title: Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy.
abstract: Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microbleeds. Conventional methods of magnetic resonance imaging for detection of microbleeds, and positron emission tomography with Pittsburgh Compound B imaging for amyloid deposits, can separately demonstrate the presence of microbleeds and CAA in affected brains in vivo; however, there still is a critical need for strong evidence that shows involvement of CAA in microbleed formation. Here, we show in a Tg2576 mouse model of Alzheimer's disease, that the combination of histochemical staining and an optical clearing method called optical histology, enables simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microbleeds, and amyloid deposits. Our data suggest that microbleeds are localized within the brain regions affected by vascular amyloid deposits. All observed microhemorrhages (n=39) were in close proximity (0 to 144 μm) with vessels affected by CAA. Our data suggest that the predominant type of CAA-related microbleed is associated with leaky or ruptured hemorrhagic microvasculature. The proposed methodological and instrumental approach will allow future study of the relationship between CAA and microbleeds during disease development and in response to treatment strategies.
authors.affiliation: Beckman Laser Institute and Medical Clinic, University of California, Irvine, 1002 Health Sciences Road East, Irvine, CA 92612, USA; Department of Biomedical Engineering, University of California, Irvine, 3120 Natural Sciences II, Irvine, CA 92697, USA. Electronic address: pclo@uci.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lo
authors.affiliation: Beckman Laser Institute and Medical Clinic, University of California, Irvine, 1002 Health Sciences Road East, Irvine, CA 92612, USA; Department of Biomedical Engineering, University of California, Irvine, 3120 Natural Sciences II, Irvine, CA 92697, USA. Electronic address: ccrouzet@uci.edu.
authors.forename: Christian
authors.initials: C
authors.lastname: Crouzet
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, 1207 Gillespie NRF, Irvine, CA 92697-4540, USA. Electronic address: vvasilev@uci.edu.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Vasilevko
authors.affiliation: Beckman Laser Institute and Medical Clinic, University of California, Irvine, 1002 Health Sciences Road East, Irvine, CA 92612, USA; Department of Biomedical Engineering, University of California, Irvine, 3120 Natural Sciences II, Irvine, CA 92697, USA; Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine, 2400 Engineering Hall, Irvine, CA 92697, USA. Electronic address: choib@uci.edu.
authors.forename: Bernard
authors.initials: B
authors.lastname: Choi
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D002232:Carbocyanines / Q000737:chemistry; D016657:Cerebral Amyloid Angiopathy / Q000150:complications* / Q000235:genetics; D002543:Cerebral Hemorrhage / Q000000981:diagnostic imaging* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D005456:Fluorescent Dyes / Q000737:chemistry; D020022:Genetic Predisposition to Disease; D021621:Imaging, Three-Dimensional; D008822:Mice, Transgenic; D008833:Microcirculation; D018613:Microscopy, Confocal; D055806:Microvessels / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology; D061848:Optical Imaging / Q000379:methods*; D058225:Plaque, Amyloid; D013194:Staining and Labeling / Q000379:methods*; D013844:Thiazoles / Q000737:chemistry
chemical_list: C582073:1,1'-dioleyl-3,3,3',3'-tetramethylindocarbocyanine; D052160:Benzothiazoles; D002232:Carbocyanines; D005456:Fluorescent Dyes; D013844:Thiazoles; C009462:thioflavin T
keywords: Amyloid-β; Cerebral amyloid angiopathy; DiI; Intracerebral hemorrhage; Microhemorrhages; Prussian blue; Stroke; Thioflavin S