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Journal ArticleDOI

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.

AbstractDespite 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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Citations
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01 May 1954

288 citations


Journal ArticleDOI
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.

23 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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Journal ArticleDOI
Abstract: Background 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. New method This is the second review on the topic of g-ratio mapping using MRI. Results This review 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. Comparison with existing methods Using simulations based on recently published data, this review reveals caveats to the state-of-the-art calibration methods that have been used for in vivo g-ratio mapping. 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. Conclusions We conclude that the quest to find the most appropriate MRI biomarkers to enable in vivo g-ratio mapping is ongoing, with the full potential of many novel techniques yet to be investigated.

14 citations


Journal ArticleDOI
TL;DR: The aim of this work is to present the current knowledge about the possible participation of electromagnetic fields in the occurrence and also in treatment of neurodegenerative diseases.
Abstract: The aim of this work is to present the current knowledge about the possible participation of electromagnetic fields in the occurrence and also in treatment of neurodegenerative diseases. The literature data indicate both the negative and positive effects of electromagnetic fields and not allow to draw unambiguous conclusions. Undoubtedly, the topic is still open and needs further intensive research to finally assess the mechanism of action of the electromagnetic field on neurodegenerative diseases.

10 citations


Cites background from "Physiological Dynamics in Demyelina..."

  • ...Demyelination causes slowing or loss of nerve conduction [10, 11]....

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Journal ArticleDOI
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.

9 citations


References
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Journal ArticleDOI
TL;DR: These revisions simplify the McDonald Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.
Abstract: New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.

8,100 citations


"Physiological Dynamics in Demyelina..." refers background in this paper

  • ...The differential diagnosis of MS closely follows the McDonald criteria [17]....

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Journal ArticleDOI
TL;DR: At a given time point of the disease, the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient, suggesting that MS may be a disease with heterogeneous pathogenetic mechanisms.
Abstract: Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS-like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T-cell‐mediated or T-cell plus antibody‐mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. At a given time point of the disease—as reflected in autopsy cases—the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease.

2,964 citations


"Physiological Dynamics in Demyelina..." refers background in this paper

  • ...[46] proposed four distinct immunopatterns of plaque formation found in patients at different stages of the disease....

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  • ...Other factors causing axonal dysfunction or death include a lack of trophic support from myelin and oligodendrocytes, damage from soluble or cellular immune factors still present in the inactive plaque, and chronic mitochondrial failure in the setting of increased energy demands [46]....

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Journal ArticleDOI
TL;DR: The identity of the ions which carry the various phases of the membrane current is chiefly concerned with sodium ions, since there is much evidence that the rising phase of the action potential is caused by the entry of these ions.
Abstract: In the preceding paper (Hodgkin, Huxley & Katz, 1952) we gave a general description of the time course of the current which flows through the membrane of the squid giant axon when the potential difference across the membrane is suddenly changed from its resting value, and held at the new level by a feed-back circuit ('voltage clamp' procedure). This article is chiefly concerned with the identity of the ions which carry the various phases of the membrane current. One of the most striking features of the records of membrane current obtained under these conditions was that when the membrane potential was lowered from its resting value by an amount between about 10 and 100 mV. the initial current (after completion of the quick pulse through the membrane capacity) was in the inward direction, that is to say, the reverse ofthe direction of the current which the same voltage change would have caused to flow in an ohmic resistance. The inward current was of the right order of magnitude, and occurred over the right range of membrane potentials, to be the current responsible for charging the membrane capacity during the rising phase of an action potential. This suggested that the phase of inward current in the voltage clamp records might be carried by sodium ions, since there is much evidence (reviewed by Hodgkin, 1951) that the rising phase of the action potential is caused by the entry of these ions, moving under the influence of concentration and potential differences. To investigate this possibility, we carried out voltage clamp runs with the axon surrounded by solutions with reduced sodium concentration. Choline was used as an inert cation since replacement of sodium with this ion makes the squid axon completely inexcitable, but does not reduce the resting potential (Hodgkin & Katz, 1949; Hodgkin, Huxley & Katz, 1949).

2,181 citations


"Physiological Dynamics in Demyelina..." refers background in this paper

  • ...the first thorough explanation of AP generation, was derived from experiments in unmyelinated giant axons of squid [63,64], but this early model has proven to be an invaluable tool from which later, more sophisticated models of myelinated axons have evolved....

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Journal ArticleDOI
TL;DR: Cognitive impairment in multiple sclerosis patients was not significantly associated with illness duration, depression, disease course, or medication usage, but was significantly (albeit weakly) correlated with physical disability.
Abstract: Previous frequency estimates of cognitive dysfunction in multiple sclerosis have ranged from 54 to 65 percent. These studies may overestimate the frequency in the general MS population, since the patients in these studies were recruited from clinic populations. In the present study, we administered a comprehensive neuropsychological test battery to 100 community‐based MS patients and 100 demographically matched healthy controls. Of 31 cognitive test indices examined, 48 MS patients and five controls were impaired on four or more test indices, yielding an overall frequency rate of 43% for the MS group. The pattern of cognitive decline was not uniform: MS patients were more frequently impaired on measures of recent memory, sustained attention, verbal fluency, conceptual reasoning, and visuospatial perception, and less frequently impaired on measures of language and immediate and remote memory. We developed a brief (20‐minute) screening battery empirically by selecting the four most sensitive test indices from the comprehensive battery. The brief battery yielded a sensitivity value of 71% and a specificity value of 94% in discriminating cognitively intact from impaired MS patients, as defined by the comprehensive battery. Cognitive impairment was not significantly associated with illness duration, depression, disease course, or medication usage, but was significantly (albeit weakly) correlated with physical disability. NEUROLOGY 1991;41:685‐691

1,999 citations


"Physiological Dynamics in Demyelina..." refers background in this paper

  • ...Transition from RRMS to SPMS is foreboding for the lack of therapeutics to combat the exacerbated physical and cognitive deterioration that most SPMS patients face [9,37]....

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Journal ArticleDOI
TL;DR: A significant decrease in the effector function of CD4+CD25hi regulatory T cells from peripheral blood of patients with MS as compared with healthy donors is reported.
Abstract: CD4+CD25+ regulatory T cells contribute to the maintenance of peripheral tolerance by active suppression because their deletion causes spontaneous autoimmune diseases in mice. Human CD4+ regulatory T cells expressing high levels of CD25 are suppressive in vitro and mimic the activity of murine CD4+CD25+ regulatory T cells. Multiple sclerosis (MS) is an inflammatory disease thought to be mediated by T cells recognizing myelin protein peptides. We hypothesized that altered functions of CD4+CD25hi regulatory T cells play a role in the breakdown of immunologic self-tolerance in patients with MS. Here, we report a significant decrease in the effector function of CD4+CD25hi regulatory T cells from peripheral blood of patients with MS as compared with healthy donors. Differences were also apparent in single cell cloning experiments in which the cloning frequency of CD4+CD25hi T cells was significantly reduced in patients as compared with normal controls. These data are the first to demonstrate alterations of CD4+CD25hi regulatory T cell function in patients with MS.

1,725 citations


"Physiological Dynamics in Demyelina..." refers background in this paper

  • ...Regulatory lymphocytes (Tregs) fail to suppress effector cells-mostly cytotoxic CD8+ cells [51]....

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