Cerebral Amyloid Angiopathy (CAA) vs. CAA-Related Inflammation (CAA-ri)

1. Shared Pathological Basis

2. Cerebral Amyloid Angiopathy (CAA)

Pathophysiology

• Amyloid deposits in vessel walls cause luminal narrowing, fibrinoid necrosis, and microaneurysm formation
• Vessel wall weakening and microaneurysm rupture lead to hemorrhage
• The mechanism is primarily structural/vascular, not inflammatory

Age and Demographics

• Rare before age 55; prevalence rises steeply with age (up to 60% in unselected autopsies >90 years)
• Associated with Alzheimer disease histopathology in ~50% of cases; clinical dementia in 10-30%

Clinical Presentation

• Lobar intracerebral hemorrhage (ICH) - often multiple, recurrent, in normotensive elderly patients
• Transient focal neurological episodes (TFNEs) / "amyloid spells" - caused by cortical spreading depression from convexal subarachnoid hemorrhage or superficial siderosis
• Cognitive decline - gradual, progressive
• Seizures are less prominent as a presenting feature

MRI Findings

• Multiple lobar cerebral microbleeds (CMBs) on gradient echo or SWI
• Cortical superficial siderosis (hemosiderin deposits along cortical surface)
• Convexal subarachnoid hemorrhage
• White matter hyperintensities (T2/FLAIR) from ischemic small vessel disease
• Findings tend to be bilateral and relatively symmetric

Diagnostic Criteria

Treatment

• No specific disease-modifying therapy for CAA itself
• Avoid anticoagulants (high hemorrhage risk); antiplatelet decisions are individualized
• ICH managed supportively
• TFNEs: trial of topiramate, valproate, or gabapentin (targeting cortical spreading depression), tapered after 1-3 months
• ICH recurrence rate: 5-10% per year (vs. ~2%/year for hypertensive deep ICH)

3. CAA-Related Inflammation (CAA-ri)

Pathophysiology

• CAA-ri represents an immune-mediated inflammatory response directed against vascular amyloid deposits
• Two histological subtypes:
  • Perivascular inflammation - lymphocytic infiltration around vessels (more common, better prognosis)
  • Transmural granulomatous angiitis (ABRA) - granulomatous inflammation through the vessel wall (more aggressive)
• The inflammation causes vasogenic edema, white matter injury, and blood-brain barrier disruption

Age and Demographics

• Age ≥40 years (notably younger cutoff than CAA, which typically manifests after 55)
• Rare overall; considered a rare manifestation of CAA

Clinical Presentation (rapid onset - the key distinguishing feature)

• Subacute/acute onset of:
  • New headaches
  • Seizures (prominent)
  • Rapid cognitive decline or dementia
  • Behavioral changes
  • Focal neurological deficits
• The rapid, subacute course contrasts with the more chronic, slowly progressive course of pure CAA
• Symptoms are not directly attributable to an acute ICH

MRI Findings (key distinguishing feature)

• Asymmetric subcortical white matter hyperintensities (FLAIR/T2) - often unilateral or markedly asymmetric
• White matter changes extend to U-fibers (immediately subcortical white matter), reflecting vasogenic edema
• Multiple cortico-subcortical hemorrhagic lesions still present (CMBs, macrobleeds, cortical superficial siderosis) - reflecting underlying CAA
• Contrast enhancement of white matter lesions may be seen (reflects inflammation and BBB breakdown)
• The combination of asymmetric edematous WMH + hemorrhagic CAA markers is the diagnostic hallmark

Diagnostic Criteria (Table 66.2 - Auriel et al., 2016)

Treatment - and this is the most clinically important difference

• Immunosuppressive therapy is the mainstay - CAA itself does NOT respond to and does NOT require immunosuppression
• First line: IV methylprednisolone 1 g/day for 3-5 days, followed by oral prednisone with a taper over months
• Refractory cases: add cyclophosphamide, azathioprine, or mycophenolate mofetil
• Clinical and radiographic findings are often completely reversible with treatment - this reversibility strongly supports the diagnosis
• Most cases are monophasic, but relapses occur in up to one-third of patients (Kinnecom et al., 2007) - requiring long-term maintenance immunosuppression

4. Side-by-Side Comparison Table

5. Clinical Pearl

• Bradley and Daroff's Neurology in Clinical Practice (Chapter 66), pp. 1427-1429
• Recent reviews: Inflammatory CAA - broad clinical spectrum (de Souza & Tasker, 2023, J Clin Neurol); Neuroinflammation in CAA (van den Brink et al., 2024, EBioMedicine); International CAA Association guidelines (Cordonnier et al., 2025)

CAA-ri: Relapse Rates and Long-Term Immunosuppressive Strategies - Recent Evidence (2021-2026)

1. Relapse Rates - What the Data Shows

• 80-88% of patients achieve favorable short-term functional recovery with initial immunosuppressive therapy
• Despite this, relapses occur in 38-40% of patients over 3 years - a substantially higher rate than the older "one-third" figure quoted from Kinnecom et al. (2007) in previous textbooks
• A key finding: abrupt discontinuation of IV corticosteroid pulse therapy carries a hazard ratio of 4.68 (95% CI 1.57-13.93; p=0.006) for relapse compared to a slow oral taper - making the taper strategy critical, not just the initial dose

2. Risk Factors for Relapse

3. Current Treatment Protocols (2025 Guidelines)

First-Line: Corticosteroids (Strong Recommendation)

• IV methylprednisolone 1 g/day for 5 days (some centers use 3 days)
• Alternative: high-dose oral methylprednisolone if IV not feasible

1. Start at 1 mg/kg/day (max 60 mg; reduced to max 40 mg for patients >70 years)
2. Reduce by 5 mg every 1-2 weeks until 10 mg/day is reached
3. At 10 mg: perform a repeat MRI before proceeding with the final taper
4. Final taper: 1 mg/month (very slow final phase)
5. Total taper duration: typically 3-6 months, potentially longer if relapse risk is high

• Blood pressure monitoring
• Gastrointestinal protection (PPI)
• Bone protection (calcium/vitamin D, bisphosphonate)
• Infection prevention (PCP prophylaxis)
• Screening for hypoadrenalism and osteoporosis

Second-Line: Steroid-Sparing Immunosuppressants (Weak Recommendation)

• Limited response to corticosteroids
• Poor tolerability of steroids (common in elderly)
• Relapse during steroid taper or after discontinuation
• Diagnosis is secure (confirmed CAA-ri)

4. Monitoring Response to Treatment

• Serial neurological and cognitive examination
• Repeat MRI (particularly at the 10 mg/day steroid taper checkpoint and at treatment completion)
• Blood test monitoring (glucose, blood pressure, bone/adrenal markers)
• Both clinical improvement AND radiological improvement on MRI (reversal of asymmetric WMH) should be used to gauge treatment adequacy

5. An Emerging Subtype: Iatrogenic CAA-ri (iCAA-ri)

• Occurs in patients with prior neurosurgery (mean surgical age 17.2 years; CAA-ri onset 44.7 years later at mean age 61.8)
• Thought to arise from prion-like transmission of Aβ via contaminated cadaveric dura or surgical instruments
• 2 of 6 patients died within months of CAA-ri onset despite immunosuppression - suggesting worse prognosis than spontaneous CAA-ri
• Highlights that not all CAA-ri responds equally to steroids

6. The ARIA Connection - A Paradigm Shift

1. CSF anti-Aβ autoantibodies are now recognized as highly specific biomarkers for CAA-ri - their measurement may guide diagnosis without biopsy and risk-stratify AD patients before starting amyloid immunotherapy
2. PET imaging with 11C-PK11195 (microglial activation tracer) may offer future utility in monitoring neuroinflammatory activity in CAA-ri, though not yet in routine clinical use

7. What Remains Unknown - Key Evidence Gaps

Summary of Key Evidence