PMC

Week 6 FLAIR sequence reveals bi-frontal parenchymal hyperintensity (arrows) (ARIA-E) which resolves by Week 19. Additionally Week 19 GRE-T2* sequence reveals development of bifrontal microhemeorrhages (arrows) (ARIA-H) not present on prior imaging studies. Corresponding Week 19 PIB scan reveals reduced PIB uptake (arrows) when compared to baseline in regions of ARIA-E and ARIA-H.

(Upper Left) ARIA-E: Multifocal parenchymal signal abnormalities involving white and gray matter with evidence of gyral swelling (FLAIR Sequence) (Upper Right): ARIA-H: Foci of microhemorrhage in right parietal lobe (GRE-T2* sequence). (Lower left) ARIA-E: Sulcal FLAIR hyperintensity localized to the left parietal surface, without appreciable parenchymal involvement (FLAIR Sequence). (Lower right) ARIA-E: Subtle gyral swelling with faint sulcal hyperintensity (FLAIR Sequence).

*One patient was detected with ARIA-E in the MRI re-read study while receiving placebo. **One patient detected with ARIA-E in the MRI re-read study had metastatic lung cancer and was not included among the ARIA-E cases in the risk factor analyses. The patient was censored at the time of ARIA-E detection. ARIA-E, amyloid-related imaging abnormality thought to represent parenchymal vasogenic edema and sulcal effusions.

Increasing dose and number of APOE ε4 alleles were associated with an increased risk of ARIA-E over time. In the accompanying graphs, an increased risk of ARIA-E may be readily visualized by the decrease in the Kaplan-Meier survivor function after the first two doses, based on MRI readings performed 6 weeks after the baseline and month 3 infusions, in both subjects treated with the highest dose (2 mg/kg) and in APOE ε4 homozygotes. No increased risk was apparent for the presence small hemosiderin deposits at baseline.

In the figure, a cerebral vessel evolves over the course of AD from a normal state (A) to one with AD-like vascular pathology (B) associated with vascular amyloid deposition, disrupted vascular integrity, and impaired perivascular pathways. Age and APOE ε4 genotype may contribute to these changes. After initiation of a treatment predicted to remove beta amyloid from the cerebral vasculature such as immunotherapy, a period of time may exist in some patients when vessels with pre-existing amyloid vascular pathology are transiently more susceptible to vascular extravasation events as beta amyloid is removed from the vessel wall. These events are visualized on MRI as ARIA when fluid, protein, or red cells leak into surrounding tissues (C). The likelihood and timing of such events may depend, in part, on the degree to which the vascular structural integrity was previously disrupted by beta-amyloid deposition, the efficiency of vascular beta-amyloid clearance, and local inflammation. Mobilization of parenchymal beta amyloid to perivascular drainage pathways that are impaired could also give rise to a transient paradoxical increase in vascular beta amyloid following anti-beta-amyloid immunotherapy. With maintained vascular beta-amyloid clearance and recovery of vascular structural integrity, the risk of such extravasation events would be predicted to decrease (D). Portions of this figure were adapted with permission from Weller RO et al. Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease.