What is cerebral amyloid angiopathy (CAA)?

What is Cerebral Amyloid Angiopathy?

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease characterized by the deposition of β-amyloid peptide in the walls of cortical and leptomeningeal arterioles and capillaries, predominantly affecting lobar brain territories and representing one of the two major causes of spontaneous intracerebral hemorrhage in the elderly. 1

Pathological Definition and Distribution

CAA involves β-amyloid accumulation specifically in the walls of small to medium-sized blood vessels of the brain, with a characteristic distribution pattern that distinguishes it from other cerebrovascular diseases 1:

• Lobar territories: Affects the leptomeninges, cerebral cortex, and cerebellar hemispheres 1
• Vessel types involved: Primarily arterioles and capillaries in the meningocortical microvasculature 1
• Spares deep structures: Unlike arteriolosclerosis (which affects basal ganglia, thalamus, and brainstem), CAA predominantly involves superficial brain regions 1

The pathological assessment can identify whether involvement is focal versus widespread, meningeal versus cortical, and arteriolar versus capillary 1.

Epidemiology and Risk Factors

CAA is an extremely common age-related pathology 1:

• Prevalence: Appears at autopsy at moderate to severe extents in 30-35% of individuals in longitudinal aging studies 1
• Primary risk factors: Age and apolipoprotein E genotypes containing the ε2 or ε4 alleles 1, 2
• Association with Alzheimer's disease: Frequently coexists with Alzheimer's pathology, as both involve β-amyloid deposition 3

The apolipoprotein E ε4 allele specifically is associated with higher vascular amyloid burden 1, 2.

Clinical Manifestations

CAA presents through several distinct clinical syndromes 3, 4:

Hemorrhagic Complications

• Lobar intracerebral hemorrhage: The most serious complication, occurring in deep lobar territories rather than deep brain structures 1, 3
• Convexity subarachnoid hemorrhage: Can cause transient focal neurological episodes 3, 4
• Microhemorrhages: Lobar microhemorrhages detected on MRI are markers of CAA, whereas deep microhemorrhages suggest hypertensive angiopathy 1
• Superficial siderosis: Cortical superficial siderosis is an indicator of CAA and bleeding risk 1

Ischemic Manifestations

• Cognitive decline: CAA contributes significantly to progressive cognitive decline and dementia in the elderly 2, 5
• Vessel dysfunction: β-amyloid deposition can produce reduced cerebral blood flow and ischemic lesions 5
• White matter disease: Associated with white matter hyperintensities on MRI 1, 2

Inflammatory Variant

• CAA-related inflammation: A minority of patients develop an autoimmune inflammatory reaction with spontaneous inflammatory response to vascular amyloid deposits 1, 3, 4
• Presentation: Shows clinical and neuroimaging features including leptomeningeal, grey matter, and white matter involvement 1
• Treatment responsiveness: Often responsive to immunosuppressive treatment, with findings reversing either spontaneously or with steroids 1, 6

Diagnostic Imaging Features

MRI reveals characteristic patterns of small vessel disease in CAA 2:

• Cerebral microhemorrhages: High prevalence in lobar locations detected on susceptibility-weighted imaging 1, 2
• White matter hyperintensities: Particularly in frontal and parieto-occipital regions 1
• Cortical superficial siderosis: Indicator of prior bleeding from CAA-affected vessels 1
• Leptomeningeal signal changes: Can show increased signal that may be misinterpreted as subarachnoid hemorrhage 1

Mechanisms of Vascular Injury

CAA weakens cerebral blood vessels through multiple mechanisms 1, 5:

• Vessel wall damage: β-amyloid accumulation increases vascular fragility and permeability 2
• Microaneurysm formation: CAA-associated microangiopathy can lead to microaneurysms and fibroid necrosis 1
• Impaired blood flow: Amyloid deposition alters vessel physiology and reduces cerebral perfusion 5
• Perivascular hemorrhage: Weakened vessel walls lead to blood leakage forming microhemorrhages 1

Clinical Implications for Treatment Decisions

The presence of CAA significantly impacts multiple clinical decisions 3, 4:

• Antithrombotic therapy risk: Patients with CAA have higher risk of hemorrhagic complications with anticoagulation 2, 4
• Anticoagulation considerations: Vitamin K antagonists are associated with twofold increased risk of intracerebral hemorrhage compared to direct oral anticoagulants 2
• Anti-amyloid immunotherapy: CAA affects safety considerations for anti-β-amyloid treatments in Alzheimer's disease 1, 4
• Hemorrhage recurrence: Number of microhemorrhages predicts risk of subsequent lobar hemorrhage 1

Relationship to Other Pathologies

CAA must be distinguished from arteriolosclerosis, the other major cause of spontaneous intracerebral hemorrhage 1:

• Arteriolosclerosis: Concentric hyalinized vascular wall thickening affecting deep territories (basal ganglia, thalamus, brainstem), associated with hypertension and diabetes 1
• CAA: β-amyloid deposition affecting lobar territories, associated with age and APOE genotype 1
• Co-occurrence: Both pathologies commonly coexist as age-related conditions 1

The location of hemorrhage provides the key clinical clue: deep hemorrhages suggest arteriolosclerosis, while lobar hemorrhages suggest CAA 1.