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  • 1.
    Almén, Markus Sällman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Moschonis, George
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chrousos, George P.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Genome wide analysis reveals association of a FTO gene variant with epigenetic changes2012In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 99, no 3, p. 132-137Article in journal (Refereed)
    Abstract [en]

    Variants of the FTO gene show strong association with obesity, but the mechanisms behind this association remain unclear. We determined the genome wide DNA methylation profile in blood from 47 female preadolescents. We identified sites associated with the genes KARS, TERF2IP, DEXI, MSI1,STON1 and BCAS3 that had a significant differential methylation level in the carriers of the FTO risk allele (rs9939609). In addition, we identified 20 differentially methylated sites associated with obesity. Our findings suggest that the effect of the FTO obesity risk allele may be mediated through epigenetic changes. Further, these sites might prove to be valuable biomarkers for the understanding of obesity and its comorbidites.

  • 2.
    Alsehli, Ahmed M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Al-Sabri, Mohamed H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia2021In: Frontiers in Bioscience-Landmark, Vol. 26, no 12, p. 1453-1463Article in journal (Refereed)
    Abstract [en]

    Importance: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. Aims: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. Methods: A cross-sectional cohort study based on baseline data collected between 2006–2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. Results: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42 × 10−4). A similar effect was observed for PCSK9 rs11591147-T allele (1.07 [1.01–1.14]; 0.014), while the two gene variants of HMGCR were associated with a reduced risk for insomnia (rs17238484-G: 0.97 [0.95 to 0.99]; 0.014 and rs12916-T: 0.97 [0.96 to 0.99]; 0.002). In regard to chronotype, there was no effect of either statin treatment or HMGCR SNPs, but the PCSK9 rs11591147-T allele was associated with a higher evening preference (1.17 [1.06 to 1.29]; 0.001). Conclusion: Our data suggests that statin treatment can pose an increased risk for insomnia in in the European population. Interestingly, there was no agreement between the effects of statins and the effects of reduced HMGCR activity based on genetic variants, suggesting that the observed unfavourable effect of statins on sleep is conveyed through other targets. This further explains why the literature on statin effects on sleep is not conclusive. Finally our data encourage further investigations into the molecular processes linking statins, HMGCR and PCSK9 to sleep behaviour.

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  • 3.
    Asp, Amanda
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Bla Straket 7,POB 430, SE-40530 Gothenburg, Sweden.
    Lund, Frida
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Bla Straket 7,POB 430, SE-40530 Gothenburg, Sweden.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wasling, Pontus
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Bla Straket 7,POB 430, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Neurol, Gothenburg, Sweden.
    Impaired procedural memory in narcolepsy type 12022In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 146, no 2, p. 186-193Article in journal (Refereed)
    Abstract [en]

    Objectives Sleep enhances the consolidation of memories. Here, we investigated whether sleep-dependent memory consolidation differs between healthy subjects and narcolepsy type 1 (NT1) patients.

    Material and Methods We recruited 18 patients with NT1 and 24 healthy controls. The consolidation of spatial (declarative memory; 2-dimensional object location) and procedural (non-declarative memory; finger sequence tapping) memories was examined across one night of at-home sleep. Sleep was measured by an ambulatory sleep recording device.

    Results The overnight gain in the number of correctly recalled sequences in the finger-tapping test was smaller for NT1 patients than healthy subjects (+8.1% vs. +23.8% from pre-sleep learning to post-sleep recall, p = .035). No significant group differences were found for the overnight consolidation of spatial memory. Compared to healthy subjects, the sleep of NT1 patients was significantly more fragmented and shallow. However, no significant correlations were found between sleep parameters and overnight performance changes on the memory tests in the whole group.

    Conclusion The sleep-dependent consolidation of procedural but not spatial memories may be impaired among patients with NT1. Therefore, future studies are warranted to examine whether sleep improvement, for example, using sodium oxybate, can aid the sleep-dependent formation of procedural memories among NT1 patients.

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  • 4.
    Baldanzi, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sayols-Baixeras, Sergi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. CIBER Cardiovascular Diseases (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Dekkers, Koen F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hammar, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nguyen, Diem
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lin, Yi-Ting
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Division of Family Medicine and Primary Care, Department of Neurobiology, Care Science and Society, Karolinska Institute, Huddinge, Sweden; Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Taiwan.
    Ahmad, Shafqat
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Preventive Medicine Division, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA.
    Bak Holm, Jacob
    Nielsen, Henrik Bjørn
    Brunkwall, Louise
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Koskiniemi, Sanna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology and Immunology.
    Phillipson, Mia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology. The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
    Bergström, Göran
    Engström, Gunnar
    Smith, J. Gustav
    Orho-Melander, Marju
    Ärnlöv, Johan
    Kennedy, Beatrice
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    OSA Is Associated With the Human Gut Microbiota Composition and Functional Potential in the Population-Based Swedish CardioPulmonary bioImage Study2023In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 164, no 2, p. 503-516Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep-breathing disorder linked to increased risk of cardiovascular disease. Intermittent hypoxia and intermittent airway obstruction, hallmarks of OSA, have been shown in animal models to induce substantial changes to the gut microbiota composition and subsequent transplantation of fecal matter to other animals induced changes in blood pressure and glucose metabolism.

    RESEARCH QUESTION: Does obstructive sleep apnea in adults associate with the composition and metabolic potential of the human gut microbiota?

    STUDY DESIGN AND METHODS: We used respiratory polygraphy data from up to 3,570 individuals aged 50-64 from the population-based Swedish CardioPulmonary bioImage Study combined with deep shotgun metagenomics of fecal samples to identify cross-sectional associations between three OSA parameters covering apneas and hypopneas, cumulative sleep time in hypoxia and number of oxygen desaturation events with gut microbiota composition. Data collection about potential confounders was based on questionnaires, on-site anthropometric measurements, plasma metabolomics, and linkage with the Swedish Prescribed Drug Register.

    RESULTS: We found that all three OSA parameters were associated with lower diversity of species in the gut. Further, the OSA-related hypoxia parameters were in multivariable-adjusted analysis associated with the relative abundance of 128 gut bacterial species, including higher abundance of Blautia obeum and Collinsela aerofaciens. The latter species was also independently associated with increased systolic blood pressure. Further, the cumulative time in hypoxia during sleep was associated with the abundance of genes involved in nine gut microbiota metabolic pathways, including propionate production from lactate. Lastly, we observed two heterogeneous sets of plasma metabolites with opposite association with species positively and negatively associated with hypoxia parameters, respectively.

    INTERPRETATION: OSA-related hypoxia, but not the number of apneas/hypopneas, is associated with specific gut microbiota species and functions. Our findings lay the foundation for future research on the gut microbiota-mediated health effects of OSA.

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  • 5.
    Bandstein, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schultes, Bernd
    eSwiss Med & Surg Ctr, Interdisciplinary Obes Ctr, St Gallen, Switzerland..
    Ernst, Barbara
    eSwiss Med & Surg Ctr, Interdisciplinary Obes Ctr, St Gallen, Switzerland..
    Thurnheer, Martin
    eSwiss Med & Surg Ctr, Interdisciplinary Obes Ctr, St Gallen, Switzerland..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The Role of FTO and Vitamin D for the Weight Loss Effect of Roux-en-Y Gastric Bypass Surgery in Obese Patients2015In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 25, no 11, p. 2071-2077Article in journal (Refereed)
    Abstract [en]

    A recent study in children demonstrated that the rs9939609 single-nucleotide polymorphism in the fat mass and obesity (FTO) gene influences prospective weight gain, however, only in those who were vitamin D-deficient. If this might also be the case for Roux-en-Y gastric bypass (RYGB), surgery-induced weight loss is however unknown. The objective of this study is to examine if the magnitude of RYGB surgery-induced weight loss after 2 years depends on patients' FTO rs9939609 genotype (i.e., TT, AT, and AA) and presurgery vitamin D status (< 50 nmol/L equals deficiency). Before and at 24 months after RYGB surgery, BMI was measured in 210 obese patients (mean BMI 45 kg/m(2), 72 % females). Serum 25-hydroxyvitamin D3 levels were also repeatedly measured. Following surgery, vitamin D was supplemented. Possible weight loss differences between genotypes were tested with multiple linear regressions. The per-allele effect of each FTO A-allele on excessive BMI loss (EBMIL) was 3 % (P = 0.02). When split by baseline status, the EBMIL of vitamin D-deficient patients carrying AA exceeded that of vitamin D-deficient patients carrying TT by similar to 14 % (P = 0.03). No such genotypic differences were found in patients without presurgery vitamin D deficiency. Post-surgery serum levels of vitamin D did not differ between groups. Our data suggest that presurgery vitamin D levels influence the size of genotype effects of FTO rs9939609 on RYGB surgery-induced weight loss in obese patients.

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  • 6.
    Bandstein, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Voisin, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schultes, Bernd
    eSwiss Medical & Surgical Center, Interdisciplinary Obesity Center, St. Gallen, Switzerland.
    Ernst, Barbara
    eSwiss Medical & Surgical Center, Interdisciplinary Obesity Center, St. Gallen, Switzerland.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A genetic risk score is associated with weight loss following Roux-Y gastric bypass surgery2016In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 26, no 9, p. 2183-2189Article in journal (Refereed)
    Abstract [en]

    Currently, Roux-en Y gastric bypass (RYGB) is the most efficient therapy for severe obesity. Weight loss after surgery is, however, highly variable and genetically influenced. Genome-wide association studies have identified several single nucleotide polymorphisms (SNP) associated with body mass index (BMI) and waist-hip ratio (WHR). We aimed to identify two genetic risk scores (GRS) composed of weighted BMI and WHR-associated SNPs to estimate their impact on excess BMI loss (EBMIL) after RYGB surgery. Two hundred and thirty-eight obese patients (BMI 45.1 +/- 6.2 kg/m(2), 74 % women), who underwent RYGB, were genotyped for 35 BMI and WHR-associated SNPs and were followed up after 2 years. SNPs with high impact on post-surgical weight loss were filtered out using a random forest model. The filtered SNPs were combined into a GRS and analyzed in a linear regression model. An up to 11 % lower EBMIL with higher risk score was estimated for two GRS models (P = 0.026 resp. P = 0.021) composed of seven BMI-associated SNPs (closest genes: MC4R, TMEM160, PTBP2, NUDT3, TFAP2B, ZNF608, MAP2K5, GNPDA2, and MTCH2) and of three WHR-associated SNPs (closest genes: HOXC13, LYPLAL1, and DNM3-PIGC). Patients within the lowest GRS quartile had higher EBMIL compared to patients within the other three quartiles in both models. We identified two GRSs composed of BMI and WHR-associated SNPs with significant impact on weight loss after RYGB surgery using random forest analysis as a SNP selection tool. The GRS may be useful to pre-surgically evaluate the risks for patients undergoing RYGB surgery.

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  • 7.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Acute Effects of Coffee Consumption.2023In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 388, no 22, p. 2105-, article id 2105Article in journal (Refereed)
  • 8.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Antihypertensive medication prior to nocturnal sleep reduces the risk of new-onset type 2 diabetes in hypertensive patients: a role for slow-wave sleep?2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 2, p. 390-391Article in journal (Refereed)
  • 9.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Interindividual Variance in Adult Hippocampal Neurogenesis: A Matter of Lifestyle?2013In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 23, no 12, p. 1484-1485Article in journal (Refereed)
  • 10.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Link Between Short Sleep and Obesity in Humans A Matter of Age?2013In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 144, no 2, p. 711-711Article in journal (Refereed)
  • 11.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Söderberg, Stefan
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The fat mass and obesity-associated gene (FTO) is linked to higher plasma levels of the hunger hormone ghrelin and lower serum levels of the satiety hormone leptin in older adults2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 11, p. 3955-3959Article in journal (Refereed)
    Abstract [en]

    The mechanisms through which common polymorphisms in the fat mass and obesity-associated gene (FTO) drive the development of obesity in humans are poorly understood. By using C: ross-sectional data from 985 elderly (50% females) who participated at age 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors, circulating levels of ghrelin and leptin were measured after an overnight fast. In addition, subjects were genotyped for FTO rs17817449 (AA, n=345 (35%); AC/CA, n=481 (48.8%); CC, n=159 (16.1%). Linear regression analyses controlling for sex, self-reported physical activity level, fasting plasma glucose, and body mass index were utilized. A positive relationship between the number of FTO C risk alleles and plasma ghrelin levels was found (P=0.005; relative plasma ghrelin difference between CC and AA carriers = ∼9%). In contrast, serum levels of the satiety enhancing hormone leptin were inversely linked to the number of FTO C risk alleles (P=0.001; relative serum leptin difference between CC and AA carriers = ∼11%). These associations were also found when controlling for waist circumference. The present findings suggest that FTO may facilitate weight gain in humans by shifting the endocrine balance from the satiety hormone leptin toward the hunger promoting hormone ghrelin.

  • 12.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Barclay, J. L.
    Ott, V.
    Oster, H.
    Hallschmid, M.
    Acute sleep deprivation delays the glucagon-like peptide 1 peak response to breakfast in healthy men2013In: Nutrition & Diabetes, ISSN 2044-4052, E-ISSN 2044-4052, Vol. 3, p. e78-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Previous experiments have demonstrated that acute sleep loss impairs glucose homeostasis and increases food intake in humans. The incretin hormone glucagon-like peptide 1 (GLP-1) enhances postprandial insulin secretion and promotes satiety. Hypothesizing that the detrimental metabolic effects of sleep curtailment imply alterations in GLP-1 signaling, we investigated 24-h serum total GLP-1 concentrations during total sleep deprivation (TSD) and a normal sleep/wake cycle (comprising similar to 8h of sleep) in 12 healthy young men. METHODS: Sessions started at 1800 h, and subjects were provided with standardized meals. Assessments of serum GLP-1 took place in 1.5- to 3-h intervals, focusing on the response to breakfast intake (3.8 MJ). RESULTS: Across conditions, 24-h concentration profiles of GLP-1 were characterized by the expected postprandial increases (P<0.001). Although there were no differences in magnitude between conditions (P>0.11), the postprandial GLP-1 peak response to breakfast intake was delayed by similar to 90 min following sleep loss in comparison with regular sleep (P<0.02). CONCLUSIONS: Results indicate that acute TSD exerts a mild, but discernible effect on the postprandial dynamics of circulating GLP-1 concentrations in healthy men.

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  • 13.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Blennow, Kaj
    Sahlgrens Univ Hosp, Clin Neurochem Lab, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden..
    Zetterberg, Henrik
    Sahlgrens Univ Hosp, Clin Neurochem Lab, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden.;UCL Inst Neurol, Dept Neurodegenerat Dis, London, England.;UCL, UK Dementia Res Inst, London, England..
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Effects of acute sleep loss on diurnal plasma dynamics of CNS health biomarkers in young men2020In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 94, no 11, p. E1181-E1189Article in journal (Refereed)
    Abstract [en]

    Objective: Disrupted sleep increases CSF levels of tau and beta -amyloid (A beta) and is associated with an increased risk of Alzheimer disease (AD). Our aim was to determine whether acute sleep loss alters diurnal profiles of plasma-based AD-associated biomarkers.

    Methods: In a 2-condition crossover study, 15 healthy young men participated in 2 standardized sedentary in-laboratory conditions in randomized order: normal sleep vs overnight sleep loss. Plasma levels of total tau (t-tau), A beta 40, A beta 42, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using ultrasensitive single molecule array assays or ELISAs, in the fasted state in the evening prior to, and in the morning after, each intervention.

    Results: In response to sleep loss (+17.2%), compared with normal sleep (+1.8%), the evening to morning ratio was increased for t-tau (p = 0.035). No changes between the sleep conditions were seen for levels of A beta 40, A beta 42, NfL, or GFAP (all p > 0.10). The AD risk genotype rs4420638 did not significantly interact with sleep loss-related diurnal changes in plasma levels of A beta 40 or A beta 42 (p > 0.10). Plasma levels of A beta 42 (-17.1%) and GFAP (-12.1%) exhibited an evening to morning decrease across conditions (p < 0.05).

    Conclusions: Our exploratory study suggests that acute sleep loss results in increased blood levels of t-tau. These changes provide further evidence that sleep loss may have detrimental effects on brain health even in younger individuals. Larger cohorts are warranted to delineate sleep vs circadian mechanisms, implications for long-term recurrent conditions (e.g., in shift workers), as well as interactions with other lifestyle and genetic factors.

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  • 14.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brede, Swantje
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lehnert, Hendrik
    Schultes, Bernd
    Born, Jan
    Hallschmid, Manfred
    Intranasal Insulin Enhances Postprandial Thermogenesis and Lowers Postprandial Serum Insulin Levels in Healthy Men2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 1, p. 114-118Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

     Animal studies indicate a prominent role of brain insulin signaling in the regulation of peripheral energy metabolism. We determined the effect of intranasal insulin, which directly targets the brain, on glucose metabolism and energy expenditure in humans.

    RESEARCH DESIGN AND METHODS

    In a double-blind, placebo-controlled, balanced within-subject comparison, 19 healthy normal-weight men (18-26 years old) were intranasally administered 160 IU human insulin after an overnight fast. Energy expenditure assessed via indirect calorimetry and blood concentrations of glucose, insulin, C-peptide, and free fatty acids (FFAs) were measured before and after insulin administration and the subsequent consumption of a high-calorie liquid meal of 900 kcal.

    RESULTS

    Intranasal insulin, compared with placebo, increased postprandial energy expenditure, i.e., diet-induced thermogenesis, and decreased postprandial concentrations of circulating insulin and C-peptide, whereas postprandial plasma glucose concentrations did not differ from placebo values. Intranasal insulin also induced a transient decrease in prandial serum FFA levels.

    CONCLUSIONS

    Enhancing brain insulin signaling by means of intranasal insulin administration enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that central nervous insulin contributes to the control of whole-body energy homeostasis in humans.

  • 15.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Burgos, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kempton, Matthew J
    Nordenskjöld, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nylander, Ruta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Craft, Suzanne
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Impaired Insulin Sensitivity as Indexed by the HOMA Score Is Associated With Deficits in Verbal Fluency and Temporal Lobe Gray Matter Volume in the Elderly2012In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 35, no 3, p. 488-494Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    Impaired insulin sensitivity is linked to cognitive deficits and reduced brain size. However, it is not yet known whether insulin sensitivity involves regional changes in gray matter volume. Against this background, we examined the association between insulin sensitivity, cognitive performance, and regional gray matter volume in 285 cognitively healthy elderly men and women aged 75 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

    RESEARCH DESIGN AND METHODS

    Insulin sensitivity was calculated from fasting serum insulin and plasma glucose determinations using the homeostasis model assessment of insulin resistance (HOMA-IR) method. Cognitive performance was examined by a categorical verbal fluency. Participants also underwent a magnetic resonance imaging (MRI) brain scan. Multivariate analysis using linear regression was conducted, controlling for potential confounders (sex, education, serum LDL cholesterol, mean arterial blood pressure, and abdominal visceral fat volume).

    RESULTS

    The HOMA-IR was negatively correlated with verbal fluency performance, brain size (S1), and temporal lobe gray matter volume in regions known to be involved in speech production (Brodmann areas 21 and 22, respectively). No such effects were observed when examining diabetic (n = 55) and cognitively impaired (n = 27) elderly subjects as separate analyses.

    CONCLUSIONS

    These cross-sectional findings suggest that both pharmacologic and lifestyle interventions improving insulin signaling may promote brain health in late life but must be confirmed in patient studies.

  • 16.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nordenskjöld, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Burgos, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Le Grevès, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Association between physical activity and brain health in older adults2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 1, p. 83-90Article in journal (Refereed)
    Abstract [en]

    In the present cross-sectional study, we examined physical activity (PA) and its possible association with cognitive skills and brain structure in 331 cognitively healthy elderly. Based on the number of self-reported light and hard activities for at least 30 minutes per week, participants were assigned to 4 groups representing different levels of PA. The cognitive skills were assessed by the Mini Mental State Examination score, a verbal fluency task, and the Trail-making test as a measure of visuospatial orientation ability. Participants also underwent a magnetic resonance imaging of the brain. Multiple regression analysis revealed that greater PA was associated with a shorter time to complete the Trail-making test, and higher levels of verbal fluency. Further, the level of self-reported PA was positively correlated with brain volume, white matter, as well as a parietal lobe gray matter volume, situated bilaterally at the precuneus. These present cross-sectional results indicate that PA is a lifestyle factor that is linked to brain structure and function in late life.

  • 17.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    O'Daly, Owen G
    Almèn, Markus S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Morell, Arvid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Åberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Gingnell, Malin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Schultes, Bernd
    Hallschmid, Manfred
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute Sleep Deprivation Enhances the Brain's Response to Hedonic Food Stimuli: An fMRI Study2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 3, p. E443-447Article in journal (Refereed)
    Abstract [en]

    Context:

    There is growing recognition that a large number of individuals living in Western society are chronically sleep deprived. Sleep deprivation is associated with an increase in food consumption and appetite. However, the brain regions that are most susceptible to sleep deprivation-induced changes when processing food stimuli are unknown.

    Objective:

    Our objective was to examine brain activation after sleep and sleep deprivation in response to images of food.

    Intervention:

    Twelve normal-weight male subjects were examined on two sessions in a counterbalanced fashion: after one night of total sleep deprivation and one night of sleep. On the morning after either total sleep deprivation or sleep, neural activation was measured by functional magnetic resonance imaging in a block design alternating between high- and low-calorie food items. Hunger ratings and morning fasting plasma glucose concentrations were assessed before the scan, as were appetite ratings in response to food images after the scan.

    Main Outcome Measures:

    Compared with sleep, total sleep deprivation was associated with an increased activation in the right anterior cingulate cortex in response to food images, independent of calorie content and prescan hunger ratings. Relative to the postsleep condition, in the total sleep deprivation condition, the activation in the anterior cingulate cortex evoked by foods correlated positively with postscan subjective appetite ratings. Self-reported hunger after the nocturnal vigil was enhanced, but importantly, no change in fasting plasma glucose concentration was found.

    Conclusions:

    These results provide evidence that acute sleep loss enhances hedonic stimulus processing in the brain underlying the drive to consume food, independent of plasma glucose levels. These findings highlight a potentially important mechanism contributing to the growing levels of obesity in Western society.

  • 18.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brytting, Maria
    Markström, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute sleep deprivation has no lasting effects on the human antibody titer response following a novel influenza A H1N1 virus vaccination2012In: BMC Immunology, E-ISSN 1471-2172, Vol. 13, p. 1-Article in journal (Refereed)
    Abstract [en]

    Background: Experimental studies in humans have yielded evidence that adaptive immune function, including the production of antigen-specific antibodies, is distinctly impaired when sleep is deprived at the time of first antigen exposure. Here we examined the effects of a regular 24- hour sleep-wake cycle (including 8 hours of nocturnal sleep) and a 24-hour period of continuous wakefulness on the 7 week antibody production in 11 males and 13 females in response to the H1N1 (swine flu) virus vaccination. The specific antibody titer in serum was assayed by the hemagglutination inhibition test on the days 5, 10, 17, and 52 following vaccination.

    Results: In comparison to the sleep group, sleep-deprived males but not females had reduced serum concentration of H1N1-specific antibodies five days after vaccination, whereas antibody titers at later time points did not differ between the conditions.

    Conclusions: These findings concur with the notion that sleep is a supportive influence in the very early stage of an adaptive immune response to a viral antigen. However, our results do not support the view that acute sleep deprivation has lasting effects on the human antibody titer response to influenza vaccination.

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  • 19.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hogenkamp, Pleunie S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Giedratis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Self-reported sleep disturbance is associated with Alzheimer's disease risk in men2015In: Alzheimer's & Dementia: Journal of the Alzheimer's Association, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 9, p. 1090-1097Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the association between self-reported sleep disturbances and dementia risk.

    METHODS: Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of β-amyloid (Aβ) peptides 1-40 and 1-42 were measured at ages 70, 77, and 82 years.

    RESULTS: Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P < .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P < .001). No group differences were found in Aβ levels.

    CONCLUSION: Improving sleep quality may help reduce the neurodegenerative risk in older men.

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  • 20.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Could a good night's sleep improve COVID-19 vaccine efficacy?2021In: The Lancet Respiratory Medicine, ISSN 2213-2600, E-ISSN 2213-2619, Vol. 9, no 5, p. 447-448Article in journal (Other academic)
  • 21.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nilsson, Emil K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hogenkamp, Pleunie S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Massena, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pettersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zetterberg, Henrik
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute sleep deprivation increases serum levels of neuron-specific enolase (NSE) and S100 calcium binding protein B (S-100B) in healthy young men2014In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 37, no 1, p. 195-198Article in journal (Refereed)
    Abstract [en]

    STUDY OBJECTIVES:

    To investigate whether total sleep deprivation (TSD) affects circulating concentrations of neuron-specific enolase (NSE) and S100 calcium binding protein B (S-100B) in humans. These factors are usually found in the cytoplasm of neurons and glia cells. Increasing concentrations of these factors in blood may be therefore indicative for either neuronal damage, impaired blood brain barrier function, or both. In addition, amyloid β (Aβ) peptides 1-42 and 1-40 were measured in plasma to calculate their ratio. A reduced plasma ratio of Aβ peptides 1-42 to 1-40 is considered an indirect measure of increased deposition of Aβ 1-42 peptide in the brain.

    DESIGN:

    Subjects participated in two conditions (including either 8-h of nocturnal sleep [22:30-06:30] or TSD). Fasting blood samples were drawn before and after sleep interventions (19:30 and 07:30, respectively).

    SETTING:

    Sleep laboratory.

    PARTICIPANTS:

    15 healthy young men.

    RESULTS:

    TSD increased morning serum levels of NSE (P = 0.002) and S-100B (P = 0.02) by approximately 20%, compared with values obtained after a night of sleep. In contrast, the ratio of Aβ peptides 1-42 to 1-40 did not differ between the sleep interventions.

    CONCLUSIONS:

    Future studies in which both serum and cerebrospinal fluid are sampled after sleep loss should elucidate whether the increase in serum neuron-specific enolase and S100 calcium binding protein B is primarily caused by neuronal damage, impaired blood brain barrier function, or is just a consequence of increased gene expression in non-neuronal cells, such as leukocytes.

  • 22.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Chapman, Colin D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Growth Hormone-Releasing Hormone Improves Cognitive Function in Older Adults: Sleep On It2013In: JAMA neurology, ISSN 2168-6157, Vol. 70, no 4, p. 529-530Article in journal (Refereed)
  • 23.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Franklin, Karl A
    Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Sweden.
    Bukhari, Shervin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ljunggren, Mirjam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Sex-specific association of the lunar cycle with sleep2022In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 804, article id 150222Article in journal (Refereed)
    Abstract [en]

    Using one-night sleep recordings from 852 subjects all living in Uppsala, Sweden, the present study represents one of the largest polysomnography investigations into the association of the 29.53-day long lunar cycle with sleep among men and women and across a wide age range (22-81 years). Following the day after the new moon until the day of the full moon (also named the waxing period), the moon's illumination increases, and the timing of the meridian of the moon is gradually shifted from noontime toward midnight. In contrast, from the day after the full moon until the day of the new moon (also named the waning period), the moon's illumination decreases, and the timing of the meridian of the moon is gradually shifted from early night hours toward noontime. Thus, we focused on the contrast between the waxing and waning periods. Sleep duration was shorter on nights during the waxing period as compared to waning period (P < 0.001). In addition, a significant interaction effect of participants' sex with the lunar period on sleep was noted (P < 0.05). Men, but not women, exhibited lower sleep efficiency (P < 0.001 and P = 0.748, respectively) and were longer awake after sleep onset (P = 0.010 and P = 0.890, respectively) on nights during the waxing period. All associations were robust to adjustment for confounders (including regular sleep disturbances). Our findings suggest that the effects of the lunar cycle on human sleep are more pronounced among men. Based on the cross-sectional design of the study, no firm conclusions can be drawn on the causality of the relations.

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  • 24.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Frey, William H., II
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schultes, Bernd
    Born, Jan
    Hallschmid, Manfred
    Intranasal insulin as a therapeutic option in the treatment of cognitive impairments2011In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 46, no 2-3, p. 112-115Article in journal (Refereed)
    Abstract [en]

    The brain is a major target of circulating insulin. Enhancing central nervous insulin action has been shown to improve memory functions in animals as well as in humans, benefitting in particular hippocampus-dependent (declarative) memory. As Alzheimer's disease (AD) is associated with reduced central nervous insulin signaling and attenuated permeation of blood-borne insulin across the blood-brain-barrier, the cognitive decline in AD patients may at least in part be derived from impaired brain insulin signaling. Thus, therapeutic strategies to overcome central nervous system insulin deficiency and resistance might be an attractive option in the treatment of cognitive impairments like AD. Insulin can be effectively delivered directly to the brain via the intranasal route that enables the hormone to bypass the blood-brain barrier and modulate central nervous functions. This review summarizes a series of studies demonstrating beneficial effects of intranasal insulin on memory functions both in healthy humans and in patients with cognitive impairments such as AD. These experiments in humans consistently indicate that enhancing brain insulin signaling by intranasal administration of the hormone improves hippocampus-dependent memory in the absence of adverse side effects. Considering that insulin also acts as a neuroprotective signal, up-regulating brain insulin levels by intranasal insulin administration appears to be a promising approach in the treatment and prevention of central nervous system insulin deficiency and resistance as found in AD.

  • 25.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Grillo, Claudia A.
    Univ South Carolina, Sch Med, Dept Pharmacol Physiol & Neurosci, Columbia, SC 29208 USA..
    Insulin Resistance as a Therapeutic Target in the Treatment of Alzheimer's Disease: A State-of-the-Art Review2018In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 12, article id 215Article, review/survey (Refereed)
    Abstract [en]

    Research in animals and humans has shown that type 2 diabetes and its prodromal state, insulin resistance, promote major pathological hallmarks of Alzheimer's disease (AD), such as the formation of amyloid plaques and neurofibrillary tangles (NFT). Worrisomely, dysregulated amyloid beta (A beta) metabolism has also been shown to promote central nervous system insulin resistance; although the role of tau metabolism remains controversial. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted insulin signaling. They also provide strong support for the hypothesis that pharmacologically restoring brain insulin signaling could represent a promising strategy to curb the development and progression of AD. In this context, great hopes have been attached to the use of intranasal insulin. This drug delivery method increases cerebrospinal fluid concentrations of insulin in the absence of peripheral side effects, such as hypoglycemia. With this in mind, the present review will also summarize current knowledge on the efficacy of intranasal insulin to mitigate major pathological symptoms of AD, i.e., cognitive impairment and deregulation of A beta and tau metabolism.

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  • 26.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hallschmid, Manfred
    Lassen, Arne
    Mahnke, Christin
    Schultes, Bernd
    Schiöth, Helgi Birgir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Born, Jan
    Lange, Tanja
    Acute sleep deprivation reduces energy expenditure in healthy men2011In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 93, no 6, p. 1229-1236Article in journal (Refereed)
    Abstract [en]

    Background

    Epidemiologic evidence indicates that chronic sleep curtailment increases risk of developing obesity, but the mechanisms behind this relation are largely unknown.

    Objective

    We examined the influence of a single night of total sleep deprivation on morning energy expenditures and food intakes in healthy humans.

    Design

    According to a balanced crossover design, we examined 14 normal-weight male subjects on 2 occasions during a regular 24-h sleep-wake cycle (including 8 h of nocturnal sleep) and a 24-h period of continuous wakefulness. On the morning after regular sleep and total sleep deprivation, resting and postprandial energy expenditures were assessed by indirect calorimetry, and the free-choice food intake from an opulent buffet was tested in the late afternoon at the end of the experiment. Circulating concentrations of ghrelin, leptin, norepinephrine, cortisol, thyreotropin, glucose, and insulin were repeatedly measured over the entire 24-h session.

    Results

    In comparison with normal sleep, resting and postprandial energy expenditures assessed on the subsequent morning were significantly reduced after sleep deprivation by approximate to 5% and 20%, respectively (P < 0.05 and P < 0.0001). Nocturnal wakefulness increased morning plasma ghrelin concentrations (P < 0.02) and nocturnal and daytime circulating concentrations of thyreotropin, cortisol, and norepinephrine (P < 0.05) as well as morning postprandial plasma glucose concentrations (P < 0.05). Changes in food intakes were variable, and no differences between wake and sleep conditions were detected.

    Conclusion

    Our findings show that one night of sleep deprivation acutely reduces energy expenditure in healthy men, which suggests that sleep contributes to the acute regulation of daytime energy expenditure in humans.

  • 27.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rönnemaa, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schultes, Bernd
    Interdisciplinary Obesity Center, Kantonsspital St. Gallen.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 6, p. 1159.e1-1159.e5Article in journal (Refereed)
    Abstract [en]

    Humans carrying the prevalent rs9939609 A allele of the fat mass and obesity-associated (FTO) gene are more susceptible to developing obesity than noncarries. Recently, polymorphisms in the FTO gene of elderly subjects have also been linked to a reduced volume in the frontal lobe as well as increased risk for incident Alzheimer disease. However, so far there is no evidence directly linking the FTO gene to functional cognitive processes. Here we examined whether the FTO rs9939609 A allele is associated with verbal fluency performance in 355 elderly men at the age of 82 years who have no clinically apparent cognitive impairment. Retrieval of verbal memory is a good surrogate measure reflecting frontal lobe functioning. Here we found that obese and overweight but not normal weight FTO A allele carriers showed a lower performance on verbal fluency than non-carriers (homozygous for rs9939609 T allele). This effect was not observed for a measure of general cognitive performance (i.e., Mini-Mental State Examination score), thereby indicating that the FTO gene primarily affects frontal lobe-dependent cognitive processes in elderly men.

  • 28.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Mateus Brandao, Luiz Eduardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Merikanto, Ilona
    Department of Public Health Solutions, Finnish Institute for Health and Welfare, 00271 Helsinki, Finland; Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, 00100 Helsinki, Finland; Orton Orthopaedics Hospital, 00280 Helsinki, Finland.
    Partinen, Markku
    Helsinki Sleep Clinic, Vitalmed Research Center, 00420 Helsinki, Finland; Department of Neurosciences, Clinicum, University of Helsinki, 00100 Helsinki, Finland.
    Bjorvatn, Bjørn
    Department of Global Public Health and Primary Care, University of Bergen, 5009 Bergen, Norway; Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, 5021 Bergen, Norway.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
    Meal and Sleep Timing before and during the COVID-19 Pandemic: A Cross-Sectional Anonymous Survey Study from Sweden2021In: Clocks & Sleep, E-ISSN 2624-5175, Vol. 3, no 2, p. 251-258Article in journal (Refereed)
    Abstract [en]

    The COVID-19 pandemic and related restrictions, such as stay-at-home-orders, have significantly altered daily routines and lifestyles. Given their importance for metabolic health, we herein compared sleep and meal timing parameters during vs. before the COVID-19 pandemic based on subjective recall, in an anonymous Swedish survey. Among 191 adults (mean age: 47 years; 77.5% females), we show that social jetlag, i.e., the mismatch in sleep midpoint between work and free days, was reduced by about 17 min during the pandemic compared with the pre-pandemic state (p < 0.001). Concomitantly, respondents' sleep midpoint was shifted toward morning hours during workdays (p < 0.001). A later daily eating midpoint accompanied the shift in sleep timing (p = 0.001). This effect was mainly driven by a later scheduled first meal (p < 0.001). No difference in the timing of the day's last meal was found (p = 0.814). Although our survey was limited in terms of sample size and by being cross-sectional, our results suggest that the delay in sleep timing due to the COVID-19 pandemic was accompanied by a corresponding shift in the timing of early but not late meals.

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  • 29.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Partinen, Markku
    University of Helsinki, Helsinki, Finland.
    Bjorvatn, Bjørn
    University of Bergen, Bergen, Norway; Haukeland University Hospital, Bergen, Norway.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Northwestern University, Chicago, Illinois.
    Sleep in Female Healthcare Workers during COVID-19: A Cross-sectional Survey Study in Sweden during the Flattening of the First Wave of the Pandemic2021In: Annals of the American Thoracic Society, ISSN 2329-6933, E-ISSN 2325-6621, Vol. 18, no 8, p. 1418-1420Article in journal (Other academic)
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  • 30.
    Benedict, Christian
    et al.
    Department of Neuroendocrinology, University of Lübeck, Lübeck, Germany.
    Scheller, Jürgen
    Rose-John, Stefan
    Born, Jan
    Marshall, Lisa
    Enhancing influence of intranasal interleukin-6 on slow-wave activity and memory consolidation during sleep2009In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, no 10, p. 3629-3636Article in journal (Refereed)
    Abstract [en]

    The cytokine IL-6 has been considered to exert neuromodulating influences on the brain, with promoting influences on sleep. Sleep enhances the consolidation of memories, and, in particular, late nocturnal sleep also represents a period of enhanced IL-6 signaling, due to a distinctly enhanced availability of soluble IL-6 receptors during this period, enabling trans-signaling of IL-6 to neurons. Thus, a contribution of IL-6 to sleep-dependent memory consolidation is hypothesized. To test this hypothesis, we compared effects of intranasally administered IL-6 (vs. placebo) on sleep-dependent consolidation of declarative (neutral and emotional texts, 2-dimensional object location) and procedural (finger sequence tapping) memories in 17 healthy young men. IL-6 distinctly improved the sleep-related consolidation of emotional text material (P<0.03), which benefits mostly from sleep in the second night-half, in which rapid eye movement sleep (REM) dominates the non-REM-REM sleep cycle. During this second night-half, the amount of electroencephalogram slow-wave activity (0.5-4 Hz) distinctly increased after IL-6 (P<0.01). Other types of memory were not affected. The ability of IL-6 to enhance sleep-associated emotional memory consolidation highlights an example of a functional interaction between the central nervous and immune system.

  • 31.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Television Watching and Effects on Food Intake: Distress vs Eustress2015In: JAMA Internal Medicine, ISSN 2168-6106, E-ISSN 2168-6114, Vol. 175, no 3, p. 468-468Article in journal (Refereed)
  • 32.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Shostak, Anton
    Lange, Tanja
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schultes, Bernd
    Born, Jan
    Oster, Henrik
    Hallschmid, Manfred
    Diurnal Rhythm of Circulating Nicotinamide Phosphoribosyltransferase (Nampt/Visfatin/PBEF): Impact of Sleep Loss and Relation to Glucose Metabolism2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 2, p. E218-E222Article in journal (Refereed)
    Abstract [en]

    Context

     Animal studies indicate that nicotinamide phosphoribosyltransferase [Nampt/visfatin/pre-B-cell colony-enhancing factor (PBEF)] contributes to the circadian fine-tuning of metabolic turnover. However, it is unknown whether circulating Nampt concentrations, which are elevated in type 2 diabetes and obesity, display a diurnal rhythm in humans.

    Objective

     Our objective was to examine the 24-h profile of serum Nampt in humans under conditions of sleep and sleep deprivation and relate the Nampt pattern to morning postprandial glucose metabolism.

    Intervention

    Fourteen healthy men participated in two 24-h sessions starting at 1800 h, including either regular 8-h-night sleep or continuous wakefulness. Serum Nampt and leptin were measured in 1.5- to 3-h intervals. In the morning, plasma glucose and serum insulin responses to standardized breakfast intake were determined.

    Main Outcome Measures

     Under regular sleep-wake conditions, Nampt levels displayed a pronounced diurnal rhythm, peaking during early afternoon (P < 0.001) that was inverse to leptin profiles peaking in the early night. When subjects stayed awake, the Nampt rhythm was preserved but phase advanced by about 2 h (P < 0.05). Two-hour postprandial plasma glucose concentrations were elevated after sleep loss (P < 0.05), whereas serum insulin was not affected. The relative glucose increase due to sleep loss displayed a positive association with the magnitude of the Nampt phase shift (r = 0.54; P < 0.05).

    Conclusions

    Serum Nampt concentrations follow a diurnal rhythm, peaking in the afternoon. Sleep loss induces a Nampt rhythm phase shift that is positively related to the impairment of postprandial glucose metabolism due to sleep deprivation, suggesting a regulatory impact of Nampt rhythmicity on glucose homeostasis.

  • 33.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vogel, Heike
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Jonas, Wenke
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Woting, Anni
    German Inst Human Nutr Potsdam Rehbrucke, Dept Gastrointestinal Microbiol, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany..
    Blaut, Michael
    German Inst Human Nutr Potsdam Rehbrucke, Dept Gastrointestinal Microbiol, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany..
    Schuermann, Annette
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gut microbiota and glucometabolic alterations in response to recurrent partial sleep deprivation in normal-weight young individuals2016In: Molecular Metabolism, ISSN 2212-8778, Vol. 5, no 12, p. 1175-1186Article in journal (Refereed)
    Abstract [en]

    Objective: Changes to the microbial community in the human gut have been proposed to promote metabolic disturbances that also occur after short periods of sleep loss (including insulin resistance). However, whether sleep loss affects the gut microbiota remains unknown. Methods: In a randomized within-subject crossover study utilizing a standardized in-lab protocol (with fixed meal times and exercise schedules), we studied nine normal-weight men at two occasions: after two nights of partial sleep deprivation (PSD; sleep opportunity 02: 45-07: 00 h), and after two nights of normal sleep (NS; sleep opportunity 22: 30-07: 00 h). Fecal samples were collected within 24 h before, and after two in-lab nights, of either NS or PSD. In addition, participants underwent an oral glucose tolerance test following each sleep intervention. Results: Microbiota composition analysis (V4 16S rRNA gene sequencing) revealed that after two days of PSD vs. after two days of NS, individuals exhibited an increased Firmicutes: Bacteroidetes ratio, higher abundances of the families Coriobacteriaceae and Erysipelotrichaceae, and lower abundance of Tenericutes (all P < 0.05) - previously all associated with metabolic perturbations in animal or human models. However, no PSD vs. NS effect on beta diversity or on fecal short-chain fatty acid concentrations was found. Fasting and postprandial insulin sensitivity decreased after PSD vs. NS (all P < 0.05). Discussion: Our findings demonstrate that short-term sleep loss induces subtle effects on human microbiota. To what extent the observed changes to the microbial community contribute to metabolic consequences of sleep loss warrants further investigations in larger and more prolonged sleep studies, to also assess how sleep loss impacts the microbiota in individuals who already are metabolically compromised. (C) 2016 The Author(s). Published by Elsevier GmbH.

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  • 34.
    Benjamins, Jeroen S.
    et al.
    Univ Utrecht, Social Hlth & Org Psychol, Utrecht, Netherlands.;Univ Utrecht, Helmholtz Inst, Expt Psychol, Utrecht, Netherlands..
    Hooge, Ignace T. C.
    Univ Utrecht, Helmholtz Inst, Expt Psychol, Utrecht, Netherlands..
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Smeets, Paul A. M.
    Univ Utrecht, UMC Utrecht Brain Ctr, Utrecht, Netherlands.;Wageningen Univ, Div Human Nutr & Hlth, Wageningen, Netherlands.;Univ Med Ctr, Image Sci Inst, Utrecht, Netherlands..
    van der Laan, Laura N.
    Tilburg Univ, Tilburg Sch Humanities & Digital Sci, Dept Commun & Cognit, POB 90153, NL-5000 LE Tilburg, Netherlands..
    The influence of acute partial sleep deprivation on liking, choosing and consuming high- and low-energy foods2021In: Food Quality and Preference, ISSN 0950-3293, E-ISSN 1873-6343, Vol. 88, article id 104074Article in journal (Refereed)
    Abstract [en]

    A wealth of cross-sectional studies found a link between sleep deprivation and food-related outcomes like energy intake and BMI. Recent experimental studies suggest that this link is causal. However, the mechanisms through which sleep deprivation influences intake remain unclear. Here, we tested two prevailing hypotheses: that sleep deprivation leads to 1) increased food reward sensitivity and 2) decreased food-related self-control. In a within-subject study (n = 60 normal-weight females), we compared outcome measures under normal sleep and partial sleep deprivation conditions. Our outcome measures were 1) proxies for food reward sensitivity - liking of high and low energy foods, 2) binary food choices ranging in level of self-control conflict, and 3) intake of high and low energy foods. Eye-movements during food choice were measured with an eye-tracker to gain insights in implicit food choice processes. Food reward sensitivity outcomes showed a lower liking of low energy foods after partial sleep deprivation. More high energy foods were chosen after partial sleep deprivation independent of the level of self-control conflict. Intake of high energy foods was higher in the partial sleep deprivation condition. Lastly, the number of gaze switches between high and low energy foods, an implicit measure of conflict in choice, was lower in the high-conflict trials after sleep deprivation than after a normal night sleep. To conclude, the increased intake of high energy foods after sleep deprivation may be driven by a decreased liking of low energy foods, rather than an increased liking of high energy foods. Further, sleep deprivation may affect self-control conflict detection as indicated by a lower number of gaze switches between food options.

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  • 35. Berezin, Linor
    et al.
    Waseem, Rida
    Merikanto, Ilona
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Holzinger, Brigitte
    De Gennaro, Luigi
    Wing, Yun Kwok
    Bjorvatn, Bjørn
    Korman, Maria
    Morin, Charles M
    Espie, Colin
    Landtblom, Anne-Marie
    Penzel, Thomas
    Matsui, Kentaro
    Hrubos-Strøm, Harald
    Mota-Rolim, Sérgio
    Nadorff, Michael R
    Plazzi, Giuseppe
    Reis, Catia
    Chan, Rachel Ngan Yin
    Cunha, Ana Suely
    Yordanova, Juliana
    Bjelajac, Adrijana Koscec
    Inoue, Yuichi
    Dauvilliers, Yves
    Partinen, Markku
    Chung, Frances
    Habitual short sleepers with pre-existing medical conditions are at higher risk of Long COVID.2023In: Journal of Clinical Sleep Medicine (JCSM), ISSN 1550-9389, E-ISSN 1550-9397Article in journal (Refereed)
    Abstract [en]

    STUDY OBJECTIVES: Preliminary evidence suggests that the risk of Long COVID is higher among people with pre-existing medical conditions. Based on its proven adjuvant role in immunity, habitual sleep duration may alter the risk for developing Long COVID. The objective of this study was to determine whether the odds of Long COVID are higher amongst those with pre-existing medical conditions, and whether the strength of this association varies by habitual sleep duration.

    METHODS: Using data from 13,461 respondents from 16 countries who participated in the 2021 survey based International COVID Sleep Study II (ICOSS II), we studied the associations between habitual sleep duration, pre-existing medical conditions, and Long COVID.

    RESULTS: Of 2,508 individuals who had COVID-19, 61% reported at least one Long COVID symptom. Multivariable logistic regression analysis showed that the risk of having Long COVID was 1.8-fold higher for average-length sleepers (6-9h/night) with pre-existing medical conditions compared to those without pre-existing medical conditions [aOR 1.84 (1.18-2.90), P=0.008]. The risk of Long COVID was 3-fold higher for short sleepers with pre-existing medical conditions [aOR 2.95 (1.04-8.4), P=0.043] and not significantly higher for long sleepers with pre-existing conditions [aOR 2.11 (0.93-4.77), P=0.073] compared to average-length sleepers without pre-existing conditions.

    CONCLUSIONS: Habitual short nighttime sleep duration exacerbated the risk of Long COVID in individuals with pre-existing conditions. Restoring nighttime sleep to average duration represents a potentially modifiable behavioral factor to lower the odds of Long COVID for at-risk patients.

  • 36. Bjorvatn, Bjørn
    et al.
    Merikanto, Ilona
    Reis, Catia
    Korman, Maria
    Bjelajac, Adrijana Koscec
    Holzinger, Brigitte
    De Gennaro, Luigi
    Wing, Yun Kwok
    Morin, Charles M
    Espie, Colin A
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Landtblom, Anne-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Matsui, Kentaro
    Hrubos-Strøm, Harald
    Mota-Rolim, Sérgio
    Nadorff, Michael R
    Plazzi, Giuseppe
    Chan, Rachel Ngan Yin
    Partinen, Markku
    Dauvilliers, Yves
    Chung, Frances
    Forthun, Ingeborg
    Shift workers are at increased risk of severe COVID-19 compared with day workers: Results from the international COVID sleep study (ICOSS) of 7141 workers.2023In: Chronobiology International, ISSN 0742-0528, E-ISSN 1525-6073, Vol. 40, no 2, p. 114-122Article in journal (Refereed)
    Abstract [en]

    The present study had two main aims. First, to investigate whether shift/night workers had a higher prevalence and severity of COVID-19 compared with day workers. Second, to investigate whether people regularly working in face-to-face settings during the pandemic exhibited a higher prevalence and severity of COVID-19 compared with those having no need to be in close contact with others at work. Data consisted of 7141 workers from 15 countries and four continents who participated in the International COVID Sleep Study-II (ICOSS-II) between May and December 2021. The associations between work status and a positive COVID-19 test and several indications of disease severity were tested with chi-square tests and logistic regressions adjusted for relevant confounders. In addition, statistical analyses were conducted for the associations between face-to-face work and COVID-19 status. Results showed that shift/night work was not associated with an increased risk of COVID-19 compared to day work. Still, shift/night workers reported higher odds for moderate to life-threatening COVID-19 (adjusted odds ratio (aOR) = 2.71, 95%-confidence interval = 1.23-5.95) and need for hospital care (aOR = 5.66, 1.89-16.95). Face-to-face work was associated with an increased risk of COVID-19 (aOR = 1.55, 1.12-2.14) but not with higher disease severity. In conclusion, shift/night work was not associated with an increased risk of COVID-19, but when infected, shift/night workers reported more severe disease. Impaired sleep and circadian disruption commonly seen among shift/night workers may be mediating factors. Working face-to-face increased the risk of COVID-19, likely due to increased exposure to the virus. However, face-to-face work was not associated with increased disease severity.

  • 37. Bolstad, Courtney J
    et al.
    Holzinger, Brigitte
    Scarpelli, Serena
    De Gennaro, Luigi
    Yordanova, Juliana
    Koumanova, Silvia
    Mota-Rolim, Sérgio
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bjorvatn, Bjørn
    Chan, Ngan Yin
    Chung, Frances
    Dauvilliers, Yves
    Espie, Colin A
    Inoue, Yuichi
    Korman, Maria
    Koscec Bjelajac, Adrijana
    Landtblom, Anne-Marie
    Matsui, Kentaro
    Merikanto, Ilona
    Morin, Charles M
    Partinen, Markku
    Penzel, Thomas
    Plazzi, Giuseppe
    Reis, Cátia
    Ross, Biserka
    Wing, Yun Kwok
    Nadorff, Michael R
    Nightmare frequency is a risk factor for suicidal ideation during the COVID-19 pandemic.2024In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, p. e14165-, article id e14165Article in journal (Refereed)
    Abstract [en]

    The association between nightmare frequency (NMF) and suicidal ideation (SI) is well known, yet the impact of the COVID-19 pandemic on this relation is inconsistent. This study aimed to investigate changes in NMF, SI, and their association during the COVID-19 pandemic. Data were collected in 16 countries using a harmonised questionnaire. The sample included 9328 individuals (4848 women; age M[SD] = 46.85 [17.75] years), and 17.60% reported previous COVID-19. Overall, SI was significantly 2% lower during the pandemic vs. before, and this was consistent across genders and ages. Most countries/regions demonstrated decreases in SI during this pandemic, with Austria (-9.57%), Sweden (-6.18%), and Bulgaria (-5.14%) exhibiting significant declines in SI, but Italy (1.45%) and Portugal (2.45%) demonstrated non-significant increases. Suicidal ideation was more common in participants with long-COVID (21.10%) vs. short-COVID (12.40%), though SI did not vary by COVID-19 history. Nightmare frequency increased by 4.50% during the pandemic and was significantly higher in those with previous COVID-19 (14.50% vs. 10.70%), during infection (23.00% vs. 8.10%), and in those with long-COVID (18.00% vs. 8.50%). The relation between NMF and SI was not significantly stronger during the pandemic than prior (rs = 0.18 vs. 0.14; z = 2.80). Frequent nightmares during the pandemic increased the likelihood of reporting SI (OR = 1.57, 95% CI 1.20-2.05), while frequent dream recall during the pandemic served a protective effect (OR = 0.74, 95% CI 0.59-0.94). These findings have important implications for identifying those at risk of suicide and may offer a potential pathway for suicide prevention.

  • 38.
    Brandao, Luiz Eduardo M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Westholm, Jakub Orzechowski
    Martikainen, Teemu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Westerlund, Nestori
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lampola, Lauri
    Popa, Alexandru
    Vogel, Heike
    Schürmann, Annette
    Dickson, Suzanne L
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Acute sleep loss alters circulating fibroblast growth factor 21 levels in humans: A randomised crossover trial.2022In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 31, no 2, article id e13472Article in journal (Refereed)
    Abstract [en]

    The hormone fibroblast growth factor 21 (FGF21) modulates tissue metabolism and circulates at higher levels in metabolic conditions associated with chronic sleep-wake disruption, such as type 2 diabetes and obesity. In the present study, we investigated whether acute sleep loss impacts circulating levels of FGF21 and tissue-specific production, and response pathways linked to FGF21. A total of 15 healthy normal-weight young men participated in a randomised crossover study with two conditions, sleep loss versus an 8.5-hr sleep window. The evening before each intervention, fasting blood was collected. Fasting, post-intervention morning skeletal muscle and adipose tissue samples underwent quantitative polymerase chain reaction and DNA methylation analyses, and serum FGF21 levels were measured before and after an oral glucose tolerance test. Serum levels of FGF21 were higher after sleep loss compared with sleep, both under fasting conditions and following glucose intake (~27%-30%, p = 0.023). Fasting circulating levels of fibroblast activation protein, a protein which can degrade circulating FGF21, were not altered by sleep loss, whereas DNA methylation in the FGF21 promoter region increased only in adipose tissue. However, even though specifically the muscle exhibited transcriptional changes indicating adverse alterations to redox and metabolic homeostasis, no tissue-based changes were observed in expression of FGF21, its receptors, or selected signalling targets, in response to sleep loss. In summary, we found that acute sleep loss resulted in increased circulating levels of FGF21 in healthy young men, which may occur independent of a tissue-based stress response in metabolic peripheral tissues. Further studies may decipher whether changes in FGF21 signalling after sleep loss modulate metabolic outcomes associated with sleep or circadian disruption.

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  • 39.
    Brandao, Luiz Eduardo M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Martikainen, Teemu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Merikanto, Ilona
    Holzinger, Brigitte
    Morin, Charles M
    Espie, Colin A
    Bolstad, Courtney J
    Leger, Damien
    Chung, Frances
    Plazzi, Giuseppe
    Dauvilliers, Yves
    Matsui, Kentaro
    De Gennaro, Luigi
    Sieminski, Mariusz
    Nadorff, Michael R
    Chan, Ngan Yin
    Wing, Yun Kwok
    Mota-Rolim, Sérgio Arthuro
    Inoue, Yuichi
    Partinen, Markku
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Bjorvatn, Bjorn
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
    Social Jetlag Changes During the COVID-19 Pandemic as a Predictor of Insomnia - A Multi-National Survey Study2021In: Nature and Science of Sleep, ISSN 1179-1608, Vol. 13, p. 1711-1722Article in journal (Refereed)
    Abstract [en]

    Purpose: Lifestyle and work habits have been drastically altered by restrictions due to the COVID-19 pandemic. Whether the associated changes in sleep timing modulate the risk of suffering from symptoms of insomnia, the most prevalent sleep disorder, is however incompletely understood. Here, we evaluate the association between the early pandemic-associated change in 1) the magnitude of social jetlag (SJL) - ie, the difference between sleep timing on working vs free days - and 2) symptoms of insomnia.

    Patients and Methods: A total of 14,968 anonymous participants (mean age: 40 years; 64% females) responded to a standardized internet-based survey distributed across 14 countries. Using logistic multivariate regression, we examined the association between the degree of social jetlag and symptoms of insomnia, controlling for important confounders like social restriction extension, country specific COVID-19 severity and psychological distress, for example.

    Results: In response to the pandemic, participants reported later sleep timing, especially during workdays. Most participants (46%) exhibited a reduction in their SJL, whereas 20% increased it; and 34% reported no change in SJL. Notably, we found that both increased and decreased SJL, as a result of the COVID-19 pandemic, were associated with later sleep midpoint (indicating a later chronotype) as well as more recurrent and moderate-to-severe symptoms of insomnia (about 23-54% higher odds ratio than subjects with unchanged SJL). Primarily those with reduced SJL shifted their bedtimes to a later timepoint, compared with those without changes in SJL.

    Conclusion: Our findings offer important insights into how self-reported changes to the stability of sleep/wake timing, as reflected by changes in SJL, can be a critical marker of the risk of experiencing insomnia-related symptoms - even when individuals manage to reduce their social jetlag. These findings emphasize the clinical importance of analyzing sleep-wake regularity.

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  • 40.
    Brooks, Samantha J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Barker, Gareth J
    O'Daly, Owen G
    Brammer, Michael
    Williams, Steven Cr
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Treasure, Janet
    Campbell, Iain C
    Restraint of appetite and reduced regional brain volumes in anorexia nervosa: a voxel-based morphometric study2011In: BMC Psychiatry, E-ISSN 1471-244X, Vol. 11, p. 179-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Previous Magnetic Resonance Imaging (MRI) studies of people with anorexia nervosa (AN) have shown differences in brain structure. This study aimed to provide preliminary extensions of this data by examining how different levels of appetitive restraint impact on brain volume.

    METHODS:

    Voxel based morphometry (VBM), corrected for total intracranial volume, age, BMI, years of education in 14 women with AN (8 RAN and 6 BPAN) and 21 women (HC) was performed. Correlations between brain volume and dietary restraint were done using Statistical Package for the Social Sciences (SPSS).

    RESULTS:

    Increased right dorsolateral prefrontal cortex (DLPFC) and reduced right anterior insular cortex, bilateral parahippocampal gyrus, left fusiform gyrus, left cerebellum and right posterior cingulate volumes in AN compared to HC. RAN compared to BPAN had reduced left orbitofrontal cortex, right anterior insular cortex, bilateral parahippocampal gyrus and left cerebellum. Age negatively correlated with right DLPFC volume in HC but not in AN; dietary restraint and BMI predicted 57% of variance in right DLPFC volume in AN.

    CONCLUSIONS:

    In AN, brain volume differences were found in appetitive, somatosensory and top-down control brain regions. Differences in regional GMV may be linked to levels of appetitive restraint, but whether they are state or trait is unclear. Nevertheless, these discrete brain volume differences provide candidate brain regions for further structural and functional study in people with eating disorders.

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  • 41.
    Brooks, Samantha J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Burgos, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kempton, M J
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nordenskjöld, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nylander, Ruta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Late-life obesity is associated with smaller global and regional gray matter volumes: a voxel-based morphometric study2013In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 37, no 2, p. 230-236Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: 

    Obesity adversely affects frontal lobe brain structure and function. Here we sought to show that people who are obese versus those who are of normal weight over a 5-year period have differential global and regional brain volumes.

    DESIGN: 

    Using voxel-based morphometry, contrasts were done between those who were recorded as being either obese or of normal weight over two time points in the 5 years prior to the brain scan. In a post-hoc preliminary analysis, we compared scores for obese and normal weight people who completed the trail-making task.

    SUBJECTS: 

    A total of 292 subjects were examined following exclusions (for example, owing to dementia, stroke and cortical infarcts) from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort with a body mass index of normal weight (<25 kg m−2) or obese (30 kg m−2).

    RESULTS: 

    People who were obese had significantly smaller total brain volumes and specifically, significantly reduced total gray matter (GM) volume (GMV) (with no difference in white matter or cerebrospinal fluid). Initial exploratory whole brain uncorrected analysis revealed that people who were obese had significantly smaller GMV in the bilateral supplementary motor area, bilateral dorsolateral prefrontal cortex (DLPFC), left inferior frontal gyrus and left postcentral gyrus. Secondary more stringent corrected analyses revealed a surviving cluster of GMV difference in the left DLPFC. Finally, post-hoc contrasts of scores on the trail-making task, which is linked to DLPFC function, revealed that obese people were significantly slower than those of normal weight.

    CONCLUSION: 

    These findings suggest that in comparison with normal weight, people who are obese have smaller GMV, particularly in the left DLPFC. Our results may provide evidence for a potential working memory mechanism for the cognitive suppression of appetite that may lower the risk of developing obesity in later life.

  • 42.
    Brooks, Samantha J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Allzen, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Exposure to subliminal arousing stimuli induces robust activation in the amygdala, hippocampus, anterior cingulate, insular cortex and primary visual cortex: A systematic meta-analysis of fMRI studies2012In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 59, no 3, p. 2962-2973Article, review/survey (Refereed)
    Abstract [en]

    Functional Magnetic Resonance Imaging (fMRI) demonstrates that the subliminal presentation of arousing stimuli can activate subcortical brain regions independently of consciousness-generating top-down cortical modulation loops. Delineating these processes may elucidate mechanisms for arousal, aberration in which may underlie some psychiatric conditions. Here we are the first to review and discuss four Activation Likelihood Estimation (ALE) meta-analyses of fMRI studies using subliminal paradigms. We find a maximum of 9 out of 12 studies using subliminal presentation of faces contributing to activation of the amygdala, and also a significantly high number of studies reporting activation in the bilateral anterior cingulate, bilateral insular cortex, hippocampus and primary visual cortex. Subliminal faces are the strongest modality, whereas lexical stimuli are the weakest. Meta-analyses independent of studies using Regions of Interest (ROI) revealed no biasing effect Core neuronal arousal in the brain, which may be at first independent of conscious processing, potentially involves a network incorporating primary visual areas, somatosensory, implicit memory and conflict monitoring regions. These data could provide candidate brain regions for the study of psychiatric disorders associated with aberrant automatic emotional processing.

  • 43.
    Brooks, Samantha Jane
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi Birgir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A debate on current eating disorder diagnoses in light of neurobiological findings: is it time for a spectrum model?2012In: BMC Psychiatry, E-ISSN 1471-244X, Vol. 12, p. 76-Article in journal (Refereed)
    Abstract [en]

    Background: Sixty percent of eating disorders do not meet criteria for anorexia- or bulimia nervosa, as defined by the Diagnostic and Statistical Manual version 4 (DSM-IV). Instead they are diagnosed as 'eating disorders not otherwise specified' (EDNOS). Discrepancies between criteria and clinical reality currently hampering eating disorder diagnoses in the DSM-IV will be addressed by the forthcoming DSM-V. However, future diagnoses for eating disorders will rely on current advances in the fields of neuroimaging and genetics for classification of symptoms that will ultimately improve treatment. Discussion: Here we debate the classification issues, and discuss how brain imaging and genetic discoveries might be interwoven into a model of eating disorders to provide better classification and treatment. The debate concerns: a) current issues in the classification of eating disorders in the DSM-IV, b) changes proposed for DSM-V, c) neuroimaging eating disorder research and d) genetic eating disorder research. Summary: We outline a novel evidence-based 'impulse control' spectrum model of eating disorders. A model of eating disorders is proposed that will aid future diagnosis of symptoms, coinciding with contemporary suggestions by clinicians and the proposed changes due to be published in the DSM-V.

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  • 44. Bruenner, Y. F.
    et al.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Freiherr, J.
    Targeting the brain through the nose. Effects of intranasally administered insulin2013In: Nervenarzt, ISSN 0028-2804, E-ISSN 1433-0407, Vol. 84, no 8, p. 949-954Article, review/survey (Refereed)
    Abstract [en]

    The assumption that the human brain is an insulin-independent organ was disproved with the discovery of insulin receptors in the central nervous system in the year 1978. Evidence has been provided for a high density of insulin receptors in brain regions responsible for cognitive memory processes (hippocampus) and for the regulation of appetite (hypothalamus). Accordingly, in animal studies an increased insulin level in the central nervous system leads to an improvement of hippocampal memory function and a decrease of food intake. Similar results were obtained in humans using the method of intranasal administration of insulin. Intranasal insulin reaches the brain and the cerebrospinal fluid via the olfactory epithelium and olfactory nerve fiber bundles leading through the lamina cribrosa to the olfactory bulb. Thus, this method renders the investigation of specific insulin effects in humans possible. The therapeutic potential of an intranasal insulin administration for the treatment of diseases for which an imbalance of the central nervous insulin metabolism is discussed (e.g. Alzheimer's disease, diabetes mellitus and obesity) can only be estimated with the help of further clinical studies.

  • 45. Bruenner, Yvonne F.
    et al.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Freiherr, Jessica
    Intranasal Insulin Reduces Olfactory Sensitivity in Normosmic Humans2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 10, p. E1626-E1630Article in journal (Refereed)
    Abstract [en]

    Context: High densities of insulin receptors are found throughout the human brain, including the olfactory bulb, an essential brain area for odor processing. This brain region is the phylogenetically oldest part of the olfactory central nervous system. Objective: We hypothesized that enhanced brain insulin signaling would modulate olfactory processing in humans. Design: We applied a double-blind, placebo-controlled, balanced within-subject design. Setting: This study was conducted in the research unit of a university hospital. Interventions/Participants/Main Outcome Measures: A single dose of either insulin (40 IU) or placebo was intranasally administered to 17 normal-weight normosmic participants (7 women). Subjects' olfactory abilities were examined by means of an olfactory threshold test (odorant n-butanol) and an olfactory discrimination test. In addition, circulating concentrations of glucose, insulin, and cortisol levels were measured. Results: After intranasal insulin administration, subjects' sensitivity for the odorant n-butanol was significantly decreased compared with that for the placebo condition (-13%; P = .025), whereas olfactory discrimination ability was not (P = .841). While serum insulin and serum cortisol were not altered after intranasal insulin administration, there was a small but significant drop in plasma glucose levels. Importantly, a correlational analysis demonstrated that this treatment-induced drop in plasma glucose was not related to the effects of intranasal insulin on olfactory sensitivity. Conclusions: These findings suggest that intranasal insulin impairs olfactory sensitivity for a non-food odorant, whereas no such effects were found for olfactory discrimination. Thus, variations in brain insulin signaling most likely have implications for the olfactory threshold of normosmic humans. Bearing in mind the fact that insulin acts as an anorexigenic signal in the human brain, further studies are needed to test whether intranasal insulin also impairs the ability of humans to perceive food-related odors.

  • 46. Bruenner, Yvonne F.
    et al.
    Kofoet, Anja
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Freiherr, Jessica
    Central Insulin Administration Improves Odor-Cued Reactivation of Spatial Memory in Young Men2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 1, p. 212-219Article in journal (Refereed)
    Abstract [en]

    Context: Insulin receptors are ubiquitously found in the human brain, comprising the olfactory bulb, essential for odor processing, and the hippocampus, important for spatial memory processing. Objective: The present study aimed at examining if intranasal insulin, which is known to transiently increase brain insulin levels in humans, would improve odor-cued reactivation of spatial memory in young men. Design: We applied a double-blind, placebo-controlled, counterbalanced within-subject design. Setting: The study was conducted at the research unit of a university hospital. Interventions/Participants/Main Outcome Measures: Following intranasal administration of either insulin (40 I.U.) or placebo, male subjects (n = 18) were exposed to eight odors. During each odor exposure, a green-colored field was presented on a 17-in. computer screen. During immediate recall (comprising 3 runs), the participants were re-exposed to each odor cue, and were asked to select the corresponding field (with visual feedback after each response). The delayed recall was scheduled similar to 10 min later (without feedback). To test if insulin's putative effect on odor-place memory would be domain-specific, participants also performed a separate place and odor recognition task. Results: Intranasal insulin improved the delayed but not immediate odor-cued recall of spatial memory. This effect was independent of odor type and in the absence of systemic side effects (eg, fasting plasma glucose levels remained unaltered). Place and odor recognition were unaffected by the insulin treatment. Conclusions: These findings suggest that acute intranasal insulin improves odor-cued reactivation of spatial memory in young men.

  • 47.
    Bruenner, Yvonne F.
    et al.
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Aachen, Germany..
    Rodriguez-Raecke, Rea
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Aachen, Germany..
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Freiherr, Jessica
    Rhein Westfal TH Aachen, Diagnost & Intervent Neuroradiol, Aachen, Germany..
    Modulation of odor-cued memory processing by intranasal insulin2015In: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 40, no 7, p. 603-603Article in journal (Other academic)
  • 48.
    Brünner, Yvonne F.
    et al.
    Uniklin RWTH Aachen, Diagnost & Intervent Neuroradiol, Pauwelsstr 30, D-52074 Aachen, Germany..
    Rodriguez-Raecke, Rea
    Uniklin RWTH Aachen, Diagnost & Intervent Neuroradiol, Pauwelsstr 30, D-52074 Aachen, Germany..
    Mutic, Smiljana
    Uniklin RWTH Aachen, Diagnost & Intervent Neuroradiol, Pauwelsstr 30, D-52074 Aachen, Germany..
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Freiherr, Jessica
    Uniklin RWTH Aachen, Diagnost & Intervent Neuroradiol, Pauwelsstr 30, D-52074 Aachen, Germany.;Fraunhofer Inst Proc Engn & Packaging IVV, D-85354 Freising Weihenstephan, Germany..
    Neural correlates of olfactory and visual memory performance in 3D-simulated mazes after intranasal insulin application2016In: Neurobiology of Learning and Memory, ISSN 1074-7427, E-ISSN 1095-9564, Vol. 134, no Part B, p. 256-263Article in journal (Refereed)
    Abstract [en]

    This fMRI study intended to establish 3D-simulated mazes with olfactory and visual cues and examine the effect of intranasally applied insulin on memory performance in healthy subjects. The effect of insulin on hippocampus-dependent brain activation was explored using a double-blind and placebo-controlled design. Following intranasal administration of either insulin (40 ID) or placebo, 16 male subjects participated in two experimental MRI sessions with olfactory and visual mazes. Each maze included two separate runs. The first was an encoding maze during which subjects learned eight olfactory or eight visual cues at different target locations. The second was a recall maze during which subjects were asked to remember the target cues at spatial locations. For eleven included subjects in the fMRI analysis we were able to validate brain activation for odor perception and visuospatial tasks. However, we did not observe an enhancement of declarative memory performance in our behavioral data or hippocampal activity in response to insulin application in the fMRI analysis. It is therefore possible that intranasal insulin application is sensitive to the methodological variations e.g. timing of task execution and dose of application. Findings from this study suggest that our method of 3D-simulated mazes is feasible for studying neural correlates of olfactory and visual memory performance.

  • 49. Cable, Jennifer
    et al.
    Schernhammer, Eva
    Hanlon, Erin C
    Vetter, Céline
    Cedernaes, Jonathan
    Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
    Makarem, Nour
    Dashti, Hassan S
    Shechter, Ari
    Depner, Christopher
    Ingiosi, Ashley
    Blume, Christine
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Gottlieb, Elie
    Benedict, Christian
    Van Cauter, Eve
    St-Onge, Marie-Pierre
    Sleep and circadian rhythms: pillars of health-a Keystone Symposia report2021In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1506, no 1, p. 18-34Article in journal (Refereed)
    Abstract [en]

    The human circadian system consists of the master clock in the suprachiasmatic nuclei of the hypothalamus as well as in peripheral molecular clocks located in organs throughout the body. This system plays a major role in the temporal organization of biological and physiological processes, such as body temperature, blood pressure, hormone secretion, gene expression, and immune functions, which all manifest consistent diurnal patterns. Many facets of modern life, such as work schedules, travel, and social activities, can lead to sleep/wake and eating schedules that are misaligned relative to the biological clock. This misalignment can disrupt and impair physiological and psychological parameters that may ultimately put people at higher risk for chronic diseases like cancer, cardiovascular disease, and other metabolic disorders. Understanding the mechanisms that regulate sleep circadian rhythms may ultimately lead to insights on behavioral interventions that can lower the risk of these diseases. On February 25, 2021, experts in sleep, circadian rhythms, and chronobiology met virtually for the Keystone eSymposium "Sleep & Circadian Rhythms: Pillars of Health" to discuss the latest research for understanding the bidirectional relationships between sleep, circadian rhythms, and health and disease.

  • 50.
    Cai, Gui-Hong
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Elmstahl, S.
    Lund Univ, Div Geriatr Med, Dept Hlth Sci, Lund, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Both weight at age 20 and weight gain have an impact on sleep disturbances later in life – results of the epihealth study2017In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 40, no Supplement 1, p. E195-E195Article in journal (Other academic)
1234 1 - 50 of 183
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