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Midlife Systemic Inflammation, Late-Life White Matter Integrity, and Cerebral Small Vessel Disease: The
Keenan A Walker1, Melinda C Power2, Ron C Hoogeveen2
1From the Department of Neurology (K.A.W., R.F.G.) and Department of Internal Medicine (E.S.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Epidemiology and Biostatistics, George Washington University Milken Institute School of Public Health (M.C.P.); Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX (R.C.H., C.M.B.); Center for Cardiovascular Disease Prevention, Houston Methodist DeBakey Heart and Vascular Center, TX (R.C.H., C.M.B.); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (A.R.F.); Department of Neurology (D.S.K.) and Department of Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Medicine, University of Mississippi Medical Center, Jackson (B.G.W.); and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (R.F.G., E.S.). kwalke26@jhmi.edu.
Background And Purpose:
It is currently unclear whether midlife systemic inflammation promotes the development of white matter (WM) abnormalities and small vessel disease in the elderly. We examined the association of midlife systemic inflammation with late-life WM hyperintensity volume, deep and periventricular WM microstructural integrity (fractional anisotropy and mean diffusivity [MD]), cerebral infarcts, and microbleeds in a biracial prospective cohort study.
Methods:
Linear and logistic regression examined the relation between midlife high-sensitivity C-reactive protein (CRP)-a nonspecific marker of inflammation-and brain magnetic resonance imaging markers assessed 21 years later in the Atherosclerosis Risk in Communities Study.
Results:
We included 1485 participants (baseline age, 56[5]; 28% black). After adjusting for demographic factors and cardiovascular disease, each SD increase in midlife CRP was associated with lower fractional anisotropy (-0.09 SD; 95% confidence interval, -0.15 to -0.02) and greater MD (0.08 SD; 95% confidence interval, 0.03-0.15) in deep WM and lower fractional anisotropy (-0.07 SD; 95% confidence interval, -0.13 to 0.00) in periventricular WM. We found stronger associations between CRP and periventricular WM microstructural integrity among black participants (P interaction=0.011). Although an association between higher CRP levels and greater WM hyperintensity volume was found only among APOE ε4-positive participants in our primary analysis (0.14 SD; 95% confidence interval, 0.01-0.26; P interaction=0.028), this relationship extended to the entire sample after accounting for differential attrition. Midlife CRP was not associated with the presence of cerebral infarcts or microbleeds in late life.
Conclusions:
Our findings support the hypothesis that midlife systemic inflammation may promote the development of chronic microangiopathic structural WM abnormalities in the elderly.
Insights
Midlife systemic inflammation, indicated by C-reactive protein (CRP), is linked to white matter abnormalities in older adults. This suggests inflammation may drive age-related brain changes and microangiopathy.
Area of Science:
- Neurology
- Gerontology
- Inflammation Research
Background:
- The link between midlife systemic inflammation and late-life brain abnormalities, including white matter (WM) changes and small vessel disease, remains unclear.
- Systemic inflammation may play a role in the development of age-related neurological conditions.
Purpose of the Study:
- To investigate the association between midlife systemic inflammation and late-life brain markers.
- To examine how inflammation impacts white matter hyperintensity volume, microstructural integrity, cerebral infarcts, and microbleeds.
Main Methods:
- Utilized data from the Atherosclerosis Risk in Communities Study, a biracial prospective cohort.
- Employed linear and logistic regression to analyze the relationship between midlife high-sensitivity C-reactive protein (CRP) and brain MRI markers assessed 21 years later.
- Included 1485 participants, adjusting for demographic factors and cardiovascular disease.
Main Results:
- Increased midlife CRP levels were associated with reduced white matter microstructural integrity (lower fractional anisotropy, higher mean diffusivity) in deep and periventricular WM.
- Stronger associations were observed between CRP and periventricular WM integrity in Black participants.
- An association between higher CRP and white matter hyperintensity volume was noted in APOE ε4-positive individuals, extending to the entire sample after accounting for attrition.
Conclusions:
- Midlife systemic inflammation may contribute to the development of chronic microangiopathic white matter abnormalities in older age.
- Findings support the role of inflammation in promoting structural brain changes associated with aging and small vessel disease.
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