Atherosclerotic burden and cerebral small vessel disease: exploring the link through microvascular aging and cerebral microhemorrhages

Abstract

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). This review paper delves into the hypothesis that atherosclerosis, a prevalent age-related large vessel disease, extends its pathological influence into the cerebral microcirculation, thereby contributing to the development and progression of CSVD, with a specific focus on CMHs. We explore the concept of vascular aging as a continuum, bridging macrovascular pathologies like atherosclerosis with microvascular abnormalities characteristic of CSVD. We posit that the same risk factors precipitating accelerated aging in large vessels (i.e., atherogenesis), primarily through oxidative stress and inflammatory pathways, similarly instigate accelerated microvascular aging. Accelerated microvascular aging leads to increased microvascular fragility, which in turn predisposes to the formation of CMHs. The presence of hypertension and amyloid pathology further intensifies this process. We comprehensively overview the current body of evidence supporting this interconnected vascular hypothesis. Our review includes an examination of epidemiological data, which provides insights into the prevalence and impact of CMHs in the context of atherosclerosis and CSVD. Furthermore, we explore the shared mechanisms between large vessel aging, atherogenesis, microvascular aging, and CSVD, particularly focusing on how these intertwined processes contribute to the genesis of CMHs. By highlighting the role of vascular aging in the pathophysiology of CMHs, this review seeks to enhance the understanding of CSVD and its links to systemic vascular disorders. Our aim is to provide insights that could inform future therapeutic approaches and research directions in the realm of neurovascular health.

Keywords: Aging; Arteriosclerosis; Atherosclerosis; Blood–brain barrier; Leukoaraiosis; Microbleed; Peripheral artery disease; Stroke; Vascular dementia; White matter hyperintensities; White matter injury.

Fig. 1

Continuum of accelerated vascular aging: bridging atherosclerotic diseases and cerebral small vessel disease (CSVD). This schematic figure illustrates the central role of fundamental cellular and molecular mechanisms of aging, collectively driving the progression of both macrovascular and microvascular aging. The top portion of the figure highlights the interconnected hallmarks of aging, including oxidative stress, mitochondrial dysfunction, cellular senescence, and a heightened inflammatory state. These synergistic aging processes induce age-related functional and phenotypic changes in endothelial cells (EC) and vascular smooth muscle cells (VSMC), contributing to the pathogenesis of a range of vascular diseases associated with aging. Lifestyle risk factors such as unhealthy diets, smoking, sedentary behavior, and environmental risk factors like air pollution further accelerate these vascular aging processes. This leads to atherogenesis in large arteries, manifesting as carotid artery stenosis (CAS), coronary artery disease (CAD), and peripheral artery disease (PAD), as well as cerebral small vessel disease (CSVD) in the cerebral microcirculation. The model suggests that atherosclerotic vascular diseases and CSVD originate from common aging processes, accounting for the frequent co-occurrence of CAS, CAD and/or PAD, and neuroimaging manifestations of CSVD, such as cerebral microhemorrhages (CMHs) and white matter hyperintensities (WMH), in the elderly