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White matter intercompartmental water exchange rates determined from detailed modeling of the myelin sheath.

ABSTRACT: PURPOSE:Magnetization exchange (ME) between hydrogen protons of water and large molecules (semisolids [SS]) in lipid bilayers is an important factor in MRI signal generation and can be exploited to study white matter pathology. Current models used to quantify ME in white matter generally consider water to reside in 1 or 2 distinct compartments, ignoring the complexities of the myelin sheath's multicompartment structure of alternating myelin SS and myelin water (MW) layers. Here, we investigated the effect of this by fitting ME data obtained from human brain at 7 T with a multilayer model of myelin. METHODS:A multi-echo acquisition for a T2 * -based separation of MW from other water signals was combined with various preparation pulses to change the (relative) state of the SS and water pools and analyzed by fitting with a multilayer exchange model. RESULTS:The estimated lifetime within a single MW layer was 260 µs, corresponding to a lipid bilayer permeability of 6.7 µm/s. The magnetization lifetime of the aggregate of all MW was estimated at 13 ms, shorter than previously reported values in the range of 40 to 140 ms. CONCLUSION:Contrary to expectations and previous reports, ME between protons in myelin SS and water is not limited by the myelin sheath but rather by the exchange between SS and water protons. The analysis of ME contrast should account for the relatively short MW lifetime and affects the interpretation of tissue compartmentalization from MRI contrasts such as T1 - and diffusion-weighting.

SUBMITTER: van Gelderen P

PROVIDER: S-EPMC6258332 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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White matter intercompartmental water exchange rates determined from detailed modeling of the myelin sheath.

van Gelderen Peter P Duyn Jeff H JH

Magnetic resonance in medicine 20180919 1

<h4>Purpose</h4>Magnetization exchange (ME) between hydrogen protons of water and large molecules (semisolids [SS]) in lipid bilayers is an important factor in MRI signal generation and can be exploited to study white matter pathology. Current models used to quantify ME in white matter generally consider water to reside in 1 or 2 distinct compartments, ignoring the complexities of the myelin sheath's multicompartment structure of alternating myelin SS and myelin water (MW) layers. Here, we inves ...[more]

PMID: 30230605

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Project description:White matter hyperintensities negatively impact white matter structure and relate to cognitive decline in aging. Diffusion tensor imaging detects changes to white matter microstructure, both within the white matter hyperintensity and extending into surrounding (perilesional) normal-appearing white matter. However, diffusion tensor imaging markers are not specific to tissue components, complicating the interpretation of previous microstructural findings. Myelin water imaging is a novel imaging technique that provides specific markers of myelin content (myelin water fraction) and interstitial fluid (geometric mean T2). Here we combined diffusion tensor imaging and myelin water imaging to examine tissue characteristics in white matter hyperintensities and perilesional white matter in 80 individuals (47 older adults and 33 individuals with chronic stroke). To measure perilesional normal-appearing white matter, white matter hyperintensity masks were dilated in 2 mm segments up to 10 mm in distance from the white matter hyperintensity. Fractional anisotropy, mean diffusivity, myelin water fraction, and geometric mean T2 were extracted from white matter hyperintensities and perilesional white matter. We observed a spatial gradient of higher mean diffusivity and geometric mean T2, and lower fractional anisotropy, in the white matter hyperintensity and perilesional white matter. In the chronic stroke group, myelin water fraction was reduced in the white matter hyperintensity but did not show a spatial gradient in perilesional white matter. Across the entire sample, white matter metrics within the white matter hyperintensity related to whole-brain white matter hyperintensity volume; with increasing white matter hyperintensity volume there was increased mean diffusivity and geometric mean T2, and decreased myelin water fraction in the white matter hyperintensity. Normal-appearing white matter adjacent to white matter hyperintensities exhibits characteristics of a transitional stage between healthy white matter and white matter hyperintensities. This effect was observed in markers sensitive to interstitial fluid, but not in myelin water fraction, the specific marker of myelin concentration. Within the white matter hyperintensity, interstitial fluid was higher and myelin concentration was lower in individuals with more severe cerebrovascular disease. Our data suggests white matter hyperintensities have penumbra-like effects in perilesional white matter that specifically reflect increased interstitial fluid, with no changes to myelin concentration. In contrast, within the white matter hyperintensity there are varying levels of demyelination, which vary based on the severity of cerebrovascular disease. Diffusion tensor imaging and myelin imaging may be useful clinical markers to predict white matter hyperintensity formation, and to stage neuronal damage within white matter hyperintensities.

Project description:BackgroundVascular dementia (VAD) is the second most common type of dementia lacking effective treatments. Pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor, displays protective effects in multiple cerebral diseases. In this study, we aimed to investigate the therapeutic effects and potential mechanisms of PTX in VAD.MethodsBilateral common carotid artery stenosis (BCAS) mouse model was established to mimic VAD. Mouse behavior was tested by open field test, novel object recognition test, Y-maze and Morris water maze (MWM) tests. Histological staining, magnetic resonance imaging (MRI) and electron microscopy were used to define white matter integrity. The impact of PTX on microglia phagocytosis, peroxisome proliferator-activated receptors-γ (PPAR-γ) activation and Mer receptor tyrosine kinase (Mertk) expression was assessed by immunofluorescence, western blotting and flow cytometry with the application of microglia-specific Mertk knockout mice, Mertk inhibitor and PPAR-γ inhibitor.ResultsHere, we found that PTX treatment alleviated cognitive impairment in novel object recognition test, Y-maze and Morris water maze tests. Furthermore, PTX alleviated white matter injury in corpus callosum (CC) and internal capsule (IC) areas as shown by histological staining and MRI analysis. PTX-treatment group presented thicker myelin sheath than vehicle group by electron microscopy. Mechanistically, PTX facilitated microglial phagocytosis of myelin debris by up-regulating the expression of Mertk in BCAS model and primary cultured microglia. Importantly, microglia-specific Mertk knockout blocked the therapeutic effects of PTX in BCAS model. Moreover, Mertk expression was regulated by the nuclear translocation of PPAR-γ. Through modulating PPAR-γ, PTX enhanced Mertk expression.ConclusionsCollectively, our results demonstrated that PTX showed therapeutic potentials in VAD and alleviated ischemic white matter injury via modulating Mertk-mediated myelin clearance in microglia.

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White matter intercompartmental water exchange rates determined from detailed modeling of the myelin sheath.

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White matter intercompartmental water exchange rates determined from detailed modeling of the myelin sheath.

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