What is the recommended approach for diagnosing Cerebral Amyloid Angiopathy (CAA)?

Diagnosis of Cerebral Amyloid Angiopathy (CAA)

Brain MRI without contrast is the primary diagnostic imaging modality for CAA, with diagnosis based on clinical-radiological criteria rather than requiring pathological confirmation in most cases. 1

Primary Diagnostic Approach

Clinical-Radiological Diagnosis (Preferred Method)

A clinical diagnosis of "probable CAA" can be established in patients aged 60 years or older presenting with multiple lobar hemorrhages confined to cortical-subcortical regions, without alternative causes of hemorrhage. 2

The diagnostic algorithm proceeds as follows:

• Age criterion: Patient must be ≥60 years old 2
• Hemorrhage pattern: Multiple hemorrhages restricted to lobar (cortical-subcortical) brain regions 2
• Exclusion of alternatives: No other identifiable cause of hemorrhage (trauma, coagulopathy, vascular malformation, tumor) 1

Essential MRI Sequences

MRI plays a critical role in detecting microhemorrhages associated with CAA and should include specific blood-sensitive sequences. 1

Required sequences include:

• T2 gradient-echo or susceptibility-weighted imaging (SWI)*: Essential for detecting microbleeds and superficial siderosis with high sensitivity 1, 3
• T2 FLAIR: Identifies white matter hyperintensities and cortical-subcortical changes 1
• DWI (diffusion-weighted imaging): Evaluates for acute ischemic changes 3
• Preferably performed on 3T scanner: Provides greater sensitivity for detecting microhemorrhages 4

Key Radiological Features

Gradient-echo MRI facilitates diagnosis by showing previous hemorrhages with high sensitivity, and approximately 50% of CAA patients develop new petechial hemorrhages during 1.5 years of follow-up. 2

Characteristic imaging findings include:

• Lobar microhemorrhages: Multiple cortical-subcortical microbleeds, particularly in posterior regions 1, 5
• Superficial siderosis: Hemosiderin deposition along cortical surface 3
• White matter hyperintensities: Often present but nonspecific 1, 5
• Cortical-subcortical hemorrhages: May be accompanied by subarachnoid, subdural, or intraventricular extension 5

Pathological Diagnosis (Gold Standard)

Pathological diagnosis remains the gold standard but is typically reserved for autopsy or when tissue is available from surgical intervention. 1

Histopathological Assessment

When tissue is available, the following approach is recommended:

• Staining methods: Congo red or thioflavin stains and amyloid-β immunocytochemistry provide optimal assessment 1
• Sampling sites: Middle cerebral artery-anterior cerebral artery watershed zones bilaterally are appropriate regions to screen for CAA 1
• Key assessments: Document focal versus widespread involvement, meningeal versus cortical distribution, and arteriolar versus capillary involvement 1
• Severity grading: Vonsattel grading evaluates degree of individual arterial wall involvement, multiplied by number of affected arteries per section 1
• Associated findings: Record perivascular hemorrhage (hemosiderin, hematoidin), CAA-associated inflammation, microaneurysm formation, and fibroid necrosis 1

Clinical Presentation Patterns

CAA presents with a spectrum of neurological manifestations including lobar intracerebral hemorrhage, brain ischemia, and cognitive decline. 6, 7

Key clinical scenarios:

• Acute hemorrhage: CT is the initial imaging study of choice for suspected acute cortical hemorrhage 5
• Cognitive impairment: Progressive decline affecting memory, executive function, and processing speed 3, 7
• Transient neurologic events: May occur without permanent deficits 5
• Asymptomatic cases: Many cases remain clinically silent 5

Age-Specific Considerations

Early-onset CAA (age <60 years) warrants specific investigation for genetic or iatrogenic causes. 8

For patients presenting before age 60:

• Genetic testing: Consider monogenic causes including APP mutations, PSEN1/PSEN2 mutations for amyloid-β CAA 8
• Non-amyloid-β CAA genes: Evaluate ITM2B, CST3, GSN, PRNP, and TTR mutations 8
• Iatrogenic causes: Newly recognized subtype requires specific investigation 8
• Family history: Essential component of evaluation in early-onset cases 8

Biomarker Considerations

Apolipoprotein E ε2 and ε4 alleles are associated with increased risk and earlier age of first hemorrhage, but are neither sensitive nor specific for CAA diagnosis. 2

Current limitations:

• APOE genotyping: Not recommended as a diagnostic test due to insufficient sensitivity and specificity 2
• Blood biomarkers: Not established for CAA diagnosis (unlike Alzheimer's disease) 2
• Future directions: Development of new markers for CAA presence remains a major challenge 2

Differential Diagnosis and Exclusions

Accurate recognition of imaging findings is important in guiding clinical decision making and excluding other causes of cortical-subcortical hemorrhage. 5

Must exclude:

• Hypertensive hemorrhage: Typically involves deep structures (basal ganglia, thalamus, pons, cerebellum) rather than lobar regions 1
• Vascular malformations: Catheter angiography may be needed if suggested by noninvasive testing 1
• Tumors: Primary CNS neoplasms or metastatic disease 1
• Coagulopathy: Review medication history and coagulation studies 1
• Trauma: Clinical history essential 1

Monitoring and Follow-up

MRI monitoring is critical for tracking disease progression and detecting new hemorrhages. 1, 2

Follow-up strategy:

• Repeat MRI: Consider if clinical decline occurs to track structural changes 3
• Cognitive assessment: Regular neuropsychological testing focusing on memory, executive function, and processing speed 3
• New hemorrhages: Gradient-echo sequences detect progression with high sensitivity 2

Critical Management Implications

The presence and number of microbleeds on gradient echo or susceptibility-weighted imaging fundamentally alters antithrombotic management. 3

Treatment considerations:

• <5 microbleeds: Antithrombotic therapy can generally proceed 3
• >5 microbleeds: Exercise extreme caution with antithrombotic therapy 3
• Lobar microhemorrhages with CAA pattern: Decision analysis studies recommend against anticoagulation even with atrial fibrillation 3
• ARIA monitoring: Critical for patients receiving amyloid-modifying therapies, as substantial lobar microhemorrhages likely reflect CAA presence and severity 1