Physiological Dynamics in Demyelinating Diseases: Unraveling Complex Relationships through Computer Modeling
07 Sep 2015-International Journal of Molecular Sciences (Multidisciplinary Digital Publishing Institute (MDPI))-Vol. 16, Iss: 9, pp 21215-21236
TL;DR: This work will discuss how computational modeling applied to questions at different biological levels can help link together disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism.
Abstract: Despite intense research, few treatments are available for most neurological disorders. Demyelinating diseases are no exception. This is perhaps not surprising considering the multifactorial nature of these diseases, which involve complex interactions between immune system cells, glia and neurons. In the case of multiple sclerosis, for example, there is no unanimity among researchers about the cause or even which system or cell type could be ground zero. This situation precludes the development and strategic application of mechanism-based therapies. We will discuss how computational modeling applied to questions at different biological levels can help link together disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism. By making testable predictions and revealing critical gaps in existing knowledge, such models can help direct research and will provide a rigorous framework in which to integrate new data as they are collected. Nowadays, there is no shortage of data; the challenge is to make sense of it all. In that respect, computational modeling is an invaluable tool that could, ultimately, transform how we understand, diagnose, and treat demyelinating diseases.
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TL;DR: The data showed that repeatability and comparability depend largely on the marker for the FVF (NODDI outperformed TFD), and that they were improved by masking, and that the calibration procedure is crucial, for example, calibration to a lower g‐ratio value than the commonly used one.
Abstract: A recent method, denoted in vivo g-ratio-weighted imaging, has related the microscopic g-ratio, only accessible by ex vivo histology, to noninvasive MRI markers for the fiber volume fraction (FVF) and myelin volume fraction (MVF). Different MRI markers have been proposed for g-ratio weighted imaging, leaving open the question which combination of imaging markers is optimal. To address this question, the repeatability and comparability of four g-ratio methods based on different combinations of, respectively, two imaging markers for FVF (tract-fiber density, TFD, and neurite orientation dispersion and density imaging, NODDI) and two imaging markers for MVF (magnetization transfer saturation rate, MT, and, from proton density maps, macromolecular tissue volume, MTV) were tested in a scan-rescan experiment in two groups. Moreover, it was tested how the repeatability and comparability were affected by two key processing steps, namely the masking of unreliable voxels (e.g., due to partial volume effects) at the group level and the calibration value used to link MRI markers to MVF (and FVF). Our data showed that repeatability and comparability depend largely on the marker for the FVF (NODDI outperformed TFD), and that they were improved by masking. Overall, the g-ratio method based on NODDI and MT showed the highest repeatability (90%) and lowest variability between groups (3.5%). Finally, our results indicate that the calibration procedure is crucial, for example, calibration to a lower g-ratio value (g = 0.6) than the commonly used one (g = 0.7) can change not only repeatability and comparability but also the reported dependency on the FVF imaging marker. Hum Brain Mapp 39:24-41, 2018. © 2017 Wiley Periodicals, Inc.
38 citations
Cites background from "Physiological Dynamics in Demyelina..."
...It has been suggested that in the healthy condition axons and their microscopic substructures (e.g., their g-ratio) are finely tuned biological devices and that changes of their composition can lead to clinical syndromes [Coggan et al., 2015]....
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..., their g-ratio) are finely tuned biological devices and that changes of their composition can lead to clinical syndromes [Coggan et al., 2015]....
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TL;DR: In this paper, the authors present a review of the most recent developments in the field, while also providing methodological background pertinent to aggregate g-ratio weighted mapping, and discussing pitfalls associated with these approaches.
38 citations
Posted Content•
TL;DR: A second review on the topic of g-ratio mapping using MRI with a summary of the most recent developments in the field providing methodological background is published.
Abstract: The g-ratio, quantifying the comparative thickness of the myelin sheath encasing an axon, is a geometrical invariant that has high functional relevance because of its importance in determining neuronal conduction velocity. Advances in MRI data acquisition and signal modelling have put in vivo mapping of the g-ratio, across the entire white matter, within our reach. This capacity would greatly increase our knowledge of the nervous system: how it functions, and how it is impacted by disease. This is the second review on the topic of g-ratio mapping using MRI. As such, it summarizes the most recent developments in the field, while also providing methodological background pertinent to aggregate g-ratio weighted mapping, and discussing pitfalls associated with these approaches. Using simulations based on recently published data, this review demonstrates the relevance of the calibration step for three myelin-markers (macromolecular tissue volume, myelin water fraction, and bound pool fraction). It highlights the need to estimate both the slope and offset of the relationship between these MRI-based markers and the true myelin volume fraction if we are really to achieve the goal of precise, high sensitivity g-ratio mapping in vivo. Other challenges discussed in this review further evidence the need for gold standard measurements of human brain tissue from ex vivo histology. We conclude that the quest to find the most appropriate MRI biomarkers to enable in vivo g-ratio mapping is ongoing, with the potential of many novel techniques yet to be investigated.
25 citations
Cites background from "Physiological Dynamics in Demyelina..."
...As the central nervous system appears to communicate at physical limits to constrain metabolic demands (Salami et al., 2003; Hartline and Colman, 2007; Coggan et al., 2015), small deviations from the optimal g-ratio value (0....
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TL;DR: Over expression of glial fibrillary acidic protein (GFAP) confirms the neuronal damage, suggesting the evidences for behavioural changes, and mitochondrial damage, depleted energy level and decreased ATPase activities were observed in mice exposed to Fe2O3-NPs.
Abstract: Iron oxide (Fe2O3) nanoparticles (NPs) attract the attention of clinicians for its unique magnetic and paramagnetic properties, which are exclusively used in neurodiagnostics and therapeutics among the other biomedical applications. Despite numerous research findings has already proved neurotoxicity of Fe2O3-NPs, factors affecting neurobehaviour has not been elucidated. In this study, mice were exposed to Fe2O3-NPs (25 and 50 mg/kg body weight) by oral intubation daily for 30 days. It was observed that Fe2O3-NPs remarkably impair motor coordination and memory. In the treated brain regions, mitochondrial damage, depleted energy level and decreased ATPase (Mg2+, Ca2+ and Na+/K+) activities were observed. Disturbed ion homeostasis and axonal demyelination in the treated brain regions contributes to poor motor coordination. Increased intracellular calcium ([Ca2+]i) and decreased expression of growth associated protein 43 (GAP43) impairs vesicular exocytosis could result in insufficient signal between neurons. In addition, levels of dopamine (DA), norepinephrine (NE) and epinephrine (EP) were found to be altered in the subjected brain regions in correspondence to the expression of monoamine oxidases (MAO). Along with all these factors, over expression of glial fibrillary acidic protein (GFAP) confirms the neuronal damage, suggesting the evidences for behavioural changes.
15 citations
References
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TL;DR: In vivo imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD, and suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.
Abstract: In multiple sclerosis, a common inflammatory disease of the central nervous system, immune-mediated axon damage is responsible for permanent neurological deficits. How axon damage is initiated is not known. Here we use in vivo imaging to identify a previously undescribed variant of axon damage in a mouse model of multiple sclerosis. This process, termed 'focal axonal degeneration' (FAD), is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation. Notably, most swollen axons persist unchanged for several days, and some recover spontaneously. Early stages of FAD can be observed in axons with intact myelin sheaths. Thus, contrary to the classical view, demyelination-a hallmark of multiple sclerosis-is not a prerequisite for axon damage. Instead, focal intra-axonal mitochondrial pathology is the earliest ultrastructural sign of damage, and it precedes changes in axon morphology. Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD. Indeed, neutralization of ROS and RNS rescues axons that have already entered the degenerative process. Finally, axonal changes consistent with FAD can be detected in acute human multiple sclerosis lesions. In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.
647 citations
"Physiological Dynamics in Demyelina..." refers background in this paper
...Losing the energy savings afforded by saltatory conduction induces compensatory mitochondrial energy production that can result in oxidative damage and neurodegeneration [53,60,61]....
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...There are many ways mitochondrial function can go awry and the compensatory pathways are equally complicated [53,60,61]....
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...Pattern III is thought to be related to hypoxia-induced lesions which are driven by defects in mitochondrial function [53], whereas pattern IV lesions are associated with profound non-apoptotic death of oligodendrocytes in periplaque white matter....
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TL;DR: The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGo-1 knockout indicate that Lingo-1 signaling may be critical for CNSMyelination.
Abstract: The control of myelination by oligodendrocytes in the CNS is poorly understood. Here we show that LINGO-1 is an important negative regulator of this critical process. LINGO-1 is expressed in oligodendrocytes. Attenuation of its function by dominant-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation and increased myelination competence. Attenuation of LINGO-1 results in downregulation of RhoA activity, which has been implicated in oligodendrocyte differentiation. Conversely, overexpression of LINGO-1 leads to activation of RhoA and inhibition of oligodendrocyte differentiation and myelination. Treatment of oligodendrocyte and neuron cocultures with LINGO-1-Fc resulted in highly developed myelinated axons that have internodes and well-defined nodes of Ranvier. The contribution of LINGO-1 to myelination was verified in vivo through the analysis of LINGO-1 knockout mice. The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGO-1 knockout indicate that LINGO-1 signaling may be critical for CNS myelination.
609 citations
"Physiological Dynamics in Demyelina..." refers background in this paper
...Binding of LINGO-1 to Nogo receptors prevents remyelinating processes in the CNS; inhibition of this interaction thus enables significant remyelination in animals with experimental autoimmune encephalomyelitis [49]....
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TL;DR: This paper reviewed several exciting new hypotheses on grey matter pathogenesis, including meningeal inflammation as a cause of subpial cortical damage, but also selective vulnerability of neuronal subpopulations, growth factor dysregulation, glutamate excitotoxicity, mitochondrial abnormalities, and the "use-it-and-lose-it" principle.
Abstract: Summary Multiple sclerosis (MS) has been classically regarded as a white matter disease. However, recent histopathological studies have convincingly shown that grey matter regions are also heavily affected. Grey matter damage starts early in the disease and substantially affects clinico-cognitive functioning. Detection of cortical grey matter lesions by use of standard MRI techniques has proved challenging, and more advanced techniques are needed. At present, the causes of grey matter damage are unclear. We review several exciting new hypotheses on grey matter pathogenesis, including meningeal inflammation as a cause of subpial cortical damage, but also selective vulnerability of neuronal subpopulations, growth factor dysregulation, glutamate excitotoxicity, mitochondrial abnormalities, and the "use-it-and-lose-it" principle. These hypotheses remain to be validated over the coming years, and could substantially affect our current views on MS pathogenesis.
534 citations
TL;DR: Grey matter demyelination and neuronal loss could contribute to disability and cognitive dysfunctions in MS.
Abstract: The aim of our study is to evaluate the extent and distribution of grey matter demyelinating lesions in multiple sclerosis (MS), addressing also neuronal loss and synaptic loss. Whole coronal sections of 6 MS brains and 6 control brains were selected. Immunohistochemistry was performed for myelin basic protein, neurofilaments, synaptophysin, ubiquitin, and activated caspase-3. Neuronal density and optical density of synaptophysin staining were estimated in cortical lesions and compared with those observed in corresponding areas of normal (i.e. nondemyelinated) cortex in the same section. Demyelinating lesions were observed in the cerebral cortex, in the thalamus, basal ganglia, and in the hippocampus. The percentage of demyelinated cortex was remarkable in 2 cases of secondary progressive MS (48% and 25.5%, respectively). Neuronal density was significantly reduced in cortical lesions (18-23% reduction), if compared with adjacent normal cortex, in the 2 cases showing the higher extent of cortical demyelination; in the same cases, very rare apoptotic neurons expressing caspase-3 were observed in cortical lesions and not in adjacent normal cortex. No significant decrease in optical density of synaptophysin staining was observed in cortical lesions. Grey matter demyelination and neuronal loss could contribute to disability and cognitive dysfunctions in MS.
490 citations
Journal Article•
TL;DR: Multiple sclerosis (MS) typically presents in adults 20 to 45 years of age; occasionally, it presents in childhood or late middle age.
Abstract: 5and 50% of patients will need help walking within 15 years after the onset of the disease. 6 Twice as many women are affected as men, and persons of Northern European descent appear to be at highest risk for MS. 2,7 The disease is diagnosed on the basis of clinical findings and supporting evidence from ancillary tests, such as magnetic resonance imaging (MRI) of the brain and examination of the cerebrospinal fluid (CSF). MS typically presents in adults 20 to 45 years of age; occasionally, it presents in childhood or late middle age. 7
486 citations