Pathological correlates of brain arterial calcifications

Abstract

Background: In clinical practice, calcifications seen on CT studies within the large brain arteries are often referred as a surrogate marker for cholesterol-mediated atherosclerosis. However, limited data exists to support the association between calcification and atherosclerosis. In this study, we examined if intracranial arterial calcifications were associated with cholesterol-mediated intracranial large artery atherosclerosis (ILAA) within the arteries of the Circle of Willis in an autopsy based sample. Methods: We carried out a cross-sectional analysis of histopathological characteristics of brain large arteries obtained from autopsy cases. Brain large arteries were examined for evidences of calcifications, which were rated as macroscopic (coalescent) and microscopic (scattered). In addition to calcification, we also obtained measurement of the arterial wall and the presence of ILAA and non-atherosclerotic arterial fibrosis. We built hierarchical models adjusted for demographic and vascular risk factors to assess the relationship between calcification and ILAA. Results: In univariate analysis, the presence of any arterial calcifications was associated with cerebral infarcts (29% v. 14%, p<0.01). Multi-variate analysis revealed that among all calcifications, coalescent calcifications were not associated with ILAA. In contrast, scattered calcifications were associated with ILAA (p<0.001), decreased lumen diameter (−1.87 +/− 0.41 mm p≤0.001) and increased luminal stenosis (0.03 +/− 0.01% p≤0.006). These findings were independent of age, sex or other vascular risk factors. Conclusions: This study demonstrates that coalescent calcifications in brain large arteries, although associated with morbidity, are not synonymous with cholesterol driven ILAA. Understanding the precise pathological components of cerebrovascular disease, including non-atherosclerotic arterial calcifications, will help develop individualized therapies beyond amelioration of traditional risk factors such as hyperlipidemia.

Understanding the Clinical Implications of Intracranial Arterial Calcification Using Brain CT and Vessel Wall Imaging

“…Priors studies have demonstrated that compared with the deep, coalescent calcification, superficial and scattered calcification was more associated with plaque instability (41,42). Furthermore, some scattered micro-calcifications that may be more related to culprit plaques (43) are beyond the resolution of a CT scan (44), which may lead to an underestimation of the prevalence of calcification in plaques. Lastly, since IAC is more prevalent in Asians, African Americans, and Hispanics than in Caucasians (20,26), larger studies involving other populations are needed to increase the generalizability of these findings.…”

Intracranial Atherosclerosis in Stroke Patients, Which Risk Factors Are Important? A Study From Mixed Ethnic Population in Singapore.

“…Although ICAD can be diagnosed with noninvasive imaging techniques like transcranial doppler and MRA, the gold standard for the diagnosis is DSA. (12,13,14,15) Autopsy studies are limited on ICAD and suggest that scattered calci cations (microscopic) are associated with cholesterol mediated intracranial large artery atherosclerosis, and stenosis as opposed to coalescent (macroscopic) calci cations (16). Another study concluded that only intimal calci cation as opposed to internal elastic lamina and adventitial calci cation was associated with ICAD.…”

Arterial Calcification and Its Association With Stroke: Implication of Risk, Prognosis, Treatment Response, and Prevention

“…They found that intimal calcification, medial calcification, and severity of calcification in IICA were all associated with stroke ( Golüke et al, 2020 ). Recently, a histopathology study of 211 autopsy cases also revealed that the presence of calcification in the circle of Willis was associated with ischemic infarcts ( Shapiro et al, 2019 ). Combined together, these results substantiated an association between IAC and the risk of stroke.…”

“…Recently, a histopathological study categorized calcifications in the circle of Willis into large calcifications (“coalescent”), which can be detected on CT, and small calcifications (“scattered”), which are likely undetectable on CT. They found that small calcifications were associated with cholesterol-driven intracranial large artery atherosclerosis while large calcifications were not associated with atherosclerosis ( Shapiro et al, 2019 ). Small calcification, or microcalcification, is not merely a process induced by atherosclerotic inflammation but it can also elicit a pro-inflammatory response in macrophages ( Nadra et al, 2005 ).…”