Targeting prion amyloid deposits in vivo.

Abstract

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 beta-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-X04 or similar derivatives could be used as PET imaging agents to improve the diagnosis of human prion diseases associated with amyloid deposition.

• Authors: Marcin Sadowski, Joanna Pankiewicz, Henrieta Scholtzova, Julia Tsai, Yongsheng Li, Richard I Carp, Harry C Meeker, Pierluigi Gambetti, Manik Debnath, Chester A Mathis, Li Shao, Wen-Biao Gan, William E Klunk, Thomas Wisniewski
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 63 Issue 7 Pg. 775-84 (Jul 2004) ISSN: 0022-3069 [Print] England
• PMID: 15290902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 1,4-bis(4'-hydroxystyryl)-2-methoxybenzene
• Alkenes
• Amyloid beta-Peptides
• Benzene Derivatives
• Stilbenes

Topics

• Alkenes (metabolism, pharmacokinetics)
• Amyloid beta-Peptides (analysis)
• Animals
• Benzene Derivatives (metabolism, pharmacokinetics)
• Brain (metabolism, pathology)
• Disease Models, Animal
• Humans
• Metabolic Clearance Rate (drug effects, physiology)
• Mice
• Plaque, Amyloid (metabolism, pathology)
• Predictive Value of Tests
• Prion Diseases (diagnostic imaging, metabolism, pathology)
• Reproducibility of Results
• Scrapie (diagnostic imaging, metabolism, pathology)
• Stilbenes
• Tomography, Emission-Computed (methods)