Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Imaging and Biology
Published in: Molecular Imaging and Biology 1/2019

01-02-2019 | Research Article

Near-infrared Fluorescence Ocular Imaging (NIRFOI) of Alzheimer’s Disease

Authors: Jian Yang, Jing Yang, Yuyan Li, Yungen Xu, Chongzhao Ran

Published in: Molecular Imaging and Biology | Issue 1/2019

Login to get access

Abstract

Purpose

Near-infrared fluorescence (NIRF) imaging has been widely used in preclinical studies; however, its low tissue penetration represents a daunting problem for translational clinical imaging of neurodegenerative diseases. The retina is known as an extension of the central nerve system (CNS), and it is widely considered as a window to the brain. Therefore, the retina can be considered as an alternative organ for investigating neurodegenerative diseases, and an eye represents an ideal NIRF imaging organ, due to its minimal opacity.

Procedures

NIRF ocular imaging (NIRFOI), for the first time, was explored for imaging of Alzheimer’s disease (AD) via utilizing “smart” fluorescent probes CRANAD-X (X = − 2, − 3, − 30, − 58, and − 102) for amyloid beta (Aβ), and CRANAD-61 for reactive oxygen species (ROS). Mice were intravenously injected the fluorescence dyes and images from the eyes were captured with an IVIS imaging system at different time points.

Results

All of the tested NIRF probes could be used to differentiate transgenic AD mice and WT mice, and NIRFOI could provide much higher sensitivity for imaging Aβs than NIRF brain imaging did. Our data suggested that NIRFOI could capture the imaging signals from both soluble and insoluble Aβ species. Moreover, we demonstrated that NIRFOI with CRANAD-102 could be used to monitor the therapeutic effects of BACE-1 inhibitor LY2811376. Compared to NIRF brain imaging, NIRFOI provided a larger change of Aβ levels before and after LY2811376 treatment. In addition, we demonstrated that CRANAD-61 could be used to image reactive oxygen species in the eyes.

Conclusion

The large detection margin by NIRFOI is very important for both diagnosis and therapy response monitoring. Compared to fluorescence microscopic imaging, NIRFOI captures signals with a wide angle (large field of view (FOV)) and can be used to detect soluble Aβs. We believe that NIRFOI has remarkable translational potential for future human studies and can be a potential imaging technology for fast, cheap, accessible, and reliable screening of AD in the future.
Appendix
Available only for authorised users
Literature
1.
Rudin M, Weissleder R (2003) Molecular imaging in drug discovery and development. Nat Rev Drug Discov 2:123–131CrossRefPubMed
2.
Kobayashi H, Ogawa M, Alford R, Choyke PL, Urano Y (2010) New strategies for fluorescent probe design in medical diagnostic imaging. Chem Rev 110:2620–2640CrossRefPubMedPubMedCentral
3.
Staderini M, Martin MA, Bolognesi ML, Menendez JC (2015) Imaging of beta-amyloid plaques by near infrared fluorescent tracers: a new frontier for chemical neuroscience. Chem Soc Rev 44:1807–1819CrossRefPubMed
4.
Cui M, Ono M, Watanabe H, Kimura H, Liu B, Saji H (2014) Smart near-infrared fluorescence probes with donor-acceptor structure for in vivo detection of beta-amyloid deposits. J Am Chem Soc 136:3388–3394CrossRefPubMed
5.
6.
Dubois B, Feldman HH, Jacova C, DeKosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6:734–746CrossRefPubMed
7.
Klunk WE, Koeppe RA, Price JC et al (2015) The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alz Dement 11:1–15 e11–14CrossRef
8.
Jack CR Jr, Garwood M, Wengenack TM, Borowski B, Curran GL, Lin J, Adriany G, Gröhn OHJ, Grimm R, Poduslo JF (2004) In vivo visualization of Alzheimer’s amyloid plaques by magnetic resonance imaging in transgenic mice without a contrast agent. Magn Reson Med 52:1263–1271CrossRefPubMedPubMedCentral
9.
Knight MJ, McCann B, Kauppinen RA, Coulthard EJ (2016) Magnetic resonance imaging to detect early molecular and cellular changes in Alzheimer’s disease. Front Aging Neurosci 8:139CrossRefPubMedPubMedCentral
10.
London A, Benhar I, Schwartz M (2013) The retina as a window to the brain-from eye research to CNS disorders. Nat Rev Neurol 9:44–53CrossRefPubMed
11.
Nguyen CTO, Hui F, Charng J, Velaedan S, van Koeverden AK, Lim JKH, He Z, Wong VHY, Vingrys AJ, Bui BV, Ivarsson M (2017) Retinal biomarkers provide “insight” into cortical pharmacology and disease. Pharmacol Therap 175:151–177CrossRef
12.
Ning A, Cui J, To E, Ashe KH, Matsubara J (2008) Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Invest Ophthalmol Vis Sci 49:5136–5143CrossRefPubMed
13.
Emptage L, Hunter JJ, Kisilak ML et al (2016) Retinal amyloid stained with CRANAD-28 is visible in vivo with fluorescence imaging but not OCT in a canine model of Alzheimer’s disease. Invest Ophthalmol Vis Sci 57:SP 2218
14.
Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, Miller CA, Ko MHK, Black KL, Schwartz M, Farkas DL (2011) Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. NeuroImage 54(Suppl 1):S204–S217CrossRefPubMed
15.
Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, Anderson DH (2002) The Alzheimer’s Abeta-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci of USA 99:11830–11835CrossRef
16.
Ratnayaka JA, Serpell LC, Lotery AJ (2015) Dementia of the eye: the role of amyloid beta in retinal degeneration. Eye (Lond) 29:1013–1026CrossRef
17.
Koronyo Y, Biggs D, Barron E, Boyer DS, Pearlman JA, Au WJ, Kile SJ, Blanco A, Fuchs DT, Ashfaq A, Frautschy S, Cole GM, Miller CA, Hinton DR, Verdooner SR, Black KL, Koronyo-Hamaoui M (2017) Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease. JCI Insight 2:e93621CrossRefPubMedCentral
18.
Tsai Y, Lu B, Ljubimov AV, Girman S, Ross-Cisneros FN, Sadun AA, Svendsen CN, Cohen RM, Wang S (2014) Ocular changes in TgF344-AD rat model of Alzheimer’s disease. Invest Ophthalmol Vis Sci 55:523–534CrossRefPubMedPubMedCentral
19.
Isas JM, Luibl V, Johnson LV, Kayed R, Wetzel R, Glabe CG, Langen R, Chen J (2010) Soluble and mature amyloid fibrils in drusen deposits. Invest Ophthalmol Vis Sci 51:1304–1310CrossRefPubMedPubMedCentral
20.
Luibl V, Isas JM, Kayed R, Glabe CG, Langen R, Chen J (2006) Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers. J Clin Invest 116:378–385CrossRefPubMedPubMedCentral
21.
Anderson DH, Talaga KC, Rivest AJ, Barron E, Hageman GS, Johnson LV (2004) Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res 78:243–256CrossRefPubMed
22.
Ran C, Xu X, Raymond SB, Ferrara BJ, Neal K, Bacskai BJ, Medarova Z, Moore A (2009) Design, synthesis, and testing of difluoroboron-derivatized curcumins as near-infrared probes for in vivo detection of amyloid-beta deposits. J Am Chem Soc 131:15257–15261CrossRefPubMedPubMedCentral
23.
Zhang X, Tian Y, Li Z, Tian X, Sun H, Liu H, Moore A, Ran C (2013) Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer’s disease. J Am Chem Soc 135:16397–16409CrossRefPubMedPubMedCentral
24.
Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, Ran C (2015) Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease. Proc Natl Acad Sci USA 112:9734–9739CrossRefPubMedPubMedCentral
25.
Li Y, Yang J, Liu H, Yang J, du L, Feng H, Tian Y, Cao J, Ran C (2017) Tuning the stereo-hindrance of a curcumin scaffold for the selective imaging of the soluble forms of amyloid beta species. Chem Sci 8:7710–7717CrossRefPubMedPubMedCentral
26.
May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM, Stout SL, Timm DE, Smith LaBell E, Gonzales CR, Nakano M, Jhee SS, Yen M, Ereshefsky L, Lindstrom TD, Calligaro DO, Cocke PJ, Greg Hall D, Friedrich S, Citron M, Audia JE (2011) Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor. J Neurosci 31:16507–16516CrossRefPubMedPubMedCentral
27.
Yang J, Zhang X, Yuan P, Yang J, Xu Y, Grutzendler J, Shao Y, Moore A, Ran C (2017) Oxalate-curcumin-based probe for micro- and macroimaging of reactive oxygen species in Alzheimer’s disease. Proc Natl Acad Sci U S A 114:12384–12389CrossRefPubMedPubMedCentral
28.
Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17:1005–1013CrossRefPubMed
29.
Delatour B, Guegan M, Volk A, Dhenain M (2006) In vivo MRI and histological evaluation of brain atrophy in APP/PS1 transgenic mice. Neurobiol Aging 27:835–847CrossRefPubMed
30.
31.
McLean CA, Cherny RA, Fraser FW et al (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46:860–866CrossRefPubMed
32.
Manczak M, Reddy PH (2012) Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer’s disease. Hum Mol Genet 21:5131–5146CrossRefPubMedPubMedCentral
33.
34.
Gasparini L, Crowther RA, Martin KR et al (2011) Tau inclusions in retinal ganglion cells of human P301S tau transgenic mice: effects on axonal viability. Neurobiol Aging 32:419–433CrossRefPubMed
35.
36.
Gupta N, Fong J, Ang LC, Yucel YH (2008) Retinal tau pathology in human glaucomas. Can J Ophthalmol 43:53–60CrossRefPubMed
37.
Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, Zhang MR, Trojanowski JQ, Lee VMY, Ono M, Masamoto K, Takano H, Sahara N, Iwata N, Okamura N, Furumoto S, Kudo Y, Chang Q, Saido TC, Takashima A, Lewis J, Jang MK, Aoki I, Ito H, Higuchi M (2013) Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 79:1094–1108CrossRefPubMed
Metadata
Title
Near-infrared Fluorescence Ocular Imaging (NIRFOI) of Alzheimer’s Disease
Authors
Jian Yang
Jing Yang
Yuyan Li
Yungen Xu
Chongzhao Ran
Publication date
01-02-2019
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 1/2019
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-018-1213-z

Other articles of this Issue 1/2019

Molecular Imaging and Biology 1/2019 Go to the issue

Correction

Correction to: a Phase 2 Study of 16α-[18F]-Fluoro-17β-Estradiol Positron Emission Tomography (FES-PET) as a Marker of Hormone Sensitivity in Metastatic Breast Cancer (MBC)

Review Article

The Evolving Role of FDG-PET/CT in the Diagnosis, Staging, and Treatment of Breast Cancer

Research Article

A Novel PET Probe “[18F]DiFA” Accumulates in Hypoxic Region via Glutathione Conjugation Following Reductive Metabolism

Research Article

Relationship Between Clinicopathological Characteristics and PET/CT Uptake in Esophageal Squamous Cell Carcinoma: [18F]Alfatide versus [18F]FDG

Research Article

Site-Specific Fluorescent Labeling of Antibodies and Diabodies Using SpyTag/SpyCatcher System for In Vivo Optical Imaging

Research Article

Tumor Formation of Adult Stem Cell Transplants in Rodent Arthritic Joints