OBJECTIVE: Imaging of myelin tracts in vivo would greatly improve the monitoring of demyelinating diseases such as multiple sclerosis (MS). To date, no imaging technique specifically targets demyelination and remyelination. Recently, amyloid markers related to Congo red have been shown to bind to central nervous system (CNS) myelin. Here we questioned whether the thioflavine-T derivative 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), which also binds to amyloid plaques, could serve as a myelin marker. METHODS: PIB fixation to myelin was studied by fluorescence in the normal and dysmyelinating mouse brain, as well as in the postmortem brain of MS patients. Positron emission tomography (PET) experiments were conducted using [¹¹C]PIB in baboons and in a proof of concept clinical study in 2 MS patients. RESULTS: Applied directly on tissue sections or after intraperitoneal injection, PIB stained CNS myelin, and the decrease in the level of fixation paralleled the amount of myelin loss in a dysmyelinating mutant. In normally myelinated areas of postmortem MS brain, demyelinated and remyelinated lesions were clearly distinguishable by the differential intensity of labeling observed with PIB. PET using intravenously injected radiolabeled [¹¹C]PIB imaged CNS myelin in baboons and humans. In MS patients, the dynamic analysis of PET acquisitions allowed quantitative assessment of demyelination. INTERPRETATION: PIB could be used as an imaging marker to quantify myelin loss and repair in demyelinating diseases.
OBJECTIVE: Imaging of myelin tracts in vivo would greatly improve the monitoring of demyelinating diseases such as multiple sclerosis (MS). To date, no imaging technique specifically targets demyelination and remyelination. Recently, amyloid markers related to Congo red have been shown to bind to central nervous system (CNS) myelin. Here we questioned whether the thioflavine-T derivative 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), which also binds to amyloid plaques, could serve as a myelin marker. METHODS:PIB fixation to myelin was studied by fluorescence in the normal and dysmyelinatingmouse brain, as well as in the postmortem brain of MSpatients. Positron emission tomography (PET) experiments were conducted using [¹¹C]PIB in baboons and in a proof of concept clinical study in 2 MSpatients. RESULTS: Applied directly on tissue sections or after intraperitoneal injection, PIB stained CNS myelin, and the decrease in the level of fixation paralleled the amount of myelin loss in a dysmyelinating mutant. In normally myelinated areas of postmortem MS brain, demyelinated and remyelinated lesions were clearly distinguishable by the differential intensity of labeling observed with PIB. PET using intravenously injected radiolabeled [¹¹C]PIB imaged CNS myelin in baboons and humans. In MSpatients, the dynamic analysis of PET acquisitions allowed quantitative assessment of demyelination. INTERPRETATION:PIB could be used as an imaging marker to quantify myelin loss and repair in demyelinating diseases.
Authors: Noble George; Emily G Gean; Ayon Nandi; Boris Frolov; Eram Zaidi; Ho Lee; James R Brašić; Dean F Wong Journal: CNS Drugs Date: 2015-04 Impact factor: 5.749