An interactive meta-analysis of MRI biomarkers of myelin

Several MRI measures have been proposed as in vivo biomarkers of myelin, each with applications ranging from plasticity to pathology. Despite the availability of these myelin-sensitive modalities, specificity and sensitivity have been a matter of discussion. Debate about which MRI measure is the most suitable for quantifying myelin is still ongoing. In this study, we performed a systematic review of published quantitative validation studies to clarify how different these measures are when compared to the underlying histology. We analysed the results from 43 studies applying meta-analysis tools, controlling for study sample size and using interactive visualization (https://neurolibre.github.io/myelin-meta-analysis). We report the overall estimates and the prediction intervals for the coefficient of determination and find that MT and relaxometry-based measures exhibit the highest correlations with myelin content. We also show which measures are, and which measures are not statistically different regarding their relationship with histology

Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology

Recent years have seen an increased understanding of the importance of myelination in healthy brain function and neuropsychiatric diseases. Non-invasive microstructural magnetic resonance imaging (MRI) holds the potential to expand and translate these insights to basic and clinical human research, but the sensitivity and specificity of different MR markers to myelination is a subject of debate. To consolidate current knowledge on the topic, we perform a systematic review and meta-analysis of studies that validate microstructural imaging by combining it with myelin histology. We find meta-analytic evidence for correlations between various myelin histology metrics and markers from different MRI modalities, including fractional anisotropy, radial diffusivity, macromolecular pool, magnetization transfer ratio, susceptibility and longitudinal relaxation rate, but not mean diffusivity. Meta-analytic correlation effect sizes range widely, between = 0.26 and = 0.82. However, formal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication bias, thus preventing the establishment of a single most sensitive strategy to measure myelin with MRI. To facilitate further progress, we provide a detailed characterisation of the evaluated studies as an online resource. We also share a set of 12 recommendations for future studies validating putative MR-based myelin markers and deploying them in vivo in humans

Myelin quantification with MRI:A systematic review of accuracy and reproducibility

Objectives: Currently, multiple sclerosis is treated with anti-inflammatory therapies, but these treatments lack efficacy in progressive disease. New treatment strategies aim to repair myelin damage and efficacy evaluation of such new therapies would benefit from validated myelin imaging techniques. Several MRI methods for quantification of myelin density are available now. This systematic review aims to analyse the performance of these MRI methods. Methods: Studies comparing myelin quantification by MRI with histology, the current gold standard, or assessing reproducibility were retrieved from PubMed/MEDLINE and Embase (until December 2019). Included studies assessed both myelin histology and MRI quantitatively. Correlation or variance measurements were extracted from the studies. Non-parametric tests were used to analyse differences in study methodologies. Results: The search yielded 1348 unique articles. Twenty-two animal studies and 13 human studies correlated myelin MRI with histology. Eighteen clinical studies analysed the reproducibility. Overall bias risk was low or unclear. All MRI methods performed comparably, with a mean correlation between MRI and histology of R-2 = 0.54 (SD = 0.30) for animal studies, and R-2 = 0.54 (SD = 0.18) for human studies. Reproducibility for the MRI methods was good (ICC = 0.75-0.93, R-2 = 0.90-0.98, COV = 1.3-27%), except for MTR (ICC= 0.05-0.51). Conclusions: Overall, MRI-based myelin imaging methods show a fairly good correlation with histology and a good reproducibility. However, the amount of validation data is too limited and the variability in performance between studies is too large to select the optimal MRI method for myelin quantification yet

Development of techniques for time-lapse imaging of the dynamics of glial-axonal interactions in the central nervous system

Background: Myelination is an exquisite and dynamic example of heterologous cell-cell interaction, which consists of the concentric wrapping of multiple layers of oligodendrocyte membrane around neuronal axons. Understanding the mechanism by which oligodendrocytes ensheath axons may bring us closer to designing strategies to promote remyelination in demyelinating diseases. The main aim of this study was to follow glial-axonal interactions over time both in vitro and ex vivo to visualise the various stages of myelination. Methodology/Principal findings: Two approaches have been taken to follow myelination over time i) time-lapse imaging of mixed CNS myelinating cultures generated from mouse spinal cord to which exogenous GFP-labelled murine cells were added, and ii) ex vivo imaging of the spinal cord of shiverer (Mbp mutant) mice, transplanted with GFP-labelled murine neurospheres. The data demonstrate that oligodendrocyte-axonal interactions are dynamic events with continuous retraction and extension of oligodendroglial processes. Using cytoplasmic and membrane-GFP labelled cells to examine different components of the myelin-like sheath, evidence from time-lapse fluorescence microscopy and confocal microscopy suggest that the oligodendrocytes’ cytoplasm-filled processes initially spiral around the axon in a corkscrew-like manner. This is followed subsequently by focal expansion of the corkscrew process to form short cuffs which then extend longitudinally along the axons. From this model it is predicted that these spiral cuffs must extend over each other first before extending to form internodes of myelin. Conclusion: These experiments show the feasibility of visualising the dynamics of glial-axonal interaction during myelination over time. Moreover, these approaches complement each other with the in vitro approach allowing visualisation of an entire internodal length of myelin and the ex vivo approach validating the in vitro data

Hypoxia Delays Oligodendrocyte Progenitor Cell Migration and Myelin Formation by Suppressing Bmp2b Signaling in Larval Zebrafish

Hypoxia in newborns tends to result in developmental deficiencies in the white matter of the brain. As previous studies of the effects of hypoxia on neuronal development in rodents and human infants have been unable to use in vivo imaging, insight into the dynamic development of oligodendrocytes (OLs) in the central nervous system under hypoxia is limited. Here, we developed a visual model to study OL development using sublethal postnatal hypoxia in zebrafish larvae. We observed that hypoxia significantly suppressed OL progenitor cell migration toward the dorsum using in vivo imaging. Further, we found that hypoxia affected myelination, as indicated by thinner myelin sheaths and by a downregulation of myelin basic protein expression. Bmp2b protein expression was also significantly downregulated following hypoxia onset. Using gain of function and loss of function experiments, we demonstrated that the Bmp2b protein was associated with the regulation of OL development. Thus, our work provides a visual hypoxia model within which to observe OL development in vivo, and reveals the underlying mechanisms involved in these processes

Imaging Myelin Basic Protein expression in a model of remyelination by Magnetic Resonance Imaging using an Organic Anion Transporter Protein gene reporter system.

Demyelination occurs in several CNS diseases. If demyelinated axons are not remyelinated they become vulnerable to irreversible degeneration. There is, therefore, a clinical need for therapies that enhance remyelination. This can be achieved by 1) pharmacologically targeting endogenous oligodendrocyte progenitor cells (OPCs) responsible for remyelination or 2) transplantation of myelinogenic cells (including OPCs). The first approach is appropriate for diseases with no defect in the myelinating cells, such as multiple sclerosis (MS), while the second approach is suitable for genetic disorders of myelination such as Pelizaeus Merzbacher disease (PMD). Translation into the clinic has or will shortly begin for both approaches. However, there are no current outcome measures providing direct evidence of OPCs differentiation to assess the efficacy of a remyelination therapy. This thesis presents data which it is hoped will form the foundation of a novel outcome measure for such therapies. It demonstrates that, by using a novel MRI gene reporter system; OATP, and controlling its expression under a Myelin Basic Protein promoter, OPCs can take up gadolinium based contrast, and be detected using T1 weighted MRI imaging in vitro and ex vivo. Using a constitutively active promoter, transplanted cells can be detected by an in vivo model of remyelination. It is hoped that this data will form the foundation for the development of an outcome measure for assessing the efficacy of new, pro-remyelination therapies, and provide a non- invasive, longitudinal, and translational imaging technique for use in drug discovery, or even personalised medicine.Wellcome Trus

White matter integrity in mice requires continuous myelin synthesis at the inner tongue

Myelin, the electrically insulating sheath on axons, undergoes dynamic changes over time. However, it is composed of proteins with long lifetimes. This raises the question how such a stable structure is renewed. Here, we study the integrity of myelinated tracts after experi- mentally preventing the formation of new myelin in the CNS of adult mice, using an inducible Mbp null allele. Oligodendrocytes survive recombination, continue to express myelin genes, but they fail to maintain compacted myelin sheaths. Using 3D electron microscopy and mass spectrometry imaging we visualize myelin-like membranes failing to incorporate adaxonally, most prominently at juxta-paranodes. Myelinoid body formation indicates degradation of existing myelin at the abaxonal side and the inner tongue of the sheath. Thinning of compact myelin and shortening of internodes result in the loss of about 50% of myelin and axonal pathology within 20 weeks post recombination. In summary, our data suggest that functional axon-myelin units require the continuous incorporation of new myelin membranes