Immune Activation in Amyloid-β-Related Angiitis Correlates with Decreased Parenchymal Amyloid-β Plaque Load

Abstract

Background: Primary angiitis of the central nervous system (PACNS) is a rare but serious condition. A fraction of patients suffering from PACNS concurrently exhibit pronounced cerebral amyloid angiopathy (CAA) which is characterized by deposits of amyloid-β (Aβ) in and around the walls of small and medium-sized arteries of the brain. PACNS with CAA has been identified as a distinct disease entity, termed Aβ-related angiitis (ABRA). Evidence points to an immune reaction to vessel wall Aβ as the trigger of vasculitis. Objective: To investigate whether the inflammatory response to Aβ has (1) any effect on the status of immune activation in the brain parenchyma and (2) leads to clearance of Aβ from brain parenchyma. Methods: We studied immune activation and Aβ load by quantitative immunohistochemical analysis in brain parenchyma adjacent to affected vessels in 11 ABRA patients and 10 matched CAA controls. Results: ABRA patients showed significantly increased immune activation and decreased Aβ loads in the brain parenchyma adjacent to affected vessels. Conclusion: Our results are in line with the hypothesis of ABRA being the result of an excessive immune response to Aβ and show that this can lead to enhanced clearance of Aβ from the brain parenchyma by immune-mediated mechanisms.

Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer's Disease

“…This case therefore adds further support to a growing body of literature linking CAA-ri to radiological features described as ARIA [10]. Whilst the precise underlying pathogenetic mechanisms are not yet fully understood, previous observations of CD68 + macrophages and CD4 + Tcell recruitment at sites of Aβ-related angiitis [11,12] and CSF anti-Aβ autoantibodies in patients with spontaneous CAA-ri [6,13] support the notion of an autoimmune response against vascular Aβ [10].…”

Anti-Aβ Autoantibodies in Amyloid Related Imaging Abnormalities (ARIA): Candidate Biomarker for Immunotherapy in Alzheimer’s Disease and Cerebral Amyloid Angiopathy

“…First, like in immunotherapy, the acute phase of CAA-ri is characterized by a specific immune reaction mediated by an increased amount of autologous CSF antibodies against the perivascular deposited Aβ typical of CAA ( 13 , 16 , 21 , 44 – 46 ). Although observed in a single case study, autoantibodies have been found to be intrathecally produced and specifically increased only in CSF, while no changes has been found in the plasma, thus reflecting the immune/inflammatory mechanisms restricted to the brain ( 13 ).…”

Distinct microglia profile in Creutzfeldt–Jakob disease and Alzheimer's disease is independent of disease kinetics

“…Slides were pre‐screened by light microscopy and three representative regions of interest (ROI; 0.5 mm 2 ) were electronically scanned at high magnification (×400) as high‐resolution images (1900 × 1200 pixels), using NanoZoomer 2.0‐HT (Hamamatsu Ltd., Hamamatsu, Japan). Immunosignals were morphometrically assessed (using ImageJ image analysis software, Wayne Rasband, Version 1.51d, Bethesda, Maryland, USA), revealing the area fraction (the percentage of pixels that have been highlighted in red in thresholded images), according to established protocols …”

“…Immunosignals were morphometrically assessed (using ImageJ image analysis software, Wayne Rasband, Version 1.51d, Bethesda, Maryland, USA), revealing the area fraction (the percentage of pixels that have been highlighted in red in thresholded images), according to established protocols. 38…”