Validation of 3- and 5-point severity scales to assess ARIA-E

Abstract

Introduction: Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) offer the promise of disease modification and are emerging treatment options in Alzheimer's disease. Anti-Aβ mAbs require brain magnetic resonance imaging (MRI) examinations to detect anti-amyloid-induced amyloid-related imaging abnormalities (ARIA), important adverse drug reactions associated with some anti-Aβ mAbs currently available in the United States and in clinical development. We present a simple rating system for ARIA-edema (ARIA-E) that can assess severity on a 3- or 5-point scale based upon a single linear measurement of the largest area of lesion, and dissemination in space, termed the 3-point Severity Scale of ARIA-E (SSAE-3) and the 5-point Severity Scale of ARIA-E (SSAE-5), respectively.

Methods: MRI results were collected from 75 participants from the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) studies of gantenerumab. Three neuroradiologists experienced with the detection of ARIA-E were selected to read all cases independently. One rater was then chosen for a second read to assess intra-reader reproducibility.

Results: The three raters had high agreement in identifying and grading ARIA-E. The Cohen/Fleiss kappa (κ) scores (95% confidence interval [CI]) for the inter- and intra-reader comparisons for SSAE-3 and SSAE-5 were 0.79 (0.70-1.00), 0.94 (0.94-1.00), 0.73 (0.66-1.00), and 0.90 (0.90-1.00), respectively.

Discussion: Our study suggests that SSAE-3 and SSAE-5 are valid ARIA-E rating scales for use in routine clinical practice by experienced radiologists in specialized settings. The application of these scales in everyday use in clinical practice will support the expansion of anti-Aβ mAbs as a treatment option for people living with Alzheimer's disease.

Highlights: A simple rating scale is needed to rate severity of amyloid-related imaging abnormalities-edema (ARIA-E) in both research and clinical settings.The 3- and 5-point Severity Scales of ARIA-E (SSAE-3/-5) have good inter- and intra-reader agreement.The SSAE-3/-5 have been used in most major Alzheimer's disease (AD) trials to date and are suitable for large-scale use in routine clinical practice, which may help support the expansion of anti-amyloid antibodies as treatment options for AD.

Keywords: Alzheimer's disease; amyloid; amyloid beta; amyloid plaques; diagnostic imaging.

FIGURE 1

Representative FLAIR slice illustrating each SSAE‐3 and SSAE‐5 severity level. (A) Monofocal right occipital occurrence <5 cm, corresponding to mild severity on both SSAE‐3 and SSAE‐5 scales. (B) Multifocal right and left occipital occurrences, each <5 cm, corresponding to moderate severity with SSAE‐3 and mild+ severity with SSAE‐5. (C) Monofocal left occipital occurrence of 5–10 cm in greatest dimension, classified as moderate on both SSAE‐3 and SSAE‐5 scales. (D) Multifocal right and left occipital occurrences, the largest being 5–10 cm, corresponding to moderate severity with SSAE‐3 and moderate+ severity with SSAE‐5. (E) Large ARIA‐E occurrence >10 cm in the right hemisphere, expanding across multiple brain territories, together with a smaller occurrence in the left frontal lobe. Irrespective of the number of regions involved, this is scored severe with both scales due to its largest extent. ARIA‐E, amyloid‐related imaging abnormalities–edema; FLAIR, fluid‐attenuated inversion recovery; SSAE, severity scale of ARIA‐E.

FIGURE 2

Example of baseline and ARIA‐E images provided to readers with sulcal hyperintensities (A), sulcal effacement/swelling (B), and parenchymal hyperintensities (C). (A) Typical purely sulcal hyperintensity, resulting from proteinaceous content leakage within the sulcus without significant impact on brain parenchyma or effacement of adjacent sulci. (B) Sulcal effacement in the left parietal lobe on two consecutive slices, without significant associated parenchymal or sulcal hyperintensity. Such a pattern is uncommon as it is very hard to detect. Diagnostic confidence is increased here by the confirmation on adjacent slices and use of image registration to remove bias from repositioning and partial volume effect. (C) Sulcal hyperintensity (blue oval) accompanied by overall swelling causing sulcal effacement (green oval). Parenchymal hyperintensity (bilaterally, red oval). Brain sulci are no longer visible in the vicinity, due to swelling. ARIA‐E, amyloid‐related imaging abnormalities–edema.