Targeting Prion Amyloid Deposits In Vivo

• Published in: Journal of neuropathology and experimental neurology Vol. 63; no. 7; pp. 775 - 784
• Main Authors: SADOWSKI, MARCIN, PANKIEWICZ, JOANNA, SCHOLTZOVA, HENRIETA, TSAI, JULIA, LI, YONGSHENG, CARP, RICHARD I, MEEKER, HARRY C, GAMBETTI, PIERLUIGI, DEBNATH, MANIK, MATHIS, CHESTER A, SHAO, LI, GAN, WEN-BIAO, KLUNK, WILLIAM E, WISNIEWSKI, THOMAS
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.07.2004; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Alkenes - metabolism; Alkenes - pharmacokinetics; Amyloid beta-Peptides - analysis; Animals; Benzene Derivatives - metabolism; Benzene Derivatives - pharmacokinetics; Biological and medical sciences; Brain - metabolism; Brain - pathology; Disease Models, Animal; Humans; Medical sciences; Metabolic Clearance Rate - drug effects; Metabolic Clearance Rate - physiology; Mice; Neurology; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Predictive Value of Tests; Prion Diseases - diagnostic imaging; Prion Diseases - metabolism; Prion Diseases - pathology; Reproducibility of Results; Scrapie - diagnostic imaging; Scrapie - metabolism; Scrapie - pathology; Stilbenes; Tomography, Emission-Computed - methods; Nervous system diseases; Targeting; Scrapie; Imaging; Two-photon microscopy; Amyloid; Prion; Methoxy-X04
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/63.7.775

The diagnosis of prion diseases in humans is challenging due to a lack of specific and sensitive non-invasive tests. Many forms of human prion disease including variant Creutzfeldt-Jakob disease (vCJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and 10% of sporadic CJD cases are associated with amyloid deposition. Several positron emission tomography (PET) ligands have recently been developed to directly image β-amyloid associated with Alzheimer disease. One of them, methoxy-X04, is a fluorescent derivative of Congo red with high binding affinity toward amyloid fibrils and good blood-brain barrier permeability. Using methoxy-X04, we investigated whether amyloid-targeting ligands can be also employed for direct imaging of amyloid deposits associated with some prion diseases. Such a method could potentially become a novel diagnostic approach for these conditions. Studies were performed on MB mice infected with the 87V mouse-adapted scrapie strain. Labeling of PrP amyloid plaques in brains of presymptomatic and symptomatic mice was demonstrated using in vivo transcranial two-photon microscopy after systemic administration of methoxy-X04. During real-time imaging, PrP amyloid deposits could be clearly distinguished 15 min after intravenous administration of methoxy-X04. The ligand showed rapid clearance from brain areas that did not contain amyloid deposits. PrP amyloid deposits could also be detected by direct application of methoxy-X04 on cerebellar sections from GSS patients. These results suggest that methoxy-XO4 or similar derivatives could be used as PET imaging agents to improve the diagnosis of human prion diseases associated with amyloid deposition.