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

Behavioral correlates of direct current-coupled electrographic activity in premature infants.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThe co-expression of behavioral and neural events represents a situation conducive to Hebbian-type neuroplasticity and may provide a reasonable explanation for how the amount of movement during the perinatal period contributes to neuromotor development. Direct current-coupled electrographic recordings in premature infants indicate that the majority of the electrographic activity is exhibited in a slow frequency range that is either distorted or not visible using traditional recording methods. Therefore, we provide a description of the behavioral correlates of direct current-coupled electrographic recordings in six premature human infants (3 males and 3 females; 30-34 weeks). We report, in concert with prior data, that electrographic activity and movements occur in tightly coupled discrete bouts. Surprisingly, spontaneous activity transients, which are slow, high amplitude, multiband electrographic events, typically precede startles; thereby revealing a previously unknown coupling of early neural and behavioral events in humans. Taken together, the present findings open novel venues for studying and dissecting mammalian neuromotor development

Estrogen-progestin use and breast cancer characteristics in lean and overweight postmenopausal women.

To access publisher's full text version of this article click on the hyperlink belowBreast cancer associated with estrogen-progestin (EP) therapy may have more favorable characteristics than cancer in never users, but results are conflicting. It is not well known either whether Body Mass Index (BMI) modifies this association. We investigated breast cancer characteristics in EP users for lean (BMI < 25 kg/m(2)) and overweight women (BMI ≥ 25 kg/m(2)).The Icelandic Cancer Detection Clinic cohort, with information on breast cancer risk factors for 90% of Icelandic women, was linked with the population-based Icelandic Cancer Registry. A total of 781 women with invasive breast cancer diagnosed 51 years or older were matched with 7761 controls from the cohort. Conditional logistic regression was used for estimating adjusted odds ratios (OR) and 95% confidence intervals (CI) according to tumor characteristics, stratified by BMI. Polytomous logistic regression was applied in a case-only analysis for testing whether the risk associated with EP use differed according to tumor characteristics.Ever EP users had a twofold higher risk of breast cancer compared with never users (OR 2.05, 95% CI 1.71-2.45). In lean women, EP use was significantly less likely to be associated with grade 2 or 3 tumors than grade 1 tumors, contrary to overweight women for whom risk was increased irrespective of grade. EP use in overweight women was associated with a higher risk of lobular than ductal cancer (OR 2.75, 95% CI 1.29-5.87).Among lean EP users, tumor characteristics were more favorable than among never users. This effect was not observed for overweight women.Icelandic Cancer Societ

Data quality at the Icelandic Cancer Registry: comparability, validity, timeliness and completeness.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.The nationwide Icelandic Cancer Registry (ICR) was established in 1954 and has been extensively used for research from the outset although formal quality assessment of the registry database has not previously been undertaken. In this paper we report the first formal evaluation of the comparability, validity, timeliness and completeness of the ICR. Data from the ICR for the period 1955-2009 (41 994 cancer diagnoses) were used, applying established quantitative and semi-quantitative methods. In order to evaluate the completeness of the ICR, record linkage was performed between the ICR and the population-based Hospital Discharge Registry to identify potential missing cases for tumour diagnoses in 2000 and 2001. The registration is in accordance with internationally accepted standards. It has high validity, but random variation in rates is prominent in this small population. Record linkage with the Hospital Discharge Registry revealed that in addition to the 2459 cancers registered in 2000-2001, 21 cases were missing, indicating 99.15% completeness. Tumours of the central nervous system constituted 71%, and haematological malignancies 19% of these missing entries. The ICR has high completeness, validity and timeliness and is comparable to the cancer registries of the other Nordic Countries. As cancer registries have many important roles, it is of great importance that their data are at all times as complete and valid as possible. Thus the ICR aims to constantly improve and update the data gathering process.European Union sixth framework Network of Excellenc

Evaluation of the Long-Term Anti-Human Papillomavirus 6 (HPV6), 11, 16, and 18 Immune Responses Generated by the Quadrivalent HPV Vaccine

This quadrivalent human papillomavirus (qHPV) (HPV6, -11, -16, and -18) vaccine long-term follow-up (LTFU) study is an ongoing extension of a pivotal clinical study (FUTURE II) taking place in the Nordic region. The LTFU study was designed to evaluate the effectiveness, immunogenicity, and safety of the qHPV vaccine (Gardasil) for at least 10 years following completion of the base study. The current report presents immunogenicity data from testing samples of the year 5 LTFU visit (approximately 9 years after vaccination). FUTURE II vaccination arm subjects, who consented to being followed in the LTFU, donated serum at regular intervals and in 2012. Anti-HPV6, -11, -16, and -18 antibodies were detected by the competitive Luminex immunoassay (cLIA), and in addition, serum samples from 2012 were analyzed by the total IgG Luminex immunoassay (LIA) (n = 1,598). cLIA geometric mean titers (GMTs) remained between 70% and 93% of their month 48 value depending on HPV type. For all HPV types, the lower bound of the 95% confidence interval (CI) for the year 9 GMTs remained above the serostatus cutoff value. The proportion of subjects who remained seropositive based on the IgG LIA was higher than the proportion based on cLIA, especially for anti-HPV18. As expected, the anti-HPV serum IgG and cLIA responses were strongly correlated for all HPV types. Anti-HPV GMTs and the proportion of vaccinated individuals who are seropositive remain high for up to 9 years of follow-up after vaccination

Patient-reported Outcomes and Clinical Response in Patients with Moderate-to-severe Plaque Psoriasis Treated with Tonsillectomy : A Randomized Controlled Trial

Psoriasis is a chronic inflammatory skin disease with profound effects on patients' health-related quality of life (HRQoL). Twenty-nine patients with plaque psoriasis and a history of streptococcal-associated psoriasis exacerbations were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and followed for 24 months. Patients were evaluated with the Psoriasis Disability Index, Psoriasis Life Stress Inventory and Psoriasis Area and Severity Index. HRQoL and psoriasis-related stress improved significantly in the tonsillectomy group compared with the control group (p = 0.037 and p = 0.002, respectively), with a mean 50% improvement in HRQoL and a mean 59% improvement in psoriasis-induced stress. Clinical improvement correlated significantly with improved HRQoL (r = 0.297, p = 0.008) and psoriasis-related stress (r = 0.310, p = 0.005). Of the tonsillectomized patients, 87% concluded that the procedure was worthwhile. Tonsillectomy may improve quality of life for selected patients with plaque psoriasis

Midlife metabolic factors and prostate cancer risk in later life

To access publisher's full text version of this article click on the hyperlink belowMetabolic syndrome is associated with several cancers, but evidence for aggressive prostate cancer is sparse. We prospectively investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a cohort of Icelandic men. Men in the Reykjavik Study (n = 9,097, enrolled 1967-1987) were followed for incident (n = 1,084 total; n = 378 advanced; n = 148 high-grade) and fatal (n = 340) prostate cancer until 2014. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for (1) measured metabolic factors at cohort entry (body mass index (BMI), blood pressure, triglycerides, fasting blood glucose) and (2) a metabolic syndrome score (range 0-4) combining the risk factors: BMI ≥30 kg/m2 ; systolic blood pressure (SBP) ≥130 or diastolic blood pressure (DBP) ≥85 mm Hg or taking antihypertensives; triglycerides ≥150 mg/dl; fasting blood glucose ≥100 mg/dl or self-reported type 2 diabetes. Hypertension and type 2 diabetes were associated with a higher risk of total, advanced, high-grade, and fatal prostate cancer, independent of BMI. Neither BMI nor triglycerides were associated with prostate cancer risk. Higher metabolic syndrome score (3-4 vs 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p trend = 0.08), although this finding was not statistically significant. Our findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer.National Cancer Institute at the National Institutes of Health American Institute for Cancer Research Nordic HealthWhole Grain Food (HELGA) Dana-Farber/Harvard Cancer Center SPORE in Prostate Cance

Improvement of psoriasis after tonsillectomy is associated with a decrease in the frequency of circulating T cells that recognize streptococcal determinants and homologous skin determinants.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Exacerbation of chronic psoriasis can be associated with streptococcal throat infections, and T cells that respond to peptide sequences common to streptococcal M proteins and skin keratins have been detected in patients' blood. To our knowledge, we have conducted the first blinded, prospective study to assess the impact of tonsillectomy on psoriasis. Twenty-nine patients with chronic psoriasis and history of exacerbation after sore throat were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and monitored for 2 y clinically and by enumeration of circulating skin homing T cells that respond to short homologous M protein or keratin peptides. Thirteen patients (86%) showed sustained improvement after tonsillectomy ranging from 30 to 90% reduction in disease severity. Furthermore, there was a close correlation between the degree of clinical improvement in individual patients and reduction in the frequency of peptide-reactive skin-homing T cells in their circulation. No corresponding clinical or immunologic changes were observed among the controls. These findings indicate that tonsillectomy may have a beneficial effect on chronic psoriasis because the palatine tonsils generate effector T cells that recognize keratin determinants in the skin.Icelandic Research Fund, Icelandic Research Fund for Graduate Students, University of Iceland, National University Hospital in Iceland

Human papillomavirus genotype-specific risks for cervical intraepithelial lesions

Prevalence of different HPV genotypes is changing after HPV vaccination. The associated risks are needed for optimizing cervical cancer screening. To estimate HPV type-specific prevalence, odds ratio (OR), and positive predictive value (PPV) for cervical cytological abnormalities, we determined 41 different HPV genotypes in cervical samples from a population-based sample of 8351 women aged 18–51 years before HPV vaccination era (V501-033; NCT01077856). Prevalence of HPV16 was 4.9% (95% CI: 4.4–5.5) with the PPV for high-grade cytology 11.2%, and OR 11.9 (95% CI: 8.5–16.5). Carcinogenic HPVs included in the nonavalent vaccine (HPV16,18,31,33,45,52,58) had a population prevalence of 14.4% (95% CI: 13.5–15.4), with PPV of 8.0% (95% CI: 6.8–9.3) and OR 23.7 (95% CI: 16.0–63.5) for high-grade cytology. HPV types currently included in most screening tests, but not vaccinated against (HPV35,39,51,56,59,66,68) had a joint prevalence of 8.5% (95% CI: 7.8–9.2) with PPV of 4.4% (95% CI: 3.3–5.7) and OR of 2.9 (95% CI: 2.0–4.0) for high-grade cytology. The other 27 non-carcinogenic genotypes had a prevalence of 11.8%, PPV of 2.9% (95% CI:2.1–3.9), and OR 1.5 (95% CI: 1.1–2.2.) for high-grade cytology. These results suggest that HPV screening tests in the post-vaccination era might perform better if restricted to the HPV types in the nonavalent vaccine and screening for all 14 HPV types might result in suboptimal balance of harms and benefits