What is cerebral amyloid angiopathy in older adults?

What is Cerebral Amyloid Angiopathy?

Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease characterized by progressive accumulation of amyloid-beta (Aβ) peptide in the walls of cortical and leptomeningeal blood vessels, resulting in vessel fragility that leads to lobar intracerebral hemorrhage, cognitive impairment, and other neurological complications. 1, 2

Pathophysiology

CAA predominantly affects lobar territories of the brain, in contrast to hypertensive arteriosclerosis which affects deep brain structures. 3 The disease process involves:

• Deposition of amyloid-beta protein in cerebrovascular walls weakens vessel integrity and increases vascular permeability, leading to both hemorrhagic and ischemic complications 3, 1
• The apolipoprotein E ε2 and ε4 alleles are primary genetic risk factors, with ε4 carriers showing higher vascular amyloid burden 3
• Amyloid accumulation can be assessed using Congo red or thioflavin stains and amyloid-β immunocytochemistry, with evaluation of focal versus widespread involvement, meningeal versus cortical distribution, and arteriolar versus capillary involvement 4

Clinical Manifestations

CAA presents with several distinct clinical syndromes:

Hemorrhagic Complications

• Lobar intracerebral hemorrhage is the most common presentation, with approximately 7% annual recurrence risk in patients with prior CAA-related ICH 5, 2
• Cortical microhemorrhages detected on susceptibility-weighted imaging (SWI) or gradient-echo sequences are highly specific markers, appearing as punctate areas of signal loss 4, 5, 6
• Cortical superficial siderosis results from repeated microbleeds in the subarachnoid space, with prevalence of only 0.7% in population studies but serving as a strong indicator of CAA 4
• Convexity subarachnoid hemorrhage can occur, often associated with transient focal neurological episodes 7, 6

Cognitive and Ischemic Manifestations

• CAA contributes significantly to age-related cognitive decline and dementia, independent of hemorrhagic complications 3, 2
• White matter hyperintensities on FLAIR imaging reflect ischemic changes, with severity correlating with amyloid burden particularly in parietal-occipital regions 4
• Cortical microinfarcts (not visible to naked eye but detected histologically) contribute to cognitive impairment 4

Inflammatory Variants

• CAA-related inflammation presents with vasogenic edema, leptomeningeal involvement, and granulomatous inflammation around affected vessels, often responsive to immunosuppressive treatment 4, 2
• This inflammatory response shares features with amyloid-related imaging abnormalities (ARIA) seen with anti-amyloid immunotherapies, including FLAIR hyperintensities in parenchyma and leptomeninges 4

Diagnostic Approach

MRI with T1, T2, FLAIR, and susceptibility-weighted imaging (SWI) or gradient-echo (GRE) sequences is mandatory for diagnosis and risk stratification—CT alone is insufficient as it cannot detect microhemorrhages or superficial siderosis. 5, 1

Imaging Markers

• Multiple juxtacortical microhemorrhages on SWI in lobar distribution are highly specific for CAA, distinguishing it from hypertensive angiopathy which causes deep microhemorrhages 5, 1
• The Boston criteria version 2.0 provide standardized diagnostic framework based on imaging findings 1, 7
• White matter hyperintensities should be quantified using validated scales such as the Fazekas scale 5
• Serial imaging tracks disease progression and hemorrhage risk 5

Additional Diagnostic Tools

• Amyloid PET imaging with Pittsburgh Compound B can detect CAA but cannot distinguish vascular from parenchymal deposits 6
• CSF markers including Aβ40 levels and anti-Aβ antibodies may aid diagnosis, particularly for CAA-related inflammation 6

Clinical Significance and Risk Stratification

The presence of CAA fundamentally alters clinical decision-making regarding antithrombotic therapy, anticoagulation for atrial fibrillation, and eligibility for anti-amyloid immunotherapy. 1, 2, 7

Key Risk Considerations

• Baseline microhemorrhages increase risk of developing vasogenic edema with amyloid-modifying therapies (35% vs 6% without baseline microhemorrhages) 4
• Uncontrolled hypertension correlates with higher amyloid burden, particularly in APOE ε4 carriers 8
• The combination of CAA and hypertension has multiplicative effects on both hemorrhagic and ischemic stroke risk 8