Hypertension may associate with cerebral small vessel disease and infarcts through the pathway of intracranial atherosclerosis

Abstract

Hypertension, a major modifiable risk factor for cardiovascular diseases, is linked to late-life neurocognitive disorders such as vascular dementia and Alzheimer's disease (AD). This study explores the associations between hypertension, intracranial atherosclerotic disease (ICAD), cerebral small vessel disease (cSVD), and Alzheimer's disease neuropathologic change (ADNC) in a large community-based autopsy study. This cross-sectional study used data from the Biobank for Aging Studies of the University of São Paulo Medical School. Sociodemographic and clinical information was gathered from a reliable next-of-kin informant. Neurofibrillary tangles, neuritic plaques, lacunar infarcts, hyaline arteriolosclerosis, and cerebral amyloid angiopathy were evaluated. Causal mediation analyses with natural effect models were performed to examine indirect associations of hypertension with cerebrovascular pathologies and ADNC through morphometric measurements of intracranial artery lumen obstruction. Hypertensive participants (n = 354) presented a higher rate of stenosed arteries (obstruction ≥ 50 %), critically stenosed arteries (obstruction ≥ 70 %), and more severe ICAD, shown by higher maximum and mean obstruction indexes compared to nonhypertensive participants (n = 166). These measurements of atherosclerosis were associated with neurofibrillary tangles and cSVD lesions. Hypertension was indirectly associated with hyaline arteriolosclerosis and lacunar infarcts through the pathway of ICAD. Presenting hypertension indirectly increased the odds of displaying hyaline arteriolosclerosis by 26 % (95 % CI: 1.08, 1.45, p = 0.002) and lacunar infarcts by 17 % (95 % CI: 1.01, 1.35, p = 0.029). Cognitive and APOE ε4 carrier status did not alter the investigated associations. In this community sample, hypertension was indirectly associated with cSVD through ICAD.

Keywords: Blood pressure; Circle of Willis; Dementia; Neuropathology; Small vessel disease.

Fig. 1.

Artery sections. (A) The Circle of Willis with its 12 arteries. (B) Section of the largest arterial obstruction at a right internal carotid artery. Blue: contour of the total sectioned area. Yellow: contour of the lumen area.

Fig. 2.

Directed acyclic graph illustrating the conceptual causal mediation model of the associations between hypertension, intracranial atherosclerosis, and neuropathological lesions. The effect is decomposed into a direct (red line) and indirect pathway (green line). Confounding variables were age, sex, race, education, diabetes, dyslipidemia, coronary artery disease, body mass index, alcohol use, and smoking, and APOE ε4 when available.

Fig. 3.

Comparison of obstruction index measures and the number of stenosed intracranial arteries between hypertensive and nonhypertensive participants. (A) Highest intracranial obstruction indexes by hypertension status. (B) Mean obstruction indexes by hypertension status. Individual participants’ obstruction indexes are represented as dots along the horizontal axis. (C) Stacked bar plot showing the number of stenosed arteries (≥ 50 % lumen occlusion) by hypertension status. (D) Bar plot showing the number of critically stenosed arteries (≥ 70 % lumen occlusion) by hypertension status. ***p-value > 0.001, unpaired t-test.

Fig. 4.

Odds Ratios and 95 % confidence intervals for direct (red) and indirect effects (green) of hypertension on neuropathology lesions through intracranial atherosclerosis measurements. OI: obstruction index. SA: stenosed arteries (≥ 50 % lumen occlusion). CSA: critically stenosed arteries (≥ 70 % lumen occlusion).