Long-term monitoring of chronic demyelination and remyelination in a rat ischemic stroke model using macromolecular proton fraction mapping

Remyelination is a key process enabling post-stroke brain tissue recovery and plasticity. This study aimed to explore the feasibility of demyelination and remyelination monitoring in experimental stroke from the acute to chronic stage using an emerging myelin imaging biomarker, macromolecular proton fraction (MPF). After stroke induction by transient middle cerebral artery occlusion, rats underwent repeated MRI examinations during 85 days after surgery with histological endpoints for the animal subgroups on the 7th, 21st, 56th, and 85th days. MPF maps revealed two sub-regions within the infarct characterized by distinct temporal profiles exhibiting either a persistent decrease by 30%–40% or a transient decrease followed by return to nearly normal values after one month of observation. Myelin histology confirmed that these sub-regions had nearly similar extent of demyelination in the sub-acute phase and then demonstrated either chronic demyelination or remyelination. The remyelination zones also exhibited active axonal regrowth, reconstitution of compact fiber bundles, and proliferation of neuronal and oligodendroglial precursors. The demyelination zones showed more extensive astrogliosis from the 21st day endpoint. Both sub-regions had substantially depleted neuronal population over all endpoints. These results histologically validate MPF mapping as a novel approach for quantitative assessment of myelin damage and repair in ischemic stroke

Quantitative assessment of demyelination in ischemic stroke in vivo using macromolecular proton fraction mapping

A recent MRI method, fast macromolecular proton fraction (MPF) mapping, was used to quantify demyelination in the transient middle cerebral artery occlusion (MCAO) rat stroke model. MPF and other quantitative MRI parameters (T1, T2, proton density, and apparent diffusion coefficient) were compared with histological and immunohistochemical markers of demyelination (Luxol Fast Blue stain, (LFB)), neuronal loss (NeuN immunofluorescence), axonal loss (Bielschowsky stain), and inflammation (Iba1 immunofluorescence) in three animal groups ( n = 5 per group) on the 1st, 3rd, and 10th day after MCAO. MPF and LFB optical density (OD) were significantly reduced in the ischemic lesion on all days after MCAO relative to the symmetrical regions of the contralateral hemisphere. Percentage changes in MPF and LFB OD in the ischemic lesion relative to the contralateral hemisphere significantly differed on the first day only. Percentage changes in LFB OD and MPF were strongly correlated (R = 0.81, P < 0.001) and did not correlate with other MRI parameters. MPF also did not correlate with other histological variables. Addition of T2 into multivariate regression further improved agreement between MPF and LFB OD (R = 0.89, P < 0.001) due to correction of the edema effect. This study provides histological validation of MPF as an imaging biomarker of demyelination in ischemic stroke