NEUROIMAGING FINDINGS

ARIA consists of two primary classes of MRI signal abnormalities: ARIA-E (edema/effusion) and ARIA-H (hemorrhage), each with distinct imaging features that are crucial for accurate diagnosis and informed clinical decisions. Anti-Aβ therapy exacerbates the vulnerability of vessels affected by preexisting amyloid pathology, leading to vascular extravasation events. This vascular vulnerability is particularly pronounced in carriers of the ApoE4 allele, who exhibit increased amyloid deposition and reduced perivascular clearance [1,3]. 

The disruption of the blood-brain barrier during Aβ clearance mirrors inflammatory mechanisms seen in conditions like CAA-related inflammation, further exacerbating neurovascular compromise and contributing to ARIA. Antibody-mediated inflammation further amplifies vascular dysfunction, resembling mechanisms observed in amyloid angiopathy and inflammatory CAA [1,3,6].

ARIA-E arises from the leakage of proteinaceous fluid into the interstitial and sulcal spaces, while ARIA-H results from the extravasation of blood products through structurally compromised vessel walls. The degree of vascular permeability is determined by factors such as the severity of amyloid angiopathy, the efficacy of amyloid clearance, and the intensity of the accompanying local inflammatory response [3].

Fig 4: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

Fig 6: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

ARIA-E

ARIA-E is defined as the extravasation of fluid into interstitial spaces, resulting in vasogenic edema or sulcal effusion localized in the leptomeningeal or subpial spaces. These abnormalities manifest as hyperintense areas on T2-FLAIR sequences, often altering cortical folds and adjacent sulcal spaces. The sulcal effusion may indicate proteinaceous fluid leakage confined to these spaces. ARIA-E predominantly affects the occipital lobes, with involvement of parietal and frontal regions in severe cases [2,3].

Fig 7: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

• Vasogenic edema: Hyperintensities on T2-FLAIR sequences, predominantly in posterior cortical and subcortical regions. These lesions are typically transient, asymptomatic, and not associated with restricted diffusion, helping differentiate ARIA-E from ischemia [1,3].
  

  Fig 9: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).
  

  Fig 10: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

• Sulcal effusions: Hyperintense accumulations in leptomeningeal/subpial spaces without restricted diffusion. These reflect fluid exudation rather than active inflammation or ischemic insult.
  

  Fig 11: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

Gyral swelling and mass effect may accompany ARIA-E, especially in higher grade cases. When edema and effusion coexist, they are typically observed within the same anatomical region. The severity of ARIA-E depends on the location and extent of abnormalities, guiding therapeutic decisions, including dose adjustment or discontinuation of anti-amyloid treatment. Corticosteroid therapy has been anecdotally reported to mitigate severe ARIA-E, promoting faster resolution of symptoms and imaging findings[1-3]. 

ARIA-H

ARIA-H refers to microhemorrhages, macrohemorrhages, and superficial siderosis, characterized by hemosiderin deposition due to extravasation of blood products [2,3].

Fig 8: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

• Microhemorrhages. Small hypointense lesions (≤10 mm) visualized on T2* or SWI sequences. These circular or elliptical lesions result from micro ruptures in small blood vessels, allowing iron-containing blood products to leak into the brain parenchyma. Gradient echo sequences (T2*/SWI) offer superior sensitivity compared to T2 or FLAIR imaging for detecting these subtle changes.
  

  Fig 12: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

• Superficial siderosis. Curvilinear low-signal areas observed near the brain surface on T2* or SWI sequences. Unlike microhemorrhages, the leakage in superficial siderosis traverses into the subpial space or subarachnoid compartment. This distinction is critical for determining the severity and subtype of ARIA-H.
  

  Fig 13: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).
  

  Fig 14: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

Rare cases of macrohemorrhages have also been reported, often necessitating the discontinuation of therapy due to the potential for significant complications. The shared pathological mechanism for hemorrhagic ARIA subtypes involves vascular smooth muscle disruption, leading to the leakage of heme products into the surrounding compartments. Macrohemorrhages typically occur later in the treatment course and are strongly associated with anticoagulant or antiplatelet treatment use [1,2,7].

Fig 15: © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

The extent and distribution of hemosiderin deposition, including the number of affected areas, serve as markers for grading ARIA-H severity and guiding clinical interventions. ApoE4 carriers are at a significantly higher risk of ARIA-H, particularly in patients with baseline microhemorrhages [3]. 

ARIA GRADING SEVERITY 

ARIA severity grading classifies ARIA-E and ARIA-H based on lesion size, number, and distribution on MRI, aiding in treatment decisions and patient management.

Table 1: ARIA severity grading criteria. Adapted from Agarwal et al. RadioGraphics 2023 43:9

OPTIMIZED MRI PROTOCOL FOR ARIA DETECTION

Implementing a robust MRI protocol is essential for accurately detecting and monitoring ARIA across its subtypes.

• Imaging sequences 
  • T2-FLAIR. The cornerstone for diagnosing ARIA-E, highlighting vasogenic edema and sulcal effusions. Use ≤1 mm isotropic voxel size or ≤5 mm section thickness for optimal resolution.
•  
  • SWI or T2*. Crucial in the detection of ARIA-H, these sequences enhance the visualization of microhemorrhages and superficial siderosis by capturing hemosiderin deposition with higher sensitivity. SWI provides significant advantages over T2* for detecting ARIA-H, with superior sensitivity to small haemorrhages and hemosiderin deposits. It provides improved contrast and also minimizes blooming artefacts, offering a more accurate depiction of hemorrhagic burden. T2* is faster and more accessible but has limited sensitivity and resolution. SWI is preferred for precise evaluation, with T2* as an alternative if SWI is unavailable.
•  
  • DWI sequences. Essential for ruling out ischemic stroke, particularly in distinguishing ARIA-E lesions from ischemic events. 

• Imaging Parameters. When available, use high-field MRI scanners to maximize sensitivity to small hemorrhagic and edematous changes. Longer echo times and lower readout bandwidth enhance the detection microhemorrhages and siderosis. Contrast administration is generally unnecessary for ARIA detection but may help differentiate it from other pathologies when required.

• Timing. In addition to the initial screening MRI, follow-up MRIs should be scheduled before the 5th and 7th infusions (during titration) and again before the 12th infusion or if neurological symptoms occur. For patients with mild ARIA findings, additional follow-ups at shorter intervals, such as 4–6 weeks, may help monitor lesion progression and guide timely therapeutic adjustments [2,5,6].

• Interpretation
• Careful evaluation of cortical folds and sulci is critical for ARIA-E diagnosis. Differentiating ARIA-H subtypes -microhemorrhages versus superficial siderosis- requires attention to lesion shape, size, and compartmental distribution.

• Be mindful of the "blooming effect" on SWI/T2* sequences, which can exaggerate the size of microhemorrhages. Use the same MRI protocol for follow-up studies to allow accurate comparison.

• Collaborate closely with experienced neuroradiologists for the interpretation of subtle ARIA findings, particularly in patients with pre-existing microhemorrhages.

Differential Diagnosis

Accurately distinguishing ARIA from other conditions with overlapping imaging features is essential to avoid misclassification and guide appropriate management. The key differentials include [1-3]:

Table 2: Differential diagnosis (I). © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

Table 3: Differential diagnosis (II). © Radiology Department. Clínica Universidad de Navarra. Pamplona (Spain).

Pitfalls

Common pitfalls in ARIA evaluation include overestimation due to blooming artefacts, inconsistent imaging protocols compromising comparability, and overlap with preexisting pathologies. Subtle findings in asymptomatic cases, evolving lesion dynamics, and challenges in grading severity highlight the need for standardized criteria, high-resolution imaging, and regular follow-up.  

Table 4: Potential pitfalls to bear in mind when assessing ARIA.