Deborah Janowitz1, Mohamad Habes2,3,4, Jon B Toledo5, Anke Hannemann6, Stefan Frenzel7, Jan Terock7,8, Christos Davatzikos9, Wolfgang Hoffmann10,11, Hans Jörgen Grabe7,11. 1. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany. janowitz@uni-greifswald.de. 2. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany. habesm@uphs.upenn.edu. 3. Section of Biomedical Image Analysis, Department of Radiology, University of Pennsylvania, 3700 Hamiton Walk, Richards Building, Philadelphia, PA, 19104, USA. habesm@uphs.upenn.edu. 4. Institute for Community Medicine, University Medicine Greifswald, Ellernholzstr. 1-2, 17475, Greifswald, Germany. habesm@uphs.upenn.edu. 5. Department of Neurology, Stanley H. Appel Department of Neurology, Houston Methodist Hospital, 6560 Fannin St. Scurlock Tower, Houston, TX, 77030, USA. 6. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, F.-Sauerbruchstr, 17475, Greifswald, Germany. 7. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany. 8. Department of Psychiatry and Psychotherapy, HELIOS Hospital Stralsund, University Medicine Greifswald, Rostocker Chaussee 70, 18437, Stralsund, Germany. 9. Section of Biomedical Image Analysis, Department of Radiology, University of Pennsylvania, 3700 Hamiton Walk, Richards Building, Philadelphia, PA, 19104, USA. 10. Institute for Community Medicine, University Medicine Greifswald, Ellernholzstr. 1-2, 17475, Greifswald, Germany. 11. German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Ellernholzstr. 1-2, 17475, Greifswald, Germany.
Abstract
Inflammaging describes the complexity between low-grade chronic inflammation with the pathogenesis of brain aging and Alzheimer´s disease (AD). We aimed to find associations of inflammatory markers: i) white blood cell count (WBC), ii) high-sensitivity C-reactive protein (hs-CRP), and iii) fibrinogen with brain structures, sensitive neuroimaging markers of advanced brain aging and AD-like atrophy, and cognitive aging scores. We analyzed magnetic resonance imaging (MRI) scans of 2204 participants from the Study of Health in Pomerania-2 (SHIP-2) and SHIP-Trend (55.6% women, mean age 52.4±13.7 years). Associations of the inflammatory markers with specific brain signatures of brain aging (SPARE-BA), AD-like brain atrophy (SPARE-AD) and white matter disease (white matter hyperintensities volume (WMHV)) were investigated. Furthermore we explored their association with general brain structures including total brain volume (TBV), gray matter volume (GMV), and white matter volume (WMV), as well as cognitive scores (Nurnberger Age Inventory (NAI); Verbal Learning and Memory Test (VLMT). We adjusted for multiple vascular risk factors (VRF; e.g. smoking and blood pressure) and corresponding medication use to take their brain aging effects into account and corrected for false-discovery rate (FDR). Results: WBC was inversely associated with SPARE-BA (FDR-adjusted p=0.003), TBV (FDR-adjusted p=0.019) and GMV (FDR-adjusted p= 0.017). GMV was also inversely associated with hs-CRP (FDR-adjusted p=0.039) and fibrinogen (FDR-adjusted p=0.039). None of the inflammatory markers was associated with WMHV. Regression analysis also revealed a trend-level interaction between intake of antiinflammatory medication and hs-CRP with brain aging (SPARE-BA; FDR-adjusted p=0.062). Inflammatatory markers are associated with neuroimaging markers, with elevated WBC leading to significant acceleration in brain aging patterns but not with AD-like imaging structural changes. Given the overlap between accelerated brain aging and AD-like atrophy, increased WBC might be associated with global dementia symptoms due to this overlap in atrophy patterns. Elevated WBC may be not causal to preclinical AD dementia, but an accessory symptom of inflammaging. At population level, our results support the relevant roles of inflammatory markers on brain aging related atrophy.
Inflammaging describes the complexity between low-grade chronic inflammation with the pathogenesis of brain aging and Alzheimer´s disease (AD). We aimed to find associations of inflammatory markers: i) white blood cell count (WBC), ii) high-sensitivity C-reactive protein (hs-CRP), and iii) fibrinogen with brain structures, sensitive neuroimaging markers of advanced brain aging and AD-like atrophy, and cognitive aging scores. We analyzed magnetic resonance imaging (MRI) scans of 2204 participants from the Study of Health in Pomerania-2 (SHIP-2) and SHIP-Trend (55.6% women, mean age 52.4±13.7 years). Associations of the inflammatory markers with specific brain signatures of brain aging (SPARE-BA), AD-like brain atrophy (SPARE-AD) and white matter disease (white matter hyperintensities volume (WMHV)) were investigated. Furthermore we explored their association with general brain structures including total brain volume (TBV), gray matter volume (GMV), and white matter volume (WMV), as well as cognitive scores (Nurnberger Age Inventory (NAI); Verbal Learning and Memory Test (VLMT). We adjusted for multiple vascular risk factors (VRF; e.g. smoking and blood pressure) and corresponding medication use to take their brain aging effects into account and corrected for false-discovery rate (FDR). Results: WBC was inversely associated with SPARE-BA (FDR-adjusted p=0.003), TBV (FDR-adjusted p=0.019) and GMV (FDR-adjusted p= 0.017). GMV was also inversely associated with hs-CRP (FDR-adjusted p=0.039) and fibrinogen (FDR-adjusted p=0.039). None of the inflammatory markers was associated with WMHV. Regression analysis also revealed a trend-level interaction between intake of antiinflammatory medication and hs-CRP with brain aging (SPARE-BA; FDR-adjusted p=0.062). Inflammatatory markers are associated with neuroimaging markers, with elevated WBC leading to significant acceleration in brain aging patterns but not with AD-like imaging structural changes. Given the overlap between accelerated brain aging and AD-like atrophy, increased WBC might be associated with global dementia symptoms due to this overlap in atrophy patterns. Elevated WBC may be not causal to preclinical AD dementia, but an accessory symptom of inflammaging. At population level, our results support the relevant roles of inflammatory markers on brain aging related atrophy.
Entities:
Keywords:
Alzheimers; Epidemiology; Inflammation; Neuroimaging; hs-C-reactive protein
Authors: U John; B Greiner; E Hensel; J Lüdemann; M Piek; S Sauer; C Adam; G Born; D Alte; E Greiser; U Haertel; H W Hense; J Haerting; S Willich; C Kessler Journal: Soz Praventivmed Date: 2001
Authors: A L Jefferson; J M Massaro; P A Wolf; S Seshadri; R Au; R S Vasan; M G Larson; J B Meigs; J F Keaney; I Lipinska; S Kathiresan; E J Benjamin; C DeCarli Journal: Neurology Date: 2007-03-27 Impact factor: 9.910
Authors: Mohamad Habes; Aristeidis Sotiras; Guray Erus; Jon B Toledo; Deborah Janowitz; David A Wolk; Haochang Shou; Nick R Bryan; Jimit Doshi; Henry Völzke; Ulf Schminke; Wolfgang Hoffmann; Susan M Resnick; Hans J Grabe; Christos Davatzikos Journal: Neurology Date: 2018-08-03 Impact factor: 9.910
Authors: Mohamad Habes; Guray Erus; Jon B Toledo; Nick Bryan; Deborah Janowitz; Jimit Doshi; Henry Völzke; Ulf Schminke; Wolfgang Hoffmann; Hans J Grabe; David A Wolk; Christos Davatzikos Journal: Alzheimers Dement (Amst) Date: 2018-03-05
Authors: May A Beydoun; Gregory A Dore; Jose-Atilio Canas; Hailun Liang; Hind A Beydoun; Michele K Evans; Alan B Zonderman Journal: Front Aging Neurosci Date: 2018-10-09 Impact factor: 5.750
Authors: Anar Amgalan; Alexander S Maher; Satyaki Ghosh; Helena C Chui; Paul Bogdan; Andrei Irimia Journal: Geroscience Date: 2022-07-06 Impact factor: 7.713
Authors: Danni A Gadd; Robert F Hillary; Daniel L McCartney; Liu Shi; Aleks Stolicyn; Neil A Robertson; Rosie M Walker; Robert I McGeachan; Archie Campbell; Shen Xueyi; Miruna C Barbu; Claire Green; Stewart W Morris; Mathew A Harris; Ellen V Backhouse; Joanna M Wardlaw; J Douglas Steele; Diego A Oyarzún; Graciela Muniz-Terrera; Craig Ritchie; Alejo Nevado-Holgado; Tamir Chandra; Caroline Hayward; Kathryn L Evans; David J Porteous; Simon R Cox; Heather C Whalley; Andrew M McIntosh; Riccardo E Marioni Journal: Nat Commun Date: 2022-08-09 Impact factor: 17.694
Authors: Carla R Schubert; Mary E Fischer; A Alex Pinto; Adam J Paulsen; Yanjun Chen; Guan-Hua Huang; Barbara E K Klein; Michael Y Tsai; Natascha Merten; Karen J Cruickshanks Journal: Neurol Sci Date: 2022-09-17 Impact factor: 3.830
Authors: Antoine Weihs; Stefan Frenzel; Katharina Wittfeld; Anne Obst; Beate Stubbe; Mohamad Habes; András Szentkirályi; Klaus Berger; Ingo Fietze; Thomas Penzel; Norbert Hosten; Ralf Ewert; Henry Völzke; Helena U Zacharias; Hans J Grabe Journal: Sleep Date: 2021-03-12 Impact factor: 5.849
Authors: Stefan Frenzel; Katharina Wittfeld; Mohamad Habes; Johanna Klinger-König; Robin Bülow; Henry Völzke; Hans Jörgen Grabe Journal: Front Psychiatry Date: 2020-01-14 Impact factor: 4.157
Authors: Stefan Frenzel; Katharina Wittfeld; Robin Bülow; Henry Völzke; Nele Friedrich; Mohamad Habes; Stephan B Felix; Marcus Dörr; Hans J Grabe; Martin Bahls Journal: J Am Heart Assoc Date: 2021-09-01 Impact factor: 5.501
Authors: Eleanor L S Conole; Anna J Stevenson; Susana Muñoz Maniega; Sarah E Harris; Claire Green; Maria Del C Valdés Hernández; Mathew A Harris; Mark E Bastin; Joanna M Wardlaw; Ian J Deary; Veronique E Miron; Heather C Whalley; Riccardo E Marioni; Simon R Cox Journal: Neurology Date: 2021-11-17 Impact factor: 11.800
Authors: Ramon Casanova; Fang-Chi Hsu; Ryan T Barnard; Andrea M Anderson; Rajesh Talluri; Christopher T Whitlow; Timothy M Hughes; Michael Griswold; Kathleen M Hayden; Rebecca F Gottesman; Lynne E Wagenknecht Journal: Alzheimers Dement Date: 2021-07-26 Impact factor: 16.655