Circulating IL-6 and CRP are associated with MRI findings in the elderly
The 3C-Dijon Study
Abstract
Objective:
The relation between inflammation and brain MRI findings in the elderly remains poorly known. We investigated the association of circulating interleukin-6 (IL-6) and C-reactive protein (CRP) levels with baseline and longitudinal white matter hyperintensities (WMH), silent brain infarction, and brain volumes in community-dwelling elderly free of dementia.
Methods:
We included 1,841 participants aged 65 to 80 years from the Three City-Dijon cohort. Participants followed an MRI examination at baseline and after a 4-year follow-up (n = 1,316). IL-6 and CRP concentrations were measured at baseline from fasting blood samples. WMH were detected with an automatic imaging processing method and gray matter, hippocampal, white matter, and CSF volumes were estimated with voxel-based morphometry. Silent brain infarctions were assessed visually and defined as focal lesions of ≥3 mm in the absence of stroke. We used analysis of covariance and logistic regression to model the associations between inflammatory biomarkers and brain MRI findings adjusting for potential confounders.
Results:
In cross-sectional analyses, higher IL-6 levels were associated with higher WMH volumes (p < 0.01), lower gray matter (p = 0.001) and hippocampal (p = 0.01) volumes, and increasing CSF volumes (p = 0.002) in a dose-relationship pattern. Similar but weaker relations were observed for CRP. We observed no associations between baseline inflammatory biomarker levels and the evolution of MRI findings over 4 years.
Conclusions:
IL-6, and, to a lesser degree, CRP levels were associated with WMH severity as well as global markers of brain atrophy. These results suggest that an inflammatory process may be involved in both age-associated brain alterations.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
File (appendix_e-1.docx)
- Download
- 11.09 KB
STUDY FUNDING
The 3C Study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale (INSERM), the Victor Segalen-Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, Ministry of Research–INSERM Programme “Cohortes et collections de donneés biologiques,” and the Fondation Plan Alzheimer.
REFERENCES
1.
Sullivan GW, Sarembock IJ, Linden J. The role of inflammation in vascular diseases. J Leukoc Biol 2000;67:591–602.
2.
Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology 2010;129:154–169.
3.
Muir KW, Tyrrell P, Sattar N, Warburton E. Inflammation and ischaemic stroke. Curr Opin Neurol 2007;20:334–342.
4.
Wolf PA, D'Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk profile from the Framingham Study. Stroke 1991;22:312–318.
5.
Jeerakathil T, Wolf PA, Beiser A, et al. Stroke risk profile predicts white matter hyperintensity volume: the Framingham Study. Stroke 2004;35:1857–1861.
6.
Das RR, Seshadri S, Beiser AS, et al. Prevalence and correlates of silent cerebral infarcts in the Framingham offspring study. Stroke 2008;39:2929–2935.
7.
Seshadri S, Wolf PA, Beiser A, et al. Stroke risk profile, brain volume, and cognitive function: the Framingham Offspring Study. Neurology 2004;63:1591–1599.
8.
Baune BT, Ponath G, Rothermundt M, Roesler A, Berger K. Association between cytokines and cerebral MRI changes in the aging brain. J Geriatr Psychiatry Neurol 2009;22:23–34.
9.
Fornage M, Chiang YA, O'Meara ES, et al. Biomarkers of inflammation and MRI-defined small vessel disease of the brain: The Cardiovascular Health Study. Stroke 2008;39:1952–1959.
10.
Hoshi T, Kitagawa K, Yamagami H, Furukado S, Hougaku H, Hori M. Relations of serum high-sensitivity C-reactive protein and interleukin-6 levels with silent brain infarction. Stroke 2005;36:768–772.
11.
Schmidt R, Schmidt H, Pichler M, et al. C-reactive protein, carotid atherosclerosis, and cerebral small-vessel disease: results of the Austrian Stroke Prevention Study. Stroke 2006;37:2910–2916.
12.
van Dijk EJ, Prins ND, Vermeer SE, et al. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation 2005;112:900–905.
13.
Wada M, Nagasawa H, Kurita K, et al. Cerebral small vessel disease and C-reactive protein: results of a cross-sectional study in community-based Japanese elderly. J Neurol Sci 2008;264:43–49.
14.
Wright CB, Moon Y, Paik MC, et al. Inflammatory biomarkers of vascular risk as correlates of leukoariosis. Stroke 2009;40:3466–3471.
15.
Jefferson AL, Massaro JM, Wolf PA, et al. Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study. Neurology 2007;68:1032–1038.
16.
Vascular factors and risk of dementia: design of the Three-City Study and baseline characteristics of the study population. Neuroepidemiology 2003;22:316–325.
17.
Maillard P, Delcroix N, Crivello F, et al. An automated procedure for the assessment of white matter hyperintensities by multispectral (T1, T2, PD) MRI and an evaluation of its between-centre reproducibility based on two large community databases. Neuroradiology 2008;50:31–42.
18.
DeCarli C, Fletcher E, Ramey V, Harvey D, Jagust WJ. Anatomical mapping of white matter hyperintensities (WMH): exploring the relationships between periventricular WMH, deep WMH, and total WMH burden. Stroke 2005;36:50–55.
19.
Zhu YC, Tzourio C, Soumare A, Mazoyer B, Dufouil C, Chabriat H. Severity of dilated Virchow-Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease: a population-based study. Stroke 2010;41:2483–2490.
20.
Lemaitre H, Crivello F, Grassiot B, Alperovitch A, Tzourio C, Mazoyer B. Age- and sex-related effects on the neuroanatomy of healthy elderly. Neuroimage 2005;26:900–911.
21.
Dufouil C, Richard F, Fievet N, et al. APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology 2005;64:1531–1538.
22.
Wersching H, Duning T, Lohmann H, et al. Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function. Neurology 2010;74:1022–1029.
23.
Lim JS, Kwon HM. Risk of “silent stroke” in patients older than 60 years: risk assessment and clinical perspectives. Clin Interv Aging 2010;5:239–251.
24.
Zhu YC, Dufouil C, Tzourio C, Chabriat H. Silent brain infarcts: a review of MRI diagnostic criteria. Stroke 2011;42:1140–1145.
25.
Kim KW, MacFall JR, Payne ME. Classification of white matter lesions on magnetic resonance imaging in elderly persons. Biol Psychiatry 2008;64:273–280.
26.
Moody DM, Brown WR, Challa VR, Ghazi-Birry HS, Reboussin DM. Cerebral microvascular alterations in aging, leukoaraiosis, and Alzheimer's disease. Ann NY Acad Sci 1997;826:103–116.
27.
ten Dam VH, van den Heuvel DM, de Craen AJ, et al. Decline in total cerebral blood flow is linked with increase in periventricular but not deep white matter hyperintensities. Radiology 2007;243:198–203.
28.
Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease: systematic review and meta-analysis. Neurobiol Aging 2009;30:337–352.
29.
Simpson JE, Fernando MS, Clark L, et al. White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responses. Neuropathol Appl Neurobiol 2007;33:410–419.
30.
Simpson JE, Ince PG, Higham CE, et al. Microglial activation in white matter lesions and nonlesional white matter of ageing brains. Neuropathol Appl Neurobiol 2007;33:670–683.
31.
DeCarli C, Massaro J, Harvey D, et al. Measures of brain morphology and infarction in the Framingham Heart Study: establishing what is normal. Neurobiol Aging 2005;26:491–510.
32.
Marsland AL, Gianaros PJ, Abramowitch SM, Manuck SB, Hariri AR. Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults. Biol Psychiatry 2008;64:484–490.
33.
Karas GB, Scheltens P, Rombouts SA, et al. Global and local gray matter loss in mild cognitive impairment and Alzheimer's disease. Neuroimage 2004;23:708–716.
34.
Apostolova LG, Thompson PM. Mapping progressive brain structural changes in early Alzheimer's disease and mild cognitive impairment. Neuropsychologia 2008;46:1597–1612.
35.
Gorelick PB. Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. Ann NY Acad Sci 2010;1207:155–162.
36.
Iadecola C. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 2010;120:287–296.
37.
Schwab C, McGeer PL. Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders. J Alzheimers Dis 2008;13:359–369.
38.
Spooren A, Kolmus K, Laureys G, et al. Interleukin-6, a mental cytokine. Brain Res Rev 2011;67:157–183.
39.
Schmidt R, Ropele S, Enzinger C, et al. White matter lesion progression, brain atrophy, and cognitive decline: the Austrian Stroke Prevention Study. Ann Neurol 2005;58:610–616.
40.
Godin O, Maillard P, Crivello F, et al. Association of white-matter lesions with brain atrophy markers: the three-city Dijon MRI study. Cerebrovasc Dis 2009;28:177–184.
Information & Authors
Information
Published In
Copyright
Copyright © 2012 by AAN Enterprises, Inc.
Publication History
Received: May 18, 2011
Accepted: October 18, 2011
Published online: February 22, 2012
Published in issue: March 6, 2012
Disclosure
C.L. Satizabal reports no disclosures. Dr. Zhu is funded by the French Chinese Foundation for Science and Applications (FFCSA), the China Scholarship Council (CSC), and the Association de Recherche en Neurologie Vasculaire (ARNEVA). Dr. Mazoyer reports no disclosures. Dr. Dufouil serves as an Associate Editor for the Journal of Alzheimer's Disease and serves as a consultant for Eisai Inc. Dr. Tzourio serves on scientific advisory boards for Merck Sharp & Dohme and Fondation Plan Alzheimer; has received speaker honoraria from Abbott; serves on the editorial boards of Neuroepidemiology and the Journal of Hypertension; and receives research support from Agence Nationale de la Recherche and Fondation Plan Alzheimer.
Authors
Author Contributions
C.L. Satizabal performed the statistical analysis and contributed to the interpretation of the data and the drafting of the manuscript for intellectual content. Dr. Zhu performed the assessment of silent brain infarctions in MRI and contributed to revising the manuscript for intellectual content. Dr. Mazoyer contributed to the design and conceptualization of the study. Dr. Dufouil contributed to the design and conceptualization of the study and revising the manuscript for intellectual content. Dr. Tzourio contributed to the design and conceptualization of the study, supervised the analysis of the data and the interpretation of the results, and revised the manuscript for intellectual content.
Metrics & Citations
Metrics
Citation information is sourced from Crossref Cited-by service.
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
- Clonal hematopoiesis of indeterminate potential (CHIP) in cerebromicrovascular aging: implications for vascular contributions to cognitive impairment and dementia (VCID), GeroScience, (2025).https://doi.org/10.1007/s11357-025-01654-1
- Exploratory Analysis of Cerebrospinal Fluid IL-6 and IL-17A Levels in Subcortical Small-Vessel Disease Compared to Alzheimer’s Disease: A Pilot Study, Diagnostics, 15, 6, (669), (2025).https://doi.org/10.3390/diagnostics15060669
- Machine learning-based risk prediction of mild cognitive impairment in patients with chronic heart failure: A model development and validation study, Geriatric Nursing, 62, (145-156), (2025).https://doi.org/10.1016/j.gerinurse.2025.01.022
- Research Progress in the Pathogenesis of Cognitive Dysfunction in White Matter Hyperintensities: A Narrative Review, Journal of Integrative Neuroscience, 24, 2, (2025).https://doi.org/10.31083/JIN24840
- CSF IL-6, GDF-15, GFAP and NfL levels in early Alzheimer disease: a pilot study, Therapeutic Advances in Neurological Disorders, 18, (2025).https://doi.org/10.1177/17562864251314773
- White Matter Hyperintensities: Cerebral Small‐Vessel Diseases and White Matter Microstructural Impairments, iRADIOLOGY, 3, 1, (5-25), (2025).https://doi.org/10.1002/ird3.121
- Resting-state functional connectivity is correlated with peripheral inflammatory markers in patients with major depressive disorder and healthy controls, Journal of Affective Disorders, 370, (207-216), (2025).https://doi.org/10.1016/j.jad.2024.11.017
- Associations of high-sensitivity C-reactive protein with neuropsychological outcomes and cerebral white matter hyperintensities in older adults at risk of dementia, Brain, Behavior, & Immunity - Health, 43, (100924), (2025).https://doi.org/10.1016/j.bbih.2024.100924
- Associations between inflammation and striatal dopamine D2-receptor availability in aging, Journal of Neuroinflammation, 22, 1, (2025).https://doi.org/10.1186/s12974-025-03355-0
- Loneliness Modulates Inflammation to Affect the Neurocognitive Function of Older Adults, PsychoNeuroImmunology, (459-492), (2025).https://doi.org/10.1007/978-3-031-73061-0_14
- See more
Loading...
View Options
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.
If you need immediate support or to place an order, please call or email customer service:
- 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
- 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
- [email protected]
We appreciate your patience during this time and apologize for any inconvenience.