Pancreatic metabolism, blood flow, and β-cell function in obese humans.

Context: Glucolipotoxicity is believed to induce pancreatic &beta;-cell dysfunction in obesity. Previously, it has not been possible to study pancreatic metabolism and blood flow in humans. Objective: The objective of the study was to investigate whether pancreatic metabolism and blood flow are altered in obesity using positron emission tomography (PET). In the preclinical part, the method was validated in animals. Design: This was a cross-sectional study. Setting: The study was conducted in a clinical research center. Participants: Human studies consisted of 52 morbidly obese and 25 healthy age-matched control subjects. Validation experiments were done with rodents and pigs. Interventions: PET and magnetic resonance imaging studies using a glucose analog ([18F]fluoro-2-deoxy-d-glucose), a palmitate analog [14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid], and radiowater ([15O]H2O) were performed. In animals, a comparison between ex vivo and in vivo data was performed. Main Outcome Measures: Pancreatic glucose/fatty acid (FA) uptake, fat accumulation, and blood flow parameters of &beta;-cell function were measured. Results: PET proved to be a feasible method to measure pancreatic metabolism. Compared with healthy participants, obese participants had elevated pancreatic FA uptake (P &lt; .0001), more fat accumulation (P = .0001), lowered glucose uptake both during fasting and euglycemic hyperinsulinemia, and blunted blood flow (P &lt; .01) in the pancreas. Blood flow, FA uptake, and fat accumulation were negatively associated with multiple markers of &beta;-cell function. Conclusions: Obesity leads to changes in pancreatic energy metabolism with a substrate shift from glucose to FAs. In morbidly obese humans, impaired pancreatic blood flow may contribute to &beta;-cell dysfunction and in the pathogenesis of type 2 diabetes. &nbsp;</div

Validation of [18F]fluorodeoxyglucose and positron emission tomography (PET) for the measurement of intestinal metabolism in pigs, and evidence of intestinal insulin resistance in patients with morbid obesity

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ASIC-E4: Interplay of Beta-Amyloid, Synaptic Density and Neuroinflammation in Cognitively Normal Volunteers With Three Levels of Genetic Risk for Late-Onset Alzheimer's Disease – Study Protocol and Baseline Characteristics

Background: Detailed characterization of early pathophysiological changes in preclinical Alzheimer's disease (AD) is necessary to enable development of correctly targeted and timed disease-modifying treatments. ASIC-E4 study (“Beta-Amyloid, Synaptic loss, Inflammation and Cognition in healthy APOE ε4 carriers”) combines state-of-the-art neuroimaging and fluid-based biomarker measurements to study the early interplay of three key pathological features of AD, i.e., beta-amyloid (Aβ) deposition, neuroinflammation and synaptic dysfunction and loss in cognitively normal volunteers with three different levels of genetic (APOE-related) risk for late-onset AD. Objective: Here, our objective is to describe the study design, used protocols and baseline demographics of the ASIC-E4 study. Methods/Design: ASIC-E4 is a prospective observational multimodal imaging study performed in Turku PET Centre in collaboration with University of Gothenburg. Cognitively normal 60–75-year-old-individuals with known APOE ε4/ε4 genotype were recruited via local Auria Biobank (Turku, Finland). Recruitment of the project has been completed in July 2020 and 63 individuals were enrolled to three study groups (Group 1: APOE ε4/ε4, N = 19; Group 2: APOE ε4/ε3, N = 22; Group 3: APOE ε3/ε3, N = 22). At baseline, all participants will undergo positron emission tomography imaging with tracers targeted against Aβ deposition (11C-PIB), activated glia (11C-PK11195) and synaptic vesicle glycoprotein 2A (11C-UCB-J), two brain magnetic resonance imaging scans, and extensive cognitive testing. In addition, blood samples are collected for various laboratory measurements and blood biomarker analysis and cerebrospinal fluid samples are collected from a subset of participants based on additional voluntary informed consent. To evaluate the predictive value of the early neuroimaging findings, neuropsychological evaluation and blood biomarker measurements will be repeated after a 4-year follow-up period. Discussion: Results of the ASIC-E4 project will bridge the gap related to limited knowledge of the synaptic and inflammatory changes and their association with each other and Aβ in “at-risk” individuals. Thorough in vivo characterization of the biomarker profiles in this population will produce valuable information for diagnostic purposes and future drug development, where the field has already started to look beyond Aβ

Genetic variants and blood pressure in a population-based cohort: the cardiovascular risk in young Finns study

Clinical relevance of a genetic predisposition to elevated blood pressure was quantified during the transition from childhood to adulthood in a population-based Finnish cohort (N=2,357). Blood pressure was measured at baseline in 1980 (age 3–18 years) and in follow-ups in 1983, 1986, 2001 and 2007. Thirteen single nucleotide polymorphisms associated with blood pressure were genotyped and three genetic risk scores associated with systolic and diastolic blood pressure and their combination were derived for all participants. Effects of the genetic risk score were 0.47 mmHg for systolic and 0.53 mmHg for diastolic blood pressure (both p<0.01). The combination genetic risk score was associated with diastolic blood pressure from age 9 onwards (β=0.68 mmHg, p=0.015). Replications in 1194 participants of the Bogalusa Heart Study showed essentially similar results. The participants in the highest quintile of the combination genetic risk score had a 1.82-fold risk of hypertension in adulthood (p<0.0001) compared with the lowest quintile, independent of a family history of premature hypertension. These findings show that genetic variants are associated with preclinical blood pressure traits in childhood, individuals with several susceptibility alleles have on average a 0.5 mmHg higher blood pressure and this trajectory continues from childhood to adulthood

Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses

Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases

Pretargeted PET Imaging of trans-Cyclooctene-Modified Porous Silicon Nanoparticles

Pretargeted positron emission tomography (PET) imaging based on bioorthogonal chemical reactions has proven its potential in immunoimaging. It may also have great potential in nanotheranostic applications. Here, we report the first successful pretargeted PET imaging of trans-cyclooctene-modified mesoporous silicon nanoparticles, using F-18-labeled tetrazine as a tracer. The inverse electron-demand Diels-Alder cycloaddition (IEDDA) reaction was fast, resulting in high radioactivity accumulation in the expected organs within 10 min after the administration of the tracer. The highest target-to-background ratio was achieved 120 min after the tracer injection. A clear correlation between the efficiency of the in vivo IEDDA labeling reaction and the injected amount of the tracer was observed. The radioactivity accumulation decreased with the increased amount of the co-injected carrier, indicating saturation in the reaction sites. This finding was supported by the in vitro results. Our study suggests that pretargeted imaging has excellent potential in nanotheranostic PET imaging when using high-specific-activity tracers

Increased Brain Fatty Acid Uptake in Metabolic Syndrome

OBJECTIVE: To test whether brain fatty acid uptake is enhanced in obese subjects with metabolic syndrome (MS) and whether weight reduction modifies it. RESEARCH DESIGN AND METHODS: We measured brain fatty acid uptake in a group of 23 patients with MS and 7 age-matched healthy control subjects during fasting conditions using positron emission tomography (PET) with [(11)C]-palmitate and [(18)F]fluoro-6-thia-heptadecanoic acid ([(18)F]-FTHA). Sixteen MS subjects were restudied after 6 weeks of very low calorie diet intervention. RESULTS: At baseline, brain global fatty acid uptake derived from [(18)F]-FTHA was 50% higher in patients with MS compared with control subjects. The mean percentage increment was 130% in the white matter, 47% in the gray matter, and uniform across brain regions. In the MS group, the nonoxidized fraction measured using [(11)C]-palmitate was 86% higher. Brain fatty acid uptake measured with [(18)F]-FTHA-PET was associated with age, fasting serum insulin, and homeostasis model assessment (HOMA) index. Both total and nonoxidized fractions of fatty acid uptake were associated with BMI. Rapid weight reduction decreased brain fatty acid uptake by 17%. CONCLUSIONS: To our knowledge, this is the first study on humans to observe enhanced brain fatty acid uptake in patients with MS. Both fatty acid uptake and accumulation appear to be increased in MS patients and reversed by weight reduction

Quantification of the purinergic P2X(7) receptor with [C-11]SMW139 improves through correction for brain-penetrating radiometabolites

The membrane-based purinergic 7 receptor (P2X(7)R) is expressed on activated microglia and the target of the radioligand [C-11]SMW139 for in vivo assessment of neuroinflammation. This study investigated the contribution of radiolabelled metabolites which potentially affect its quantification. Ex vivo high-performance liquid chromatography with a radio detector (radioHPLC) was used to evaluate the parent and radiometabolite fractions of [C-11]SMW139 in the brain and plasma of eleven mice. Twelve healthy humans underwent 90-min [C-11]SMW139 brain PET with arterial blood sampling and radiometabolite analysis. The volume of distribution was estimated by using one- and two- tissue compartment (TCM) modeling with single (V-T) and dual (V-Tp) input functions. RadioHPLC showed three major groups of radiometabolite peaks with increasing concentrations in the plasma of all mice and humans. Two radiometabolite peaks were also visible in mice brain homogenates and therefore considered for dual input modeling in humans. 2TCM with single input function provided V-T estimates with a wide range (0.10-10.74) and high coefficient of variation (COV: 159.9%), whereas dual input function model showed a narrow range of V-Tp estimates (0.04-0.24; COV: 33.3%). In conclusion, compartment modeling with correction for brain-penetrant radiometabolites improves the in vivo quantification of [C-11]SMW139 binding to P2X(7)R in the human brain.</p

Mapping the Birch and Grass Pollen Seasons in the UK Using Satellite Sensor Time-series

Grass and birch pollen are two major causes of seasonal allergic rhinitis (hay fever) in the UK and parts of Europe affecting around 15-20% of the population. Current prediction of these allergens in the UK is based on (i) measurements of pollen concentrations at a limited number of monitoring stations across the country and (ii) general information about the phenological status of the vegetation. Thus, the current prediction methodology provides information at a coarse spatial resolution only. Most station-based approaches take into account only local observations of flowering, while only a small number of approaches take into account remote observations of land surface phenology. The systematic gathering of detailed information about vegetation status nationwide would therefore be of great potential utility. In particular, there exists an opportunity to use remote sensing to estimate phenological variables that are related to the flowering phenophase and, thus, pollen release. In turn, these estimates can be used to predict pollen release at a fine spatial resolution. In this study, time-series of MERIS Terrestrial Chlorophyll Index (MTCI) data were used to predict two key phenological variables: the start of season and peak of season. A technique was then developed to estimate the flowering phenophase of birch and grass from the MTCI time-series. For birch, the timing of flowering was defined as the time after the start of the growing season when the MTCI value reached 25% of the maximum. Similarly, for grass this was defined as the time when the MTCI value reached 75% of the maximum. The predicted pollen release dates were validated with data from nine pollen monitoring stations in the UK. For both birch and grass, we obtained large positive correlations between the MTCI-derived start of pollen season and the start of the pollen season defined using station data, with a slightly larger correlation observed for birch than for grass. The technique was applied to produce detailed maps for the flowering of birch and grass across the UK for each of the years from 2003 to 2010. The results demonstrate that the remote sensing-based maps of onset flowering of birch and grass for the UK together with the pollen forecast from the Meteorology Office and National Pollen and Aerobiology Research Unit (NPARU) can potentially provide more accurate information to pollen allergy sufferers in the UK