Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1.

Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in patients with MS vs. 1.1 in control subjects, suggesting that, in MS, ET-1 is released from the brain to the cerebral circulation. Next, we performed ET-1 immunohistochemistry on postmortem white matter brain samples and found that the likely source of ET-1 release are reactive astrocytes in MS plaques. We then used arterial spin-labeling MRI to noninvasively measure CBF and assess the effect of the administration of the ET-1 antagonist bosentan. CBF was significantly lower in patients with MS than in control subjects and increased to control values after bosentan administration. These data demonstrate that reduced CBF in MS is mediated by ET-1, which is likely released in the cerebral circulation from reactive astrocytes in plaques. Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.

Cylinders or walls? A new computational model to estimate the MR transverse relaxation rate dependence on trabecular bone architecture.

OBJECTIVE: Bone density is distributed in a complex network of interconnecting trabecular plates and rods that are interspersed with bone marrow. A computational model to assess the dependence of the relaxation rate on the geometry of bone can consider the distribution of bone material in the form of two components: cylinders and open walls (walls with gaps). We investigate whether the experimentally known dependence of the transverse relaxation rate on the trabecular bone structure can be usefully interpreted in terms of these two components. MATERIALS AND METHODS: We established a computer model based on an elementary computational cell. The model includes a variable number of open walls and infinitely long cylinders as well as multiple geometric parameters. The transverse relaxation rate is computed as a function of these parameters. Within the model, increasing the trabecular spacing with a fixed trabecular radius is equivalent to thinning the trabeculae while maintaining constant spacing. RESULTS: Increasing the number of cylinder and wall gap elements beyond their nearest neighbors does not change the transverse relaxation rate. Although the absolute contribution to the relaxation due to open walls is on average more important than that due to cylinders, the latter drops off rapidly. The change on transverse relaxation rate is larger for changing cylinder geometry than for changing wall geometry, as it can be seen from the effect on the relaxation rate when trabecular spacing is varied, compared to varying the size of wall gaps. CONCLUSION: Our results provide strong evidence that trabecular thinning, which is associated with increasing age, decreases the relaxation rates. The effect of thinning plates and rods on the transverse relaxation can be understood in terms of simple cylinders and open walls. A reduction in the relaxation rate can be seen as an indication of thinning cylinders, corresponding to reduced bone stability and ultimately, osteoporosis.

Cerebral white matter blood flow and energy metabolism in multiple sclerosis.

BACKGROUND: Cerebral blood flow (CBF) is reduced in normal-appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but the underlying mechanism is unknown. OBJECTIVE: The objective of this article is to assess the relationship between reduced NAWM CBF and both axonal mitochondrial metabolism and astrocytic phosphocreatine (PCr) metabolism. METHODS: Ten healthy controls and 25 MS subjects were studied with 3 Tesla magnetic resonance imaging. CBF was measured using pseudo-continuous arterial spin labeling. N-acetylaspartate/creatine (NAA/Cr) ratios (axonal mitochondrial metabolism) were obtained using (1)H-MR spectroscopy and PCr/ß-ATP ratios using (31)P-MR spectroscopy. In centrum semiovale NAWM, we assessed correlations between CBF and both NAA/Cr and PCr/ß-ATP ratios. RESULTS: Subjects with MS had a widespread reduction in CBF of NAWM (centrum semiovale, periventricular, frontal and occipital), and gray matter (frontoparietal cortex and thalamus). Compared to controls, NAA/Cr in NAWM of the centrum semiovale of MS subjects was decreased, whereas PCr/ß-ATP was increased. We found no correlations between CBF and PCr/ß-ATP. CBF and NAA/Cr correlated in controls (p = 0.02), but not in MS subjects (p = 0.68). CONCLUSIONS: Our results suggest that in MS patients there is no relationship between reduced CBF in NAWM and impaired axonal mitochondrial metabolism or astrocytic PCr metabolism.

Magnetic resonace-based attenuation correction for micro-single-photon emission computed tomography.

Attenuation correction is necessary for quantification in micro-single-photon emission computed tomography (micro-SPECT). In general, this is done based on micro-computed tomographic (micro-CT) images. Derivation of the attenuation map from magnetic resonance (MR) images is difficult because bone and lung are invisible in conventional MR images and hence indistinguishable from air. An ultrashort echo time (UTE) sequence yields signal in bone and lungs. Micro-SPECT, micro-CT, and MR images of 18 rats were acquired. Different tracers were used: hexamethylpropyleneamine oxime (brain), dimercaptosuccinic acid (kidney), colloids (liver and spleen), and macroaggregated albumin (lung). The micro-SPECT images were reconstructed without attenuation correction, with micro-CT-based attenuation maps, and with three MR-based attenuation maps: uniform, non-UTE-MR based (air, soft tissue), and UTE-MR based (air, lung, soft tissue, bone). The average difference with the micro-CT-based reconstruction was calculated. The UTE-MR-based attenuation correction performed best, with average errors ≤ 8% in the brain scans and ≤ 3% in the body scans. It yields nonsignificant differences for the body scans. The uniform map yields errors of ≤ 6% in the body scans. No attenuation correction yields errors ≥ 15% in the brain scans and ≥ 25% in the body scans. Attenuation correction should always be performed for quantification. The feasibility of MR-based attenuation correction was shown. When accurate quantification is necessary, a UTE-MR-based attenuation correction should be used.

Assessment of intrafractional movement and internal motion in radiotherapy of rectal cancer using megavoltage computed tomography.

PURPOSE: The aim of this study was to provide estimates of setup and internal margins of patients treated for rectal carcinoma using helical tomotherapy and to assess possible margin adaptations. Using helical tomotherapy, highly conformal dose distributions can be created, and the integrated megavoltage computed tomography (MVCT) modality allows very precise daily patient positioning. In clinical protocols, however, margins originating from traditional setup procedures are still being applied. This work investigates whether this modality can aid in redefining treatment margins. METHODS AND MATERIALS: Ten patients who were treated with tomotherapy underwent MVCT scanning before and after 10 treatments. Using automatic registration the necessary setup margin was investigated by means of bony landmarks. Internal margins were assessed by delineating and describing the mesorectal movement. RESULTS: Based on bony landmarks, movement of patients during treatments was limited to 2.45 mm, 1.99 mm, and 1.09 mm in the lateral, longitudinal, and vertical direction, respectively. Systematic errors were limited to <1 mm. Measured movement of the mesorectal space was -1.6 mm (+/- 4.2 mm) and 0.1 mm (+/- 4.0 mm) for left and right lateral direction. In the antero-posterior direction, mean shifts were -2 mm (+/- 6.8 mm) and -0.4 mm (+/- 3.8 mm). Mean shifts in the cranio-caudal direction were respectively -3.2 mm (+/- 5.6 mm) and -3.2 mm (+/- 6.8 mm). CONCLUSIONS: The use of the integrated MVCT on the tomotherapy system can minimize the setup margin for rectal cancer, and can also be used to adequately describe the internal margin allowing for direct treatment margin adaptation.

An assessment of the use of skin flashes in helical tomotherapy using phantom and in-vivo dosimetry.

BACKGROUND AND PURPOSE: In helical tomotherapy the nature of the optimizing and planning systems allows the delivery of dose on the skin using a build-up compensating technique (skin flash). However, positioning errors or changes in the patient's contour can influence the correct dosage in these regions. This work studies the behavior of skin-flash regions using phantom and in-vivo dosimetry. MATERIALS AND METHODS: The dosimetric accuracy of the tomotherapy planning system in skin-flash regions is checked using film and TLD on phantom. Positioning errors are induced and the effect on the skin dose is investigated. Further a volume decrease is simulated using bolus material and the results are compared. RESULTS: Results show that the tomotherapy planning system calculates dose on skin regions within 2 SD using TLD measurements. Film measurements show drops of dose of 2.8% and 26% for, respectively, a 5mm and 10mm mispositioning of the phantom towards air and a dose increase of 9% for a 5mm shift towards tissue. These measurements are confirmed by TLD measurements. A simulated volume reduction shows a similar behavior with a 2.6% and 19.4% drop in dose, measured with TLDs. CONCLUSION: The tomotherapy system allows adequate planning and delivery of dose using skin flashes. However, exact positioning is crucial to deliver the dose at the exact location.

Age-related differences in muscle recruitment and reaction-time performance.

Previously, we showed that prolonged reaction-time (RT) in older persons is related to increased antagonist muscle co-activation, occurring already before movement onset. Here, we studied whether a difference in temporal agonist and antagonist muscle activation exists between young and older persons during an RT-test. We studied Mm. Biceps (antagonist muscle) & Triceps (agonist muscle) Brachii activation time by sEMG in 60 young (26 ± 3 years) and 64 older (80 ± 6 years) community-dwelling subjects during a simple point-to-point RT-test (moving a finger using standardized elbow-extension from one pushbutton to another following a visual stimulus). RT was divided in pre-movement-time (PMT, time for stimulus processing) and movement-time (MT, time for motor response completion). Muscle activation time 1) following stimulus onset (PMAT) and 2) before movement onset (MAT) was calculated. PMAT for both muscles was significantly longer for the older subjects compared to the young (258 ± 53 ms versus 224 ± 37 ms, p=0.042 for Biceps and 280 ± 70 ms versus 218 ± 43 ms for Triceps, p<0.01). Longer agonist muscle PMAT was significantly related to worse PMT and RT in young (respectively r=0.76 & r=0.68, p<0.001) and elderly (respectively r=0.42 & r=0.40, p=0.001). In the older subjects we also found that the antagonist muscle activated significantly earlier than the agonist muscle (-22 ± 55 ms, p=0.003). We conclude that in older persons, besides the previously reported increased antagonist muscle co-activation, the muscle firing sequence is also profoundly altered. This is characterized by a delayed muscle activation following stimulus onset, and a significantly earlier recruitment of the antagonist muscle before movement onset.

Using Magnetic Resonance for Predicting Femoral Strength: Added Value with respect to Bone Densitometry.

BACKGROUND AND PURPOSE: To evaluate the added value of MRI with respect to peripheral quantitative computed tomography (pQCT) and dual energy X-ray absorptiometry (DXA) for predicting femoral strength. MATERIAL AND METHODS: Bone mineral density (BMD) of eighteen femur specimens was assessed with pQCT, DXA, and MRI (using ultrashort echo times (UTE) and the MicroView software). Subsequently biomechanical testing was performed to assess failure load. Simple and multiple linear regression were used with failure load as the dependent variable. RESULTS: Simple linear regression allowed a prediction of failure load with either pQCT, DXA, or MRI in an r(2) range of 0.41-0.48. Multiple linear regression with pQCT, DXA, and MRI yielded the best prediction (r(2) = 0.68). CONCLUSIONS: The accuracy of MRI, using UTE and MicroView software, to predict femoral strength compares well with that of pQCT or DXA. Furthermore, the inclusion of MRI in a multiple-regression model yields the best prediction.

MicroFilament Analyzer identifies actin network organizations in epidermal cells of Arabidopsis thaliana roots.

The plant cytoskeleton plays a crucial role in the cells' growth and development during different developmental stages and it undergoes many rearrangements. In order to describe the arrangements of the F-actin cytoskeleton in root epidermal cells of Arabidopsis thaliana, the recently developed software MicroFilament Analyzer (MFA) was exploited. This software enables high-throughput identification and quantification of the orientation of filamentous structures on digital images in a highly standardized and fast way. Using confocal microscopy and transgenic GFP-FABD2-GFP plants the actin cytoskeleton was visualized in the root epidermis. MFA analysis revealed that during the early stages of cell development F-actin is organized in a mainly random pattern. As the cells grow, they preferentially adopt a longitudinal organization, a pattern that is also preserved in the largest cells. In the evolution from young to old cells, an approximately even distribution of transverse, oblique or combined orientations is always present besides the switch from random to a longitudinal oriented actin cytoskeleton.

Diffusion tensor imaging of white matter tracts in the dog brain.

Diffusion weighted imaging sequences are now widely available on Magnetic Resonance Imaging (MRI) scanners. Diffusion Tensor Imaging (DTI) of the brain is able to show white matter tracts and is now commonly used in human medicine to study brain anatomy, tumors, structural pathways,… The purpose of this study was to show the interest of DTI to reveal the white matter fibers in the dogs' brain. DTI MR Images for this study were obtained with a 3 T system of 4 dogs euthanized for other reasons than neurological disorders. Combined fractional anisotropic (FA) and directional maps were obtained in the first 2 hours after death. The heads were amputated immediately after scanning and stored in 10% formalin until preparation for dissection. An experienced anatomist tracked white matter tracts with clinical relevance using the scanner software. The selected tracts were REFVIDume rendered and correlated with gross dissection. Using DTI we were able to track relevant neurological connections, such as the corticospinal tract, the optic and the cerebellar tract. The three dimensional anatomy is better presented using modern visualization techniques. DTI seems to be a valuable tool in order to present clinically relevant white matter tracts to neurological clinicians and researchers.

Age-related differences in pre-movement antagonist muscle co-activation and reaction-time performance.

Multiple causes contribute to the prolonged reaction-times (RT) observed in elderly persons. The involvement of antagonist muscle co-activation remains unclear. Here the Mm. Biceps and Triceps Brachii activation in 64 apparently healthy elderly (80 ± 6 years) and 60 young (26 ± 3 years) subjects were studied during a simple RT-test (moving a finger using standardized elbow-extension from one pushbutton to another following a visual stimulus). RT was divided in pre-movement-time (PMT, time for stimulus processing) and movement-time (MT, time for motor response completion). RT-performance was significantly worse in elderly compared to young; the slowing was more pronounced for MT than PMT (respectively 101 ± 10 ms and 41 ± 6 ms slower, p<0.01). Elderly subjects showed significantly higher (p<0.01) antagonist muscle co-activation during the PMT-phase, which was significantly related to worse MT and RT (p<0.01). During the MT-phase, antagonist muscle co-activation was similar for both groups. It can be concluded that increased antagonist muscle co-activation in elderly persons occurs in an early phase, already before the start of the movement. These findings provide further understanding of the underlying mechanisms of age-related slowing of human motor performance.

MRI-based attenuation correction for PET/MRI using ultrashort echo time sequences.

UNLABELLED: One of the challenges in PET/MRI is the derivation of an attenuation map to correct the PET image for attenuation. Different methods have been suggested for deriving the attenuation map from an MR image. Because the low signal intensity of cortical bone on images acquired with conventional MRI sequences makes it difficult to detect this tissue type, these methods rely on some sort of anatomic precondition to predict the attenuation map, raising the question of whether these methods will be usable in the clinic when patients may exhibit anatomic abnormalities. METHODS: We propose the use of the transverse relaxation rate, derived from images acquired with an ultrashort echo time sequence to classify the voxels into 1 of 3 tissue classes (bone, soft tissue, or air), without making any assumptions on patient anatomy. Each voxel is assigned a linear attenuation coefficient corresponding to its tissue class. A reference CT scan is used to determine the voxel-by-voxel accuracy of the proposed method. The overall accuracy of the MRI-based attenuation correction is evaluated using a method that takes into account the nonlocal effects of attenuation correction. RESULTS: As a proof of concept, the head of a pig was used as a phantom for imaging. The new method yielded a correct tissue classification in 90% of the voxels. Five human brain PET/CT and MRI datasets were also processed, yielding slightly worse voxel-by-voxel performance, compared to a CT-derived attenuation map. The PET datasets were reconstructed using the segmented MRI attenuation map derived with the new method, and the resulting images were compared with segmented CT-based attenuation correction. An average error of around 5% was found in the brain. CONCLUSION: The feasibility of using the transverse relaxation rate map derived from ultrashort echo time MR images for the estimation of the attenuation map was shown on phantom and clinical brain data. The results indicate that the new method, compared with CT-based attenuation correction, yields clinically acceptable errors. The proposed method does not make any assumptions about patient anatomy and could therefore also be used in cases in which anatomic abnormalities are present.