Targeting prion amyloid deposits in vivo.
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.
Department of Neurology, New York University School of Medicine, New York, New York 10016, USA.
Marcin
M
Sadowski
Joanna
J
Pankiewicz
Henrieta
H
Scholtzova
Julia
J
Tsai
Yongsheng
Y
Li
Richard I
RI
Carp
Harry C
HC
Meeker
Pierluigi
P
Gambetti
Manik
M
Debnath
Chester A
CA
Mathis
Li
L
Shao
Wen-Biao
WB
Gan
William E
WE
Klunk
Thomas
T
Wisniewski
D000475:Alkenes / Q000378:metabolism / Q000493:pharmacokinetics; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D001555:Benzene Derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D051379:Mice; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D011237:Predictive Value of Tests; D017096:Prion Diseases / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D015203:Reproducibility of Results; D012608:Scrapie / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D013267:Stilbenes; D014055:Tomography, Emission-Computed / Q000379:methods*
C465418:1,4-bis(4'-hydroxystyryl)-2-methoxybenzene; D000475:Alkenes; D016229:Amyloid beta-Peptides; D001555:Benzene Derivatives; D013267:Stilbenes