Eva Scheurer

Quantitative susceptibility mapping (QSM) as a means to measure brain iron? A post mortem validation study

Quantitative susceptibility mapping (QSM) is a novel technique which allows determining the bulk magnetic susceptibility distribution of tissue in vivo from gradient echo magnetic resonance phase images. It is commonly assumed that paramagnetic iron is the predominant source of susceptibility variations in gray matter as many studies have reported a reasonable correlation of magnetic susceptibility with brain iron concentrations in vivo. Instead of performing direct comparisons, however, all these studies used the putative iron concentrations reported in the hallmark study by Hallgren and Sourander (1958) for their analysis. Consequently, the extent to which QSM can serve to reliably assess brain iron levels is not yet fully clear. To provide such information we investigated the relation between bulk tissue magnetic susceptibility and brain iron concentration in unfixed (in situ) post mortem brains of 13 subjects using MRI and inductively coupled plasma mass spectrometry. A strong linear correlation between chemically determined iron concentration and bulk magnetic susceptibility was found in gray matter structures (r = 0.84, p < 0.001), whereas the correlation coefficient was much lower in white matter (r = 0.27, p < 0.001). The slope of the overall linear correlation was consistent with theoretical considerations of the magnetism of ferritin supporting that most of the iron in the brain is bound to ferritin proteins. In conclusion, iron is the dominant source of magnetic susceptibility in deep gray matter and can be assessed with QSM. In white matter regions the estimation of iron concentrations by QSM is less accurate and more complex because the counteracting contribution from diamagnetic myelinated neuronal fibers confounds the interpretation.

Quantitative MR Imaging of Brain Iron: A Postmortem Validation Study

PURPOSE To investigate the relationship between transverse relaxation rates R2 and R2*, the most frequently used surrogate markers for iron in brain tissue, and chemically determined iron concentrations. MATERIALS AND METHODS This study was approved by the local ethics committee, and informed consent was obtained from each individuals next of kin. Quantitative magnetic resonance (MR) imaging was performed at 3.0 T in seven human postmortem brains in situ (age range at death, 38-81 years). Following brain extraction, iron concentrations were determined with inductively coupled plasma mass spectrometry in prespecified gray and white matter regions and correlated with R2 and R2* by using linear regression analysis. Hemispheric differences were tested with paired t tests. RESULTS The highest iron concentrations were found in the globus pallidus (mean ± standard deviation, 205 mg/kg wet mass ± 32), followed by the putamen (mean, 153 mg/kg wet mass ± 29), caudate nucleus (mean, 92 mg/kg wet mass ± 15), thalamus (mean, 49 mg/kg wet mass ± 11), and white matter regions. When all tissue samples were considered, transverse relaxation rates showed a strong linear correlation with iron concentration throughout the brain (r² = 0.67 for R2, r² = 0.90 for R2*; P < .001). In white matter structures, only R2* showed a linear correlation with iron concentration. Chemical analysis revealed significantly higher iron concentrations in the left hemisphere than in the right hemisphere, a finding that was not reflected in the relaxation rates. CONCLUSION Because of their strong linear correlation with iron concentration, both R2 and R2* can be used to measure iron deposition in the brain. Because R2* is more sensitive than R2 to variations in brain iron concentration and can detect differences in white matter, it is the preferred parameter for the assessment of iron concentration in vivo.

Susceptibility induced gray–white matter MRI contrast in the human brain

MR phase images have shown significantly improved contrast between cortical gray and white matter regions compared to magnitude images obtained with gradient echo sequences. A variety of underlying biophysical mechanisms (including iron, blood, myelin content, macromolecular chemical exchange, and fiber orientation) have been suggested to account for this observation but assessing the individual contribution of these factors is limited in vivo. For a closer investigation of iron and myelin induced susceptibility changes, postmortem MRI of six human corpses (age range at death: 56–80 years) was acquired in situ. Following autopsy, the iron concentrations in the frontal and occipital cortex as well as in white matter regions were chemically determined. The magnetization transfer ratio (MTR) was used as an indirect measure for myelin content. Susceptibility effects were assessed separately by determining R2* relaxation rates and quantitative phase shifts. Contributions of myelin and iron to local variations of the susceptibility were assessed by univariate and multivariate linear regression analysis. Mean iron concentration was lower in the frontal cortex than in frontal white matter (26 ± 6 vs. 45 ± 6 mg/kg wet tissue) while an inverse relation was found in the occipital lobe (cortical gray matter: 41 ± 10 vs. white matter: 34 ± 10 mg/kg wet tissue). Multiple regression analysis revealed iron and MTR as independent predictors of the effective transverse relaxation rate R2* but solely MTR was identified as source of MR phase contrast. R2* was correlated with iron concentrations in cortical gray matter only (r = 0.42, p < 0.05). In conclusion, MR phase contrast between cortical gray and white matter can be mainly attributed to variations in myelin content, but not to iron concentration. Both, myelin and iron impact the effective transverse relaxation rate R2* significantly. Magnitude contrast is limited because it only reflects the extent but not the direction of the susceptibility shift.

Virtopsy: Forensic Traumatology of the Subcutaneous Fatty Tissue; Multislice Computed Tomography (MSCT) and Magnetic Resonance Imaging (MRI) as Diagnostic Tools

Traumatic lesions of the subcutaneous fatty tissue provide important clues for forensic reconstruction. The interpretation of these patterns requires a precise description and recording of the position and extent of each lesion. During conventional autopsy, this evaluation is performed by dissecting the skin and subcutaneous tissues in successive layers. In this way, depending on the force and type of impact (right angle or tangent), several morphologically distinct stages of fatty tissue damage can be differentiated: perilobular hemorrhage (I), contusion (II), or disintegration (III) of the fat lobuli, and disintegration with development of a subcutaneous cavity (IV). In examples of virtopsy cases showing blunt trauma to the skin and fatty tissue, we analyzed whether these lesions can also be recorded and classified using multislice computed tomography (MSCT) and magnetic resonance imaging (MRI). MSCT has proven to be a valuable screening method to detect the lesions, but MRI is necessary in order to properly differentiate and classify the grade of damage. These noninvasive radiological diagnostic tools can be further developed to play an important role in forensic examinations, in particular when it comes to evaluating living trauma victims.

Clinical forensic radiology in strangulation victims: forensic expertise based on magnetic resonance imaging (MRI) findings

Based on only one objective and several subjective signs, the forensic classification of strangulation incidents concerning their life-threatening quality can be problematic. Reflecting that it is almost impossible to detect internal injuries of the neck with the standard forensic external examination, we examined 14 persons who have survived manual and ligature strangulation or forearm choke holds using MRI technique (1.5-T scanner). Two clinical radiologists evaluated the neck findings independently. The danger to life was evaluated based on the “classical” external findings alone and in addition to the radiological data. We observed hemorrhaging in the subcutaneous fatty tissue of the neck in ten cases. Other frequent findings were hemorrhages of the neck and larynx muscles, the lymph nodes, the pharynx, and larynx soft tissues. Based on the classical forensic strangulation findings with MRI, eight of the cases were declared as life-endangering incidents, four of them without the presence of petechial hemorrhage but with further signs of impaired brain function due to hypoxia. The accuracy of future forensic classification of the danger to life will probably be increased when it is based not only on one objective and several subjective signs but also on the evidence of inner neck injuries. However, further prospective studies including larger cohorts are necessary to clarify the value of the inner neck injuries in the forensic classification of surviving strangulation victims.

Observation and identification of metabolites emerging during postmortem decomposition of brain tissue by means of in situ 1H-magnetic resonance spectroscopy.

Postmortem decomposition of brain tissue was investigated by 1H‐magnetic resonance spectroscopy (MRS) in a sheep head model and selected human cases. Aiming at the eventual estimation of postmortem intervals in forensic medicine, this study focuses on the characterization and identification of newly observed metabolites. In situ single‐voxel 1H‐MRS at 1.5 T was complemented by multidimensional homo‐ and heteronuclear high‐resolution NMR spectroscopy of an extract of sheep brain tissue. The inclusion of spectra of model solutions in the program LC Model confirmed the assignments in situ. The first postmortem phase was characterized mainly by changes in the concentrations of metabolites usually observed in vivo and by the appearance of previously reported decay products. About 3 days postmortem, new metabolites, including free trimethylammonium, propionate, butyrate, and iso‐butyrate, started to appear in situ. Since the observed metabolites and the time course is comparable in sheep and human brain tissue, the model system seems to be appropriate. Magn Reson Med 48:915–920, 2002.

Assessment of trace elements in human brain using inductively coupled plasma mass spectrometry.

Recent brain research reveals a major role of trace elements in various diseases such as multiple sclerosis, Alzheimers and Wilsons disease. The majority of published tissue concentrations dates back decades, and was assessed with various methods. Little is known about hemispherical differences, the correlation of trace elements or age-dependent changes in the human brain. Thus, the aim of this study was to examine trace element concentrations in different human brain regions after whole brain formalin fixation. 549 samples of 13 brain regions were investigated in 11 deceased subjects without known history of brain pathology. Regional wet-to-dry mass ratios and concentrations of iron, copper, magnesium, manganese, calcium and zinc were determined using inductively coupled plasma mass spectrometry. Cortical gray matter revealed higher water content (wet-to-dry mass ratios 5.84-6.40) than white matter regions (wet-to-dry mass ratios 2.95-3.05). Element concentrations displayed specific regional differences. Good linear correlation of concentrations between elements was found for iron/copper as well as for manganese/magnesium (Spearmans rank correlation coefficient 0.74 and 0.65, respectively). Significant inter-hemispherical differences were found for copper in occipital white matter, for magnesium and calcium in putamen and for iron and copper in temporal white matter. An age dependent increase was seen in cortical gray matter for calcium, for magnesium in all regions except in cortical gray matter, for copper in substantia nigra and for zinc in occipital cortex. The presented trace element concentrations can serve as a fundamental basis for further brain research. Wet-to-dry mass ratios allow a comparison with reference data from other studies.

Fructose and Galactose Enhance Post-Exercise Human Liver Glycogen Synthesis

PURPOSE Both liver and muscle glycogen stores play a fundamental role in exercise and fatigue, but the effect of different CHO sources on liver glycogen synthesis in humans is unclear. The aim was to compare the effect of maltodextrin (MD) drinks containing galactose, fructose, or glucose on postexercise liver glycogen synthesis. METHODS In this double-blind, triple crossover, randomized clinical trial, 10 well-trained male cyclists performed three experimental exercise sessions separated by at least 1 wk. After performing a standard exercise protocol to exhaustion, subjects ingested one of three 15% CHO solutions, namely, FRU (MD + fructose, 2:1), GAL (MD + galactose, 2:1), or GLU (MD + glucose, 2:1), each providing 69 g CHO·h(-1) during 6.5 h of recovery. Liver glycogen changes were followed using (13)C magnetic resonance spectroscopy. RESULTS Liver glycogen concentration increased at faster rates with FRU (24 ± 2 mmol·L(-1)·h(-1), P < 0.001) and with GAL (28 ± 3 mmol·L(-1)·h(-1), P < 0.001) than with GLU (13 ± 2 mmol·L(-1)·h(-1)). Liver volumes increased (P < 0.001) with FRU (9% ± 2%) and with GAL (10% ± 2%) but not with GLU (2% ± 1%, NS). Net glycogen synthesis appeared linear and was faster with FRU (8.1 ± 0.6 g·h(-1), P < 0.001) and with GAL (8.6 ± 0.9 g·h(-1), P < 0.001) than with GLU (3.7 ± 0.5 g·h(-1)). CONCLUSIONS When ingested at a rate designed to saturate intestinal CHO transport systems, MD drinks with added fructose or galactose were twice as effective as MD + glucose in restoring liver glycogen during short-term postexercise recovery.

Traumatic extra-axial hemorrhage: Correlation of postmortem MSCT, MRI, and forensic-pathological findings†

To evaluate the diagnostic accuracy of in situ postmortem multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) in the detection of primary traumatic extra‐axial hemorrhage.

Forensic Application of Postmortem Diffusion-Weighted and Diffusion Tensor MR Imaging of the Human Brain in Situ

BACKGROUND AND PURPOSE: DWI and DTI of the brain have proved to be useful in many neurologic disorders and in traumatic brain injury. This prospective study aimed at the evaluation of the influence of the PMI and the cause of death on the ADC and FA for the application of DWI and DTI in forensic radiology. MATERIALS AND METHODS: DWI and DTI of the brain were performed in situ in 20 deceased subjects with mapping of the ADC and FA. Evaluation was performed in different ROIs, and the influence of PMI and cause of death was assessed. RESULTS: Postmortem ADC values of the brain were decreased by 49%–72% compared with healthy living controls. With increasing PMI, ADCs were significantly reduced when considering all ROIs together and, particularly, GM regions (all regions, P < .05; GM, P < .01), whereas there was no significant effect in WM. Concerning the cause of death, ADCs were significantly lower in mechanical and hypoxic brain injury than in brains from subjects having died from heart failure (traumatic brain injury, P < .005; hypoxia, P < .001). Postmortem FA was not significantly different from FA in living persons and showed no significant influence of PMI or cause of death. CONCLUSIONS: Performing postmortem DWI and DTI of the brain in situ can provide valuable information for application in forensic medicine. ADC could be used as an indicator of PMI and could help in the assessment of the cause of death.