Multimodal in Vivo and Postmortem Analysis of ARIA-Relevant Pathophysiology

Passive immunotherapy with anti-amyloid-β (Aβ) antibodies has emerged as the first FDA-approved disease-modifying approach for Alzheimer’s disease (AD). Treatment benefits come at the cost of clinical and radiological side effects, collectively called Amyloid-Related Imaging Abnormalities (ARIA), consisting of edema and leptomeningeal effusion (ARIA-E) or hemorrhages and superficial siderosis (ARIA-H). Increased Aβ transport across vessel walls and induction of immune and complement activation are hypothesized to lead to increased vascular leakage as the underlying mechanism, suggestive of pre-existing and worsening cerebral amyloid angiopathy as a key element in disease pathogenesis. Human autopsy studies are critically needed for further neuropathological characterization, confirmation of disease mechanisms, and the development of novel biomarkers and preventive strategies. We are proposing a multi-pronged approach to gap the bridge between ante-mortem neuroimaging and fluid biomarker evaluations to autopsy studies by combining traditional neuropathology approaches with modern digital pathology techniques and MRI-guided tissue sampling. Bringing together a team of experienced investigators with complementary expertise, we are proposing four aims to accomplish our goals: 1) We will refine our postmortem 7T MRI brain imaging pipeline by adding sequences optimized for the detection of vascular pathologies and improving our image quality and scanning conditions through several engineering steps. 2) Using our active ADRD and Down Syndrome brain banking cohorts, we will optimize co-registration methods for alignment of pre- and postmortem MR images with postmortem tissue sections. These alignment methods will allow atlas-based anatomical mapping and bi-directional lesion mapping from and to histology slides. 3) We will perform detailed neuropathological and biochemical characterization of CAA-affected vessels to identify tissue-based risk factors for CAA-associated vascular leakage and microhemorrhages, using traditional Aβ antibodies as well as Lecanemab and Donanemab biosimilars. 4) We will build a clinical research registry of patients treated with anti-Aβ antibodies and perform serial measurements of fluid biomarkers of neurodegeneration, inflammation, vascular pathologies, and anti-Aβ autoantibodies and complement these assessments by 7T MRI studies at the time of ARIA occurrence. This multidisciplinary resource development approach will put us in an ideal position to investigate disease patterns in future ARIA cases and link autopsy information back to antemortem clinical, radiological, and fluid biomarker profiles. Our refined postmortem imaging protocols, co-registration approaches, and digital pathology algorithms will be readily shared with the research community at large and will not only benefit studies into ARIA but neurodegenerative processes in general. If funded, we will closely collaborate with other funded sites to harmonize approaches, align protocols, and make autopsy tissue and plasma samples of our clinical cohort available to jointly promote research into ARIA pathogenesis.