'Nordic values’ and schooling during COVID-19 : how to balance comprehensive education and sustainable pandemic regulations

Peer reviewedPublisher PD

Investigation into the molecular mechanisms of norepinephrine and serotonin transporters in Attention Deficit/Hyperactivity Disorder

Die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) ist eine häufige neuropsychiatrische Entwicklungsstörung bei Kindern, die oft bis ins Erwachsenenalter fortdauert. Die Störung ist gekennzeichnet durch Symptome von Hyperaktivität, Impulsivität und Unaufmerksamkeit, die das tägliche Leben stört. Die Behandlung besteht aus Pharmakotherapie und/oder Verhaltenstherapie. Die Neurobiologie der ADHS ist komplex und nicht vollständig bekannt. Neuroimaging-Studien haben Gehirnregionen aufgezeigt, von denen angenommen wird, dass sie strukturelle Anomalien oder funktionelle Veränderungen bei ADHS aufweisen. Die Störung ist stark vererbbar und mehrere Gene wurden mit der Ätiologie in Verbindung gebracht; eine große Anzahl von Studien umfasst Gene, die an der Neurotransmission beteiligt sind, insbesondere innerhalb der monoaminergen Neurotransmittern wie Dopamin, Noradrenalin und Serotonin. Obwohl stark vererbbar, spielen auch Umweltfaktoren eine Rolle in der Pathophysiologie. Das Ziel dieser Arbeit bestand darin, zwei Proteine der Neurotransmittersysteme Noradrenalin und Serotonin im Zusammenhang mit ADHD mittels PET zu untersuchen. Wir verwendeten den Radioliganden (S, S)-[18F]FMeNER-D2 zur Evaluierung des Noradrenalintransporters (NET) und [11C]DASB für den Serotonintransporter (SERT). Zusätzlich kombinierten wir die NET-Bildgebung mit Genotypisierung und Sequenzierung des NET, um die genetische und epigenetische Assoziation zu untersuchen. Schließlich wurde auch eine interregionale Korrelationsanalyse für die Bewertung von SERT-Verteilungsmustern bei ADHS angewendet. In unserer ersten Veröffentlichung konnten wir genotypabhängige Unterschiede in genetischen Varianten des NET in der in vivo NET-Verfügbarkeit im Thalamus und im Cerebellum feststellen. Weiterhin fanden wir eine genotypabhängige inverse Korrelation zwischen Verhaltenssymptomen der Hyperaktivität / Impulsivität und der NET-Expression im Cerebellum, die eine U-förmige Kurve für eine optimale Funktion nahelegt. In unserer zweiten Publikation mit interregionaler Korrelationsanalyse fanden wir Unterschiede in der Verfügbarkeit von SERT für den Precuneus und Hippocampus bei Patienten. Eine höhere interregionale Assoziation zwischen diesen Regionen wurde für die ADHS-Gruppe im Vergleich zu gesunden Kontrollen gefunden. Unsere Ergebnisse legen einen dysfunktionalen serotonergen Mechanismus nahe, der bei ADHD im Precuneus und im Hippocampus auftritt. Die letzte Publikation befasste sich mit dem epigenetischen Einfluss der Promotorregion des NET bei ADHS. Es wurde eine erhöhte Methylierung bei Patienten im Vergleich zur Kontrollgruppe in einer definierten Region des Gens gefunden. Eine negative Korrelation wurde auch zwischen einer CpG-Stelle und der NET-Expression in verschiedenen Hirnregionen festgestellt. Eine negative Assoziation wurde außerdem zwischen Verhaltenssymptomen und Methylierungslevel bei Patienten festgestellt. Die Ergebnisse unserer Publikationen unterstützen eine veränderte monoaminerge Neurotransmission bei ADHS auf genetischer, epigenetischer und molekularer Ebene der Konnektivität. Zukünftige Forschung sollte eine größere Anzahl der Probanden umfassen und die möglichen Wechselwirkungseffekte zwischen Genen und Umweltfaktoren auf dem Gehirn erforschen.Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children that frequently continues into adulthood. The disorder is characterized by symptoms of hyperactivity, impulsivity and inattention and severely interrupts daily life. Treatment consists of pharmacotherapy and/or behavioral therapy. The neurobiology of ADHD is complex and not entirely established. Neuroimaging studies have implicated brain regions that are believed to have structural abnormalities or functional alterations in ADHD. The disorder is highly heritable and several genes have been implicated in the etiology. Many studies include genes involved in neurotransmission, specifically within the monoaminergic systems including dopamine, norepinephrine and serotonin. Although highly heritable, environmental factors also play its role in the pathophysiology. The aim of the thesis was to investigate the in vivo expression of norepinephrine- and serotonin transporter proteins with the application of PET in combination with different methods such as genotyping, bisulfite sequencing and interregional correlation analysis. We applied the ligand (S,S)-[18F]FMeNER-D2 to evaluate the norepinephrine transporter (NET) and [11C]DASB for the serotonin transporter (SERT). Imaging of the NET was combined with genotyping and sequencing of the NET to assess the genetic and epigenetic influence. We also applied interregional correlation analysis for the assessment of SERT patterns in ADHD. In our first publication, we detected genotype dependent differences in NET genetic variants on in vivo NET availability in the thalamus and the cerebellum. Furthermore, we found genotype dependent inverse correlation between behavioral symptoms of hyperactivity/impulsivity and NET expression in the cerebellum, underlining the U-shaped curve and indicating that a perfect balance of norepinephrine is needed for proper attentional performance during cognitive or behavioral tasks. In our second publication using interregional correlation analysis we detected differences in the SERT availability for the precuneus and hippocampus in patients. Higher interregional association between those regions was found for the ADHD group in comparison to healthy controls. Our results indicate that an imbalance in the serotonergic neurotransmission is present in the precuneus and hippocampus in patients with ADHD. The last publication addressed the epigenetic influence of the promoter region of the NET in ADHD. Increased methylation was found in patients compared to controls in a defined region of the gene. Negative correlation was also detected between a CpG site and the NET expression in several brain regions. A negative association was also detected for behavioral symptoms and methylation levels in patients. The findings of our publications lend support to an altered norepinephrinergic and serotonergic neurotransmission in ADHD on a genetic, epigenetic and on a molecular connectivity level. Future research should include larger sample sizes and explore the potential interaction effects between genes and environmental factors on the brain.Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersArbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprüftMedizinische Universität Wien, Diss., 2018(VLID)347635

Task-relevant brain networks identified with simultaneous PET/MR imaging of metabolism and connectivity

Except for task-specific functional MRI, the vast majority of imaging studies assessed human brain function at resting conditions. However, tracking task-specific neuronal activity yields important insight how the brain responds to stimulation. We specifically investigated changes in glucose metabolism, functional connectivity and white matter microstructure during task performance using several recent methodological advancements. Opening the eyes and right finger tapping had elicited an increased glucose metabolism in primary visual and motor cortices, respectively. Furthermore, a decreased metabolism was observed in the regions of the default mode network, which allowed absolute quantification of commonly described deactivations during cognitive tasks. These brain regions showed widespread task-specific changes in functional connectivity, which stretched beyond their primary resting-state networks and presumably reflected the level of recruitment of certain brain regions for each task. Finally, the corresponding white matter fiber pathways exhibited changes in axial and radial diffusivity during the tasks, which were regionally distinctive for certain tract groups. These results highlight that even simple task performance leads to substantial changes of entire brain networks. Exploiting the complementary nature of the different imaging modalities may reveal novel insights how the brain processes external stimuli and which networks are involved in certain tasks.(VLID)473577

Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)-[F-18]FMeNER-D-2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI-TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype-dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (-3081 A/T) and a 5-untranslated region (5UTR) SNP (-182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD. Hum Brain Mapp 37:884-895, 2016. (c) 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.P 22981-B09(VLID)307914

Parcellation of the Human Cerebral Cortex Based on Molecular Targets in the Serotonin System Quantified by Positron Emission Tomography In vivo

Parcellation of distinct areas in the cerebral cortex has a long history in neuroscience and is of great value for the study of brain function, specialization, and alterations in neuropsychiatric disorders. Analysis of cytoarchitectonical features has revealed their close association with molecular profiles based on protein density. This provides a rationale for the use of in vivo molecular imaging data for parcellation of the cortex with the advantage of whole-brain coverage. In the current work, parcellation was based on expression of key players of the serotonin neurotransmitter system. Positron emission tomography was carried out for the quantification of serotonin 1A (5-HT1A, n = 30) and 5-HT2A receptors (n = 22), the serotonin-degrading enzyme monoamine oxidase A (MAO-A, n = 32) and the serotonin transporter (5-HTT, n = 24) in healthy participants. Cortical protein distribution maps were obtained using surface-based quantification. Based on k-means clustering, silhouette criterion and bootstrapping, five distinct clusters were identified as the optimal solution. The defined clusters proved of high explanatory value for the effects of psychotropic drugs acting on the serotonin system, such as antidepressants and psychedelics. Therefore, the proposed method constitutes a sensible approach towards integration of multimodal imaging data for research and development in neuropharmacology and psychiatry. Key words: cortex, cortical reconstruction, molecular imaging, parcellation, PET, serotoni

Characteristics and Outcomes of People With Gout Hospitalized Due to COVID-19 : Data From the COVID-19 Global Rheumatology Alliance Physician-Reported Registry

Objective To describe people with gout who were diagnosed with coronavirus disease 2019 (COVID-19) and hospitalized and to characterize their outcomes. Methods Data on patients with gout hospitalized for COVID-19 between March 12, 2020, and October 25, 2021, were extracted from the COVID-19 Global Rheumatology Alliance registry. Descriptive statistics were used to describe the demographics, comorbidities, medication exposures, and COVID-19 outcomes including oxygenation or ventilation support and death. Results One hundred sixty-three patients with gout who developed COVID-19 and were hospitalized were included. The mean age was 63 years, and 85% were male. The majority of the group lived in the Western Pacific Region (35%) and North America (18%). Nearly half (46%) had two or more comorbidities, with hypertension (56%), cardiovascular disease (28%), diabetes mellitus (26%), chronic kidney disease (25%), and obesity (23%) being the most common. Glucocorticoids and colchicine were used pre-COVID-19 in 11% and 12% of the cohort, respectively. Over two thirds (68%) of the cohort required supplemental oxygen or ventilatory support during hospitalization. COVID-19-related death was reported in 16% of the overall cohort, with 73% of deaths documented in people with two or more comorbidities. Conclusion This cohort of people with gout and COVID-19 who were hospitalized had high frequencies of ventilatory support and death. This suggests that patients with gout who were hospitalized for COVID-19 may be at risk of poor outcomes, perhaps related to known risk factors for poor outcomes, such as age and presence of comorbidity