Stem cell therapy for white matter disorders: don’t forget the microenvironment!

White matter disorders (WMDs) are a major source of handicap at all ages. They often lead to progressive neurological dysfunction and early death. Although causes are highly diverse, WMDs share the property that glia (astrocytes and oligodendrocytes) are among the cells primarily affected, and that myelin is either not formed or lost. Many WMDs might benefit from cell replacement therapies. Successful preclinical studies in rodent models have already led to the first clinical trials in humans using glial or oligodendrocyte progenitor cells aiming at (re)myelination. However, myelin is usually not the only affected structure. Neurons, microglia, and astrocytes are often also affected and are all important partners in creating the right conditions for proper white matter repair. Composition of the extracellular environment is another factor to be considered. Cell transplantation therapies might therefore require inclusion of non-oligodendroglial cell types and target more than only myelin repair. WMD patients would likely benefit from multimodal therapy approaches involving stem cell transplantation and microenvironment-targeting strategies to alter the local environment to a more favorable state for cell replacement. Furthermore most proof-of-concept studies have been performed with human cells in rodent disease models. Since human glial cells show a larger regenerative capacity than their mouse counterparts in the host mouse brain, microenvironmental factors affecting white matter recovery might be overlooked in rodent studies. We would like to stress that cell replacement therapy is a highly promising therapeutic option for WMDs, but a receptive microenvironment is crucia

Quantitative MRI in leukodystrophies

Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies

Cavitating Leukoencephalopathy With Posterior Predominance Caused by a Deletion in the APOPT1 Gene in an Indian Boy.

A 5-year-old Indian boy presented with subacute onset regression of milestones associated with seizures and spasticity. The symptoms started after an attack of measles. The magnetic resonance imaging (MRI) of the brain showed cavitating leukodystrophy with posterior predominance. Molecular analysis of the APOPT1 gene, a recently described gene associated with mitochondrial leukodystrophy, showed the patient to be homozygous for a 12.82-kilobase deletion, including coding exon 3. Deletion of exon 3 produces a frameshift, predicting the translation of a truncated protein (p.Glu121Valfs*4). The patient was started on mitochondrial cocktail regimen of thiamine, riboflavin, coenzyme Q and carnitine. Although he initially showed some improvement, he died 6 months after the onset of his illness.Genetic testing for the patient was done as part of the APOPT1 research project funded by MRC (MRC-QQR grant 2015-2020 and ERC advanced grant ERC FP7-322424

Umberto Eco, Narratives of Conspiracy and the Anti-Semite Among Us

http://www.quest-cdecjournal.it/discussion.php?id=3

Axonal abnormalities in vanishing white matter

ObjectiveWe aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter. MethodsAxons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single- and double-mutant mice and patient brain tissue. In addition, astrocyte-forebrain co-culture studies were performed. ResultsIn the corpus callosum of Eif2b5-mutant mice, myelin sheath thickness, axonal diameter, and G-ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G-ratio in Eif2b5-mutant mice. In more severely affected Eif2b4-Eif2b5 double-mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5-mutant mice. Co-cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal. InterpretationIn vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention

Approach for Predicting Production Scenarios Focused on Cross Impact Analysis

AbstractOne of the most consistent challenges in business is anticipating what the future holds and what impact it may have on current production systems. The scenario technique is a well-established method for developing and forecasting multiple future development paths for companies. However, this method is mostly employed to develop and to support strategic long-term decisions. The core idea of the approach introduced in this paper is to convey the future impact of today's decisions on production systems to employees involved in production planning processes. With the help of immersive visualization, performed in virtual reality (VR) systems, planning participants can perceive how the factory must adapt to fit future demands.In this paper, the focus is on the fourth phase of the scenario technique – so called scenario development – and, in particular, the cross impact analysis. With this methodology, the interrelations, or cross impacts of the different basic elements are determined. The cross impact analysis results serve as a basis for the development of a standardized tool that can be used to create probable production scenarios out of given production systems. This standardized tool will facilitate the usage of the scenario technique for factory planning projects, as it focuses the immense diversity of future uncertainties companies are faced with on the factory level

Homozygous UBA5 Variant Leads to Hypomyelination with Thalamic Involvement and Axonal Neuropathy

The enzyme ubiquitin-like modifier activating enzyme 5 (UBA5) plays an important role in activating ubiquitin-fold modifier 1 (UFM1) and its associated cascade. UFM1 is widely expressed and known to facilitate the post-translational modification of proteins. Variants in UBA5 and UFM1 are involved in neurodevelopmental disorders with early-onset epileptic encephalopathy as a frequently seen disease manifestation. Using whole exome sequencing, we detected a homozygous UBA5 variant (c.895C > T p. [Pro299Ser]) in a patient with severe global developmental delay and epilepsy, the latter from the age of 4 years. Magnetic resonance imaging showed hypomyelination with atrophy and T2 hyperintensity of the thalamus. Histology of the sural nerve showed axonal neuropathy with decreased myelin. Functional analyses confirmed the effect of the Pro299Ser variant on UBA5 protein function, showing 58% residual protein activity. Our findings indicate that the epilepsy currently associated with UBA5 variants may present later in life than previously thought, and that radiological signs include hypomyelination and thalamic involvement. The data also reinforce recently reported associations between UBA5 variants and peripheral neuropathy

Applicability of multiple quantitative magnetic resonance methods in genetic brain white matter disorders

Background and purpose: Magnetic resonance imaging (MRI) measures of tissue microstructure are important for monitoring brain white matter (WM) disorders like leukodystrophies and multiple sclerosis. They should be sensitive to underlying pathological changes. Three whole-brain isotropic quantitative methods were applied and compared within a cohort of controls and leukodystrophy patients: two novel myelin water imaging (MWI) techniques (multi-compartment relaxometry diffusion-informed MWI: MCR-DIMWI, and multi-echo T2 relaxation imaging with compressed sensing: METRICS) and neurite orientation dispersion and density imaging (NODDI).// Methods: For 9 patients with different leukodystrophies (age range 0.4-62.4 years) and 15 control subjects (2.3-61.3 years), T1-weighted MRI, fluid-attenuated inversion recovery, multi-echo gradient echo with variable flip angles, METRICS, and multi-shell diffusion-weighted imaging were acquired on 3 Tesla. MCR-DIMWI, METRICS, NODDI, and quality control measures were extracted to evaluate differences between patients and controls in WM and deep gray matter (GM) regions of interest (ROIs). Pearson correlations, effect size calculations, and multi-level analyses were performed.// Results: MCR-DIMWI and METRICS-derived myelin water fractions (MWFs) were lower and relaxation times were higher in patients than in controls. Effect sizes of MWF values and relaxation times were large for both techniques. Differences between patients and controls were more pronounced in WM ROIs than in deep GM. MCR-DIMWI-MWFs were more homogeneous within ROIs and more bilaterally symmetrical than METRICS-MWFs. The neurite density index was more sensitive in detecting differences between patients and controls than fractional anisotropy. Most measures obtained from MCR-DIMWI, METRICS, NODDI, and diffusion tensor imaging correlated strongly with each other.// Conclusion: This proof-of-concept study shows that MCR-DIMWI, METRICS, and NODDI are sensitive techniques to detect changes in tissue microstructure in WM disorders