Cerebral Atherosclerosis: Pathology, Risks, and Insights

Cerebral atherosclerosis occurs when arteries supplying the brain narrow due to plaque buildup, increasing the risk of stroke and other complications. This progressive disease can remain silent for years before causing significant neurological consequences, making early recognition crucial for prevention and management.

Understanding its development and impact on cerebral circulation helps identify at-risk individuals and improve treatment strategies.

Pathological Basis

Cerebral atherosclerosis begins with endothelial dysfunction, disrupting vascular homeostasis. The endothelium, a single layer of cells lining arterial walls, regulates vascular tone, prevents thrombosis, and modulates inflammation. Chronic insults such as hypertension, hyperlipidemia, and smoking weaken endothelial function, increasing permeability and allowing low-density lipoprotein (LDL) cholesterol to infiltrate the arterial intima. This triggers a cascade of pathological events that progressively impair cerebral blood flow.

Once LDL particles penetrate the endothelium, they oxidize, prompting the recruitment of monocytes from the bloodstream. These immune cells differentiate into macrophages, which engulf oxidized LDL, forming foam cells—the hallmark of early atherosclerotic lesions. Over time, foam cells aggregate into fatty streaks, the first visible sign of atherosclerosis in cerebral arteries. While these early lesions may not immediately obstruct blood flow, they foster inflammation and accelerate disease progression. The arterial wall thickens as smooth muscle cells migrate from the media to the intima, proliferate, and secrete extracellular matrix components, further narrowing the lumen.

As the disease advances, arterial integrity deteriorates. Lipids, necrotic debris, and fibrotic tissue accumulate, forming complex plaques that may remain stable or become prone to rupture. Stable plaques have a thick fibrous cap that protects the lipid core from circulating blood, reducing the risk of acute thrombosis. Unstable plaques, with thin fibrous caps and large necrotic cores, are more likely to rupture. When this occurs, thrombogenic material enters the bloodstream, triggering platelet aggregation and clot formation, which can lead to transient ischemic attacks or ischemic strokes, depending on the severity of obstruction.

Plaque Formation And Composition

Atherosclerotic plaque formation in cerebral arteries is a dynamic process that alters vascular structure and function. The earliest lesions, fatty streaks, result from lipid-laden cells accumulating within the arterial intima. These deposits primarily consist of oxidized LDL cholesterol, which disrupts cellular signaling and prompts smooth muscle cells to migrate and proliferate. This migration contributes to a fibrous matrix that encapsulates lipid cores, transforming fatty streaks into complex plaques.

Mature plaques contain a lipid-rich necrotic core, fibrous tissue, and calcified regions. The necrotic core, formed by lipid breakdown and cellular debris, is highly thrombogenic. Surrounding it is a fibrous cap composed of collagen, elastin, and proteoglycans, which stabilizes the plaque. Thicker caps are more resistant to rupture, while thinner caps are prone to fissuring, increasing the risk of thrombosis.

Plaque calcification also plays a role in disease progression. Microcalcifications within the fibrous cap can weaken structural integrity, increasing rupture risk, while extensive calcification may stabilize plaques by reinforcing the arterial wall. Imaging studies indicate that cerebral plaques with spotty or fragmented calcifications are more often linked to ischemic events, highlighting the significance of plaque composition in stroke risk.

Arterial Remodeling

As cerebral atherosclerosis progresses, arterial walls undergo structural changes that influence disease trajectory. Arterial remodeling refers to vessel adaptations in response to plaque accumulation and altered blood flow. In some cases, outward remodeling occurs, where the external elastic membrane expands to preserve luminal diameter despite growing plaque volume. This initially maintains adequate blood flow, delaying symptoms. However, once compensation is exceeded, luminal narrowing impairs cerebral perfusion.

Conversely, inward or constrictive remodeling worsens stenosis by reducing arterial diameter alongside plaque growth. This maladaptive response, often seen in high-risk lesions, increases the likelihood of ischemic events. Studies using intravascular ultrasound (IVUS) and high-resolution MRI have shown that constrictive remodeling is associated with lipid-rich plaques and thin fibrous caps, making them more prone to rupture. As arterial walls stiffen due to extracellular matrix deposition and calcification, vascular compliance decreases, heightening the risk of cerebrovascular complications.

Inflammatory Changes

Chronic inflammation drives cerebral atherosclerosis, perpetuating vascular damage and destabilizing plaques. Endothelial dysfunction triggers an immune response, as injured arterial walls release chemotactic signals that attract leukocytes. These immune cells release pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), exacerbating vascular injury.

Inflammation also alters vascular smooth muscle cells, shifting them from a contractile to a synthetic phenotype. This leads to excessive extracellular matrix deposition and fibrous cap remodeling, increasing plaque vulnerability. Additionally, inflammatory mediators stimulate matrix metalloproteinases (MMPs), enzymes that degrade structural proteins within the arterial wall. Elevated MMP activity weakens fibrous caps, making plaques prone to rupture—one of the primary triggers of ischemic events.

Neurological Manifestations

Progressive narrowing of cerebral arteries leads to neurological deficits, which vary in severity depending on blood flow restriction. In early stages, cerebral atherosclerosis may be asymptomatic, as collateral circulation helps maintain perfusion. However, as stenosis worsens, neurons become increasingly vulnerable to ischemia, leading to cognitive decline, motor dysfunction, and sensory disturbances. Patients may experience memory lapses, difficulty concentrating, or slowed processing speed, which can resemble early vascular cognitive impairment.

When plaque rupture occurs, neurological consequences can be immediate. Embolic events from unstable plaques may cause transient ischemic attacks (TIAs) or ischemic strokes. TIAs, or “mini-strokes,” present as temporary symptoms such as unilateral weakness, slurred speech, or visual disturbances, typically resolving within 24 hours. These episodes signal an elevated risk of major stroke. Complete arterial occlusion results in permanent ischemic injury and infarction, leading to lasting neurological deficits. The affected brain region dictates symptoms, with middle cerebral artery involvement often causing hemiparesis and aphasia, while vertebrobasilar artery disease may result in dizziness, ataxia, or bilateral motor impairments.

Imaging Techniques

Diagnosing cerebral atherosclerosis requires advanced imaging to assess arterial structure and function. Non-invasive techniques such as magnetic resonance angiography (MRA) and computed tomography angiography (CTA) provide high-resolution images of arterial lumens, detecting stenotic lesions and plaque burden. MRA, which uses magnetic resonance imaging, is particularly useful for evaluating intracranial arteries without ionizing radiation. CTA, employing contrast-enhanced computed tomography, offers superior spatial resolution for detecting calcified plaques and vessel narrowing.

High-resolution vessel wall MRI allows direct visualization of arterial walls, distinguishing stable fibrous plaques from high-risk lipid-rich lesions. For functional assessment of cerebral perfusion, transcranial Doppler ultrasound measures blood flow velocity in major intracranial arteries. Positron emission tomography (PET) imaging with targeted tracers has also been explored for detecting vascular inflammation, which contributes to plaque instability. These imaging advancements improve stroke risk stratification and guide targeted interventions.

Common Arterial Sites

Atherosclerotic lesions in cerebral arteries follow distinct patterns, with certain segments more susceptible due to hemodynamic stress and vascular geometry. The internal carotid arteries, particularly at the carotid bifurcation, are frequently affected due to turbulent blood flow, promoting endothelial dysfunction and lipid accumulation. Stenosis at this site is a major cause of ischemic strokes, as embolic material from unstable plaques can travel distally to occlude intracranial arteries.

Within the intracranial circulation, the middle cerebral artery (MCA) is commonly involved. As the largest branch of the internal carotid artery, the MCA supplies critical cortical and subcortical regions responsible for motor and sensory function. Significant stenosis or occlusion in this artery often results in severe neurological deficits, including hemiparesis and language impairments. The basilar artery, supplying the brainstem and posterior circulation, is another high-risk site. Atherosclerotic narrowing here increases the risk of brainstem infarction, which can manifest as vertigo, dysarthria, and impaired consciousness. Identifying these vulnerable sites through imaging and clinical evaluation allows for targeted interventions to prevent stroke and preserve neurological function.