Antibody-mediated Positron Emission Tomography Imaging of Brain Amyloid-beta Pathology.

摘要

Alzheimer's disease is the most common form of dementia and is classified as a progressive neurodegenerative disease that impairs memory and cognition. Definitive diagnosis requires access to brain tissue and clinicians rely primarily on behavioural observation. Few specific, reliable, and well-characterized quantitative tools are in development. The accumulation of misfolded amyloid-beta protein in the brain is one of the hallmark pathological features of Alzheimer's disease. Molecular imaging strategies have focused on measuring the amount of cerebral amyloid-beta. Antibody-mediated molecular imaging of amyloid-beta offers a promising strategy to measure specific types of amyloid-beta pathology in the central nervous system. This work characterizes the attempted translation of 4 anti-amyloid-beta antibodies from histological tools to live animal positron emission tomography imaging contrast agents. Several mass transfer properties of the classical anti-amyloid-beta antibody 6E10 were measured as a function of age in the TgCRND8 mouse model of Alzheimer's disease. 6E10 was used to extensively label amyloid-beta plaques after direct injection into the cortex of TgCRND8 mice. 6E10 was subsequently covalently modified with poly(ethylene glycol) (PEG) in order to increase the blood concentration and promote higher brain uptake of the compound. PEG-modification of 6E10 enabled differentiation of TgCRND8 mice from wild type control mice using live animal imaging. Three additional antibodies were screened in a similar fashion; two of these antibodies targeted parenchymal amyloid-beta plaques and one targeted vascular amyloid-beta deposits. One of the antibodies that targeted parenchymal amyloid-beta plaques and the antibody that targeted vascular amyloid-beta were used to differentiate between TgCRND8 and wild type control mice using live animal imaging. This work demonstrates the successful use of 3 anti-amyloid-beta antibodies to detect amyloid-beta pathology using non-invasive imaging techniques and presents a credible framework for translating promising antibodies into contrast agents.