Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy–Related Inflammation

Abstract

Background and Objectives:To investigate the natural history and outcomes following treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy-related inflammation (CAA-ri).Methods:A multicenter, hospital-based, longitudinal, prospective observational study of inpatients meeting CAA-ri diagnostic criteria, recruited through the iCAβ International Network, in the period January 2013 - March 2017. A protocol for systematic data collection at first-ever presentation and at subsequent in-person visits, including T1-weighted, GRE-T2*, fluid-suppressed T2-weighted (FLAIR), and T1 post-gadolinium contrast-enhancement images aquired on 1.5T MRI, was employed at 3, 6, 12, 24-months follow-up. Centralized reads of MRI images were performed blinded to clinical, therapeutic, and time-points information. Main outcomes were survival, clinical and radiological recovery, intracerebral hemorrhage (ICH), and recurrence of CAA-ri.Results:The study enrolled 113 participants (10.6% definite, 71.7% probable, and 17.7% possible CAA-ri), mean age 72.9 years, 43.4% female, 37.1% APOEε4 carriers. 36.3% had a history of Alzheimer’s disease, 33.6% of ICH. A history of ICH, as well as the occurrence of new ICH at follow-up, was more common in patients with cortical superficial siderosis at baseline (52.6% vs 14.3%; p< 0.0001 and 19.3% vs 3.6%; p<0.009, respectively). After the first-ever presentation of CAA-ri, 70.3% (95% CI, 61.6-78.5) and 84.1% (95% CI, 76.2-90.6) clinically recovered within three and twelve months, followed by radiological recovery in 45.1% (95% CI, 36.4 - 54.8) and 77.4% (95% CI, 67.7 - 85.9), respectively. After clinicoradiological resolution of the first-ever episode, 38,3% (95% CI, 22.9 - 59.2) had at least one recurrence within the following 24 months. Recurrence was more likely if intravenous high dose corticosteroid pulse therapy was suddenly stopped compared to slow oral tapering-off (Hazard Ratio 4.68; 95% CI, 1.57-13.93; p=0.006).Discussion:These results from the largest longitudinal cohort registry of patients with CAA-ri support the transient and potentially relapsing inflammatory nature of the clinical-radiological acute manifestations of the disease and the effectiveness of slow oral tapering-off after intravenous corticosteroid pulse therapy in preventing recurrences. Our results highlight the importance of differential diagnosis for spontaneous ARIA-like events in Aβ-driven diseases, including treatment-related ARIA in Alzheimer’s disease patients exposed to immunotherapy drugs.

Regional Associations of Cortical Superficial Siderosis and β-Amyloid-Positron-Emission-Tomography Positivity in Patients With Cerebral Amyloid Angiopathy

“…Further studies with larger cohorts, a longitudinal study design, and complementary immunohistochemical examinations would be desirable to validate our results. Longitudinal studies will be of particular interest to better understand the mechanisms linking the occurrence of amyloid-related imaging abnormalities (ARIA) occurring both spontaneously in CAA-related inflammation with high levels of anti-amyloid autoantibodies (Antolini et al, 2021) and after exposure with monoclonal antibodies against plaque-deposited Aβ of AD immunotherapy (Chantran et al, 2019).…”

Disease-Modifying Therapies for Alzheimer's Disease: More Questions than Answers

“…There are many theories about the biological basis of ARIA, but we have little direct data that provides mechanistic insight into this effect of anti-Aβ antibody administration. Spontaneous ARIA-like events are observed in AD and have been linked to the presence of cerebrovascular amyloid angiopathy (CAA) and the presence of auto-antibodies against Aβ [ 54 ]. Given the current data, it is certainly plausible to hypothesize that engagement of cerebrovascular amyloid by an antibody with immune activating effector functions results in a local immune response that results in radiographic changes, and edema, that are consistent with local inflammatory responses.…”

Clinical and Instrumental Characterization of Patients With Late-Onset Epilepsy

“…Remarkably, partial volume is unfavorable when looking for subtle cortical dysplasia, as it mimics tissue blurring, a cardinal feature of these lesions. Even the application of T2-star/GRE/SWI sequences are important for the detection of small vessel diseases, both ischemic and hemorrhagic, as Cerebral Amyloid Angiopathy (CAA) and CAA-related inflammation ( 36 , 37 ). In the differential diagnosis between seizures and transient ischemic attack (TIA), it is important to carry out a study of the cerebral vessels by means of CT angiography or magnetic resonance angiography.…”