title: Molecular targeting of Alzheimer's amyloid plaques for contrast-enhanced magnetic resonance imaging.
abstract: Smart molecular probes for both diagnostic and therapeutic purposes are expected to provide significant advances in clinical medicine and biomedical research. We describe such a probe that targets beta-amyloid plaques of Alzheimer's disease and is detectable by magnetic resonance imaging (MRI) because of contrast imparted by gadolinium labeling. Three properties essential for contrast enhancement of beta-amyloid plaques on MRI exist in this smart molecular probe, putrescine-gadolinium-amyloid-beta peptide: (1) transport across the blood-brain barrier following intravenous injection conferred by the polyamine moiety, (2) binding to plaques with molecular specificity by putrescine-amyloid-beta, and (3) magnetic resonance imaging contrast by gadolinium. MRI was performed on ex vivo tissue specimens at 7 T at a spatial resolution approximating plaque size (62.5 microm(3)), in order to prove the concept that the probe, when administered intravenously, can selectively enhance plaques. The plaque-to-background tissue contrast-to-noise ratio, which was precisely correlated with histologically stained plaques, was enhanced more than nine-fold in regions of cortex and hippocampus following intravenous administration of this probe in AD transgenic mice. Continuing engineering efforts to improve spatial resolution are underway in MRI, which may enable in vivo imaging at the resolution of individual plaques with this or similar contrast probes. This could enable early diagnosis and also provide a direct measure of the efficacy of anti-amyloid therapies currently being developed.
authors.affiliation: Molecular Neurobiology Laboratory, Department of Neurology, Mayo Clinic Rochester, Minnesota 55905, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Poduslo
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wengenack
authors.forename: Geoffry L
authors.initials: GL
authors.lastname: Curran
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
authors.forename: Einar M
authors.initials: EM
authors.lastname: Sigurdsson
authors.forename: Slobodon I
authors.initials: SI
authors.lastname: Macura
authors.forename: Bret J
authors.initials: BJ
authors.lastname: Borowski
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics; D000818:Animals; D052160:Benzothiazoles; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003287:Contrast Media / Q000494:pharmacology*; D004195:Disease Models, Animal; D005682:Gadolinium; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D015336:Molecular Probe Techniques; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D053764:Presenilin-1; D011700:Putrescine; D015203:Reproducibility of Results; D013844:Thiazoles
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D052160:Benzothiazoles; D003287:Contrast Media; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T; D005682:Gadolinium; D011700:Putrescine