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TRIXY Center of Expertise, Leiden University Treatment and Expertise Centre (LUBEC), Sandifortdreef, Leiden, The Netherlands
Leiden Institute for Brain and Cognition, Leiden University, Wassenaarseweg, Leiden, The Netherlands
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TRIXY Center of Expertise, Leiden University Treatment and Expertise Centre (LUBEC), Sandifortdreef, Leiden, The Netherlands
Leiden Institute for Brain and Cognition, Leiden University, Wassenaarseweg, Leiden, The Netherlands
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TRIXY Center of Expertise, Leiden University Treatment and Expertise Centre (LUBEC), Sandifortdreef, Leiden, The Netherlands
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, Sophia Children’s Hospital, Dr. Molewaterplein, Rotterdam, The Netherlands
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TRIXY Center of Expertise, Leiden University Treatment and Expertise Centre (LUBEC), Sandifortdreef, Leiden, The Netherlands
Department of Clinical, Neuro, and Developmental Psychology, Vrije Universiteit Amsterdam, Van der Boechorststraat, Amsterdam, The Netherlands
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TRIXY Center of Expertise, Leiden University Treatment and Expertise Centre (LUBEC), Sandifortdreef, Leiden, The Netherlands
Leiden Institute for Brain and Cognition, Leiden University, Wassenaarseweg, Leiden, The Netherlands
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Investigating sex chromosome trisomies (SCTs) may help in understanding neurodevelopmental pathways underlying the risk for neurobehavioral problems and psychopathology. Knowledge about the neurobehavioral phenotype is needed to improve clinical care and early intervention for children with SCT. This is especially relevant considering the increasing number of early diagnosed children with the recent introduction of noninvasive prenatal screening. The TRIXY Early Childhood Study is a longitudinal study designed to identify early neurodevelopmental risks in children with SCT, aged 1–7 years. This review summarizes the results from the TRIXY Early Childhood Study, focusing on early behavioral symptoms in areas of autism spectrum disorder, attention-deficit hyperactivity disorder, and communication disorders, and underlying neurocognitive mechanisms in domains of language, emotion regulation, executive functioning, and social cognition. Behavioral symptoms were assessed through structured behavior observation and parental questionnaires. Neurocognition was measured using performance tests, eyetracking, and psychophysiological measures of arousal. In total, 209 children aged 1–7 years were included: 107 children with SCT (33 XXX, 50 XXY, and 24 XYY) and 102 age-matched population controls. Study outcomes showed early behavioral symptoms in young children with SCT, and neurocognitive vulnerabilities, already from an early age onward. Neurobehavioral and neurocognitive difficulties tended to become more pronounced with increasing age and were rather robust, independent of specific karyotype, pre/postnatal diagnosis, or ascertainment strategy. A more longitudinal perspective on neurodevelopmental ‘at-risk’ pathways is warranted, also including studies assessing the effectiveness of targeted early interventions. Neurocognitive markers that signal differences in neurodevelopment may prove to be helpful in this. Focusing on early development of language, social cognition, emotion regulation, and executive functioning may help in uncovering early essential mechanisms of (later) neurobehavioral outcome, allowing for more targeted support and early intervention.
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Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, UK
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Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, UK
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Brain tumours make up nearly one-third of paediatric malignancies. Over time, advancements in oncological treatments like radiotherapy have helped reduce normal-tissue toxicity when treating cancers in the brain. However, clinicians are still facing a trade-off between treatment efficacy and potential side effects. The aim of this review is to address the late effects of cranial irradiation on the neuroendocrine system and to identify factors that make patients more vulnerable to radiation-induced endocrine sequelae. Radiation damage to the hypothalamic–pituitary axis, which orchestrates hormone release, can lead to endocrinopathy; up to 48.8% of children who have undergone cranial irradiation develop a hormone deficiency. This may lead to further health complications that can appear up to decades after the last treatment, lowering the patients’ quality of life and increasing long-term costs as lifelong hormone replacement therapy may be required. Growth hormone deficiency is the most common sequelae, followed by either thyroid or gonadotropic hormone deficiency. Adrenocorticotropic hormone deficiency tends to be the least common. Identified factors that increase the risk of late endocrine deficiency include total radiation dose, age at treatment, and time since last treatment. However, as there are various other factors that may potentiate the damage, a universal solution proven to be most effective in sparing the endocrine tissues is yet to be identified. Until then, accounting for the identified risk factors during treatment planning may in some cases help reduce the development of endocrine sequelae in childhood cancer survivors.
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Amsterdam UMC, Emma’s Children’s Hospital, Amsterdam, The Netherlands
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Many long-term childhood cancer survivors suffer from treatment-related late effects, which may occur in any organ and include a wide spectrum of conditions. Long-term follow-up (LTFU) is recommended to facilitate early diagnosis and to ensure better health outcomes. Due to the heterogeneity of these sequelae, different specialists work together in the diagnosis and treatment of these conditions. Experts from both pediatric and internal medicine are involved in age-appropriate care by providing a transition process. Hence, LTFU of childhood cancer survivors is a prototypic example of multidisciplinary care for patients with complex needs treated in a specialized setting. International collaborations of healthcare professionals and scientists involved in LTFU of childhood cancer survivors, such as the International Guideline Harmonization Group, compile surveillance recommendations that can be clinically adopted all over the world. These global networks of clinicians and researchers make a joint effort to address gaps in knowledge, increase visibility and awareness of cancer survivorship and provide an excellent example of how progress in clinical care and scientific research may be achieved by international and multidisciplinary collaboration.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Objective
To investigate the association of normal BMI with central obesity (CO), high BMI with CO, high BMI without CO, and normal BMI without CO, with function and cognition in older adults.
Methods
Cross-sectional study involving 754 participants ≥ 65 years. Data collected include demographics, cognition, and physical measurements.
Results
Females had a higher prevalence of high BMI with CO and a lower prevalence of high BMI without CO than males (61.0% vs 44.6% and 4.6% vs 15.0%, respectively). Within gender, CO groups, regardless of BMI, had lower mini-mental state examination (MMSE), handgrip strength (HGS), and longer timed-up-and-go (TUG) scores. Overall, the high BMI without CO group had the highest MMSE scores, HGS, and shortest TUG. Amongst males, HGS was significantly lower in the normal BMI with CO group (B −3.28, 95% CI −6.32 to −0.23, P = 0.04). CO, regardless of normal/high BMI, had significantly longer TUG time (B 2.65, 95% CI 0.45 to 4.84, P = 0.02; B 1.07, 95% CI 0.25 to 1.88, P = 0.01, respectively) than normal BMI without CO group. CO was associated with lower MMSE scores in both genders but significant only in males with normal BMI and CO (B −1.60, 95% CI −3.15 to −0.06, P = 0.04).
Conclusion
CO may be a better predictor of obesity and adverse outcomes in older adults. High BMI without CO was associated with better outcomes especially in males but require further validation. Prospective longitudinal studies are needed to ascertain the impact of BMI and/or CO on function, cognition, mortality, and gender differences.
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The prevalence of obesity has reached epidemic proportions and keeps growing. Obesity seems implicated in the pathogenesis of cognitive dysfunction, Alzheimer’s disease and dementia, and vice versa. Growing scientific efforts are being devoted to the identification of central mechanisms underlying the frequent association between obesity and cognitive dysfunction. Glucose brain handling undergoes dynamic changes during the life-course, suggesting that its alterations might precede and contribute to degenerative changes or signaling abnormalities. Imaging of the glucose analog 18F-labeled fluorodeoxyglucose (18FDG) by positron emission tomography (PET) is the gold-standard for the assessment of cerebral glucose metabolism in vivo. This review summarizes the current literature addressing brain glucose uptake measured by PET imaging, and the effect of insulin on brain metabolism, trying to embrace a life-course vision in the identification of patterns that may explain (and contribute to) the frequent association between obesity and cognitive dysfunction. The current evidence supports that brain hypermetabolism and brain insulin resistance occur in selected high-risk conditions as a transient phenomenon, eventually evolving toward normal or low values during life or disease progression. Associative studies suggest that brain hypermetabolism predicts low BDNF levels, hepatic and whole body insulin resistance, food desire and an unfavorable balance between anticipated reward from food and cognitive inhibitory control. Emerging mechanistic links involve the microbiota and the metabolome, which correlate with brain metabolism and cognition, deserving attention as potential future prevention targets.
INSERM U1018, Université Paris Sud, Centre for Research in Epidemiology and Population Health, Hôpital Paul Brousse, Bât 15/16, 16 Avenue Paul Vaillant Couturier, 94807 Paris, Villejuif Cedex, France
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The aim of this meta-analysis was to compare the effect of intensive vs standard glycaemic control on cognitive decline in type 2 diabetic patients. A systematic search of PubMed and ALOIS was conducted from inception up to October 30, 2014. Randomised controlled trials (RCTs) of type 2 diabetic patients comparing the rate of change in cognitive function among participants assigned to intensive vs standard glycaemic control were included. An inverse-variance-weighted random effects model was used to calculate standardised mean differences (SMDs) and 95% CIs. A total of 24 297 patients from five RCTs were included in the meta-analysis. Follow-up ranged from 3.3 to 6.2 years. The result from the pooled analysis showed that intensive glycaemic control was not associated with a slower rate of cognitive decline in patients with type 2 diabetes, compared with standard glycaemic control (SMD=0.02; 95% CI=−0.03 to 0.08) although there was some heterogeneity across individual studies (I 2=68%, P for heterogeneity=0.01). There are few diabetes control trials including cognitive endpoints and a small number of trials comparing intensive and standard treatment strategies. Currently, intensive glycaemic control should not be recommended for prevention of cognitive decline in patients with type 2 diabetes because there is no evidence of its effectiveness. Moreover, the use of intensive diabetes treatment results in an increase of risk of hypoglycaemia, which is linked to a greater risk of poor cognition.
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Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Duesseldorf, Germany
German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
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Purpose
Obese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR.
Objective
To assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent.
Methods
This cross-sectional study included 78 obese subjects (mean age 46 ± 11 years; BMI 42.2 ± 4.7 kg/m2). Glucose levels were analysed by hexokinase method and insulin levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD.
Results
A positive association between overall NAFLD Activity Score and HOMA-IR was found (r s = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, glucose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammatory foci or higher stage of fibrosis. These findings were independent of age, BMI, triglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR.
Conclusion
In this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assessed, preventing or mitigating this inflammatory response in obesity might be of importance in controlling obesity-related metabolic disturbances.
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
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Department of Medicine, Karlstad Hospital, Karlstad, Sweden
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Growth hormone deficiency (GHD) syndrome is associated with adverse levels of several risk factors for cardiovascular diseases (CVD), including metabolic inflammation. However, the impact of GHD and GH treatment on low-grade inflammation is unknown. The aim of the study was to establish the level of the low-grade inflammation biomarker soluble urokinase plasminogen activator receptor (suPAR) in adults with GHD and the response to long-term GH treatment. Measurements of suPAR and CRP were performed in bio-bank serum samples from 72 adults, 34 males and 38 females, with GHD before and during at least 5 years of GH treatment. Mean age was 52.5 ± 15.5 years, BMI 27.3 ± 5 kg/m2. Clinical evaluations and blood sampling were performed at routine visits. Data on demography, anthropometry, lab results and clinical events were retrieved from post-marketing surveillance study databases and medical records. suPAR and high-sensitive (hs) CRP were analysed using ELISA and immunochemistry, respectively. At baseline blood pressure, lipid profile and fasting glucose were within the normal reference range. Baseline geometric mean and 95% CI of suPAR was 2.9 (2.7–3.3) ng/mL and of CRP 2.3 (0.6–4.0) mg/L. Mean follow-up was 8 ± 2 years. The suPAR levels remained stable during follow-up, although individual increases were seen on occurrence or presence of co-morbidities. In contrast, levels of CRP decreased. In conclusion, the decrease in CRP and indirectly the absence of an expected increase in suPAR over time indicates a favourable effect of GH on low-grade inflammation.
The Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester, UK
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Department of Diabetes and Endocrinology, Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, UK
Diabetes and Endocrinology Department, Kettering General Hospital NHS Foundation Trust, Kettering, UK
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Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
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Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
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Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
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Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
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The Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester, UK
Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
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The Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester, UK
Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
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Aims
Physical activity has been proposed to be an effective non-pharmacological method of reducing systemic inflammation and therefore may prove particularly efficacious for women with polycystic ovary syndrome (PCOS) who have been shown to have high levels of inflammation and an increased risk of type 2 diabetes (T2DM) and cardiovascular disease (CVD). Therefore, the aim of the present study was to assess whether modest changes in daily step count could significantly reduce levels of inflammatory markers in women with PCOS.
Subjects and Methods
Sixty-five women with PCOS were assessed at baseline and again at 6 months. All had been provided with an accelerometer and encouraged to increase activity levels. Multivariate linear regression analyses (adjusted for age, ethnicity, baseline step count, change in BMI and change in accelerometer wear-time) were used to assess changes in daily step count against clinical and research biomarkers of inflammation, CVD and T2DM.
Results
Mean step count/day at baseline was 6337 (±270). An increase in step count (by 1000 steps) was associated with a 13% reduction in IL6 (β: −0.81 ng/L; 95% CI, −1.37, −0.25, P = 0.005) and a 13% reduction in CRP (β: −0.68 mg/L; 95% CI, −1.30, −0.06, P = 0.033). Additionally, there was a modest decrease in BMI (β: 0.20 kg/m2; 95% CI, −0.38, −0.01, P = 0.038). Clinical markers of T2DM and CVD were not affected by increased step count.
Conclusions
Modest increases in step count/day can reduce levels of inflammatory markers in women with PCOS, which may reduce the future risk of T2DM and CVD.
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Monocyte/macrophage-specific soluble CD163 (sCD163) concentration is associated with insulin resistance and increases with deteriorating glycemic control independently of BMI. This led to the proposal of the hypothesis that obesity-associated white adipose tissue inflammation varies between individuals. The objective was to examine the effect of male overweight/obesity and type 2 diabetes mellitus (T2DM) on associations between adiposity parameters and sCD163. A total of 23 overweight/obese non-diabetic men, 16 overweight/obese men with T2DM, and a control group of 20 normal-weight healthy men were included. Body composition and regional body fat distribution were determined by whole-body dual X-ray absorptiometry scan and abdominal computed tomography (CT) scan. Serum sCD163 concentrations were determined by ELISA. Associations between adiposity parameters and sCD163 were investigated using multiple linear regression analysis. In the normal-weight healthy men, there was no significant association between adiposity parameters and sCD163, whereas in the overweight/obese non-diabetic men, measures of general and regional adiposity were positively associated with sCD163. In the overweight/obese men with T2DM, only visceral adipose tissue (VAT) and the ratio of VAT to abdominal subcutaneous adipose tissue (SAT), a measure of relative body fat distribution between VAT and SAT depots, were positively associated with sCD163. In a multivariate analysis, including VAT, upper-body SAT, and lower-body fat, adjusted for BMI and age, VAT remained a significant predictor of sCD163 in the overweight/obese T2DM men, but not in the overweight/obese non-diabetic men. Our results indicate that VAT inflammation is exaggerated in men with T2DM, and that propensity to store excess body fat viscerally is particularly detrimental in men with T2DM.
