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Background and objectives: Amyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer's disease (AD) immunotherapy with anti-amyloid-beta (Aβ) monoclonal antibodies (mAbs). ARIA-E can also occur spontaneously in cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased cerebrospinal fluid (CSF) levels of anti-Aβ autoantibodies. Although the pathophysiological mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex-vivo studies suggest that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aβ (auto)antibody levels has never been demonstrated. Methods: Spatial distribution and temporal variations of microglial activation associated with ARIA-E and CSF anti-Aβ autoantibody levels at (sub)acute presentation and after corticosteroid therapy, in a longitudinal case series of patients with CAA-ri, an increasingly recognized spontaneous model of the iatrogenic ARIA-E in AD immunotherapy. Multimodal and multiparametric magnetic resonance imaging (MRI) for CAA and ARIA-E quantification, as measured with validated MRI scoring systems; CSF testing for anti-Aβ autoantibodies and AD biomarkers; 11C-PK11195 positron emission tomography (PET) for activated microglia. Results: At (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial co-localization with ARIA-E compared to chronic age-related white matter change (ARWMC) imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation was greater in patients having AD and severe CAA concomitant disease, compared to patients having CAA only. CSF anti-Aβ autoantibodies at presentation were high in all patients and markedly decreased at post-treatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation. Discussion: Our findings extend the current notion of ARIA-E by providing the first in vivo 11C-PK11195-PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aβ autoantibodies and comorbid AD and CAA disease..Our results highlight CSF testing for anti-Aβ autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.

Background Amyloid related imaging abnormalities (ARIA) detected by magnetic resonance imaging (MRI) are associated with a class of therapeutic anti‐amyloid‐β antibodies under investigation in Alzheimer’s disease. ARIA‐E, manifested as bright signals on the T2 fluid attenuated inversion recovery (FLAIR) sequence, are suggestive of parenchymal vasogenic edema and/or sulcal effusions, although, solid experimental support is still missing [1]. By employing a novel voxel‐based model of the MRI signal, we test whether the extravasation of fluid and plasma proteins in the brain tissue and/or sulcal spaces can indeed explain the T2 FLAIR hyperintensities characteristic for ARIA‐E. Method The modelled MRI voxel consists of myelin (my), intracellular (ic) and extracellular (ec) compartments (Figure 1). The material properties and MRI parameters (T1 and T2 relaxation times) of the physiological system come from experiments on protein solutions and human brain (Table 1). The movement of water molecules between the ic and ec compartments is assumed to be fast and to generate a well‐mixed intra/extra‐cellular (iec) compartment. The net T2 FLAIR signal within the voxel is assumed to result from the water in the my and iec compartments undergoing slow exchange and having independent magnetic relaxation. We assess how expanding the ec space with a protein‐rich fluid affects the T1 and T2 relaxation times of the ec and iec compartments and the total FLAIR signal within the voxel. Result Our model predicts that a two‐fold enlargement of the ec space, corresponding to a 12% increase in water volume, can lead to a substantial parenchymal hyperintensity on T2 FLAIR. The presence of a protein‐rich fluid, e.g. plasma, in the ec space cannot yield parenchymal hyperintensities in the absence of ec expansion. Conversely, replacing the cerebrospinal fluid from the sulci (normally appearing dark on T2 FLAIR) with protein‐rich fluid results in a signal comparable to normal grey matter and the apparent loss of sulci (Figure 2). Conclusion By linking brain tissue composition to FLAIR signal changes, our model could help unravel the pathophysiological mechanisms of ARIA‐E and, therefore, provide a useful tool for testing other potential mechanisms underpinning brain MRI abnormalities. Reference: (1) van Dyck, Biological Psychiatry, 2018, 83(4):311‐319.

After a long history of failed clinical trials, we are currently experiencing an enthusiastic era for the treatment of amyloid-related neurodegenerative diseases. Phase1b data of aducanumab, a fully human antibody against Abeta42, is giving great promises and it is now moving directly into Phase3 in prodromal AD. Ponezumab, an antibody against Abeta40, has recently entered in Phase2 for CAA. Although the differences in terms of naturally history of these diseases and of drug-target engagement, increasing data are demonstrating that CAA and AD share different similarities that can perhaps mutually influence the design, safety, biomarkers profile and final outcomes interpretation of clinical trials

Background and objective: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare and aggressive meningoencephalitis characterized by the acute onset of neurological symptoms associated with radiological evidence of cerebral vasogenic edema (VE) and cortical/subcortical microhemorrhages (MH). Here, we described the clinical, neuroradiological and biological evolution of CAA-ri, to provide future directions for the proper management of this challenging disease. Patients: From the iCAβ International Network, we identified those patients with a follow-up of >12 months. All patients were diagnosed as possible, probable or definitive CAA-ri according to the Auriel 2016 diagnostic criteria. Methods: VE and MHs were evaluated on fluid-attenuated inversion recovery (FLAIR) and T2*-weighted gradient echo (T2*-GRE) or susceptibility weighted imaging (SWI) MRI. CSF autoantibodies, TFPI, Abeta and tau were assessed. Clinical and therapeutic findings recorded. Results: 2/60 patients were identified to undergo CAA-ri recurrence, respectively at two and seven years after first presentation. At recurrence, VE colocalized with the appearance of new MHs, affecting brain areas different from those where the first event occurred. CSF autoantibodies and TFPI revealed as good diagnostic and prognostic biomarkers of VE and MHs, respectively. Conclusions: Our observations improve the understanding of the natural history of CAA-ri, highlighting the importance of a prompt diagnosis, particularly in patients who have already experienced a previous episode of CAA-ri. Although the frequency of late CAA-ri recurrence is rare, in the suspect of relapse, a prompt clinical and radiological follow-up should be considered, to obtain a timely diagnosis and medication with strong impact on the patients’ outcome. References: Piazza F, Greenberg SM, Savoiardo M, et al. Anti-amyloid beta autoantibodies in cerebral amyloid angiopathy related inflammation: implications for amyloid-modifying therapies. Annals of Neurology 2013; 73:449–58. DiFrancesco JC, Longoni M, and Piazza F. Anti-Aβ autoantibodies in amyloid related imaging abnormalities (ARIA): candidate biomarker for immunotherapy in Alzheimer’s disease and cerebral amyloid angiopathy. Front. Neurol. 2015; 25 6:207. Auriel E, Charidimou A, Gurol ME, Ni J, Van Etten ES, Martinez-Ramirez S, Boulouis G, Piazza F, DiFrancesco JC, Frosch MP, Pontes-Neto OV, Shoamanesh A, Reijmer Y, Vashkevich A, Ayres AM, Schwab KM, Viswanathan A, Greenberg S. Validation of Clinicoradiological Criteria for the Diagnosis of Cerebral Amyloid Angiopathy-Related Inflammation. JAMA Neurol. 2016; 73(2):197-202.

Background. Cerebral amyloid angiopathy-related inflammation (CAA-ri) results from autoimmune response to beta-amyloid deposits in cerebral vessels. Its clinical course and complications have seldom been described in literature. Case Report. In a patient presenting with delirium and left hemiparesis the diagnosis of CAA-ri was supported by the finding of elevated anti-amyloid autoantibodies in the cerebrospinal fluid (CSF). Steroid therapy produced significant improvements in clinical and investigational assessments, but after two months, it caused Acute Respiratory Distress Syndrome. After steroid therapy discontinuation the patient presented a rapidly progressive dementia, Guillain-Barré syndrome, new cerebral ischemic lesions, and thrombosis of the right cephalic and subclavian veins that were treated with subcutaneous heparin. After a week the patient died because of brain hemorrhage. Conclusion. This case suggests caution in steroid therapy discontinuation and antithrombotic therapy administration in patients with CAA-ri. The CSF search of anti-amyloid autoantibodies could be helpful to support the diagnosis.