title: Optical imaging in an Alzheimer's mouse model reveals amyloid-β-dependent vascular impairment.
abstract: Alzheimer's disease (AD) and cerebrovascular disease are often comorbid conditions, but the relationship between amyloid-βandin vivovascular pathophysiology is poorly understood. We utilized a multimodal, multiscale optical imaging approach, including spatial frequency domain imaging, Doppler optical coherence tomography, and confocal microscopy, to quantify AD-dependent changes in a triple transgenic mouse model (3xTg-AD) and age-matched controls. From three months of age (naïve) to 20 months (severe AD), the brain tissue concentration of total and oxy-hemoglobin (Total Hb, ctO2Hb) decreased 50 and 70%, respectively, in 3xTg-AD mice. Compared to age-matched controls, significant differences in brain hemoglobin concentrations occurred as early as eight months (Total Hb: 126 ± 5μM versus 108 ± 4μM; ctO2Hb: 86 ± 5μM versus 70 ± 3μM; for control and AD, respectively). These changes were linked to a 29% vascular volume fraction decrease and 35% vessel density reduction in the 20-month-old 3xTg-AD versus age-matched controls. Vascular reduction coincided with increased brain concentration of amyloid-βprotein, vascular endothelial growth factor (VEGF), and endothelial nitric oxide synthase (eNOS) at eight and 20 months compared to the three-month baseline. Our results suggest that amyloid-βblocks the normally reparative effects of upregulated VEGF and eNOS, and may acceleratein vivovascular pathophysiology in AD.
authors.affiliation: Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, 1002 Health Sciences Road, Irvine, California 92612 ; University of California Irvine, Department of Biomedical Engineering, 3120 Natural Sciences II, Irvine, California 92697-2715.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lin
authors.affiliation: Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, 1002 Health Sciences Road, Irvine, California 92612.
authors.forename: Gangjun
authors.initials: G
authors.lastname: Liu
authors.affiliation: University of California Irvine, Institute for Memory Impairments and Neurological Disorders, 2642 Biological Sciences III Irvine, California 92697-4545 ; University of California Irvine, Department of Neurobiology and Behavior, 2205 McGaugh Hall, Irvine, California 92697-4550.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Castello
authors.affiliation: Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, 1002 Health Sciences Road, Irvine, California 92612.
authors.forename: James J
authors.initials: JJ
authors.lastname: Yeh
authors.affiliation: Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, 1002 Health Sciences Road, Irvine, California 92612.
authors.forename: Rombod
authors.initials: R
authors.lastname: Rahimian
authors.affiliation: Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, 1002 Health Sciences Road, Irvine, California 92612.
authors.forename: Grace
authors.initials: G
authors.lastname: Lee
authors.affiliation: Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, 1002 Health Sciences Road, Irvine, California 92612.
authors.forename: Victoria
authors.initials: V
authors.lastname: Tsay
authors.affiliation: Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, 1002 Health Sciences Road, Irvine, California 92612.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Durkin
authors.affiliation: Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, 1002 Health Sciences Road, Irvine, California 92612 ; University of California Irvine, Department of Biomedical Engineering, 3120 Natural Sciences II, Irvine, California 92697-2715.
authors.forename: Bernard
authors.initials: B
authors.lastname: Choi
authors.affiliation: University of California Irvine, Institute for Memory Impairments and Neurological Disorders, 2642 Biological Sciences III Irvine, California 92697-4545 ; University of California Irvine, Department of Neurobiology and Behavior, 2205 McGaugh Hall, Irvine, California 92697-4550.
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.affiliation: Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, 1002 Health Sciences Road, Irvine, California 92612 ; University of California Irvine, Department of Biomedical Engineering, 3120 Natural Sciences II, Irvine, California 92697-2715.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Chen
authors.affiliation: University of California Irvine, Institute for Memory Impairments and Neurological Disorders, 2642 Biological Sciences III Irvine, California 92697-4545 ; University of California Irvine, Department of Neurobiology and Behavior, 2205 McGaugh Hall, Irvine, California 92697-4550.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.affiliation: Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, 1002 Health Sciences Road, Irvine, California 92612 ; University of California Irvine, Department of Biomedical Engineering, 3120 Natural Sciences II, Irvine, California 92697-2715.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Tromberg
keywords: Doppler optical coherence tomography; absorption; diffuse optical spectroscopy; hypercapnia; microvascular perfusion; neuroimaging; scattering; spatial frequency domain imaging; vascular reactivity