Inflammatory biomarkers, cerebral microbleeds, and small vessel disease

Abstract

Objective: We investigated the association between circulating biomarkers of inflammation and MRI markers of small vessel disease.Methods: We performed a cross-sectional study relating a panel of 15 biomarkers, representing systemic inflammation (high-sensitivity C-reactive protein, interleukin-6, monocyte chemotactic protein-1, tumor necrosis factor a, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), vascular inflammation (intercellular adhesion molecule 1, CD40 ligand, P-selectin, lipoproteinassociated phospholipase A 2 mass and activity, total homocysteine, and vascular endothelial growth factor), and oxidative stress (myeloperoxidase) to ischemic (white matter hyperintensities/silent cerebral infarcts) and hemorrhagic (cerebral microbleeds) markers of cerebral small vessel disease (CSVD) on MRI in 1,763 stroke-free Framingham offspring (mean age 60.2 6 9.1 years, 53.7% women). Results:We observed higher levels of circulating tumor necrosis factor receptor 2 and myeloperoxidase in the presence of cerebral microbleed (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.1-4.1 and OR 1.5, 95% CI 1.1-2.0, respectively), higher levels of osteoprotegerin (OR 1.1, 95% CI 1.0-1.2), intercellular adhesion molecule 1 (OR 1.7, 95% CI 1.1-2.5), and lipoproteinassociated phospholipase A 2 mass (OR 1.5, 95% CI 1.1-2.1), and lower myeloperoxidase (OR 0.8, 95% CI 0.7-1.0) in participants with greater white matter hyperintensity volumes and silent cerebral infarcts.Conclusions: Our study supports a possible role for inflammation in the pathogenesis of CSVD, but suggests that differing inflammatory pathways may underlie ischemic and hemorrhagic subtypes. If validated in other samples, these biomarkers may improve stroke risk prognostication and point to novel therapeutic targets to combat CSVD. Neurology ® 2015;84:825-832 GLOSSARY CAA 5 cerebral amyloid angiopathy; CI 5 confidence interval; CMB 5 cerebral microbleed; CSVD 5 cerebral small vessel disease; ICAM-1 5 intercellular adhesion molecule 1; ln 5 natural logarithm; Lp-PLA 2 5 lipoprotein-associated phospholipase A 2 ; OR 5 odds ratio; ROC 5 receiver operating characteristic; SCI 5 silent cerebral infarct; TNF-a 5 tumor necrosis factor a; TNFR2 5 tumor necrosis factor receptor 2; WMH 5 white matter hyperintensity.Cerebral small vessel disease (CSVD) assessed using brain MRI is characterized by 3 main findings that include cerebral microbleeds (CMBs), lacunes of presumed vascular origin (silent cerebral infarcts [SCIs]), and white matter hyperintensity (WMH). The vascular changes underlying ischemic and hemorrhagic CSVD likely include activation of the inflammatory cascade with endothelial failure and resulting neurovascular unit dysfunction.1-3 However, the specific mediators implicated in ischemic and hemorrhagic CSVD may differ.The Framingham Offspring Cohort provides a large, middle-age, community-based sample in which to investigate the association between systemic biomarkers of inflammation and MRI markers of CSVD. Given the complexity of i...

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

“…Although previous cross-sectional studies have demonstrated a link between systemic inflammation, reduced white matter microstructural integrity 4,15 and greater WMH volume 3,16 in older adults, it remains unknown whether systemic inflammation plays a pathogenic role in the development of these white matter changes. By demonstrating an association between white matter structural abnormalities among older adults and heightened systemic inflammation two decades earlier, our findings support the role of midlife systemic inflammation in the development of late-life white matter pathology.…”

“…Previous studies that have found an association between systemic inflammation, silent infarcts and CMBs have been cross-sectional 3,16,24,25 or have had relatively short follow-up periods 26 . It is possible that markers of systemic inflammation are only associated with cerebral infarcts or CMBs in older adults when inflammatory biomarkers are measured during late-life or at a time more proximal to the event.…”

“…Although several cross-sectional studies have found evidence for an association between systemic inflammation, SVD 3 , and reduced white matter integrity 4 among older adults, the temporal relationship between systemic inflammation, and each of these neurologic changes is still not well understood. As such, it remains unclear whether systemic inflammation contributes to the early pathogenesis of white matter changes and SVD, or if it is merely an associated feature or an epiphenomenon of these neurologic processes.…”

Hypertension and the Brain: A Risk Factor for More Than Heart Disease

“…Peripheral markers of endothelial activation like soluble vascular cellular adhesion molecule-1, soluble intercellular adhesion molecule-1 (sICAM-1), sP-selectin, and sE-selectin associate with cSVD-related MRI markers and reduced cognitive performance in patients with essential hypertension, indicating a role of endothelial activation in the pathogenesis of hypertension-mediated cSVD [75,76] . Independently, sICAM-1 levels appear to be an essential marker for lacunar stroke, early neurological deterioration and in patients with white-matter lesions [61,77] .…”

Neurocritical Care for Patients with Kidney Dysfunction

“…In a subgroup analysis of the Framingham Heart Study correlating circulating biomarkers of inflammation with brain MRI, elevated intercellular adhesion molecule-1 was associated with greater burden of WMH [89]. Intercellular adhesion molecule-1 reflects endothelial dysfunction and has also been strongly associated with progression of urinary protein loss in diabetic nephropathy [90].…”