Mathieu Boudreau

K252a and CEP1347 Are Neuroprotective Compounds That Inhibit Mixed-lineage Kinase-3 and Induce Activation of Akt and ERK

K252a is best known as a Trk inhibitor, but is also a neuroprotective compound. CEP1347, a K252a derivative, retains neuroprotective properties, but does not inhibit TrkA. CEP1347 has recently been shown to directly inhibit MAPKKKs, including MLK3, but the effect of K252a on MAPKKKs remains unknown. K252a and CEP1347 not only prevent death, but also facilitate neurite outgrowth and maintenance, somal hypertrophy, and neurotransmitter synthesis. The biochemical basis for these trophic effects remains unknown. We have compared the effects of CEP1347 and K252a on MLK and JNK signaling and on neurotrophic pathways that support survival and growth. Our data show that K252a is a potent inhibitor of MLK3 activity in vivo and in vitro (IC50 ∼ 5 nm). However, we also found that K252a and CEP1347 activate Akt and ERK and show that blockade of phosphatidylinositol 3-kinase or MEK activity ablates the effect of K252a and CEP1347 on cell survival. Activation of Akt and ERK occurs through an MLK-independent pathway that may involve c-Src. Together, these data show that the neuroprotective and neurotrophic effects of K252a and CEP1347 involve activation of several neurotrophic signaling pathways.

In vivo histology of the myelin g-ratio with magnetic resonance imaging

The myelin g-ratio, defined as the ratio between the inner and the outer diameter of the myelin sheath, is a fundamental property of white matter that can be computed from a simple formula relating the myelin volume fraction to the fiber volume fraction or the axon volume fraction. In this paper, a unique combination of magnetization transfer, diffusion imaging and histology is presented, providing a novel method for in vivo magnetic resonance imaging of the axon volume fraction and the myelin g-ratio. Our method was demonstrated in the corpus callosum of one cynomolgus macaque, and applied to obtain full-brain g-ratio maps in one healthy human subject and one multiple sclerosis patient. In the macaque, the g-ratio was relatively constant across the corpus callosum, as measured by both MRI and electron microscopy. In the human subjects, the g-ratio in multiple sclerosis lesions was higher than in normal appearing white matter, which was in turn higher than in healthy white matter. Measuring the g-ratio brings us one step closer to fully characterizing white matter non-invasively, making it possible to perform in vivo histology of the human brain during development, aging, disease and treatment.

On the accuracy of T1 mapping: searching for common ground.

There are many T1 mapping methods available, each of them validated in phantoms and reporting excellent agreement with literature. However, values in literature vary greatly, with T1 in white matter ranging from 690 to 1100 ms at 3 Tesla. This brings into question the accuracy of one of the most fundamental measurements in quantitative MRI. Our goal was to explain these variations and look into ways of mitigating them.

Quantitative analysis of the myelin g-ratio from electron microscopy images of the macaque corpus callosum

We provide a detailed morphometric analysis of eight transmission electron micrographs (TEMs) obtained from the corpus callosum of one cynomolgus macaque. The raw TEM images are included in the article, along with the distributions of the axon caliber and the myelin g-ratio in each image. The distributions are analyzed to determine the relationship between axon caliber and g-ratio, and compared against the aggregate metrics (myelin volume fraction, fiber volume fraction, and the aggregate g-ratio), as defined in the accompanying research article entitled ‘In vivo histology of the myelin g-ratio with magnetic resonance imaging’ (Stikov et al., NeuroImage, 2015).

Promise and pitfalls of g-ratio estimation with MRI

Abstract The fiber g‐ratio is the ratio of the inner to the outer diameter of the myelin sheath of a myelinated axon. It has a limited dynamic range in healthy white matter, as it is optimized for speed of signal conduction, cellular energetics, and spatial constraints. In vivo imaging of the g‐ratio in health and disease would greatly increase our knowledge of the nervous system and our ability to diagnose, monitor, and treat disease. MRI based g‐ratio imaging was first conceived in 2011, and expanded to be feasible in full brain white matter with preliminary results in 2013. This manuscript reviews the growing g‐ratio imaging literature and speculates on future applications. It details the methodology for imaging the g‐ratio with MRI, and describes the known pitfalls and challenges in doing so. HighlightsThis article reviews the recently developed g‐ratio imaging framework.Confounds in the methodology are detailed.Recent progress and applications are reviewed.

B1 mapping for bias-correction in quantitative T 1 imaging of the brain at 3T using standard pulse sequences: B1 Maps for Quantitative T 1

B1 mapping is important for many quantitative imaging protocols, particularly those that include whole‐brain T1 mapping using the variable flip angle (VFA) technique. However, B1 mapping sequences are not typically available on many magnetic resonance imaging (MRI) scanners. The aim of this work was to demonstrate that B1 mapping implemented using standard scanner product pulse sequences can produce B1 (and VFA T1) maps comparable in quality and acquisition time to advanced techniques.

B1‐sensitivity analysis of quantitative magnetization transfer imaging

To evaluate the sensitivity of quantitative magnetization transfer (qMT) fitted parameters to B1 inaccuracies, focusing on the difference between two categories of T1 mapping techniques: B1‐independent and B1‐dependent.

Sensitivity regularization of the Cramér-Rao lower bound to minimize B1 nonuniformity effects in quantitative magnetization transfer imaging

To develop and validate a regularization approach of optimizing B1 insensitivity of the quantitative magnetization transfer (qMT) pool‐size ratio (F).