Biomarkers

Amyloid-Related Imaging Abnormalities (ARIA), an adverse event associated with Alzheimer's disease anti-amyloid immunotherapies, occur in the form of edema or sulcal effusion (ARIA-E) and microhemorrhages and superficial siderosis (ARIA-H). Conventional teaching is that ARIA-H is permanent hemosiderin staining of the brain. In clinical trials we have noticed that some ARIA-H microhemorrhages that occur with regional ARIA-E appear to later resolve. The goal of this study is to illustrate that, opposed to current understanding, some ARIA-H microhemorrhages may resolve.

We identified participants from the Dominantly Inherited Alzheimer's Network Trial Unit (DIAN-TU) and open label extension (OLE) gantenerumab studies that had ARIA-E and at least one ARIA-H microhemorrhage. The T2* GRE sequence from all available MRI exams in a patient were co-registered and reviewed by a board-certified neuroradiologist. Individual microhemorrhages were tracked over the serial exams. We defined disappearing/resolving microhemorrhages as those appeared with or following ARIA-E, were visualized on at least 2 MRI exams, and were subsequently not visualized on at least 2 MRI exams.

A total of 12 patients met inclusion criteria of which 5 (41%) had microhemorrhages that resolved over 10-40 months follow-up after the incident ARIA. These microhemorrhages occurred in clusters in the region of ARIA-E, and only some of the regional microhemorrhages resolved over follow-up. Examples are shown in Figures 1-3.

The disappearance (resolution) of ARIA-H microhemorrhages is relevant to the management and continued dosing of patients receiving anti-amyloid immunotherapies as this is guided by the presence of ARIA (including cumulative treatment emergent microhemorrhages) as well as clinical symptoms. A microhemorrhage number alone may not be indicative of the potentially dynamic nature of ARIA-H.