International Journal of Molecular Sciences Review Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy Yasuteru Inoue 1,* , Yukio Ando 2, Yohei Misumi 1 and Mitsuharu Ueda 1 1 Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; [email protected] (Y.M.); [email protected] (M.U.) 2 Department of Amyloidosis Research, Nagasaki International University, Sasebo 859-3298, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-96-373-5893; Fax: +81-96-373-5895 Abstract: Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid β (Aβ) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aβ deposits results in fragile vessels and lobar intracere- bral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue in- hibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Citation: Inoue, Y.; Ando, Y.; Misumi, Aβ cytotoxicity, Aβ fibril formation, and vessel wall remodeling. Understanding the interactions Y.; Ueda, M. Current Management between cerebrovascular Aβ deposits and molecules that accumulate with Aβ may lead to discovery and Therapeutic Strategies for of effective CAA therapeutics and to the identification of biomarkers for early diagnosis. Cerebral Amyloid Angiopathy. Int. J. Mol. Sci. 2021, 22, 3869. https:// Keywords: cerebral amyloid angiopathy; amyloid β; intracerebral hemorrhage; cerebral microbleeds; doi.org/10.3390/ijms22083869 superficial siderosis; proteomic analyses Academic Editors: Masashi Tanaka, Kenjiro Ono and Satoshi Saito 1. Introduction Received: 11 March 2021 Accepted: 1 April 2021 Sporadic cerebral amyloid angiopathy (CAA) is characterized by progressive accu- Published: 8 April 2021 mulation of cerebrovascular amyloid β (Aβ) in the walls of leptomeningeal arteries and cortical capillaries in the brain. Loss of integrity of cerebral blood vessels caused by cere- Publisher’s Note: MDPI stays neutral brovascular Aβ deposits has led to spontaneous lobar intracerebral hemorrhage (ICH) with regard to jurisdictional claims in and cognitive impairment [1]. Population-based postmortem studies indicated that the published maps and institutional affil- prevalence of CAA is 20–40% in elderly people without dementia and 50–60% in elderly iations. people with dementia [2–5]. With regard to ICH, CAA-related ICH accounts for 20% of all types of ICH [6]. We previously investigated the locations of hematomas in very el- derly patients (≥80 years old) with ICHs and compared them with those of patients with ICHs who were younger than 80 years. We found that hematomas often occurred in the Copyright: © 2021 by the authors. subcortex in very elderly patients with ICH, and a high prevalence of CAA was strongly Licensee MDPI, Basel, Switzerland. implicated in ICH occurrence [7]. Furthermore, a recent meta-analysis demonstrated that This article is an open access article the annual recurrent ICH risk was higher in patients with CAA-related ICH compared distributed under the terms and with patients with CAA-unrelated ICH (7.4% vs. 1.1%) [8]. Developing a strategy to treat conditions of the Creative Commons CAA is urgently needed, but the understanding of its pathogenesis and identification of Attribution (CC BY) license (https:// molecules that may serve as therapeutic targets remain to be elucidated. This review aims creativecommons.org/licenses/by/ to: summarize the clinical, pathological, and radiological features of CAA; describe current 4.0/). Int. J. Mol. Sci. 2021, 22, 3869. https://doi.org/10.3390/ijms22083869 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 3869 2 of 15 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 15 management strategies for CAA; discuss proposed mechanisms of formation of CAA; and to: summarize the clinical, pathological, and radiological features of CAA; describe cur- clarify the CAA-related molecules that may be therapeutic targets. rent management strategies for CAA; discuss proposed mechanisms of formation of CAA; 2.and Neuropathology clarify the CAA-related of CAA-Affected molecules that Vessels may be therapeutic targets. 2. NeuropathologyWith regard to of pathology,CAA-Affected the Vessels finding of apple-green birefringence under polarized lightWith after regard Congo to red pathology, staining the has finding been of widely apple-green used tobirefringence diagnose amyloidosis,under polarized including CAAlight after (Figure Congo1A,B). red staining A β40 and has been Aβ42 widelyare the used major to diagnose forms ofamyloidosis, Aβ peptides including in the brain. AlthoughCAA (Figure Aβ 1A,B).42 differs Aβ40 from and A Aββ4240 areby the only major two forms hydrophobic of Aβ peptides residues, in the A βbrain.42 is Alt- more prone tohough aggregate Aβ42 differs compared from A withβ40 by A βonly40, leadingtwo hydrophobic to the formation residues, ofAβ fibrils42 is more more prone easily to [9]. The senileaggregate plaque compared found with in Alzheimer’sAβ40, leading to disease the formation (AD) isof predominantlyfibrils more easily composed [9]. The se- of Aβ42, whereasnile plaque the found vascular in Alzheimer’s amyloid in disease CAA exists (AD) asis Apredominantlyβ40 in the walls composed of leptomeningeal of Aβ42, and corticalwhereas arteriesthe vascular [9,10 amyloid]. Vascular in CAA Aβ existsdeposits as Aβ begin40 in the at walls the outer of leptomeningeal basement membrane and of smoothcortical arteries muscle [9,10]. cells andVascular develop Aβ deposits into circumferential begin at the outer transmural basement A membraneβ deposits, of thereby leadingsmooth muscle to degeneration cells and develop of smooth into muscle circumferential cells of thetransmural media andAβ deposits, thickening thereby of the vessel leading to degeneration of smooth muscle cells of the media and thickening of the vessel walls [11]. During advanced stages of CAA, Aβ disrupts the vascular extracellular matrix walls [11]. During advanced stages of CAA, Aβ disrupts the vascular extracellular matrix (ECM), which results in the “double-barrel” appearance because of the detachment and (ECM), which results in the “double-barrel” appearance because of the detachment and delaminationdelamination of of the the intima intima from from the themedia, media, microaneurysms, microaneurysms, and fibr andinoid fibrinoid necrosis necrosis [12]. [12]. FigureFigure 1. HistopathologicalHistopathological and and radiological radiological imaging imaging of CAA of (cerebral CAA (cerebral amyloid amyloid angiopathy). angiopathy). Rep- Rep- resentative histopathological images from a patient with severe CAA. Congo red-positive lep- resentative histopathological images from a patient with severe CAA. Congo red-positive lep- tomeningeal arteries (A) and those same arteries viewed under polarized light (B). SWI (suscepti- tomeningealbility-weighted arteries imaging) (A) MRI and shows those samea strictly arteries lobar vieweddistribution under of polarizedlobar microbleeds light (B (arrow-). SWI (susceptibility- weightedheads) (C). imaging) SWI shows MRI cSS shows(cortical a superficial strictly lobar siderosis) distribution as hypointense of lobar curvilinear microbleeds signals (arrowheads) along (C). SWIthe cortical shows gyri cSS (arrows) (cortical (D superficial). Scale bars siderosis) = 1 mm. as hypointense curvilinear signals along the cortical gyri (arrows) (D). Scale bars = 1 mm. 3. Diagnosis of CAA: Markers, Characteristic Features, and Techniques 3. DiagnosisAdvances of in CAA:neuroimaging Markers, have Characteristic enabled us to Features,establish a and clinical Techniques diagnosis of CAA withoutAdvances requiring in a neuroimaging brain biopsy. Recently, have enabled the Edinburgh us to establish criteria for a clinical CAA-related diagnosis ICH of CAA withoutwere published. requiring In addition a brain biopsy.to including Recently, the well-known the Edinburgh lobar location criteria of for CAA-related CAA-related ICH were published. In addition to including the well-known lobar location of CAA-related ICH, these criteria included a subarachnoid space extension of ICH and finger-like projections with an irregular hematoma shape, as well as the presence of the apolipoprotein E (ApoE) "4 genotype APOE-"4 [13]. Cerebral microbleeds (CMBs) are a diagnostic marker of the modified Boston criteria (Table1)[ 14]. CMBs reflect focal hemosiderin deposits caused by previous subtle hem- Int. J. Mol. Sci. 2021, 22, 3869 3 of 15 orrhages from small vessels and suggest the potential role of lobar CMBs as markers of CAA [15,16] (Figure1C). A community-based study demonstrated that the prevalence of lobar CMBs was 19% among healthy elderly subjects,