Cerebral amyloid angiopathy-related inflammation (CAA-ri) may arise because of high levels of anti-amyloid β autoantibodies, researchers reported in the April Annals of Neurology. The high autoantibody levels are an autoimmune reaction against cerebrovascular amyloid β. The researchers’ new technique for gauging CSF levels of anti-amyloid β autoantibodies thus could be a valid method of diagnosing CAA-ri.
Immunization with monoclonal anti-amyloid antibodies, such as bapineuzumab, as well as treatment with many anti-amyloid drugs, sometimes leads to amyloid-related imaging abnormalities (ARIA) that, like CAA-ri, are characterized by vasogenic edema and multiple cortical or subcortical microbleeds. Anti-amyloid β autoantibodies therefore could be potential biomarkers for ARIA in future amyloid-modifying therapies for the treatment of Alzheimer’s disease and CAA, said lead author Fabrizio Piazza, PhD, research fellow at the University of Milano-Bicocca in Monza, Italy.
A Novel ELISA for Detecting Autoantibodies Against Amyloid-β
To investigate the role of anti-amyloid b autoantibodies in the acute and remission phases of CAA-ri, Dr. Piazza and colleagues recruited 57 patients in a retrospective, multicenter, case–control study conducted in several countries. Of these patients, 10 had CAA-ri, eight had noninflammatory CAA, 14 had multiple sclerosis (MS), and 25 were controls.
The researchers performed lumbar punctures to collect CSF samples from the participants. Enzyme-linked immunosorbent assays (ELISAs) determined CSF levels of amyloid β40, amyloid β42, tau, and P-181 tau. The researchers used pretreatment with magnetic beads and a novel ELISA to detect autoantibodies against amyloid β in CSF.
Autoantibody Levels Were Higher in Patients With CAA-ri
The concentration of anti-amyloid β autoantibodies in CSF was significantly higher among patients in the acute phase of CAA-ri than in controls, patients with noninflammatory CAA, and patients with MS. The concentration of these autoantibodies returned to normal levels when the patients with CAA-ri entered the remission phase. The concentration of the autoantibodies also returned to control levels when patients received immunosuppressant therapy.
The researchers observed no statistically significant differences in CSF anti-amyloid β autoantibody levels between controls, patients with noninflammatory CAA, and patients with CAA-ri who were in remission. The CSF concentrations of amyloid β40, amyloid β42, tau, and P-181 tau were higher in the acute phase of CAA-ri than in the remission phase.
“In this study … we shed light on important aspects underlying the pathogenesis of CAA-ri, confirming a direct involvement of these antibodies during the course of the disease,” said Dr. Piazza. “The lack of an anti-amyloid β autoantibody increase in the autoimmune and inflammatory/non-CAA control group … also supports the view that the pathogenesis of CAA-ri is caused by a specific autoimmune process against the amyloid β protein, directly mediated by the anti-amyloid β autoantibodies.
Diagnostic Implications
“A direct clinical application of our results could involve patients with suspected CAA-ri, where an invasive procedure such as brain biopsy is often still needed,” he added. “Analyzing anti-amyloid β autoantibody concentration in the CSF, in association with the proper clinical and radiologic features, can be proposed as a valid alternative to current techniques for the diagnosis of CAA-ri.
“We are now coordinating an international network called Inflammatory Cerebral Amyloid Angiopathy and Alzheimer’s Disease Biomarkers Collaborative Network to recruit a large cohort of patients with CAA-ri and Alzheimer’s so we can validate our test and define diagnostic criteria and cutoff for ARIA in these diseases. In the future, our novel ELISA technique could be used in studies correlating anti-amyloid β antibody dosage to MRI data and to PET amyloid imaging,” said Dr. Piazza. “This approach could lead to important confirmation of amyloid deposition and clearance directly in vivo, in particular in the upcoming amyloid-modifying drug trials for Alzheimer’s disease, where the identification of diagnostic tools able to identify subjects at high risk to develop ARIA and useful biomarkers for primary prevention would be highly desirable to avoid the occurrence of the same side effects,” he concluded.
—Erik Greb
Senior Associate Editor