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Interactions between hydrogen protons of water molecules and macromolecules within the myelin sheath surrounding the axons are a major factor influencing the magnetic resonance (MR) contrast in white matter (WM) regions. In past decades, several studies have investigated the underlying effects and reported a wide range of R 1 rates for the myelin associated compartments at different field strengths. However, it was also shown that the experimental quantification of the compartment-specific R 1 rates is associated with large uncertainties. The current study therefore investigates the longitudinal relaxation rates within the myelin sheath using a molecular dynamic (MD) simulation. For this purpose, a realistic molecular model of the myelin sheath was employed to determine the dipole-dipole induced R 1 relaxation rate of the hydrogen protons at clinically relevant field strengths. The results obtained clearly reflect the spatial heterogeneity of R 1 with a increased relaxivity of myelin water due to a reduced molecular mobility near the membrane surface. Moreover, the calculated R 1 rates for both myelin water and macromolecules are in excellent agreement with experimental findings from the literature at different field strengths.

Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3 mo, whereas the other half received treatment from 3 mo to 5 mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.

We present a simple and robust method for the automated image analysis of quantitative cerebral water content maps acquired with MRI. The method is based on a new approach for the absolute and quantitative mapping of water content in vivo. Water content maps were automatically segmented into grey and white matter by employing the quantitative T1 information acquired as part of the water content mapping procedure. Based on the segmented maps, twenty-two parameters sensitive to both absolute water content and its spatial organisation are automatically extracted without user interaction. The parameters include, amongst others, absolute water content in grey and white matter and spatial asymmetries of the cerebral water content distribution. Significant age- and gender-related changes in the parameters determined were observed in a study of forty-four healthy subjects. Most notably, the grey matter water content decreases at a rate of 0.034%/year for females between the 3rd and 8th decade of life, whilst a much stronger decrease is observed in males which sets in after the 5th decade of life. In addition, female grey matter water content is, on average, 1.2% higher than the respective male grey matter water content. In contrast to the heterogeneity observed in grey matter, no significant physiological variation was observed for white matter water content. In addition to absolute grey matter water content, characteristic age- and gender-specific variations were also observed in most of the other variables. To check the potential loss of information associated with the large reduction of the dimensionality of the dataset to 22 parameters only, the age and gender of each individual subject were predicted by employing robust linear discriminant analysis based on only the determined twenty-two variables. The median deviation between predicted and real age was 6.3 years resulting in a high correlation coefficient between both values (r = 0.69). Gender is correctly predicted in 68.2% of all cases which improves to 87.5% when age-dependent effects are first corrected, demonstrating the high information content present in the variables even though the dimension of the dataset was significantly reduced. These results form the baseline for future studies of cerebral pathology. The method presented is fully automated, robust and flexible, making it an ideal tool for routine application in both neuroscientific studies and clinical diagnosis based on the quantitative measurement of cerebral water content.

We present a simple and robust method for the automated image analysis of quantitative cerebral water content maps acquired with MRI. The method is based on a new approach for the absolute and quantitative mapping of water content in vivo. Water content maps were automatically segmented into grey and white matter by employing the quantitative T 1 information acquired as part of the water content mapping procedure. Based on the segmented maps, twenty-two parameters sensitive to both absolute water content and its spatial organisation are automatically extracted without user interaction. The parameters include, amongst others, absolute water content in grey and white matter and spatial asymmetries of the cerebral water content distribution. Significant age- and gender-related changes in the parameters determined were observed in a study of forty-four healthy subjects. Most notably, the grey matter water content decreases at a rate of 0.034%/year for females between the 3rd and 8th decade of life, whilst a much stronger decrease is observed in males which sets in after the 5th decade of life. In addition, female grey matter water content is, on average, 1.2% higher than the respective male grey matter water content. In contrast to the heterogeneity observed in grey matter, no significant physiological variation was observed for white matter water content. In addition to absolute grey matter water content, characteristic age- and gender-specific variations were also observed in most of the other variables. To check the potential loss of information associated with the large reduction of the dimensionality of the dataset to 22 parameters only, the age and gender of each individual subject were predicted by employing robust linear discriminant analysis based on only the determined twenty-two variables. The median deviation between predicted and real age was 6.3 years resulting in a high correlation coefficient between both values ( r = 0.69). Gender is correctly predicted in 68.2% of all cases which improves to 87.5% when age-dependent effects are first corrected, demonstrating the high information content present in the variables even though the dimension of the dataset was significantly reduced. These results form the baseline for future studies of cerebral pathology. The method presented is fully automated, robust and flexible, making it an ideal tool for routine application in both neuroscientific studies and clinical diagnosis based on the quantitative measurement of cerebral water content.

Phantom systems consisting of liposome suspensions are widely employed to investigate quantitative MRI parameters mimicking cellular membranes. The proper physical understanding of the measurement results, however, requires proper models for liposomes and their interaction with the surrounding water molecules. Here, we present an MD-based approach for the theoretical prediction of R1=1/T1, the dependence of R1 on water concentration and the magnetization exchange between lipids and interacting water layer in lipids and lipid mixtures. Moreover, a new parameter is introduced which quantitatively measures the amount of hydration water (hydration water fraction, f_HW) based on conventional spoiled gradient echo MR acquisitions. Both f_HW and the magnetisation exchange rate between lipids and hydration water were determined quantitatively from spoiled gradient echo data. We observed that liposome systems behaved similarly, apart from PLPC which showed both lower hydration water fraction and lower exchange rate. The extracted parameters accurately predicted the measured water fraction-dependent R1 rates and allowed for a theoretical understanding of MR parameters in liposomes of different composition.

Quantitative magnetic resonance imaging might provide a more specific insight into disease process, progression and therapeutic response of multiple sclerosis. We present an extension of a previously published approach for the simultaneous mapping of brain T1, T2* and total water content. In addition to those three parameters, the method presented in the current work allows for the measurement of myelin bound water content, a surrogate marker of tissue myelination. Myelin water was measured based on its distinct relaxation with reduced T2*, resulting in a multiexponential decay signal. However, only 10 points could be acquired on the relaxation curve within a maximum echo time of <40ms as the quantitative protocol has been adapted previously for fast acquisitions with whole brain coverage. The sparse sampling required an adaption of the optimisation approach with additional constraints necessary in order to obtain reliable results. Therefore, the corresponding pool fractions were determined using linear optimisation instead of the standard nonnegative least squares (NNLS). The whole approach including the proper choice of constraints was optimised and validated in simulation studies. Furthermore, the independent determination of total water content allows for an absolute quantification of myelin water content, resulting in a more reliable measurement in oedemateous tissue. Whole brain maps of T1, T2*, total and myelin water content were acquired in 12 patients suffering from multiple sclerosis with mild disease grade. With an acquisition time of 10 minutes only, the presented multidimensional quantitative MRI protocol provides an interesting option for the clinical assessment and monitoring of multiple sclerosis, even on a routine basis.

The metabolic state of a cell is a key determinant in the decision to live and proliferate or to die. Consequently, balanced energy metabolism and the regulation of apoptosis are critical for the development and maintenance of differentiated organisms. Hypoxia occurs physiologically during development or exercise and pathologically in vascular disease, tumorigenesis, and inflammation, interfering with homeostatic metabolism. Here, we show that the hypoxia-inducible factor (HIF)-1–regulated glycolytic enzyme hexokinase II (HKII) acts as a molecular switch that determines cellular fate by regulating both cytoprotection and induction of apoptosis based on the metabolic state. We provide evidence for a direct molecular interactor of HKII and show that, together with phosphoprotein enriched in astrocytes (PEA15), HKII inhibits apoptosis after hypoxia. In contrast, HKII accelerates apoptosis in the absence of PEA15 and under glucose deprivation. HKII both protects cells from death during hypoxia and functions as a sensor of glucose availability during normoxia, inducing apoptosis in response to glucose depletion. Thus, HKII-mediated apoptosis may represent an evolutionarily conserved altruistic mechanism to eliminate cells during metabolic stress to the advantage of a multicellular organism.

The metabolic state of a cell is a key determinant in the decision to live and proliferate or to die. Consequently, balanced energy metabolism and the regulation of apoptosis are critical for the development and maintenance of differentiated organisms. Hypoxia occurs physiologically during development or exercise and pathologically in vascular disease, tumorigenesis, and inflammation, interfering with homeostatic metabolism. Here, we show that the hypoxia-inducible factor (HIF)-1–regulated glycolytic enzyme hexokinase II (HKII) acts as a molecular switch that determines cellular fate by regulating both cytoprotection and induction of apoptosis based on the metabolic state. We provide evidence for a direct molecular interactor of HKII and show that, together with phosphoprotein enriched in astrocytes (PEA15), HKII inhibits apoptosis after hypoxia. In contrast, HKII accelerates apoptosis in the absence of PEA15 and under glucose deprivation. HKII both protects cells from death during hypoxia and functions as a sensor of glucose availability during normoxia, inducing apoptosis in response to glucose depletion. Thus, HKII-mediated apoptosis may represent an evolutionarily conserved altruistic mechanism to eliminate cells during metabolic stress to the advantage of a multicellular organism.

The metabolic state of a cell is a key determinant in the decision to live and proliferate or to die. Consequently, balanced energy metabolism and the regulation of apoptosis are critical for the development and maintenance of differentiated organisms. Hypoxia occurs physiologically during development or exercise and pathologically in vascular disease, tumorigenesis, and inflammation, interfering with homeostatic metabolism. Here, we show that the hypoxia-inducible factor (HIF)-1-regulated glycolytic enzyme hexokinase II (HKII) acts as a molecular switch that determines cellular fate by regulating both cytoprotection and induction of apoptosis based on the metabolic state. We provide evidence for a direct molecular interactor of HKII and show that, together with phosphoprotein enriched in astrocytes (PEA15), HKII inhibits apoptosis after hypoxia. In contrast, HKII accelerates apoptosis in the absence of PEA15 and under glucose deprivation. HKII both protects cells from death during hypoxia and functions as a sensor of glucose availability during normoxia, inducing apoptosis in response to glucose depletion. Thus, HKII-mediated apoptosis may represent an evolutionarily conserved altruistic mechanism to eliminate cells during metabolic stress to the advantage of a multicellular organism.