odmerku 2500 i.e na dan. V prvih 60 dneh nosečnosti so lahko in upravljanja strojev: Zdravilo Onpattro nima vpliva ali ima zanemarljiv vpliv na (i.v.) ali enakovrednega zdravila. Bolnik mora pred vsakim zmanjšanjem odmerka previsoke ali prenizke ravni vitamina A povezane s povečanim tveganjem malformacije sposobnost vožnje in upravljanja strojev. Neželeni učinki: Najpogostejši neželeni učinki, kortikosteroida za premedikacijo prejeti vsaj 3 zaporedne i.v. infuzije zdravila Onpattro ploda. Zato je treba pred začetkom jemanja zdravila Onpattro izključiti nosečnost, ženske o katerih so poročali pri bolnikih, zdravljenih z zdravilom Onpattro, so bili periferni edem brez pojava reakcij, povezanih z infuzijo. Izpuščeni odmerek Po izpuščenem odmerku je v rodni dobi pa morajo uporabljati učinkovito kontracepcijo. Če ženska namerava zanositi, (29,7 %) in reakcije, povezane z infuzijo (18,9 %). En bolnik (0,7 %) je zdravljenje med treba zdravilo Onpattro dati čim prej. Če bolnik zdravilo Onpattro prejme v 3 dneh po je treba dajanje zdravila Onpattro in nadomestka vitamina A prekiniti in spremljati ravni kliničnimi študijami prekinil zaradi reakcije, povezane z infuzijo. Zelo pogosti (≥ 1/10): izpuščenem odmerku, naj se zdravljenje nadaljuje po prvotnem načrtu za bolnika. Če vitamina A v serumu, ki se morajo vrniti na normalno raven, preden poskusi zanositi. V reakcije povezane z infuzijo, periferni edem. Pogosti (≥ 1/100 do < 1/10): bronhitis, sinusitis, bolnik zdravilo Onpattro prejme več kot 3 dni po izpuščenem odmerku, naj se odmerjanje primeru nenačrtovane nosečnosti je treba zdravljenje z zdravilom Onpattro prekiniti. rinitis, vrtoglavica, dispneja, dispepsija, eritem, artralgija, mišični krči. Občasni (≥ 1/1000 .2023 nadaljuje vsake 3 tedne po tem dnevu. Posebne populacije Starejši bolniki Pri bolnikih, Pomožne snovi z znanim učinkom To zdravilo vsebuje 3,99 mg natrija na ml, kar je enako starih ≥ 65 let, prilagajanje odmerka ni potrebno. Okvara jeter Pri bolnikih z blago okvaro 0,2 % največjega dnevnega vnosa natrija za odrasle osebe, ki ga priporoča Svetovna do < 1/100): ekstravazacija. jeter prilagajanje odmerka ni potrebno. Zdravila Onpattro niso preučili pri bolnikih z zdravstvena organizacija, in znaša 2 g. Medsebojno delovanje z drugimi zdravili in druge Način/režim predpisovanja/izdaje zdravila: ZZ - Predpisovanje in izdaja zdravila je le -SI-AD-09 zmerno ali hudo okvaro jeter in ga ti bolniki ne smejo prejemati, razen če pričakovana oblike interakcij: Formalnih kliničnih študij medsebojnega delovanja zdravil niso izvedli. na recept, zdravilo pa se uporablja samo v javnih zdravstvenih zavodih ter pri pravnih klinična korist odtehta možno tveganje. Okvara ledvic Pri bolnikih z blago do zmerno Pri odmerkih, večjih od klinično pomembnega odmerka, so in vitro opazili indukcijo in in fizičnih osebah, ki opravljajo zdravstveno dejavnost. okvaro ledvic prilagajanje odmerka ni potrebno. Zdravila Onpattro niso preučili pri časovno odvisno zaviranje CYP2B6. Neto učinek na substrate CYP2B6 (npr. bupropion Imetnik dovoljenja za promet z zdravilom: Alnylam Netherlands B.V., Antonio bolnikih s hudo ledvično okvaro ali končno odpovedjo ledvic in ga ti bolniki ne smejo in efavirenz) in vivo ni znan. Ne pričakuje se, da bi zdravilo Onpattro povzročalo Vivaldistraat 150, 1083 HP Amsterdam, Nizozemska prejemati, razen če pričakovana klinična korist odtehta možno tveganje. Pediatrična medsebojno delovanje z drugimi zdravili ali da bi nanj vplivali zaviralci ali induktorji Številka(-e) dovoljenja za promet z zdravilom: EU/1/18/1320/001 populacija Varnost in učinkovitost zdravila Onpattro pri otrocih ali mladostnikih, mlajših encimov citokroma P450. Preiskave vitamina A TTR v serumu je nosilec vezavne Datum zadnje revizije besedila: 05/2023 od 18 let, nista bili dokazani. Podatkov ni na voljo. Način uporabe Zdravilo Onpattro je beljakovine za retinol, ki olajša prenos vitamina A v krvi. Zdravljenje z zdravilom Onpattro za intravensko uporabo. Za bolj podrobna navodila o načinu uporabe glejte Povzetek zmanjša ravni TTR v serumu, kar povzroči zmanjšanje ravni vezavne beljakovine za retinol Pred predpisovanjem se seznanite s celotnim Povzetkom glavnih značilnosti zdravila. hATTR: dedna transtiretinska amiloidoza; TTR: transtiretin Reference: 1. Alnylam Pharmaceuticals. ONPATTRO® Povzetek glavnih značilnosti zdravila. 2. Adams D, et al. N Engl J Med. 2018;379(1):11–21. 3. Solomon SD, et al. Circulation. 2019;139(4):431–443. Datum priprave materiala: september 2023. ONP Samo za strokovno javnost. Za več informacij nam pišite na: si-info@genesispharmagroup.com V Sloveniji zastopa Genesis Biopharma SL d.o.o., Savska cesta 10, 1000 Ljubljana, Slovenija. [64] 20 mg/ml koncentrat za raztopino za infundiranje (efgartigimod alfa) Zdravilo VYVGART: zdravljenje vzroka za viden učinek Dokazano izboljšanje sposobnosti bolnikov za opravljanje vsakodnevnih aktivnosti1* Prvi in edini odobreni fragment Fc, pridobljen iz IgG, za zdravljenje generalizirane miastenije gravis pri odraslih bolnikih, ki so pozitivni na protitelesa proti acetilholinskemu receptorju.2,3 Zdravilo Vyvgart je indicirano kot dodatek k standardni terapiji za zdravljenje odraslih bolnikov s splošno miastenijo gravis (gMG), ki so pozitivni na protitelesa proti acetilholinskim receptorjem (AChR).2 *Primarni cilj študije ADAPT: delež bolnikov, pozitivnih na protitelesa za AChR (AChR-Ab+), odzivnih na MG-ADL v ciklu 1; VYVGART 67,7 % (44/65), placebo 29,7 % (19/64); p < 0,0001. Okrajšave: Ab, protitelo; AChR, acetilholinski receptor; Fc domena IgG; gMG, generalizirana miastenija gravis; IgG, imunoglobulin G; MG-ADL, lestvica aktivnosti vsakdanjega življenja, specifična za miastenijo gravis. Reference: 1. Howard JF et al. Lancet Neurol 2021;20(7):526-536. 2. VYVGART. Povzetek glavnih značilnosti zdravila, september 2023. 3. Wolfe GI et al. J Neurol Sci 2021;430:118074. Skrajšan povzetek glavnih značilnosti zdravila. Pred predpisovanjem preberite celoten Povzetek glavnih značilnosti zdravila. Za to zdravilo se izvaja dodatno spremljanje varnosti. Tako bodo hitreje na voljo nove informacije o njegovi varnosti. Zdravstvene delavce naprošamo, da poročajo o katerem koli domnevnem neželenem učinku zdravila. Glejte poglavje 4.8, kako poročati o neželenih učinkih. Vyvgart 20 mg/ml koncentrat za raztopino za infundiranje (efgartigimod alfa) Kakovostna in količinska sestava: Ena viala z 20 ml vsebuje 400 mg efgartigimoda alfa (20 mg/ml). Efgartigimod alfa je fragment Fc, pridobljen iz humanega rekombinantnega imunoglobulina G1(IgG1), proizvedenega v ovarijskih celicah kitajskega hrčka s tehnologijo rekombinantne DNK. Terapevtske indikacije: Zdravilo Vyvgart je indicirano kot dodatek k standardni terapiji za zdravljenje odraslih bolnikov s splošno miastenijo gravis (gMG, generalised Myasthenia Gravis), ki so pozitivni na protitelesa proti acetilholinskim receptorjem (AChR, Acetylcholine Receptor). Odmerjanje in način uporabe: Efgartigimod alfa mora dajati zdravstveni delavec pod nadzorom zdravnika z izkušnjami pri zdravljenju bolnikov z živčno-mišičnimi motnjami. Odmerjanje: Priporočeni odmerek je 10 mg/kg v obliki 1-urne intravenske infuzije, ki jo je treba dajati v ciklih infundiranja enkrat na teden 4 tedne. Nadaljnje cikle zdravljenja aplicirajte v skladu s klinično oceno. Pogostnost ciklov zdravljenja se lahko razlikuje glede na bolnika. V kliničnem razvojnem programu je bil najzgodnejši čas za začetek naslednjega cikla zdravljenja 7 tednov od začetnega infundiranja prejšnjega cikla. Varnost uvedbe nadaljnjih ciklov prej kot 7 tednov po začetku prejšnjega cikla zdravljenja ni bila ugotovljena. Pri bolnikih s telesno maso 120 kg ali več je priporočeni odmerek 1200 mg (3 viale) na infundiranje. Izpuščeni odmerek: Če načrtovano infundiranje ni možno, se lahko zdravljenje izvaja do 3 dni pred načrtovano časovno točko ali po njej. Nato je treba nadaljevati s prvotnim režimom odmerjanja, dokler se cikel zdravljenja ne konča. Če je treba odmerek odložiti za več kot 3 dni, odmerka ne smete dajati, da zagotovite dajanje dveh zaporednih odmerkov v presledku najmanj 3 dni. Starejši: Pri bolnikih, starih 65 let ali več, odmerka ni treba prilagajati. Okvara ledvic: Podatki o varnosti in učinkovitosti pri bolnikih z blago okvaro ledvic so omejeni; prilagajanje odmerka pri teh bolnikih ni potrebno. Podatki o varnosti in učinkovitosti pri bolnikih z zmerno okvaro ledvic so zelo omejeni, za bolnike s hudo okvaro ledvic pa podatkov ni. Okvara jeter: Podatki za bolnike z okvaro jeter niso na voljo. Odmerka ni treba prilagajati. Pediatrična populacija: Podatkov ni na voljo. Način uporabe: Zdravilo se sme dajati samo z intravensko infuzijo. Zdravila ne dajajte kot intravensko potisno ali bolusno injekcijo. Pred uporabo ga je treba razredčiti z raztopino 9 mg/ml (0,9 %) natrijevega klorida za injiciranje. Zdravilo je treba dajati 1 uro. Pred dajanjem efgartigimoda alfa mora biti na voljo ustrezno zdravljenje infuzijskih reakcij in preobčutljivostnih reakcij. V primeru infuzijskih reakcij je treba infundirati počasneje, infundiranje prekiniti ali pa prenehati izvajati. Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. Posebna opozorila in previdnostni ukrepi: Sledljivost: Z namenom izboljšanja sledljivosti bioloških zdravil je treba jasno zabeležiti ime in številko serije uporabljenega zdravila. Bolniki z miastenijo gravis razreda V po merilih Ameriške fundacije za miastenijo gravis (MGFA): Zdravljenja z efgartigimodom alfa pri teh bolnikih niso proučevali. Upoštevati je treba zaporedje uvedbe zdravljenja med uveljavljenimi terapijami za MG-krizo in efgartigimodom alfa ter njihovo morebitno medsebojno delovanje. Okužbe: Ker efgartigimod alfa povzroči prehodno zmanjšanje ravni IgG, se lahko tveganje za okužbe poveča. Najpogostejše okužbe, opažene v kliničnih preskušanjih, so bile okužbe zgornjih dihal in okužbe sečil. Med zdravljenjem z zdravilom Vyvgart je treba bolnike spremljati glede kliničnih znakov in simptomov okužb. Pri bolnikih z aktivno okužbo je treba pretehtati razmerje med koristjo in tveganjem za ohranitev ali prekinitev zdravljenja z efgartigimodom alfa, dokler ni okužba odpravljena. Če se pojavijo resne okužbe, je treba razmisliti o odložitvi zdravljenja z efgartigimodom alfa, dokler ni okužba odpravljena. Infuzijske reakcije in preobčutljivostne reakcije: Pojavijo se lahko infuzijske reakcije, kot sta izpuščaj ali pruritus. V kliničnem preskušanju so bile infuzijske reakcije blage do zmerne in niso privedle do začasne ali trajne prekinitve zdravljenja. Bolnike je treba med dajanjem zdravila in še 1 uro po njem spremljati glede kliničnih znakov in simptomov infuzijskih reakcij. Če pride do reakcije, je odvisno od resnosti reakcije treba infundirati počasneje, infundiranje prekiniti ali prenehati izvajati, in uvesti ustrezne podporne ukrepe. Ko reakcija izzveni, se lahko zdravljenje previdno nadaljuje odvisno od klinične ocene. V obdobju po začetku trženja so poročali o primerih anafilaktične reakcije. Ob sumu na anafilaktično reakcijo je treba dajanje zdravila Vyvgart takoj prekiniti in začeti ustrezno zdravljenje. Bolnike je treba obvestiti o znakih in simptomih preobčutljivostnih in anafilaktičnih reakcij ter jim svetovati, naj se v primeru pojava teh reakcij takoj obrnejo na svojega zdravstvenega delavca. Imunizacije: Imunizacije s cepivi med zdravljenjem z efgartigimodom alfa niso proučevali. Varnost cepljenja z živimi ali živimi oslabljenimi cepivi in odziv na cepljenje s cepivi nista znana. Vsa cepiva je treba uporabiti v skladu s smernicami za cepljenje in vsaj 4 tedne pred začetkom zdravljenja. Pri bolnikih, ki se zdravijo, cepljenje z živimi ali živimi oslabljenimi cepivi ni priporočljivo. Vsa druga cepiva morajo biti uporabljena vsaj 2 tedna po zadnjem infundiranju v ciklu zdravljenja in 4 tedne pred začetkom naslednjega cikla. Imunogenost: Protitelesa proti efgartigimodu alfa niso imela opaznega vpliva na klinično učinkovitost ali varnost oziroma na farmakokinetične in farmakodinamične parametre. Imunosupresivi in antiholinesterazna zdravila: Pri zmanjšanju ali prekinitvi zdravljenja z nesteroidnimi imunosupresivi, kortikosteroidi in antiholinesteraznimi zdravili je treba bolnike skrbno spremljati glede znakov poslabšanja bolezni. Vsebnost natrija: To zdravilo vsebuje 67,2 mg natrija na vialo, kar ustreza 3,4 % največjega dnevnega vnosa 2 g natrija za odraslo osebo po priporočilih Svetovne zdravstvene organizacije (SZO). Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Študij medsebojnega delovanja niso izvedli. Efgartigimod alfa lahko zmanjša koncentracije spojin, ki se vežejo na humani neonatalni receptor Fc (FcRn), tj. imunoglobulinov, monoklonskih protiteles ali derivatov protiteles. Če je mogoče, je priporočljivo, da se začetek zdravljenja s temi zdravili preloži na 2 tedna po zadnjem odmerku katerega koli cikla zdravljenja z zdravilom Vyvgart. Bolnike je treba skrbno spremljati glede predvidenega odziva na učinkovitost teh zdravil. Zamenjava plazme, imunoadsorpcija in plazmafereza lahko zmanjšajo ravni efgartigimoda alfa v obtoku. Vsa cepiva je treba uporabiti v skladu s smernicami za cepljenje in vsaj 4 tedne pred začetkom cikla zdravljenja, vendar ne prej kot 2 tedna po zadnjem infundiranju v ciklu zdravljenja. Pri bolnikih, ki se zdravijo, cepljenje z živimi ali živimi oslabljenimi cepivi ni priporočljivo. Plodnost, nosečnost in dojenje: Nosečnost: Podatkov o uporabi efgartigimoda alfa pri nosečnicah ni. Znano je, da se protitelesa, vključno s terapevtskimi monoklonskimi protitelesi, aktivno prenašajo preko posteljice (po 30 tednihnosečnosti) z vezavo na FcRn. Efgartigimod alfa se lahko prenese z matere na razvijajoči se plod. Pričakuje se zmanjšanje pasivne zaščite novorojenca. Zato je treba razmisliti o tveganjih in koristih uporabe živih/živih oslabljenih cepiv pri dojenčkih, ki so bili in utero izpostavljeni efgartigimodu alfa. O zdravljenju nosečnic z zdravilom Vyvgart je treba razmisliti le, če klinične koristi odtehtajo tveganja. Dojenje: Ni podatkov o prisotnosti efgartigimoda alfa v materinem mleku, učinkih na dojenega otroka ali učinkih na proizvodnjo mleka. O zdravljenju žensk, ki dojijo, z efgartigimodom alfa je treba razmisliti le, če klinične koristi odtehtajo tveganja. Plodnost: Podatkov o vplivu efgartigimoda alfa na plodnost pri ljudeh ni na voljo. Vpliv na sposobnost vožnje in upravljanja strojev: Zdravilo Vyvgart nima vpliva ali ima zanemarljiv vpliv na sposobnost vožnje in upravljanja strojev. Neželeni učinki: Najpogosteje opaženi neželeni učinki so bile okužbe zgornjih dihal (10,7 %) in okužbe sečil (9,5 %). Pogosti (≥ 1/100 do < 1/10) neželeni učinki so bili še bronhitis, mialgija in proceduralni glavobol. V obdobju po začetku trženja so poročali o primerih anafilaktične reakcije. Pogostnost je neznana. Več informacij glede neželenih učinkov lahko najdete v Povzetku glavnih značilnosti zdravila. Način in režim predpisovanja ter izdaje zdravila: H - Predpisovanje in izdaja zdravila je le na recept, zdravilo pa se uporablja samo v bolnišnicah. Imetnik dovoljenja za promet z zdravilom: argenx BV, Industriepark-Zwijnaarde 7, 9052 Gent, Belgija Številka dovoljenja za promet z zdravilom: EU/1/22/1674/001 Datum zadnje revizije besedila: September 2023 Poročanje o neželenih učinkih Poročanje o domnevnih neželenih učinkih zdravila po izdaji dovoljenja za promet je pomembno. Omogoča namreč stalno spremljanje razmerja med koristmi in tveganji zdravila. Od zdravstvenih delavcev se zahteva, da poročajo o katerem koli domnevnem neželenem učinku zdravila na Javno agencijo RS za zdravila in medicinske pripomočke (h-farmakovigilanca@jazmp.si). Samo za strokovno javnost. Zdravilo še ni razvrščeno na listo zdravil s strani ZZZS. SI-MG-2023-98 I EU-VYV-22-00003 I Datum priprave: september 2023. [65] Diagnoza: Spletno mesto mojaMS nastaja v sodelova- multipla skleroza. nju z bolniki in strokovnjaki, ki se ukvarjajo z multiplo sklerozo. Združuje relevantne in Kaj pa zdaj? kakovostne informacije o multipli sklerozi ter zgodbe ljudi, ki se vsak dan s pogumom soočajo z njo. Stojimo vam ob strani. Obiščite mojams.si Novartis Pharma Services Inc., Podružnica v Sloveniji, Datum priprave materiala: januar 2023 Verovškova ulica 57, 1000 Ljubljana #587785 PRIDITE NA PREGLED PRIPRAVLJENI Z VPRAŠALNIKOM YourMS [66] KLINIČNE RAZISKAVE IN RAZISKAVE UPORABE V VSAKDANJI PRAKSI KAŽEJO ZDRAVILO SPINRAZA™ POMAGA BOLNIKOM DOSEČI VEČ V PRIMERJAVI S KONTROLNO SKUPINO, KI JE PREJEMALA PLACEBO, IN NARAVNIM POTEKOM BOLEZNI1,2 Skrajšan povzetek glavnih značilnosti zdravila Spinraza koagulacije krvi. • Po dajanju drugih subkutano ali intravensko apliciranih Ime zdravila: Spinraza 12 mg raztopina za injiciranje Sestava: En ml protismiselnih oligonukleotidov so opazili toksičnost za ledvice. Če je vsebuje 2,4 mg nusinersena. Indikacije: Zdravilo Spinraza je indicirano za klinično indicirano, je priporočljivo testiranje beljakovin v urinu • Pri zdravljenje 5q spinalne mišične atrofije. Odmerjanje in način uporabe: bolnikih, zdravljenih z nusinersenom v obdobju trženja, so poročali Zdravljenje z zdravilom Spinraza sme začeti le zdravnik, ki ima izkušnje z o komunikantnem hidrocefalusu, ki ni bil povezan z meningitisom zdravljenjem spinalne mišične atrofije (SMA). • Odmerjanje: Priporočeni ali krvavitvijo. Nekaterim bolnikom so vstavili ventrikulo-peritonealni odmerek je 12 mg (5 ml) na vsako uporabo. Zdravljenje z zdravilom spoj. Pri bolnikih z zmanjšano ravnijo zavesti je treba preveriti, ali imajo Spinraza je treba uvesti čimprej po postavitvi diagnoze s 4 začetnimi hidrocefalus. Trenutno so koristi in tveganja zdravljenja z nusinersenom (polnilnimi) odmerki na dan 0, 14, 28 in 63. Nato je treba dati vzdrževalni pri bolnikih z ventrikulo-peritonealnim spojem neznana in nadaljevanje odmerek enkrat na vsake 4 mesece. • Izpuščeni ali odloženi odmerki zdravljenja je treba skrbno pretehtati. • Zdravilo vsebuje manj kot 1 mmol Za priporočila o izpuščenih ali odloženih odmerkih prosimo, glejte (23 mg) natrija na 5 ml vialo, kar v bistvu pomeni ‘brez natrija’. • Zdravilo preglednico 1 v povzetku glavnih značilnosti zdravila Spinraza. • Okvara vsebuje manj kot 1 mmol (39 mg) kalija na 5 ml vialo, kar v bistvu pomeni ledvic: Pri bolnikih z okvaro ledvic nusinersena niso proučevali. Varnost ‘brez kalija’. Neželeni učinki: • Zelo pogosti: glavobol, bruhanje, bolečina in učinkovitost pri bolnikih z okvaro ledvic nista bili dokazani in je treba v hrbtu (ti učinki se lahko upoštevajo kot manifestacija postpunkcijskega te bolnike natančno opazovati. • Okvara jeter: Pri bolnikih z okvaro jeter sindroma). • Neznana pogostnost: meningitis, preobčutljivost (npr. nusinersena niso proučevali. Ne presnavlja se preko encimskega sistema angioedem, urtikarija in izpuščaj), aseptični meningitis. • V obdobju citokroma P450, zato ni verjetno, da bo pri bolnikih z okvaro jeter potrebno trženja zdravila so opazili primere komunikantnega hidrocefalusa. • prilagajanje odmerka. • Način uporabe: intratekalno z lumbalno punkcijo. Poročanje o domnevnih neželenih učinkih: Poročanje o domnevnih Kontraindikacije in interakcije: • Preobčutljivost na učinkovino ali katero neželenih učinkih zdravila po izdaji dovoljenja za promet je pomembno. koli pomožno snov. • Študij medsebojnega delovanja niso izvedli. Študije Omogoča namreč stalno spremljanje razmerja med koristmi in in vitro so pokazale, da nusinersen ni induktor ali inhibitor presnove tveganji zdravila. Od zdravstvenih delavcev se zahteva, da poročajo preko presnovne poti CYP450. Študije in vitro kažejo, da je medsebojno o katerem koli domnevnem neželenem učinku zdravila na Javna delovanje z nusinersenom malo verjetno zaradi kompeticije za vezavo agencija Republike Slovenije za zdravila in medicinske pripomočke, na plazemske beljakovine ali zaradi kompeticije s prenašalci ali inhibicije Sektor za farmakovigilanco, Nacionalni center za farmakovigilanco, prenašalcev. Opozorila/previdnostni ukrepi: • Obstaja nevarnost Slovenčeva ulica 22, SI-1000 Ljubljana, Tel: +386 (0)8 2000 500, Faks: neželenih učinkov, ki se pojavljajo v okviru postopka lumbalne punkcije +386 (0)8 2000 510, e-pošta: h-farmakovigilanca@jazmp.si, spletna stran: (npr. glavobol, bolečina v hrbtu, bruhanje). • Po dajanju drugih subkutano www.jazmp.si Imetnik dovoljenja za promet: Biogen Netherlands ali intravensko apliciranih protismiselnih oligonukleotidov so opazili B.V., Prins Mauritslaan 13, 1171 LP Badhoevedorp, Nizozemska Način trombocitopenijo in abnormalnosti koagulacije krvi, vključno z akutno izdajanja zdravila: H Opozorilo: Pred predpisovanjem preberite celoten hudo trombocitopenijo. Če je klinično indicirano, je pred dajanjem povzetek glavnih značilnosti zdravila. Datum priprave informacije: zdravila Spinraza priporočljivo laboratorijsko testiranje trombocitov in 01/2022 Prikazane slike so nastale po navdihu resničnih oseb, ki živijo s spinalno mišično atrofijo, in so namenjene zgolj ponazoritvi. Vir: 1. Povzetek glavnih značilnosti zdravila SPINRAZA™. 2. Coratti G, et al. Orphanet J Rare Dis. 2021;16:430. TM Podrobnejše informacije so na voljo pri: Biogen Pharma d.o.o., Ameriška ulica 8, 1000 Ljubljana, Slovenija tel.: 01 511 02 90, faks: 01 511 02 99; www.biogen-pharma.si Samo za strokovno javnost; Datum priprave materiala: avgust 2023; Biogen-216435 [67] BOLNIKI V ZGODNJEM STADIJU V zgodnjem stadiju polinevropatije zaradi ATTR ... ZDRAVILO VYNDAQEL: ZA STABILIZACIJO TTR1,2 TTR je naravno prisotna beljakovina, ki jo zdravilo VYNDAQEL stabilizira v njeni Zdravilo VYNDAQEL se selektivno veže na TTR, ga stabilizira nativni obliki1,3,4 in prepreči disociacijo – tako zavre amiloidno kaskado, ki ima pomembno vlogo pri napredovanju polinevropatije zaradi ATTR.1,3,4 V kliničnih in ex-vivo študijah pri bolnikih z Val30Met in brez Val30Met je zdravilo VYNDAQEL stabiliziralo 37 mutacij TTR. 1, 4-7 Zdravilo VYNDAQEL na vezavnem mestu 98 bolnikov z Val30Met % po 1,5 leta1† Stabilizacija TTR je dokazana pri številnih vrstah mutacij 98 bolnikov z Val30Met % po 1,5 leta1† 100 bolnikov brez % Val30Met po 1 letu8‡ †Na 1 črt š 0 tudije: 0 bolnikov brez 1,5-letna % rando V miz a ir l3 ana 0, Me dvoj t no p sle o 1 l pa, s p e lacteub14 o ‡ m nadzorovana ključna študija. Bolniki z Val30Met so prejemali 20 mg zdravila VYNDAQEL na dan ali placebo. Soprimarna opazovana dogodka: analiza bolnikov, odzivnih po oceni nevropatske okvare v spodnjih okončinah (NIS-LL) (poslabšanje za < 2 točki) in razlika povprečne spremembe celotne norfolške ocene kakovosti življenja pri diabetični nevropatiji (TQOL) od izhodišča med terapevtskima skupinama v populaciji z namenom zdravljenja (ZNZ) (n = 125) in populaciji, ocenljivi za učinkovitost (n = 87). Sekundarni opazovani dogodki: sprememba nevrološkega delovanja, stanja prehranjenosti in stabilizacija TTR v populaciji ZNZ.9 ‡Načrt študije: enoletna odprta študija z eno samo skupino. Bolniki brez Val30Met so prejemali 20 mg zdravila VYNDAQEL na dan. Primarni opazovani dogodek: stabilizacija TTR po 6 tednih (n = 19). Sekundarna opazovana dogodka: stabilizacija TTR po 6 mesecih (n = 18) in 12 mesecih (n = 17).5 ZGODNJE ZDRAVLJENJE, TTR = transtiretin DOLGOROČNA ZANESLJIVOST3 ATTR = transtiretinski amiloid BISTVENI PODATKI IZ POVZETKA GLAVNIH ZNAČILNOSTI ZDRAVILA VYNDAQEL 20 mg mehke kapsule lahko vpliva na biološko uporabnost drugih zdravil za peroralno uporabo, ki se jemljejo sočasno. Medsebojno Za to zdravilo se izvaja dodatno spremljanje varnosti. Tako bodo hitreje na voljo nove informacije o njegovi delovanje z drugimi zdravili: V klinični študiji pri zdravih prostovoljcih 20 mg tafamidis meglumina ni niti varnosti. Zdravstvene delavce naprošamo, da poročajo o kateremkoli domnevnem neželenem učinku zdravila. induciralo niti zaviralo encima citokroma P450 CYP3A4. Tafamidis in vitro zavira prenašalce BCRP, OAT1 in OAT3 Glejte poglavje 4.8 povzetka glavnih značilnosti zdravila, kako poročati o neželenih učinkih. Sestava in oblika ter lahko pri klinično pomembnih koncentracijah povzroči medsebojna delovanja s substrati teh prenašalcev. Študij zdravila: Ena mehka kapsula vsebuje 20 mg mikroniziranega tafamidis meglumina, kar ustreza 12,2 mg medsebojnega delovanja, v katerih bi ocenjevali vpliv drugih zdravil na tafamidis meglumin, niso izvedli. Tafamidis tafamidisa. Ena mehka kapsula vsebuje največ 44 mg sorbitola. Indikacije: Zdravljenje transtiretinske amiloidoze lahko zmanjša koncentracije celokupnega tiroksina v serumu brez spremljajoče spremembe prostega tiroksina (T4) pri odraslih bolnikih s simptomatsko polinevropatijo stadija 1 za preprečevanje pojava perifernih nevroloških okvar. ali ščitnico spodbujajočega hormona (TSH). Spremljajočih kliničnih ugotovitev, skladnih z nepravilnim delovanjem Odmerjanje in način uporabe: Zdravljenje je treba uvesti pod nadzorom zdravnika z izkušnjami pri zdravljenju ščitnice, ni bilo. Plodnost, nosečnost in dojenje: Ženske v rodni dobi morajo uporabljati ustrezno kontracepcijo bolnikov s transtiretinsko amiloidno polinevropatijo (ATTR-PN). Priporočeni odmerek je 20 mg peroralno enkrat med zdravljenjem s tafamidis megluminom in še en mesec po prenehanju zdravljenja, zaradi podaljšanega na dan. Tafamidis in tafamidis meglumin nista medsebojno zamenljiva na podlagi mg. Če po odmerjanju pride razpolovnega časa zdravila. Podatkov o uporabi tafamidis meglumina pri nosečnicah ni. Študije na živalih so do bruhanja in bolnik izbruha nepoškodovano kapsulo, naj vzame še en odmerek, če je mogoče. Če kapsule ne pokazale škodljiv vpliv na razvoj. Tafamidis meglumina ne uporabljajte pri nosečnicah in ženskah v rodni dobi, ki izbruha, dodaten odmerek ni potreben. Starejši bolniki: Prilagajanje odmerka ni potrebno. Okvara jeter in ledvic: ne uporabljajo učinkovite kontracepcije. Razpoložljivi podatki pri živalih kažejo na izločanje tafamidisa v mleko. Podatki pri bolnikih s hudo okvaro ledvic (očistek kreatinina 30 ml/min ali manj) so omejeni. Tafamidis meglumina pri Tveganja za dojenega novorojenčka/otroka ne moremo izključiti. Tafamidis meglumina se med dojenjem ne sme bolnikih s hudo okvaro jeter niso preskušali, zato je pri teh bolnikih priporočljiva previdnost. Pediatrična populacija: uporabljati. Vpliv na sposobnost vožnje in upravljanja strojev: Tafamidis meglumin naj ne bi imel vpliva ali Tafamidis ni namenjen za uporabo pri pediatrični populaciji. Način uporabe: Mehke kapsule je treba pogoltniti cele naj bi imel zanemarljiv vpliv na sposobnost vožnje in upravljanja strojev. Neželeni učinki: Zelo pogosti: okužba in se jih ne sme zdrobiti ali prerezati. Zdravilo Vyndaqel se lahko vzame s hrano ali brez nje. Kontraindikacije: sečil, okužba nožnice, driska, bolečine v zgornjem delu trebuha. Preveliko odmerjanje: Poročali so o enem Preobčutljivost na učinkovino ali katerokoli pomožno snov. Posebna opozorila in previdnostni ukrepi: Ženske neželenem dogodku blagega hordeola, povezanim z zdravljenjem. V primeru prevelikega odmerjanja je treba uvesti v rodni dobi morajo med jemanjem tafamidis meglumina uporabljati ustrezno kontracepcijo in z njeno uporabo standardne podporne ukrepe. Način in režim izdajanja zdravila: Predpisovanje in izdaja zdravila je le na recept nadaljevati še 1 mesec po prenehanju zdravljenja. Tafamidis meglumin je treba uporabiti kot dodatek običajni zdravnika specialista ustreznega področja medicine ali od njega pooblaščenega zdravnika. Imetnik dovoljenja . skrbi za zdravljenje bolnikov z ATTR-PN. Bolnike je treba nadzirati in še naprej preverjati potrebo po dodatnem za promet: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgija. Datum zadnje revizije zdravljenju, vključno s potrebo po presaditvi jeter. Ker podatkov glede uporabe tafamidis meglumina pri bolnikih besedila: 15.02.2023. VNOST po presaditvi jeter ni, je treba pri teh bolnikih zdravljenje prekiniti. To zdravilo vsebuje največ 44 mg sorbitola na kapsulo. Sorbitol je vir fruktoze. Upoštevati je treba aditivni učinek sočasne uporabe zdravil, ki vsebujejo sorbitol Pred predpisovanjem se seznanite s celotnim povzetkom glavnih značilnosti zdravila. (ali fruktozo), in sorbitola (ali fruktoze), ki ga vnesemo s hrano. Količina sorbitola v zdravilih za peroralno uporabo OVNO JAOK LITERATURA O ZA STR 1. Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a 6. Clinical Study Report for Protocol Fx-EV-001. New York, NY: Pfizer Inc; June 2010. AM randomized, controlled trial. Neurology. 2012;79(8):785–792. 7. Ando Y, Sekijima Y, Obayashi K, et al. Effects of tafamidis treatment on transthyretin (TTR) stabilization, efficacy, and 2. Coelho T, Maia LF, Martins da Silva A, et al. Long-term effects of tafamidis for the treatment of transthyretin familial safety in Japanese patients with familial amyloid polyneuropathy (TTR-FAP) with Val30Met and non-Val30Met: a amyloid polyneuropathy. J Neurol. 2013;260(11):2802–2814. phase III, open-label study. J Neurol Sci. 2016;362:266–271. 3. Povzetek glavnih značilnosti zdravila Vyndaqel, 15.2.2023. 8. Merlini G, Planté-Bordeneuve V, Judge D, et al. Effects of tafamidis on transthyretin stabilization and clinical ec 2023 S 4. Bulawa CE, Connelly S, DeVit M, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits outcomes in patients with non-Val30Met transthyretin amyloidosis. J Cardiovasc Transl Res. 2013;6(6):1011–1020. the amyloid cascade. Proc Natl Acad Sci U S A. 2012;109(24):9629–9634. 9. Clinical Study Report for Protocol Fx-005. New York, NY: Pfizer Inc; May 2011. 5. Clinical Study Report for Protocol Fx-1A-201. New York, NY: Pfizer Inc; May 2011. Pfizer Luxembourg SARL, Grand Duchy of Luxembourg, 51, Avenue J. F. Kennedy, L-1855 Pfizer, podružnica Ljubljana, Letališka cesta 29a, 1000 Ljubljana, SLOVENIJA PP-VYN-SVN-0008 Mar [68] Testiranje vrednosti kreatin kinaze (CK) bi lahko pomagalo odgovoriti na nekaj POMEMBNIH vprašanj Pomislite na testiranje vrednosti CK Zaostanek v razvoju? Naročite testiranje vrednosti CK še danes! DUCHENNOVA MIŠIČNA DISTROFIJA (DMD) JE REDKA GENETSKA MOTNJA1, 2 • DMD prizadene ~ 1 na 3600 do 6000 živorojenih dečkov1–3 • Za DMD je značilna progresivna mišična degeneracija, ki vodi do izgube pokretnosti, dihalnega in srčnega popuščanja ter kasnejše prezgodnje smrti1, 2, 4, 5 DMD JE POSLEDICA MUTACIJ V GENU ZA DISTROFIN NA X KROMOSOMU2, 5 • DMD povzročajo mutacije (delecije in duplikacije) v genu, ki kodira distrofin, pomembno komponento membrane mišične celice5, 6 • Mutacije v genu za distrofin vodijo do odsotnosti ali okvare distrofina2, 5 • Posledica tega je nenehna poškodba mišic in zamenjava mišičnih vlaken z brazgotinami in maščobo6, 7 ROJSTVO 0 1 2 3 STAROST PACIENTA 5 10 12 20+ 15 (LETA) V prvih 3 letih življenja prizadeti dojenčki Do 5. leta starosti opazimo Do starosti 10–12 let Mnogi bolniki do 15. leta Napredovali respiratorni in majhni dečki z DMD kažejo merljive izrazito mišično oslabelost8 več kot 70 % dečkov potrebujejo ponoči podporo in/ali srčni zapleti vodijo pomanjkljivosti v grobi in fini motorični funkciji8, 9 izgubi pokretnost8 neinvazivne ventilacije8 do prezgodnje smrti1, 2, 8 ZGODNJE UKREPANJE LAHKO IZBOLJŠA IZID BOLEZNI1, 2 • Ko je mišica izgubljena, • Zgodnja diagnoza je ključnega pomena • Vloga osebnih zdravnikov je ključnega pomena, saj so v idealnem je ni mogoče obnoviti7, 10 za hitro obravnavo in zdravljenje1, 2, 11 položaju za odkrivanje zgodnjih znakov živčno-mišične bolezni1, 11, 12 PRAVOČASNA IN TOČNA DIAGNOSTIKA LAHKO PACIENTU IN DRUŽINI OMOGOČI, DA PREJEMA NEGO IN PODPORO, KI JO POTREBUJE1, 2, 13 Vir: 1. van Ruiten HJ, et al. Arch Dis Child. 2014;99:1074–1077. 2. Birnkrant DJ, et al. Lancet Neurol. 2018;17:251–267. 3. Bushby K. et al. Lancet Neurol. 2010;77–93. 4. McDonald CM, et al. Muscle Nerve. 2013;48:343–356. 5. Goemans N, et al. Eur Neurol Rev. 2014;9:78–82. 6. Amato AA and Brown RH Jr. Muscular Dystrophies and other muscle diseases. In: Kasper DL, Fauci AS, Hauser SL, et al., eds., Harrison’s Principles of Internal Medicine, 19th Ed. 7. Blake DJ, et al. Physiol Rev. 2002;82:291–329. 8. Mendell JR, Lloyd-Puryear M. Muscle Nerve. 2013;48:21–26. 9. van Dommelen P, et al. Dev med Child Neurol. 2020; doi: 10.1111/dmcn.14623. 10. Laing NG, et al. Clin Biochem Rev. 2011;32:129–134. 11. Noritz GH, et al. Pediatrics. 2013;131:e2016–e2027. 12. Birnkrant DJ, et al. Lancet Neurol. 2018;17:445–455. 13. McDonald CM, Fowler WM. Phys Med Rehabil Clin N Am. 2012;23:475–493. Za več informacij se obrnite na lokalnega zastopnika: Ta material je razvil PTC Therapeutics. Swixx Biopharma d.o.o., Pot k sejmišču 35, 1231 Ljubljana - Črnuče NM-SI-2023-9-4070 T: +386 1 23 55 100 Datum priprave gradiva: september 2023 E: slovenia.info@swixxbiopharma.com Samo za strokovno javnost. [69] [70] Humani polispecifični imunoglobulin (SCIg) 165 mg/ml raztopina za injiciranje Novi SCIg namesto zdravila Cutaquig® je vse, kar poznate pri gammanormu: odmerjanje, rutina in visoka kakovost, ki jo pričakujete Cutaquig® ima dobro dokazano učinkovitost in prenašanje ter omogoča pacientom, da prilagodijo zdravljenje na domu svojemu individualnemu življenskemu slogu2,3 SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA Za to zdravilo se izvaja dodatno spremljanje varnosti. Tako bodo hitreje na voljo nove informacije o njegovi varnosti. Zdravstvene delavce naprošamo, da poročajo o katerem koli domnevnem neželenem učinku zdravila. Glejte poglavje 4.8, kako poročati o neželenih učinkih. IME ZDRAVILA Cutaquig 165 mg/ml raztopina za injiciranje. KAKOVOSTNA IN KOLIČINSKA SESTAVA: Humani polispecifični imunoglobulin (s.c. Ig). 1 ml vsebuje: Humani polispecifični imunoglobulin 165 mg. Čistost vsaj 95% IgG. Največja vsebnost IgA je 300 mikrogramov/ml. Terapevtske indikacije: Nadomestno zdravljenje odraslih ter otrok in mladostnikov (starih od 0 do 18 let) pri sindromih primarne imunske pomanjkljivosti (PIP) z okvarjenim nastajanjem protiteles, sekundarnih imunskih pomanjkljivosti (SIP) pri bolnikih, ki trpijo zaradi hudih ali ponavljajočih se okužb, neučinkovitega protimikrobnega zdravljenja in bodisi dokazane odpovedi specifičnih protiteles (PSAF) ali serumske koncentracije IgG < 4 g/l. Odmerjanje in način uporabe: Nadomestno zdravljenje je treba uvesti in spremljati pod nadzorom zdravnika, izkušenega v zdravljenju imunskih pomanjkljivosti. Odmerek in shema odmerjanja sta odvisna od indikacije. Zdravilo je treba dajati po subkutani poti. Pri nadomestnem zdravljenju bo morda treba odmerek individualno prilagoditi posameznemu bolniku, odvisno od farmakokinetičnega in kliničnega odziva. Zdravilo Cutaquig se lahko daje v rednih časovnih presledkih od vsakodnevnega odmerka do odmerka vsak drugi teden. Naslednje sheme odmerjanja so podane kot smernice. Nadomestno zdravljenje pri sindromih primarne imunske pomanjkljivosti: S shemo odmerjanja je treba doseči najnižjo koncentracijo IgG najmanj 5 do 6 g/l in jo vzdrževati znotraj mej referenčnega intervala serumskih IgG glede na starost. Morda bo znašal začetni odmerek vsaj 0,2 do 0,5 g/kg (1,2 do 3,0 ml/kg) telesne mase. Le-tega je morda treba razdeliti na več dni; najvišji dnevni odmerek znaša med 0,1 in 0,15 g/kg. Ko je doseženo stanje dinamičnega ravnovesja ravni IgG, se dajejo vzdrževalni odmerki v ponavljajočih se presledkih, da se doseže kumulativni mesečni odmerek od 0,4 do 0,8 g/kg (2,4 do 4,8 ml/kg) telesne mase. Vsak posamezni odmerek bo morda potrebno injicirati v različna mesta na telesu. Nadomestno zdravljenje pri sekundarni imunski pomanjkljivosti: Priporočeni odmerek, ki se daje v ponavljajočih se presledkih, da se doseže kumulativni mesečni odmerek od 0,2 do 0,4 g/kg (1,2 do 2,4 ml/kg) telesne mase. Hitrost infundiranja in količino zdravila, infundiranega v določeno mesto, prilagodimo glede na prenašanje posameznega bolnika. Priporočena začetna hitrost infundiranja je 15 ml/h/mesto. Od sedmega infundiranja naprej, lahko hitrost infundiranja počasi povišate na 25 ml/h/mesto. Priporočene hitrosti infundiranja na uro skupaj za vsa mesta: 30 ml/h za prvih 6 infundiranj, potem počasi zvišujemo na 50 ml/h in, v primeru, da bolnik to dobro prenaša, na 80 ml/h. Pri dojenčkih in otrocih se lahko mesto infundiranja menja na vsakih 5-15 ml. Pri odraslih se odmerke nad 30 ml lahko razdeli na željo bolnika. Število mest infundiranja ni omejeno. Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. Zdravila Cutaquig ne smete dajati intravensko. Prav tako zdravila ne smete dajati intramuskularno v primerih hude trombocitopenije in drugih motenj hemostaze. Posebna opozorila in previdnostni ukrepi: Priporočeno je, da ob vsakem dajanju zdravila Cutaquig bolniku zabeležite ime in številko serije zdravila. To zdravilo vsebuje največ 90 mg maltoze na ml kot pomožne snovi. Moteča prisotnost maltoze v testih ravni glukoze v krvi lahko povzroči lažno povečane odčitke koncentracije in posledično neustrezno odmerjanje inzulina, kar lahko povzroči smrtno nevarno hipoglikemijo in smrt. Prav tako lahko primeri dejanske hipoglikemije ostanejo nezdravljeni. Če se zdravilo Cutaquig po nesreči da v žilo, se lahko pri bolniku razvije šok. Priporočeno hitrost infundiranja, morate natančno upoštevati. Nekateri neželeni učinki se lahko pogosteje pojavijo pri bolnikih, ki prvič prejmejo humani polispecifični imunoglobulin, ali v redkih primerih, kadar se zdravilo s humanim polispecifičnim imunoglobulinom zamenja ali kadar je od zadnjega infundiranja minilo dalj časa. V primeru neželenih učinkov morate bodisi zmanjšati hitrost infundiranja ali infundiranje prekiniti. Potrebno zdravljenje je odvisno od vrste in resnosti neželenih učinkov. Če se razvije šok, je potrebno uvesti standardno medicinsko zdravljenje za šok. Prave alergijske reakcije so redke. Pojavijo se predvsem pri bolnikih s protitelesi proti IgA, ki jih je treba zdraviti posebej previdno. Pri bolnikih, ki imajo protitelesa proti IgA, pri katerih je zdravljenje s subkutanimi zdravili IgG edina možnost, je treba zdravljenje z zdravilom Cutaquig strogo nadzorovati. Redko lahko humani polispecifični imunoglobulin sproži padec krvnega tlaka z anafilaktično reakcijo tudi pri bolnikih, ki so prenašali predhodno zdravljenje s humanim polispecifičnim imunoglobulinom. Z uporabo imunoglobulinov so povezani arterijski in venski trombembolični dogodki, vključno z miokardnim infarktom, možgansko kapjo, globoko vensko trombozo in pljučno embolijo. Pred uporabo imunoglobulinov morajo biti bolniki ustrezno hidrirani. Pri bolnikih z obstoječimi dejavniki tveganja za trombotične dogodke je potrebna previdnost. V povezavi s subkutanim zdravljenjem z imunoglobulini so poročali o pojavu sindroma aseptičnega meningitisa. Pri bolnikih, ki so prejemali zdravljenje z imunoglobulini, so poročali o hudih neželenih učinkih na ledvicah, zlasti pri uporabi zdravil, ki so vsebovala saharozo (zdravilo Cutaquig ne vsebuje saharoze). Po injiciranju imunoglobulina lahko prehodno povečanje različnih pasivno prenesenih protiteles v bolnikovi krvi povzroči lažno pozitivne rezultate pri seroloških preiskavah. Pri dajanju zdravil, pripravljenih iz človeške krvi ali plazme, ni mogoče popol-noma izključiti prenosa povzročiteljev nalezljivih bolezni. To se nanaša tudi na doslej še neznane ali porajajoče se viruse in druge povzročitelje bolezni. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Uporaba imunoglobulinov lahko zmanjša učinkovitost cepiv z živimi oslabljenimi virusi, kot so cepiva proti ošpicam, rdečkam, mumpsu in noricam, za najmanj 6 tednov pa do 3 mesece. V primeru ošpic lahko opisano zmanjšanje učinkovitosti traja celo do enega leta. Neželeni učinki Občasno se lahko pojavijo neželeni učinki, kot so mrzlica, glavobol, omotica, povišana telesna temperatura, bruhanje, alergijske reakcije, navzea, artralgija, nizek krvni tlak in zmerna bolečina v križu. V redkih primerih lahko humani polispecifični imunoglobulini povzročijo nenadno zmanjšanje krvnega tlaka in v posameznih primerih anafilaktični šok, celo pri bolnikih, ki pri predhodnem zdravljenju niso pokazali znakov preobčutljivosti. Lokalne reakcije na mestih infundiranja so pogoste. Posebna navodila za shranjevanje Shranjujte v hladilniku. Ne zamrzujte. V času roka uporabnosti lahko zdravilo do 9 mesecev shranju-jete pri sobni temperaturi (shranjujte pri temperaturi do 25C) ne da bi ga v tem času ponovno hranili v hladilniku. Način in režim izdaje: H/Rp Imetnik dovoljenja za promet z zdravilom: Octapharma (IP) SPRL, Allée de la Recherche 65, 1070 Anderlecht, Belgija. Datum prve odobritve: 19. 8. 2019 Datum zadnje revizije besedila: 28. 4. 2022 Reference: 1.Povzetek glavnih značilnosti zdravila Cutaquig. 2. Kobayashi, R.H., et al., Clinical efficacy, safety and tolerability of a new subcutaneous immunoglobulin 16.5% [cutaquig®] in the treatment of patients with PID. Front Immunol, 2019. 10:40. 3. Latysheva, E., et al., Efficacy and safety of cutaquig® in adults with PID: a prospective, open-label study. Immunotherapy, 2020. Epub, doi: 10.2217/ imt-2020-0012. Samo za strokovno javnost. Pred predpisovanjem zdravila Cutaquig si preberite zadnji veljavni Povzetek glavnih značilnosti zdravil. Datum priprave informacije: avgust 2023 [71] Nevrotoksin bakterije Clostridium botulinum tipa A, brez beljakovin, ki tvorijo komplekse TERAPEVTSKE INDIKACIJE1: Pri odraslih: za simptomatsko zdravljenje blefarospazma in hemifacialnega spazma, cervikalne distonije, predvsem rotacijske oblike (spastični tortikolis), spastičnosti zgornjih udov ter kronične sialoreje, ki se pojavi zaradi nevroloških motenj. Pri otrocih in mladostnikih, starih 2 do 17 let, ki tehtajo ≥ 12 kg, indicirano za simptomatsko zdravljenje kronične sialoreje, ki se pojavi zaradi nevroloških/razvojnih nevroloških motenj. Skrajšan povzetek glavnih značilnosti zdravila XEOMIN / nevrotoksin bakterije Clostridium botulinum tipa A (150 kD), brez beljakovin, ki tvorijo komplekse Ime zdravila: XEOMIN 50 enot prašek za raztopino za injiciranje: Ena viala vsebuje 50 enot nevrotoksina bakterije Clostridium botulinum tipa A (150 kD), brez beljakovin, ki tvorijo komplekse. XEOMIN 100 enot prašek za raztopino za injiciranje: Ena viala vsebuje 100 enot nevrotoksina bakterije Clostridium botulinum tipa A (150 kD), brez beljakovin, ki tvorijo komplekse. XEOMIN 200 enot prašek za raztopino za injiciranje: Ena viala vsebuje 200 enot nevrotoksina bakterije Clostridium botulinum tipa A (150 kD), brez beljakovin, ki tvorijo komplekse Terapevtske indikacije: Pri odraslih: za simptomatsko zdravljenje blefarospazma in hemifacialnega spazma, cervikalne distonije, predvsem rotacijske oblike (spastični tortikolis), spastičnosti zgornjih udov ter kronične sialoreje, ki se pojavi zaradi nevroloških motenj. Pri otrocih in mladostnikih, starih 2 do 17 let, ki tehtajo ≥ 12 kg, indicirano za simptomatsko zdravljenje kronične sialoreje, ki se pojavi zaradi nevroloških/razvojnih nevroloških motenj. Odmerjanje in način uporabe: Zaradi različnih enot v preskusih za določanje jakosti se odmerki enot zdravila XEOMIN ne smejo zamenjati z odmerki drugih zdravil botulinskega toksina tipa A. Zdravilo XEOMIN smejo dajati samo ustrezno usposobljeni zdravniki s potrebnimi izkušnjami z uporabo botulinskega toksina tipa A. Optimalni odmerek, pogostnost in število mest injiciranja mora zdravnik določiti za vsakega bolnika posebej. Odmerek je treba titrirati. Priporočenih posameznih odmerkov zdravila XEOMIN se ne sme preseči. Blefarospazem in hemifacialni spazem: Začetni priporočeni odmerek je 1,25 do 2,5 enot na mesto injiciranja. Začetni odmerek ne sme preseči 25 enot na oko. Skupni odmerek ne sme preseči 50 enot na oko pri posamičnem zdravljenju. Zdravljenja se v splošnem ne sme ponoviti pogosteje kot na vsakih 12 tednov. Razmik med posameznimi zdravljenji je treba določiti na osnovi dejanskih kliničnih potreb posameznega bolnika. Mediana časa opažanja pojava prvega učinka je do štiri dni po injiciranju. Učinek zdravljenja z zdravilom XEOMIN na splošno traja 3–5 mesecev, lahko pa tudi bistveno manj ali dlje. Ob ponovnem zdravljenju se lahko odmerek poveča do dvakrat, če je ocenjeno, da odziv na prvo zdravljenje ni bil zadosten. Vendar je videti, da ni dodatne koristi od injiciranja več kot 5,0 enot na mesto. Bolnike s hemifacialnim spazmom je treba zdraviti enako kot bolnike z enostranskim blefarospazmom. Po rekonstituciji se raztopina zdravila XEOMIN injicira intramuskularno z ustrezno sterilno iglo (npr. velikosti 27−30 G/ 0,30−0,40 mm premera/12,5 mm dolžine). Elektromiografsko vodenje ni nujno. Priporočen volumen injiciranega zdravila je približno 0,05 do 0,1 ml. Zdravilo XEOMIN se injicira v sredinsko in stransko očesno krožno mišico zgornje veke ter stransko očesno krožno mišico spodnje veke. Če spazmi ovirajo vid, se zdravilo lahko injicira v dodatna mesta v območju obrvi, stranske očesne krožne mišice in v zgornji predel obraza. V primeru enostranske-ga blefarospazma naj bo injiciranje omejeno na prizadeto oko. Bolnike s hemifacialnim spazmom je treba zdraviti enako kot bolnike z enostranskim blefarospazmom. Izkušenj z injiciranjem zdravila XEOMIN v spodnji predel obraza, ki bi bile pridobljene v kliničnih študijah, ni. Iz literature je razvidno, da se pri bolnikih s hemifacialnim spazmom, zdravila ne sme injicirati v mišice spodnjega dela obraza zaradi povečanega tveganja za lokalno šibkost mišic po injiciranju botulinskega toksina v ta predel. Spastični tortikolis: Pri obravnavanju spastičnega tortikolisa je treba odmerjanje zdravila XEOMIN prilagoditi posameznemu bolniku, glede na položaj njegove glave in vratu, mesto morebitne bolečine, mišično hipertrofijo, telesno maso in odziv na injiciranje. Pri prvem zdravljenju se lahko injicira največ 200 enot, pri nadaljnjih zdravljenjih pa se odmerek prilagaja glede na odziv bolnika. Skupni odmerek pri katerem koli posameznem zdravljenju naj ne bo večji od 300 enot. Na posamezno mesto injiciranja se ne sme dati odmerka, večjega od 50 enot. Mediana opažanja pojava prvega učinka je sedem dni po injiciranju. Učinek zdravljenja z zdravilom XEOMIN na splošno traja 3–4 mesece, lahko pa tudi bistveno manj ali dlje. Razmiki med posameznimi zdravljenji, krajši od 10 tednov, niso priporočljivi. Razmik med posameznimi zdravljenji je treba določiti na osnovi dejanskih klinič- nih potreb posameznega bolnika. Za injiciranje v površinske mišice se uporablja ustrezna sterilna igla (npr. velikosti 25−30 G/ 0,30−0,50 mm premera/37 dolžine), za injiciranje v globlje mišice pa se lahko uporabi npr.igla velikosti 22 G/ 0,70 mm. Priporočen volumen injiciranega zdravila je približno 0,1 do 0,5 ml na mesto injiciranja. Pri zdravljenju spastičnega tortikolisa se zdravilo XEOMIN injicira v mišico obračalko glave, mišico dvigalko lopatice, mišico dvigalko reber, jermenasto mišico glave, in/ali trapezasto mišico/mišice. Seznam ni dokončen, saj je lahko vpletena katera koli mišica, odgovorna za nadzor položaja glave, in zato potrebuje zdravljenje. Če se pri izolaciji posameznih mišic pojavijo težave, je treba injiciranje opraviti z uporabo tehnik kot je elektromiografsko vodenjem ali ultrazvok. Pri izbiri ustreznega odmerka je treba upoštevati dejavnike, kot sta mišična masa in stopnja hipertrofije ali atrofije. Injiciranje na več mestih omogoča zdravilu XEOMIN enakomernejše pokritje oživčenih območij distoničnih mišic, zlasti pa je uporabno pri večjih mišicah. Optimalno število mest injiciranja je odvisno od velikosti mišice, ki jo želite kemijsko de-nervirati. Zaradi velikega tveganja za pojav neželenih učinkov (zlasti disfagije), se injiciranje v mišico obračalko glave ne sme opraviti bilateralno. To tveganje je veliko tudi pri dajanju odmerkov, ki so večji od 100 e. Spastičnost zgornjih udov: Odmerek in število mest injiciranja je treba natančno prilagoditi posameznemu bolniku, glede na velikost, število in položaj vključenih mišic, stopnjo spastičnosti in prisotnost lokalne mišične šibkosti. Največji skupni odmerek za zdravljenje spastičnosti zgornjih udov ne sme preseči 500 enot na cikel zdravljenja, v mišice ramena pa se ne sme dati več kot 250 enot. Bolniki so poročali, da so začetek delovanja zdravila opazili 4 dni po začetku zdravljenja. Največji učinek v obliki izboljšane napetosti mišic so opazili v štirih tednih. Na splošno so učinki zdravljenja trajali dvanajst tednov, lahko pa tudi bistveno manj ali dlje. Ponovno zdravljenje naj v splošnem ne sledi prej kot vsakih 12 tednov. Rekonstituirano zdravilo XEOMIN se injicira z ustrezno sterilno iglo (npr. velikosti 26 G/ premera 0,45 mm/ dolžine 37 mm za injiciranje v površinske mišice in daljšo iglo, npr. velikosti 22 G/ premera 0,7 mm/ dolžine 75 mm za injiciranje, v globlje mišice). V primeru kakršnih koli težav pri izolaciji posameznih mišic je priporočljiva lokalizacija prizadetih mišic s tehnikami kot je elektromiografsko vodenje ali ultrazvok. Injiciranje na več mestih lahko pripomore, da ima zdravilo XEOMIN enakomernejši stik z oživčenimi območji mišic, zlasti pa je uporabno pri injiciranju v večje mišice. Kronična sialoreja (odrasli): Uporabiti je treba rekonstituirano raztopino v koncentraciji 5 enot/0,1 ml. Odmerek se razdeli v razmerju 3 (parotidna žleza) : 2 (submandibularna žleza). Mesto injiciranja naj bo blizu centra žleze. Priporočeni odmerek na posamezno zdravljenje je 100 enot. Najvišjega odmerka se ne sme prekoračiti. Interval zdravljenja je treba določiti na osnovi dejanskih kliničnih potreb posameznega bolnika. Ponovitev zdravljenja, ki je krajša od 16 tednov, ni priporočljiva. Kronična sialoreja (otroci/mladostniki): Uporabiti je treba rekonstituirano raztopino v koncentraciji 2,5 enot/0,1 ml. Zdravilo XEOMIN se injicira v parotidno in submandibularno žlezo na obeh straneh (skupaj štiri injekcije na posamezno zdravljenje). Odmerek, prilagojen telesni masi, se razdeli v razmerju 3 (parotidna žleza) : 2 (submandibularna žleza). Za otroke, ki tehtajo manj kot 12 kg, ni mogoče podati priporočil za odmerjanje. Mesto injiciranja naj bo blizu centra žleze. Interval zdravljenja je treba določiti na osnovi dejanskih kliničnih potreb posameznega bolnika. Ponovitev zdravljenja, ki je krajša od 16 tednov, ni priporočljiva. Po rekonstituciji se raztopina zdravila XEOMIN injicira intraglandularno z ustrezno sterilno iglo (npr. velikosti 27−30 G/ 0,30−0,40 mm premera/12,5 mm dolžine). Pri odraslih si je pri lokalizaciji prizadetih žlez slinavk mogoče pomagati z anatomskimi točkami ali z ultrazvokom. Prednostno se uporablja lokalizacija z ultrazvokom, ker so bili ob uporabi te metode opaženi boljši izidi zdravljenja. Pri zdravljenju otrok in mladostnikov je treba uporabiti ultrazvočno vodenje. Otrokom in mladostnikom, se lahko po skrbnem ovrednotenju razmerja med koristjo in tveganjem pred injiciranjem ponudi lokalna anestezija (na primer krema z lokalnim anestetikom), sedacija ali anestezija v kombinaciji s sedacijo. Vse indikacije: Če v enem mesecu od prvega injiciranja ni učinkov zdravljenja, je treba uvesti naslednje ukrepe: klinična potrditev učinka nevrotoksina na mišico, v katero je injiciran: npr. z elektromiografskim pregledom v specializirani ustanovi; analiza razlogov za odsotnost odziva, npr. slaba izolacija mišic, v katere naj bi zdravilo injicirali, premajhen odmerek, slaba tehnika injiciranja, fiksna kontraktura, prešibek antagonist, morebiten nastanek protiteles; ponovna ocena ustreznosti zdravljenja z botulinskim nevrotoksinom tipa A; če se med prvim zdravljenjem niso pojavili neželeni učinki, se lahko opravi naslednji cikel zdravljenja pod naslednjimi pogoji: 1) prilagoditev odmerka glede na analizo zadnje odsotnosti odziva, 2) lokalizacija prizadetih mišic s tehnikami kot so elektromiografsko vodenje, 3) upoštevanje priporočenega najmanjšega intervala med začetnim in ponovnim zdravljenjem. Pediatrična populacija: Varnost in učinkovitost zdravila XEOMIN za neodobrene indikacije še nista bili dokazani. Zdravilo Xeomin je namenjeno za intramuskularno in intraglandularno (injiciranje v žleze slinavke) uporabo. Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov; splošne motnje mišične aktivnosti (npr. miastenija gravis, Lambert-Eatonov sindrom); okuženo ali vneto predvideno mesto injiciranja. Posebna opozorila in previdnostni ukrepi: Sledljivost: Z namenom izboljšanja sledljivosti bioloških zdravil je treba jasno zabeležiti ime in številko serije uporabljenega zdravila.Splošno: Pred dajanjem zdravila XEOMIN se mora zdravnik/zdravnica seznaniti z bolnikovo anatomijo in vsemi spremembami anatomije zaradi predhodnih kirurških posegov. Zdravilo XEOMIN se ne sme injicirati v žilo. Zdravilo XEOMIN je treba uporabljati previdno: v primeru kakršne koli krvavitve; če se bolniki zdravijo z zdravili proti strjevanju krvi ali drugimi zdravili, ki bi lahko zavirala strjevanje krvi. Klinični učinek botulinskega nevrotoksina tipa A se lahko s ponavljajočim injiciranjem poveča ali zmanjša. Možni razlogi za spremembe v kliničnih učinkih so lahko različne tehnike rekonstitucije, izbrani presledki med injiciranji, mesta injiciranja in mejna nihanja aktivnosti toksina zaradi biološke raznolikosti ali sekundarne neodzivnosti. Lokalno in oddaljeno širjenje učinka toksina: Neželeni učinki se lahko pojavijo zaradi injiciranja botulinskega nevrotoksina tipa A na napačno mesto, ki lahko povzroči začasno paralizo bližnjih mišičnih skupin. Večji odmerki lahko povzročijo paralizo mišic, ki so oddaljene od mesta injiciranja. Poročali so o neželenih učinkih, ki bi lahko bili povezani s širjenjem botulinskega toksina tipa A na mesta, oddaljena od mesta injiciranja. Nekateri izmed njih lahko ogrožajo življenje in poročali so o smrtnih primerih, ki so bili v nekaterih primerih povezani z disfagijo, pljučnico in/ali pomembno slabotnostjo. Pri bolnikih, ki prejmejo terapevtske odmerke, lahko pride do pretirane mišične šibkosti. Bolnikom in skrbnikom je treba svetovati, naj takoj poiščejo nujno zdravniško pomoč, če pride do težav pri požiranju, govoru ali dihanju. O disfagiji so poročali tudi po injiciranju v mesta zunaj vratne musku-lature. Predhodna živčno-mišična obolenja: Bolniki z živčno-mišičnimi obolenji so lahko izpostavljeni povečanemu tveganju za pojav pretirane mišične šibkosti, zlasti, če so zdravljeni intramuskularno. Pri teh bolnikih mora zdravljenje z botulinskim toksinom tipa A spremljati zdravnik specialist, zdravljenje pa je dovoljeno samo v primerih, kadar pričakovana korist zdravljenja odtehta morebitno tveganje. V splošnem je treba bolnike z aspiracijo ali disfagijo v anamnezi zdraviti previdno. Izjemna previdnost je potrebna, kadar pri teh bolnikih poteka zdravljenje cervikalne distonije. Zdravilo XEOMIN je treba uporabljati previdno: pri bolnikih z amiotrofično lateralno sklerozo; pri bolnikih z drugimi boleznimi, ki povzročajo periferno živčno-mišično disfunkcijo; pri izrazito šibkih ali atrofičnih ciljnih mišicah. Preobčutljivostne reakcije: Pri uporabi zdravil, ki vsebujejo botulinski nevrotoksin tipa A, so poročali o preobčutljivostnih re-akcijah. Če pride do resnih (npr. anafilaktičnih) reakcij in/ali reakcij takojšnje preobčutljivosti, je treba uvesti ustrezno zdravljenje. Tvorba protiteles: Prepogosti odmerki lahko povečajo tveganje za nastanek protiteles, kar lahko vodi v neuspešnost zdravljenja. Možnost tvorjenja protiteles se lahko zmanjša z injiciranjem najnižjega učinkovitega odmerka v najdaljših možnih presledkih med injiciranji kot je klinično indicirano. Pediatrična populacija: Pri drugih zdravilih z botulinskim toksinom tipa A so bila zelo redko podana spontana poročila o možnem oddaljenem širjenju toksina pri pediatričnih bolnikih, ki so imeli pridružene bolezni, predvsem cerebralno paralizo. V splošnem je v takšnih primerih uporabljeni odmerek presegal odmerke, ki so priporočeni za ta zdravila. Redko so bila po uporabi zdravil z botulinskim toksinom, vključno z uporabo izven navedenih indikacij (» off label« uporabo), na primer v predelu vratu, podana spontana poročila o smrtnih primerih pri otrocih s hudo obliko cerebralne paralize, ki je bila včasih povezana z aspiracijsko pljučnico. To tveganje je še posebej veliko pri pediatričnih bolnikih v slabem splošnem zdravstvenem stanju ali pri bolnikih s hudimi nevrološkimi težavami, disfagijo ali pri bolnikih, ki so nedavno preboleli aspiracijsko pljučnico ali imajo v anamnezi bolezen pljuč. Specifična opozorila vezana na posamezne: Blefarospazem in hemifacialni spazem: Da se zmanjša možnost pojava ptoze, se je treba izogibati injiciranju v bližini mišice dvigalke zgornje veke (levator palpebrae superioris). Zaradi difuzije botulinskega nevrotoksina tipa A v spodnjo poševno mišico (m. inferi-or oblique) lahko pride do diplopije. Izogibanje medialnim injekcijam v spodnjo veko lahko zmanjša pogostnost tega neželenega učinka. Zaradi antiholinergičnega učinka botulinskega toksina tipa A je treba zdravilo XEOMIN pri bolnikih, pri katerih obstaja tveganje za nastanek ozkokotnega glavkoma, uporabljati previdno. Z namenom, da se prepreči ektropij, se je treba izogibati injiciranju v območje spodnje veke, vsako okvaro epitelija pa je treba takoj intenzivno zdraviti. Za zdravljenje bodo morda potrebne zaščitne kapljice, mazila, mehke zaščitne kontaktne leče ali zaprtje očesa s povojem ali podobnim sredstvom. Zmanjšano mežikanje po injiciranju zdravila XEOMIN v krožno mišico lahko povzroči izpostavljenost roženice, stalne okvare epitelija in ulceracijo roženice, zlasti pri bolnikih z okvarami možganskih živcev (obraznega živca). Pri bolnikih s predhodnim kirurškimi posegi na očeh je treba previdno preskusiti kor-nealno zaznavo. V mehkih tkivih očesne veke lahko pride do ekhimoze. Takojšnji nežen pritisk na mesto injiciranja lahko zmanjša tveganje za njen pojav. Spastični tortikolis: Zdravilo XEOMIN je treba injicirati previdno, kadar so mesta injiciranja blizu občutljivih struktur kot so karotidna arterija, pljučni vršički in požiralnik. Predhodno akinetične bolnike ali bolnike, ki se ne gibajo, je treba opomniti, naj po injiciranju zdravila XEOMIN postopoma pričnejo z aktivnostmi. Bolnike je treba obvestiti, da injiciranje zdravila XEOMIN pri obravnavanju spastičnega tortikolisa lahko povzroči blago do hudo disfagijo s tveganjem za pojav aspiracije in dispneje. Morda bo potreben zdravniški poseg (npr. v obliki gastrične sonde za hranjenje). Omejitev odmerka, ki se injicira v mišico obračalko glave, na manj kot 100 enot lahko zmanjša pogostnost disfagije. Bolniki z manjšo maso vratnih mišic ali bolniki, pri katerih je potrebno bilateralno injiciranje v mišici obračalki glave, so izpostavljeni večjemu tveganju. Pojav disfagije se lahko pripiše širjenju farmakološkega učinka zdravila XEOMIN, ki je posledica širjenja nevrotoksina v mišice požiralnika. Spastičnost zgornjih udov: Zdravilo XEOMIN je treba injicirati previdno, kadar so mesta injiciranja blizu občutljivih struktur kot so karotidna arterija, pljučni vršički in požiralnik. Predhodno akinetične bolnike ali bolnike, ki se ne gibajo, je treba opomniti, naj po injiciranju zdravila XEOMIN postopoma pričnejo z aktivnostmi. Zdravilo XEOMIN so kot zdravilo za zdravljenje fokalne spastičnosti raziskovali v povezavi z običajnimi režimi standardne nege in ni namenjeno kot nadomestek teh načinov zdravljenja. Malo verjetno je, da je zdravilo XEOMIN učinkovito za izboljšanje obsega gibanja sklepov, ki jih je prizadela fiksna kontraktura mišice. Kronična sialoreja (odrasli/otroci/mladostniki): V primeru z zdravili povzročene sialoreje (npr. zaradi aripiprazola, klozapina, piridostigmina) je treba pred uporabo zdravila XEOMIN za zdravljenje sialoreje najprej razmisliti o zamenjavi, zmanjšanju odmerka ali celo ukinitvi zdravila, ki jo povzroča. Varnosti in učinkovitosti zdravila XEOMIN pri bolnikih, ki imajo z zdravili povzročeno sialorejo, niso raziskali. Če se pri zdravljenju z zdravilom XEOMIN pojavijo »suha usta«, je treba razmisliti o zmanjšanju odmerka. Priporočljivo je, da bolnik pred pričetkom zdravljenja obišče zobozdravnika. Zobozdravnik naj bo seznanjen z namenom zdravljenja sialoreje z zdravilom XEOMIN, da se bo lahko odločil o primernih ukrepih za preprečevanje kariesa. Interakcije: Študij medsebojnega delovanja niso izvedli. Teoretično se lahko učinek botulinskega nevrotoksina okrepi z aminoglikozidnimi antibiotiki ali drugimi zdravili, ki ovirajo živčno-mišični prenos, npr. tubokurarinskimi mišičnimi relaksanti. Pri sočasni uporabi zdravila XEOMIN in aminoglikozidov ali spektinomicina potrebna posebna previdnost. Periferne mišične relaksante je treba uporabljati previdno in po potrebi zmanjšati začetni odmerek relaksanta ali uporabiti hitro delujoča zdravila, npr. vekuronij ali atrakurij, namesto zdravil z dolgotrajnim učinkom. Dodatno lahko pri zdravljenju kronične sialoreje obsevanje glave in vratu vključno z žlezami slinavkami in/ali sočasna uporaba antiholinergičnih zdravil (npr. atropin, glikopironij, skopolamin) povečata učinek botulinskega toksina. Zdravljenje sialoreje z zdravilom XEOMIN v času zdravljenja z obsevanjem ni priporočljivo. 4-aminokinolini lahko zmanjšajo učinek zdravila XEOMIN. Plodnost, nosečnost in dojenje: Nosečnost: Ni zadostnih podatkov o uporabi botulinskega nevrotoksina tipa A pri nosečnicah. Zdravila XEOMIN se ne sme uporabljati med nosečnostjo, razen če je nujno in če morebitne koristi opravičijo tveganje. Dojenje: Zdravila XEOMIN se med dojenjem ne sme uporabljati. Plodnost: Ni kliničnih podatkov o uporabi botulinskega nevrotoksina tipa A. Povzetek neželenih učinkov: Neželeni učinki neodvisni od indikacije: lokalizirana bolečina, vnetje, parestezija, hipoestezija, občutljivost, otekanje, edem, eritem, srbenje, lokalizirana okužba, hematom, krvavitev in/ali modrice, vazovagalni odzivi, vključno s prehodno simptomatsko hipotenzijo, slabostjo, tinitusom in sinkopo, lokalizirana mišična šibkost, pretirana mišična šibkost, disfagija in aspiracijska pljučnica (zelo redko s smrtnim izidom), preobčutljivostne reakcije. Neželeni učinki na podlagi kliničnih izkušenj: Blefarospazem: Zelo pogosti: ptoza vek. Pogosti:, suhe oči, zamegljen vid, motnje vida, suha usta, bolečina na mestu injiciranja. Hemifacialni spazem: Pri hemifacialnem spazmu so pričakovani podobni neželeni učinki kot pri blefarospazmu. Spastični tortikolis: Zelo pogosti: disfagija. Pogosti: glavobol, občutek omedlevice, omotičnost, suha usta, navzea, hiperhidroza, bolečina v vratu, mišična šibkost, mialgija, mišični krči, togost mišic in skeleta, bolečina na mestu injiciranja, astenija, okužbe zgornjih dihal. Spastičnost zgornjih udov: Pogosti: suha usta. Kronična sialoreja (odrasli): Pogosti: parestezije, suha usta, disfagija. Kronična sialoreja (otroci/mladostniki): Občasni: disfagija. Izkušnje v obdobju trženja zdravila: Ob uporabi zdravila XEOMIN so po prihodu zdravila na trg z neznano pogostnostjo in ne glede na posamezne indikacije poročali o naslednjih neželenih učinkih: preobčutljivostne reakcije, kot so otekanje, edemi (tudi na mestih, oddaljenih od mesta injiciranja), eritem, pruritus, izpuščaj (lokaliziran in generaliziran) in zasoplost, mišična atrofija, gripi podobni simptomi. Način in režim predpisovanja in izdaje zdravila: Predpisovanje in izdaja zdravila je le na recept, zdravilo pa se uporablja samo v javnih zdravstvenih zavodih ter pri pravnih in fizičnih osebah, ki opravljajo zdravstveno dejavnost. Imetnik dovoljenja za promet: Merz Pharmaceuticals GmbH, Eckenheimer Landstraße 100, 60318 Frankfurt/Main, P.O. Box 11 13 53, 60048 Frankfurt/Main, Nemčija. Pred predpisovanjem, prosimo, preberite povzetek glavnih značilnosti zdravila. Datum revizije besedila: 02/2022 SI-XEO-0922-001 Samo za strokovno javnost Literatura: Povzetek glavnih značilnosti zdravila Xeomin®. [72] Vaš partner na vsakem koraku Eden od ključnih stebrov slovenskega gospodarstva: več kot 75 let izkušenj, znanja in izjemnih dosežkov. Razvoj, proizvodnja in preskrba Lendava Prevalje z generičnimi in s podobnimi Mengeš Ljubljana biološkimi zdravili. Celovita podpora strokovni in laični javnosti pri obravnavi bolnikov Bolezni centralnega živčevja Rakave bolezni Sl S a rč d no- k žilne o bolezni r B na o bole l zen ečin Sl a abokrvnost Avtoimunske bolezni Hematološke bolezni Moške bolezni NAJUGLEDNEJŠI M DELODAJALEC ikrobiota Nauglednejši delodajalec v Sloveniji več let zapored. Bogate, uporabne in stroko Bogate, vno uravnotežene vsebine za strokovno in laično javnost www.lek.si | Lek farmacevtska družba d. d., Verovškova 57, 1526 Ljubljana, Slovenija Informacija pripravljena: julij 2023 | 297900 [73] Xltek® Trex™ HD Ambulatory EEG/PSG Xltek® Trex™ HD Zajem visoko kakovostnega video/EEG posnetka doma ali na poti • Odličen za ambulatorni EEG in PSG • Najlažji prenosni EEG ojačevalnik v razredu • dve HD kameri za brezkompromisni video • brezžična sinhronizacija videa z EEG • Mobilnost in udobje pacienta zagotovljena • Dodatno napajanje za 72 ur avtonomije Medistar d.o.o., t: +386 1 511 36 00, m: info@medistar.si [74] [75]