C-Reactive Protein, Plasma Amyloid-beta Levels, and Their Interaction With Magnetic Resonance Imaging Markers

Background and Purpose Inflammation is involved in the pathogenesis of large artery atherosclerosis, ischemic stroke, and Alzheimer dementia. However, the role of inflammation in cerebral small vessel disease and neurodegeneration remains poorly understood. We hypothesize that CRP (C-reactive protein) is associated with brain structural changes and may interact with amyloid to produce vascular and degenerative damage. We examined the association of CRP levels with imaging markers of cerebral small vessel disease and neurodegeneration. Furthermore, we studied the association of CRP with plasma A (amyloid-) levels and their joint effects with imaging markers. Methods We included 2814 persons (mean age, 56.9 years; 44.8% women) from the Rotterdam Study with complete data on CRP and 1.5 T brain magnetic resonance imaging scans. A levels were measured in a subsample (n=736). Markers of cerebral small vessel disease included lacunes, white matter hyperintensities, microbleeds, and enlarged perivascular spaces. Neurodegeneration was assessed by smaller volumes of gray matter, white matter, and hippocampus. Plasma levels of A1-38, A1-40, and A1-42 were assessed using ELISA. Results Higher CRP levels were associated with larger white matter hyperintensities volume (=0.07; 95% CI, 0.00-0.13), increasing lacunar (rate ratios, 1.61; 95% CI, 1.19-2.19), enlarged perivascular spaces (rate ratios, 1.01; 95% CI, 1.00-1.03), and deep/infratentorial microbleeds (rate ratios, 1.30; 95% CI, 1.00-1.69) counts. People with high CRP levels had small gray matter volume. We also found significant interaction between CRP and A such that among persons in higher tertiles of A1-42, a strong association was observed between CRP and lacunar (P interaction, 0.004), enlarged perivascular spaces (P interaction, 0.002), and microbleed counts (P interaction, <0.001). Similarly, among persons in higher tertile of A1-38, a strong association was observed between CRP and microbleed counts (P interaction, 0.004). Conclusions Higher CRP levels were associated with subclinical markers of cerebral small vessel disease and neurodegeneration. This effect was augmented by an interaction between CRP and A levels. Future longitudinal studies focusing on joint effects of CRP and A on progression of magnetic resonance imaging markers and cognitive decline are warranted.