Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis

Abstract

Background: Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimer's disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors.

Methods: Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patient's treatment, APOE ɛ4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA.

Findings: 210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24 per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of APOE ɛ4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001).

Interpretation: ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE ɛ4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden.

Funding: Elan Corporation, Janssen Alzheimer Immunotherapy, Wyeth Pharmaceuticals, and Pfizer.

Figure 1. Flow chart of subject eligibility for risk analyses

*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.

Figure 2. MRI findings in four ARIA cases

(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).

Figure 3. Kaplan-Meier plots for ARIA-E by bapineuzumab dose (a), number of APOE ε4 alleles (b), and presence of small hemosiderin deposits at baseline (c)

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.

Figure 3. Kaplan-Meier plots for ARIA-E by bapineuzumab dose (a), number of APOE ε4 alleles (b), and presence of small hemosiderin deposits at baseline (c)

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.

Figure 3. Kaplan-Meier plots for ARIA-E by bapineuzumab dose (a), number of APOE ε4 alleles (b), and presence of small hemosiderin deposits at baseline (c)

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.

Figure 4. APOE ε4 carrier (3, 4) dosed with bapineuzumab (2·0 mg/kg)

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.

Figure 5. A–D: Vascular beta-amyloid clearance model of ARIA generation with anti-beta-amyloid treatments (22)

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.