Cerebral Microbleeds and Their Association With Inflammation and Blood-Brain Barrier Leakage in Small Vessel Disease

Abstract

Background: How cerebral microbleeds (CMBs) are formed, and how they cause tissue damage is not fully understood, but it has been suggested they are associated with inflammation, and they could also be related to increased blood-brain barrier (BBB) leakage. We investigated the relationship of CMBs with inflammation and BBB leakage in cerebral small vessel disease, and in particular, whether these 2 processes were increased in the vicinity of CMBs.

Methods: In 54 patients with sporadic cerebral small vessel disease presenting with lacunar stroke, we simultaneously assessed microglial activation using the positron emission tomography ligand [11C]PK11195 and BBB leakage using dynamic contrast enhanced magnetic resonance imaging, on a positron emission tomography-magnetic resonance imaging system. To assess local inflammation and BBB leakage, 3 one-voxel concentric shells were generated around each CMB on susceptibility-weighted imaging and resampled to positron emission tomography and T1 mapping images, respectively. In these 3 shells, we calculated the mean of PK11195 nondisplaceable binding potential (BPND) as a marker of microglial activation, as well as the mean influx rate as a marker of BBB leakage. In addition, 93 blood biomarkers related to cardiovascular disease, inflammation, and endothelial activation were measured to quantify systemic inflammation.

Results: No significant associations were found between the number of CMBs and the measures for microglial activation (β=2.6×10^-5, P=0.050) and BBB leakage (β=-0.0001, P=0.400) in the white matter. There was no difference in measures of microglial activation (P=0.403) or BBB leakage (P=0.423) across the 3 shells surrounding the CMBs. Furthermore, after correcting for multiple comparisons, no associations were observed between systemic inflammation biomarkers and the number of CMBs.

Conclusions: We found no evidence that CMBs are associated with either microglial activation assessed by [11]CPK11195 positron emission tomography or BBB leakage assessed by dynamic contrast enhanced magnetic resonance imaging, either globally or locally, in sporadic cerebral small vessel disease. There was also no association with markers of systemic inflammation.

Keywords: blood-brain barrier; cerebral small vessel diseases; inflammation; microglia; positron emission tomography.

Figure 1.

Flowchart of patient inclusion. cSVD indicates cerebral small vessel disease; DCE-MRI, dynamic contrast enhanced magnetic resonance imaging; MINERVA, Minocycline to Reduce Inflammation and Blood-Brain Barrier Leakage in Small Vessel Disease; and PET, positron emission tomography.

Figure 2.

Close-up of a cerebral microbleed (CMB) with 3 one-voxel concentric shells comprising the CMB penumbra (P); P1–3 shows penumbra progressively further away from the CMB.

Figure 3.

Spatial analysis of blood-brain barrier (BBB) leakage (influx rate [Ki]) and [11C]PK11195 binding potential (BPND) in the vicinity of cerebral microbleeds (CMB). A, Comparison of mean Ki in CMB penumbras. B, Comparison of mean BPND in penumbras.

Figure 4.

Mean 11C-PK11195 binding potential (BPND) in the penumbras of 4 new cerebral microbleeds (CMB).