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2. Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model

Author

Merlini, Mario, Rafalski, Victoria A, Coronado, Pamela E Rios, Gill, T Michael, Ellisman, Maya, Muthukumar, Gayathri, Subramanian, Keshav S, Ryu, Jae Kyu, Syme, Catriona A, Davalos, Dimitrios, Seeley, William W, Mucke, Lennart, Nelson, Robert B, and Akassoglou, Katerina

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Neurodegenerative, Dementia, Alzheimer's Disease, Brain Disorders, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Animals, Blood-Brain Barrier, Brain, CD11b Antigen, CD18 Antigens, Cognitive Dysfunction, Dendritic Spines, Disease Models, Animal, Fibrinogen, Humans, Imaging, Three-Dimensional, Mice, Microglia, Plaque, Amyloid, Reactive Oxygen Species, blood-brain barrier, coagulation, complement, dementia, dendritic spines, fibrin, iDISCO, innate immunity, multiple sclerosis, neurovascular, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Cerebrovascular alterations are a key feature of Alzheimer's disease (AD) pathogenesis. However, whether vascular damage contributes to synaptic dysfunction and how it synergizes with amyloid pathology to cause neuroinflammation and cognitive decline remain poorly understood. Here, we show that the blood protein fibrinogen induces spine elimination and promotes cognitive deficits mediated by CD11b-CD18 microglia activation. 3D molecular labeling in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. Fibrinogen-induced spine elimination was prevented by inhibiting reactive oxygen species (ROS) generation or genetic ablation of CD11b. Genetic elimination of the fibrinogen binding motif to CD11b reduced neuroinflammation, synaptic deficits, and cognitive decline in the 5XFAD mouse model of AD. Thus, fibrinogen-induced spine elimination and cognitive decline via CD11b link cerebrovascular damage with immune-mediated neurodegeneration and may have important implications in AD and related conditions.

Published
2019

3. Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration

Author

Ryu, Jae Kyu, Rafalski, Victoria A, Meyer-Franke, Anke, Adams, Ryan A, Poda, Suresh B, Rios Coronado, Pamela E, Pedersen, Lars Østergaard, Menon, Veena, Baeten, Kim M, Sikorski, Shoana L, Bedard, Catherine, Hanspers, Kristina, Bardehle, Sophia, Mendiola, Andrew S, Davalos, Dimitrios, Machado, Michael R, Chan, Justin P, Plastira, Ioanna, Petersen, Mark A, Pfaff, Samuel J, Ang, Kenny K, Hallenbeck, Kenneth K, Syme, Catriona, Hakozaki, Hiroyuki, Ellisman, Mark H, Swanson, Raymond A, Zamvil, Scott S, Arkin, Michelle R, Zorn, Stevin H, Pico, Alexander R, Mucke, Lennart, Freedman, Stephen B, Stavenhagen, Jeffrey B, Nelson, Robert B, and Akassoglou, Katerina

Subjects
Biomedical and Clinical Sciences, Immunology, Brain Disorders, Neurodegenerative, Dementia, Neurosciences, Multiple Sclerosis, Alzheimer's Disease, Aging, Hematology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Autoimmune Disease, Aetiology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Neurological, Animals, Antibodies, Monoclonal, Epitopes, Fibrinogen, Humans, Inflammation, Mice, Neurodegenerative Diseases, Rats, Biochemistry and cell biology
Abstract

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

Published
2018

4. DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Author

Richard, Melissa A, Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A, Brody, Jennifer A, Irvin, Marguerite R, Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E, Jia, Yucheng, Syme, Catriona, Salfati, Elias L, Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H, Bressler, Jan, Morrison, Alanna C, Liu, Chunyu, Mendelson, Michael M, Uitterlinden, André G, van Meurs, Joyce B, Consortium, BIOS, Heijmans, Bastiaan T, Hoen, Peter AC ’t, van Meurs, Joyce, Isaacs, Aaron, Jansen, Rick, Franke, Lude, Boomsma, Dorret I, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, van Greevenbroek, Marleen MJ, Stehouwer, Coen DA, van der Kallen, Carla JH, Schalkwijk, Casper G, Wijmenga, Cisca, Zhernakova, Alexandra, Tigchelaar, Ettje F, Slagboom, P Eline, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Veldink, Jan H, van den Berg, Leonard H, van Duijn, Cornelia M, Hofman, Albert, Jhamai, P Mila, Verbiest, Michael, Suchiman, H Eka D, Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Iterson, Maarten, van Galen, Michiel, Bot, Jan, van ’t Hof, Peter, Deelen, Patrick, Nooren, Irene, Moed, Matthijs, Vermaat, Martijn, Zhernakova, Dasha V, Luijk, René, Bonder, Marc Jan, van Dijk, Freerk, Arindrarto, Wibowo, Kielbasa, Szymon M, Swertz, Morris A, van Zwet, Erik W, Franco, Oscar H, Zhang, Guosheng, Li, Yun, Stewart, James D, Bis, Joshua C, Psaty, Bruce M, Chen, Yii-Der Ida, Kardia, Sharon LR, Zhao, Wei, Turner, Stephen T, Absher, Devin, Aslibekyan, Stella, Starr, John M, McRae, Allan F, Hou, Lifang, Just, Allan C, Schwartz, Joel D, Vokonas, Pantel S, Menni, Cristina, Spector, Tim D, Shuldiner, Alan, Damcott, Coleen M, Rotter, Jerome I, Palmas, Walter, Liu, Yongmei, and Paus, Tomáš

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Aged, Blood Pressure, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Genetic Variation, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins, Quantitative Trait Loci, Tetraspanins, BIOS Consortium, DNA methylation, Mendelian randomization, blood pressure, epigenome-wide association study, gene expression, sequence variation, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p  30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

Published
2017

5. Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage

Author

Petersen, Mark A, Ryu, Jae Kyu, Chang, Kae-Jiun, Etxeberria, Ainhoa, Bardehle, Sophia, Mendiola, Andrew S, Kamau-Devers, Wanjiru, Fancy, Stephen PJ, Thor, Andrea, Bushong, Eric A, Baeza-Raja, Bernat, Syme, Catriona A, Wu, Michael D, Coronado, Pamela E Rios, Meyer-Franke, Anke, Yahn, Stephanie, Pous, Lauriane, Lee, Jae K, Schachtrup, Christian, Lassmann, Hans, Huang, Eric J, Han, May H, Absinta, Martina, Reich, Daniel S, Ellisman, Mark H, Rowitch, David H, Chan, Jonah R, and Akassoglou, Katerina

Subjects
Biomedical and Clinical Sciences, Neurosciences, Regenerative Medicine, Stem Cell Research - Nonembryonic - Non-Human, Neurodegenerative, Multiple Sclerosis, Stem Cell Research, Brain Disorders, Autoimmune Disease, Stem Cell Research - Nonembryonic - Human, Hematology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Cardiovascular, Neurological, Activin Receptors, Type I, Animals, Blood Vessels, Bone Morphogenetic Proteins, Fibrinogen, Lysophosphatidylcholines, Mice, Mice, Inbred C57BL, Mice, Knockout, Microarray Analysis, Myelin Sheath, Oligodendrocyte Precursor Cells, Plasmids, Remyelination, Signal Transduction, NG2 cells, ancrod, cell fate, fibrin, myelin, neonatal brain injury, neuroinflammation, regeneration, stem/progenitor cells, vasculature, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fate in vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homolog 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelination in vivo. Targeting fibrinogen may be an upstream therapeutic strategy to promote the regenerative potential of CNS progenitors in diseases with remyelination failure.

Published
2017

21. Epigenetic Loci of Blood Pressure

Author

Syme, Catriona, primary, Shin, Jean, additional, Richer, Louis, additional, Gaudet, Daniel, additional, Fornage, Myriam, additional, Paus, Tomas, additional, and Pausova, Zdenka, additional

Published
2019
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22. A variant near DHCR24associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents

Author

Sliz, Eeva, Shin, Jean, Syme, Catriona, Patel, Yash, Parker, Nadine, Richer, Louis, Gaudet, Daniel, Bennett, Steffany, Paus, Tomas, and Pausova, Zdenka

Abstract

Visceral adiposity has been associated with altered microstructural properties of white matter in adolescents. Previous evidence suggests that circulating phospholipid PC(16:0/2:0) may mediate this association. To investigate the underlying biology, we performed a genome-wide association study (GWAS) of the shared variance of visceral fat, PC(16:0/2:0), and white matter microstructure in 872 adolescents from the Saguenay Youth Study. We further studied the metabolomic profile of the GWAS-lead variant in 931 adolescents. Visceral fat and white matter microstructure were assessed with magnetic resonance imaging. Circulating metabolites were quantified with serum lipidomics and metabolomics. We identified a genome-wide significant association near DHCR24 (Seladin-1)encoding a cholesterol-synthesizing enzyme (rs588709, p= 3.6 × 10−8); rs588709 was also associated nominally with each of the three traits (white matter microstructure: p= 2.1 × 10−6, PC(16:0/2:0): p= 0.005, visceral fat: p= 0.010). We found that the metabolic profile associated with rs588709 resembled that of a TM6SF2variant impacting very low-density lipoprotein (VLDL) secretion and was only partially similar to that of a HMGCRvariant. This suggests that the effect of rs588709 on VLDL lipids may arise due to altered phospholipid rather than cholesterol metabolism. The rs588709 was also nominally associated with circulating concentrations of omega-3 fatty acids in interaction with visceral fat and PC(16:0/2:0), and these fatty acid measures showed robust associations with white matter microstructure. Overall, the present study provides evidence that the DHCR24locus may link peripheral metabolism to brain microstructure, an association with implications for cognitive impairment.

Published
2021
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23. Visceral fat-related systemic inflammation and the adolescent brain: a mediating role of circulating glycerophosphocholines

Author

Syme, Catriona, primary, Pelletier, Stephanie, additional, Shin, Jean, additional, Abrahamowicz, Michal, additional, Leonard, Gabriel, additional, Perron, Michel, additional, Richer, Louis, additional, Veillette, Suzanne, additional, Gaudet, Daniel, additional, Pike, Bruce, additional, Strug, Lisa J., additional, Wang, Yun, additional, Xu, Hongbin, additional, Taylor, Graeme, additional, Bennett, Steffany, additional, Paus, Tomas, additional, and Pausova, Zdenka, additional

Published
2018
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25. DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Author

Richard, Melissa A., Richard, Melissa A., Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A., Brody, Jennifer A., Irvin, Marguerite R., Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E., Jia, Yucheng, Syme, Catriona, Salfati, Elias L., Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H., Bressler, Jan, Morrison, Alanna C., Liu, Chunyu, Mendelson, Michael M., Uitterlinden, Andre G., van Meurs, Joyce B., Franco, Oscar H., Zhang, Guosheng, Li, Yun, Stewart, James D., Bis, Joshua C., Psaty, Bruce M., Chen, Yii-Der Ida, Kardia, Sharon L. R., Zhao, Wei, Turner, Stephen T., Absher, Devin, Aslibekyan, Stella, Starr, John M., Mcrae, Allan F., Hou, Lifang, Just, Allan C., Schwartz, Joel D., Vokonas, Pantel S., Menni, Cristina, Spector, Tim D., Shuldiner, Alan, Damcott, Coleen M., Rotter, Jerome I., BIOS Consortium, van Greevenbroek, Marleen, Stehouwer, Coen, van der Kallen, Carla, Schalkwijk, Casper, Fornage, Myriam, Richard, Melissa A., Richard, Melissa A., Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A., Brody, Jennifer A., Irvin, Marguerite R., Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E., Jia, Yucheng, Syme, Catriona, Salfati, Elias L., Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H., Bressler, Jan, Morrison, Alanna C., Liu, Chunyu, Mendelson, Michael M., Uitterlinden, Andre G., van Meurs, Joyce B., Franco, Oscar H., Zhang, Guosheng, Li, Yun, Stewart, James D., Bis, Joshua C., Psaty, Bruce M., Chen, Yii-Der Ida, Kardia, Sharon L. R., Zhao, Wei, Turner, Stephen T., Absher, Devin, Aslibekyan, Stella, Starr, John M., Mcrae, Allan F., Hou, Lifang, Just, Allan C., Schwartz, Joel D., Vokonas, Pantel S., Menni, Cristina, Spector, Tim D., Shuldiner, Alan, Damcott, Coleen M., Rotter, Jerome I., BIOS Consortium, van Greevenbroek, Marleen, Stehouwer, Coen, van der Kallen, Carla, Schalkwijk, Casper, and Fornage, Myriam

Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p <1.0 x 10(-7); replication: N = 7,182, p <1.6 x 10(-3)). The replicated methylation sites are heritable (h(2) > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

Published
2017

26. Abstract 044: Sex Differences in Relative Contributions of Hemodynamic Parameters to Blood Pressure: A Population-based Study of Adolescents and Middle-aged Adults

Author

Syme, Catriona A, primary, Shin, Jean, additional, Abrahamowicz, Michal, additional, Leonard, Gabriel, additional, Perron, Michel, additional, Richer, Louis, additional, Veillette, Suzanne, additional, Gaudet, Daniel, additional, Paus, Tomas, additional, and Pausova, Zdenka, additional

Published
2017
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27. Glycerophosphocholine Metabolites and Cardiovascular Disease Risk Factors in Adolescents

Author

Syme, Catriona, primary, Czajkowski, Simon, additional, Shin, Jean, additional, Abrahamowicz, Michal, additional, Leonard, Gabriel, additional, Perron, Michel, additional, Richer, Louis, additional, Veillette, Suzanne, additional, Gaudet, Daniel, additional, Strug, Lisa, additional, Wang, Yun, additional, Xu, Hongbin, additional, Taylor, Graeme, additional, Paus, Tomas, additional, Bennett, Steffany, additional, and Pausova, Zdenka, additional

Published
2016
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30. CYP17A1 and blood pressure reactivity to stress in adolescence

Author

Van Woudenberg, Mariel, Shin, Jean, Bernard, Manon, Syme, Catriona, Abrahamowicz, Michal, Leonard, Gabriel T., Perron, Michel, Richer, Louis, Veillette, Suzanne, Gaudet, Daniel, Paus, Tomáš, Pausova, Zdenka, Van Woudenberg, Mariel, Shin, Jean, Bernard, Manon, Syme, Catriona, Abrahamowicz, Michal, Leonard, Gabriel T., Perron, Michel, Richer, Louis, Veillette, Suzanne, Gaudet, Daniel, Paus, Tomáš, and Pausova, Zdenka

Abstract

Adolescents who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges are at increased risk of developing hypertension in adulthood. BP at rest and in response to challenges is higher in males than females, beginning in early adolescence. CYP17A1 is one of the well-established gene loci of adult hypertension. Here, we investigated whether this gene locus is associated with elevated BP at rest and in response to physical (active standing) and mental (math stress) challenges in adolescence. We studied 496 male and 532 female adolescents (age 12–18 years) who were recruited from a genetic founder population. Our results showed that the variant of CYP17A1 rs10786718 was associated with enhanced BP reactivity to the mental but not physical challenge and in males but not females. In males, BP increase in response to math stress was higher in major versus minor allele homozygotes by 7.6 mm Hg (P = 8.3 x 10-6). Resting BP was not associated with the CYP17A1 variant in either sex. These results suggest that, in adolescent males but not females, CYP17A1 enhances BP reactivity to mental stress. Whether this effect contributes to the higher prevalence of hypertension in males than females later in life remains to be determined.

Published
2015

33. CYP17A1and Blood Pressure Reactivity to Stress in Adolescence

Author

Van Woudenberg, Mariel, primary, Shin, Jean, additional, Bernard, Manon, additional, Syme, Catriona, additional, Abrahamowicz, Michal, additional, Leonard, Gabriel, additional, Perron, Michel, additional, Richer, Louis, additional, Veillette, Suzanna, additional, Gaudet, Daniel, additional, Paus, Tomas, additional, and Pausova, Zdenka, additional

Published
2015
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34. The association among skeletal muscle phosphocreatine recovery, adiposity, and insulin resistance in children.

Author

Wells, Greg D., Banks, Laura, Caterini, Jessica E., Thompson, Sara, Noseworthy, Michael D., Rayner, Tammy, Syme, Catriona, McCrindle, Brian W., and Hamilton, Jill

Subjects
AEROBIC exercises, BODY weight, INSULIN resistance, METABOLISM, CHILDHOOD obesity, PHOSPHOCREATINE, REGRESSION analysis, STATISTICS, DATA analysis, OXIDATIVE stress, AEROBIC capacity, COOLDOWN, CROSS-sectional method, CASE-control method, SKELETAL muscle
Abstract

Background: Obesity is associated with cardiometabolic disturbances, which may have significant implications for musculoskeletal health and exercise tolerance. Objective: We sought to determine the association between muscle structure, function, and metabolism in adolescents across the weight spectrum. Methods: This cross‐sectional case–control study included overweight and obese participants (n = 24) 8–18 years of age with a body mass index (BMI) ≥ 85th percentile for age and gender, and non‐obese participants (n = 24) with a BMI < 85th percentile. Body composition, physical activity, peak aerobic capacity, cardiometabolic blood markers and insulin resistance (measured by the homeostatic model assessment of insulin resistance, HOMA‐IR), skeletal muscle mitochondrial oxidative capacity (via 31Phosphorous‐Magnetic Resonance Spectroscopy, 31P‐MRS, to assess phosphocreatine (PCr) recovery after exercise), and extramyocellular and intramyocellular lipid (IMCL) levels (via 1Hydrogen‐MRS) were assessed. Stepwise regression was performed to examine the factors associated with oxidative capacity. Results: bese and overweight patients had similar age, height, and physical activity to non‐obese controls, but obese and overweight participants exhibited higher insulin resistance. Obese and overweight participants had longer PCr recovery than non‐obese controls following 5x30s of moderate‐intensity exercise (51.2 ± 20.1 s vs. 23.9 ± 7.5 s, p = 0.004). In univariate correlation analysis, impaired PCr recovery was associated with a higher BMI z‐score (rs = 0.51, p < 0.001), circulating triglycerides (rs = 0.41, p = 0.005), and HOMA‐IR (rs = 0.46, p = 0.001). In stepwise multivariate regression analysis, impaired PCr recovery was associated with a higher BMI z‐score (β = 0.47, p = 0.002), but not insulin resistance (β = 0.07, p = 0.07) or circulating triglycerides (β = 0.16 p = 0.33). Conclusion: A slower phosphocreatine recovery following aerobic exercise is strongly associated with increasing adiposity. A slower metabolic recovery following aerobic exercise stress suggests that endurance exercise training in obese adolescents may be an optimal strategy to target exercise intolerance in this cohort. [ABSTRACT FROM AUTHOR]

Published
2017
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37. Routine clinical measures of adiposity as predictors of visceral fat in adolescence : a population-based magnetic resonance imaging study

Author

Goodwin, Katie, Syme, Catriona, Abrahamowicz, Michal, Leonard, Gabriel T., Richer, Louis, Perron, Michel, Veillette, Suzanne, Gaudet, Daniel, Paus, Tomáš, Pausova, Zdenka, Goodwin, Katie, Syme, Catriona, Abrahamowicz, Michal, Leonard, Gabriel T., Richer, Louis, Perron, Michel, Veillette, Suzanne, Gaudet, Daniel, Paus, Tomáš, and Pausova, Zdenka

Abstract

Objective : Visceral fat (VF) increases cardiometabolic risk more than fat stored subcutaneously. Here, we investigated how well routine clinical measures of adiposity, namely body mass index (BMI) and waist circumference (waist), predict VF and subcutaneous fat (SF) in a large population-based sample of adolescents. As body-fat distribution differs between males and females, we performed these analyses separately in each sex. Design and Methods : VF and SF were measured by magnetic resonance imaging in 1,002 adolescents (482 males, age 12–18 years). Relationships of BMI and waist with VF and SF were tested in multivariable analyses, which adjusted for potentially confounding effects of age and height. Results : In both males and females, BMI and waist were highly correlated with VF and SF, and explained 55–76% of their total variance. When VF was adjusted for SF, however, BMI and waist explained, respectively, only 0% and 4% of VF variance in males, and 4% and 11% of VF variance in females. In contrast, when SF was adjusted for VF, BMI and waist explained, respectively, 36% and 21% of SF variance in males, and 48% and 23% of SF variance in females. These relationships were similar during early and late puberty. Conclusions and Relevance : During adolescence, routine clinical measures of adiposity predict well SF but not VF. This holds for both sexes and throughout puberty. Further longitudinal studies are required to assess how well these measures predict changes of VF and SF over time. Given the clinical importance of VF, development of cost-effective imaging techniques and/or robust biomarkers of VF accumulation that would be suitable in everyday clinical practice is warranted.

Published
2013

43. Abstract 164: CYP17A1 Variant is Associated with Blood Pressure Reactivity to a Mental but not a Physical Challenge in Male Adolescents and May Be an Early Marker of Hypertension Risk

Author

Van Woudenberg, Mariel, primary, Melka, Melkaye G, additional, Bernard, Manon, additional, Syme, Catriona, additional, Abrahamowicz, Michal, additional, Leonard, Gabriel, additional, Perron, Michel, additional, Richer, Louis, additional, Veillette, Suzanna, additional, Gaudet, Daniel, additional, Paus, Tomas, additional, and Pausova, Zdenka, additional

Published
2012
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49. A Common Variant of the FTO Gene Is Associated With Not Only Increased Adiposity but Also Elevated Blood Pressure in French Canadians

Author

Pausova, Zdenka, primary, Syme, Catriona, additional, Abrahamowicz, Michal, additional, Xiao, Yongling, additional, Leonard, Gabriel T., additional, Perron, Michel, additional, Richer, Louis, additional, Veillette, Suzanne, additional, Smith, George Davey, additional, Seda, Ondrej, additional, Tremblay, Johanne, additional, Hamet, Pavel, additional, Gaudet, Daniel, additional, and Paus, Tomas, additional

Published
2009
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