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November 28, 2017; 89 (22) Article

Midlife systemic inflammatory markers are associated with late-life brain volume

The ARIC study

Keenan A. Walker, Ron C. Hoogeveen, Aaron R. Folsom, Christie M. Ballantyne, David S. Knopman, B. Gwen Windham, Clifford R. Jack, Rebecca F. Gottesman
First published November 1, 2017, DOI: https://doi.org/10.1212/WNL.0000000000004688
Keenan A. Walker
From the Departments of Neurology (K.A.W., R.F.G.) and Epidemiology (R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD; Section of Cardiology (R.C.H., C.M.B.), Baylor College of Medicine; Center for Cardiovascular Disease Prevention (R.C.H., C.M.B.), Houston Methodist DeBakey Heart and Vascular Center, TX; Division of Epidemiology and Community Health (A.R.F.), School of Public Health, University of Minnesota, Minneapolis; Departments of Neurology (D.S.K.) and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; and Department of Medicine (B.G.W.), University of Mississippi Medical Center, Jackson.
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Ron C. Hoogeveen
From the Departments of Neurology (K.A.W., R.F.G.) and Epidemiology (R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD; Section of Cardiology (R.C.H., C.M.B.), Baylor College of Medicine; Center for Cardiovascular Disease Prevention (R.C.H., C.M.B.), Houston Methodist DeBakey Heart and Vascular Center, TX; Division of Epidemiology and Community Health (A.R.F.), School of Public Health, University of Minnesota, Minneapolis; Departments of Neurology (D.S.K.) and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; and Department of Medicine (B.G.W.), University of Mississippi Medical Center, Jackson.
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Aaron R. Folsom
From the Departments of Neurology (K.A.W., R.F.G.) and Epidemiology (R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD; Section of Cardiology (R.C.H., C.M.B.), Baylor College of Medicine; Center for Cardiovascular Disease Prevention (R.C.H., C.M.B.), Houston Methodist DeBakey Heart and Vascular Center, TX; Division of Epidemiology and Community Health (A.R.F.), School of Public Health, University of Minnesota, Minneapolis; Departments of Neurology (D.S.K.) and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; and Department of Medicine (B.G.W.), University of Mississippi Medical Center, Jackson.
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Christie M. Ballantyne
From the Departments of Neurology (K.A.W., R.F.G.) and Epidemiology (R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD; Section of Cardiology (R.C.H., C.M.B.), Baylor College of Medicine; Center for Cardiovascular Disease Prevention (R.C.H., C.M.B.), Houston Methodist DeBakey Heart and Vascular Center, TX; Division of Epidemiology and Community Health (A.R.F.), School of Public Health, University of Minnesota, Minneapolis; Departments of Neurology (D.S.K.) and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; and Department of Medicine (B.G.W.), University of Mississippi Medical Center, Jackson.
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David S. Knopman
From the Departments of Neurology (K.A.W., R.F.G.) and Epidemiology (R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD; Section of Cardiology (R.C.H., C.M.B.), Baylor College of Medicine; Center for Cardiovascular Disease Prevention (R.C.H., C.M.B.), Houston Methodist DeBakey Heart and Vascular Center, TX; Division of Epidemiology and Community Health (A.R.F.), School of Public Health, University of Minnesota, Minneapolis; Departments of Neurology (D.S.K.) and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; and Department of Medicine (B.G.W.), University of Mississippi Medical Center, Jackson.
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B. Gwen Windham
From the Departments of Neurology (K.A.W., R.F.G.) and Epidemiology (R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD; Section of Cardiology (R.C.H., C.M.B.), Baylor College of Medicine; Center for Cardiovascular Disease Prevention (R.C.H., C.M.B.), Houston Methodist DeBakey Heart and Vascular Center, TX; Division of Epidemiology and Community Health (A.R.F.), School of Public Health, University of Minnesota, Minneapolis; Departments of Neurology (D.S.K.) and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; and Department of Medicine (B.G.W.), University of Mississippi Medical Center, Jackson.
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Clifford R. Jack Jr
From the Departments of Neurology (K.A.W., R.F.G.) and Epidemiology (R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD; Section of Cardiology (R.C.H., C.M.B.), Baylor College of Medicine; Center for Cardiovascular Disease Prevention (R.C.H., C.M.B.), Houston Methodist DeBakey Heart and Vascular Center, TX; Division of Epidemiology and Community Health (A.R.F.), School of Public Health, University of Minnesota, Minneapolis; Departments of Neurology (D.S.K.) and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; and Department of Medicine (B.G.W.), University of Mississippi Medical Center, Jackson.
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Rebecca F. Gottesman
From the Departments of Neurology (K.A.W., R.F.G.) and Epidemiology (R.F.G.), Johns Hopkins University School of Medicine, Baltimore, MD; Section of Cardiology (R.C.H., C.M.B.), Baylor College of Medicine; Center for Cardiovascular Disease Prevention (R.C.H., C.M.B.), Houston Methodist DeBakey Heart and Vascular Center, TX; Division of Epidemiology and Community Health (A.R.F.), School of Public Health, University of Minnesota, Minneapolis; Departments of Neurology (D.S.K.) and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; and Department of Medicine (B.G.W.), University of Mississippi Medical Center, Jackson.
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Citation
Midlife systemic inflammatory markers are associated with late-life brain volume
The ARIC study
Keenan A. Walker, Ron C. Hoogeveen, Aaron R. Folsom, Christie M. Ballantyne, David S. Knopman, B. Gwen Windham, Clifford R. Jack, Rebecca F. Gottesman
Neurology Nov 2017, 89 (22) 2262-2270; DOI: 10.1212/WNL.0000000000004688

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Abstract

Objective: To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late life using a large biracial prospective cohort study.

Methods: Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and Factor VIII) were assessed at baseline in 1,633 participants (mean age 53 [5] years, 60% female, 27% African American) enrolled in the Atherosclerosis Risk in Communities Study. Using all 5 inflammatory markers, an inflammation composite score was created for each participant. We assessed episodic memory and regional brain volumes, using 3T MRI, 24 years later.

Results: Each SD increase in midlife inflammation composite score was associated with 1,788 mm3 greater ventricular (p = 0.013), 110 mm3 smaller hippocampal (p = 0.013), 519 mm3 smaller occipital (p = 0.009), and 532 mm3 smaller Alzheimer disease signature region (p = 0.008) volumes, and reduced episodic memory (p = 0.046) 24 years later. Compared to participants with no elevated (4th quartile) midlife inflammatory markers, participants with elevations in 3 or more markers had, on average, 5% smaller hippocampal and Alzheimer disease signature region volumes. The association between midlife inflammation and late-life brain volume was modified by age and race, whereby younger participants and white participants with higher levels of systemic inflammation during midlife were more likely to show reduced brain volumes subsequently.

Conclusions: Our prospective findings provide evidence for what may be an early contributory role of systemic inflammation in neurodegeneration and cognitive aging.

GLOSSARY

AD=
Alzheimer disease;
ARIC=
Atherosclerosis Risk in Communities;
CI=
confidence interval;
DWR=
delayed word recall test;
FVIII=
Factor VIII;
MPRAGE=
magnetization-prepared rapid gradient echo;
ROI=
region of interest;
WBC=
white blood cell;
VWF=
von Willebrand factor

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received May 2, 2017.
  • Accepted in final form September 8, 2017.
  • © 2017 American Academy of Neurology
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