What is ABRA?

ABRA: Amyloid β-Related Angiitis

ABRA (Amyloid β-Related Angiitis) is a rare, treatable form of central nervous system vasculitis that occurs when inflammatory cells attack blood vessels containing amyloid-β deposits, presenting most commonly in patients over 60 years with rapid-onset cognitive decline, focal neurological deficits, or seizures, and responds well to aggressive immunosuppression with steroids and cyclophosphamide. 1, 2

Pathophysiology and Etiology

• ABRA develops when perivascular beta-amyloid in intracerebral vessels triggers an inflammatory response mediated by CD68+ macrophages and CD3+ T lymphocytes, resulting in transmural granulomatous vasculitis superimposed on cerebral amyloid angiopathy (CAA). 1, 2

• The ApoE e4/e4 genotype is present in up to 70% of ABRA patients and may play a role in disease susceptibility, with associations to autoimmune diseases reported. 2

• ABRA represents a distinct subtype of CAA where immune-mediated inflammation differentiates it from non-inflammatory CAA. 2, 3

Clinical Presentation

Patients with ABRA are typically older than 60 years but younger than those with non-inflammatory CAA, presenting with acute-onset symptoms rather than the gradual progression seen in primary CNS vasculitis. 2

Cardinal Features:

• Acute cognitive and behavioral abnormalities are the most common presenting symptoms 2
• Focal neurological deficits including hemiparesis and hemisensory loss 1, 2
• Seizures occur frequently 2
• Unusual or severe headaches 2
• Paroxysmal recurrent neurological symptoms with accelerated progression 1
• Severe cases can progress to obtundation and coma 1

Laboratory Findings:

• Elevated CSF protein levels are present in the majority of patients 2
• CSF lymphocytic leukocytosis may be present without evidence of infection 1

Diagnostic Imaging

MRI is the most important diagnostic tool and is almost always abnormal in ABRA, with characteristic findings that may allow diagnosis without brain biopsy in typical cases. 2

Characteristic MRI Findings:

• Hyperintensities on T2-weighted or FLAIR images with minimal gadolinium enhancement are the hallmark findings 2
• Microbleeds at the cortico-subcortical junction are visible on susceptibility-weighted imaging (SWI) in the majority of patients 2
• MRI abnormalities resolve with treatment and recur with disease relapse, making serial imaging valuable for monitoring 2

Monitoring for ARIA-Related ABRA:

• In patients receiving anti-amyloid monoclonal antibody therapy (lecanemab, donanemab, aducanumab), mandatory MRI monitoring is required before the 5th, 7th, and 14th infusions to detect amyloid-related imaging abnormalities (ARIA), which share significant imaging overlap with ABRA. 4
• Required sequences include DWI, T2 FLAIR, and T2* GRE or SWI 4
• The discriminating feature between ARIA and ABRA is the history of anti-amyloid MAB therapy 4
• 3T MRI provides greater sensitivity for detecting microhemorrhages and subtle tissue changes compared to 1.5T 4, 5

Definitive Diagnosis

Brain biopsy remains the gold standard for diagnosis, showing transmural granulomatous vasculitis superimposed on CAA with perivascular lymphocytic infiltrate. 1, 2

• Histopathological examination demonstrates amyloid angiopathy with extensive perivascular lymphocytic infiltrate indicative of ABRA 1
• Intraoperative rapid diagnosis with frozen section can enable prompt initiation of steroid therapy 3
• In typical cases with characteristic clinical features and MRI findings, diagnosis may be possible without biopsy, though biopsy provides definitive confirmation 2

Treatment and Outcomes

ABRA responds well to aggressive immunosuppression, with steroids as first-line therapy and additional immunosuppressants typically needed to prevent relapse. 1, 2

Treatment Protocol:

• Initiate high-dose corticosteroids immediately upon diagnosis 1, 2
• Add cyclophosphamide for severe cases or as steroid-sparing agent 1
• Continue immunosuppression long-term, as patients usually require additional immunosuppressants to prevent relapse 2

Expected Outcomes:

• Impressive neurological improvements can occur even in patients presenting with coma 1
• Significant neurological recovery typically develops over several weeks of treatment 1
• MRI abnormalities resolve with successful treatment 2

Critical Pitfalls to Avoid

• Do not delay treatment while awaiting biopsy results in patients with severe presentations including coma or rapidly progressive deficits—intraoperative frozen section can guide immediate steroid initiation. 1, 3

• Do not confuse ABRA with primary CNS vasculitis or non-inflammatory CAA; ABRA patients are relatively younger than non-inflammatory CAA patients but older than primary CNS vasculitis patients 2

• In patients on anti-amyloid monoclonal antibody therapy, do not miss the diagnosis of ARIA, which presents identically to ABRA on imaging but requires modification or cessation of MAB therapy rather than immunosuppression 4

• Do not discontinue immunosuppression prematurely, as relapse is common and MRI can detect recurrence early 2

Differential Diagnosis Considerations

When evaluating for ABRA, consider these overlapping conditions:

• CAA-related inflammation (CAA-ri) in patients receiving anti-amyloid therapy 4
• Primary CNS vasculitis (typically younger patients) 2
• Non-inflammatory CAA (typically older patients with gradual progression) 2
• Posterior reversible encephalopathy syndrome 4
• Infectious or autoimmune meningitis 1