Midlife Systemic Inflammation, Late-Life White Matter Integrity, and Cerebral Small Vessel Disease

Abstract

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 white matter hyperintensity (WMH) volume, deep and periventricular WM microstructural integrity (fractional anisotropy [FA], 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 non-specific marker of inflammation, and brain MRI markers assessed 21 years later in the Atherosclerosis Risk in Communities Study. Results We included 1,485 participants (baseline age 56(5), 28% African American). After adjusting for demographic factors and cardiovascular disease, each standard deviation (SD) increase in midlife CRP was associated with lower FA (−0.09 SD; 95% CI:−0.15, −0.02) and greater MD (0.08 SD; 95% CI:0.03, 0.15) in deep WM, and lower FA (−0.07 SD; 95% CI:−0.13, 0.00) in periventricular WM. We found stronger associations between CRP and periventricular WM microstructural integrity among African American participants (p-interaction=.011). While an association between higher CRP levels and greater WMH volume was found only among APOE ε4-positive participants in our primary analysis (0.14 SD; 95% CI:0.01, 0.26; p-interaction=.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.

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury

“…The progressive, silent development of cerebral small vessel disease necessitates the development of alternative methods for identifying those at risk. In population studies, mid-life vascular risk factors increase the risk of white matter injury resulting from cSVD [17]. However, the identification of biomarkers to assist in separating those with concurrent vascular risk factors yet no brain injury from those with vascular risk factors who already have evidence of pathology from cerebral small vessel disease is critical to developing therapeutic strategies to stem this growing public health challenge.…”

“…High levels of chronic inflammation resulting from systemic vascular risk factors such as hypertension and diabetes are proposed to exacerbate cSVD by damaging cerebral endothelia. A number of systemic inflammatory indicators have been implicated in cSVD [17,18], yet do not coalesce around a specific molecular pathway. In this study, we aimed to investigate the association of a biologically interconnected network of systemic inflammatory markers centered on the pleiotropic pro-inflammatory cytokine IL-18 with sCVD burden.…”

Action Plan for Stroke in Europe 2018–2030

“…Bununla birlikte, mikrovasküler reperfüzyon her zaman gerçekleştirilemez, hastaların tamamı endovasküler tedaviden fayda sağlamayabilir ve hastaların çoğu da reperfüzyon tedavileri için uygun değildir. (106). İnme, sitokinler, vazoaktif maddeler, alarminler ve akut faz proteinleri de dahil olmak üzere, çözünür medyatörleri ve nöral sinyalleri barındıran çok fazlı bir sistemik enflamatuar yanıtı tetiklemekte olup, ardından immün yanıtlar inhibe edildiğinden inme sonrası enfeksiyon riski artmaktadır.…”

Differential effects of serum lipoprotein-associated phospholipase A2 on periventricular and deep subcortical white matter hyperintensity in brain

“…Nevertheless, systemic inflammation may contribute to the pathogenesis of WMH in the elder population in a recent prospective study involving a large sample size. This implied that systemic inflammation was correlated with the progression of CSVD, especially in the conditions with persistent inflammation [17].…”