Reproducibility and Repeatability of MR Fingerprinting Relaxometry in the Human Brain.

Background Only sparse literature investigates the reproducibility and repeatability of relaxometry methods in MRI. However, statistical data on reproducibility and repeatability of any quantitative method is essential for clinical application. Purpose To evaluate the reproducibility and repeatability of two-dimensional fast imaging with steady-state free precession MR fingerprinting in vivo in human brains. Materials and Methods Two-dimensional section-selective MR fingerprinting based on a steady-state free precession sequence with an external radiofrequency transmit field, or B1+, correction was used to generate T1 and T2 maps. This prospective study was conducted between July 2017 and January 2018 with 10 scanners from a single manufacturer, including different models, at four different sites. T1 and T2 relaxation times and their variation across scanners (reproducibility) as well as across repetitions on a scanner (repeatability) were analyzed. The relative deviations of T1 and T2 to the average (95% confidence interval) were calculated for several brain compartments. Results Ten healthy volunteers (mean age ± standard deviation, 28.5 years ± 6.9; eight men, two women) participated in this study. Reproducibility and repeatability of T1 and T2 measures in the human brain varied across brain compartments (1.8%-20.9%) and were higher in solid tissues than in the cerebrospinal fluid. T1 measures in solid tissue brain compartments were more stable compared with T2 measures. The half-widths of the confidence intervals for relative deviations were 3.4% for mean T1 and 8.0% for mean T2 values across scanners. Intrascanner repeatability half-widths of the confidence intervals for relative deviations were in the range of 2.0%-3.1% for T1 and 3.1%-7.9% for T2. Conclusion This study provides values on reproducibility and repeatability of T1 and T2 relaxometry measured with fast imaging with steady-state free precession MR fingerprinting in brain tissues of healthy volunteers. Reproducibility and repeatability are considerably higher in solid brain compartments than in cerebrospinal fluid and are higher for T1 than for T2. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Barkhof and Parker in this issue.

Water-selective excitation of short T2 species with binomial pulses.

PURPOSE: For imaging of fibrous musculoskeletal components, ultra-short echo time methods are often combined with fat suppression. Due to the increased chemical shift, spectral excitation of water might become a favorable option at ultra-high fields. Thus, this study aims to compare and explore short binomial excitation schemes for spectrally selective imaging of fibrous tissue components with short transverse relaxation time (T2 ). METHODS: Water selective 1-1-binomial excitation is compared with nonselective imaging using a sub-millisecond spoiled gradient echo technique for in vivo imaging of fibrous tissue at 3T and 7T. RESULTS: Simulations indicate a maximum signal loss from binomial excitation of approximately 30% in the limit of very short T2 (0.1 ms), as compared to nonselective imaging; decreasing rapidly with increasing field strength and increasing T2 , e.g., to 19% at 3T and 10% at 7T for T2 of 1 ms. In agreement with simulations, a binomial phase close to 90° yielded minimum signal loss: approximately 6% at 3T and close to 0% at 7T for menisci, and for ligaments 9% and 13%, respectively. CONCLUSION: Overall, for imaging of short-lived T2 components, short 1-1 binomial excitation schemes prove to offer marginal signal loss especially at ultra-high fields with overall improved scanning efficiency.

Triple-echo steady-state T2 relaxometry of the human brain at high to ultra-high fields.

Quantitative MRI techniques, such as T2 relaxometry, have demonstrated the potential to detect changes in the tissue microstructure of the human brain with higher specificity to the underlying pathology than in conventional morphological imaging. At high to ultra-high field strengths, quantitative MR-based tissue characterization benefits from the higher signal-to-noise ratio traded for either improved resolution or reduced scan time, but is impaired by severe static (B0 ) and transmit (B1 ) field heterogeneities. The objective of this study was to derive a robust relaxometry technique for fast T2 mapping of the human brain at high to ultra-high fields, which is highly insensitive to B0 and B1 field variations. The proposed method relies on a recently presented three-dimensional (3D) triple-echo steady-state (TESS) imaging approach that has proven to be suitable for fast intrinsically B1 -insensitive T2 relaxometry of rigid targets. In this work, 3D TESS imaging is adapted for rapid high- to ultra-high-field two-dimensional (2D) acquisitions. The achieved short scan times of 2D TESS measurements reduce motion sensitivity and make TESS-based T2 quantification feasible in the brain. After validation in vitro and in vivo at 3 T, T2 maps of the human brain were obtained at 7 and 9.4 T. Excellent agreement between TESS-based T2 measurements and reference single-echo spin-echo data was found in vitro and in vivo at 3 T, and T2 relaxometry based on TESS imaging was proven to be feasible and reliable in the human brain at 7 and 9.4 T. Although prominent B0 and B1 field variations occur at ultra-high fields, the T2 maps obtained show no B0 - or B1 -related degradations. In conclusion, as a result of the observed robustness, TESS T2 may emerge as a valuable measure for the early diagnosis and progression monitoring of brain diseases in high-resolution 2D acquisitions at high to ultra-high fields.

Anatomy and variants of the triangular fibrocartilage complex and its MR appearance at 3 and 7T.

Due to the small size and complexity of its constituents, the triangular fibrocartilage complex (TFCC) has been a challenging structure for magnetic resonance (MR) imaging. Higher-field MR units, at 3T and 7T, with increased spatial resolution and the development of novel MR sequences, are promising tools for an improved visualization of the ulnocarpal complex. Anatomically, the TFCC consists of the TFC proper, the ulnomeniscal homolog, the ulnar collateral ligament, the ulnotriquetral and ulnolunate ligament, and radioulnar ligaments at the volar (palmar) and the dorsal side, as well as the sheath of the extensor carpi ulnaris tendon and the capsule of the distal radioulnar joint. This article describes the normal anatomy of the TFCC and its appearance on high-field MRI. Anatomical variants, such as the positive ulnar variance, and changes during pronation and supination are addressed.

Cisplatin-induced apoptosis in cultures of human Schwann cells.

To investigate the sensitivity of human Schwann cells to cisplatin (cis-DDP), different approaches to estimate DNA damage were used: the comet assay, morphological evaluation of the granular condensation of nuclear chromatin and the terminal transferase-mediated dUTP nick-end-labelling (TUNEL) method. The number of micronuclei (MNi), as a sign of cisplatin-induced genotoxicity, was counted. DNA damage assessed by the comet assay was already evident after 1.5 microM cisplatin treatment at all exposure times (24, 48, and 72 h). Initial morphological changes characterised by the granular condensation of nuclear chromatin were detectable after 24 h exposure to 25 microM cis-DDP, while an increased number of apoptotic cells, determined by the TUNEL method, was noted after 48 h exposure to the same concentration. The first significant increase in the number of MNi was observed in cells treated with 75 microM cis-DDP for 24 h. We demonstrate that the comet assay is a highly sensitive method for measuring cisplatin induced DNA damage. Morphological observation revealed advanced as well as less prominent alterations in the nuclear chromatin. In contrast, the TUNEL method detected only those cells with advanced DNA fragmentation.

Interferon-beta prevents cytokine-induced neutrophil infiltration and attenuates blood-brain barrier disruption.

Inflammation can contribute to brain injury, such as that resulting from ischemia or trauma. The authors have previously shown that the cytokine interferon-beta (IFN-beta) affords protection against ischemic brain injury, which was associated with a diminished infiltration of neutrophils and a reduction in blood-brain barrier (BBB) disruption. The goal of the current study was to directly assess the effects of IFN-beta on neutrophil infiltration, with the use of an in vivo assay of neutrophil infiltration with relevance to ischemic brain injury. Intrastriatal injection of recombinant rat cytokine-induced neutrophil chemoattractant-1, a member of the interleukin-8 family (1 microg in 1 microl), triggered massive infiltration of neutrophils and extensive BBB disruption 6 hours later, as measured using immunofluorescence microscopy and magnetic resonance imaging in the rat, respectively. Depleting the animals of neutrophils before interleukin-8 injection prevented BBB disruption. Treatment with IFN-beta (5 x 106 U/kg) almost completely prevented neutrophil infiltration and attenuated BBB damage. Gelatinase zymography showed matrix metalloproteinase-9 expression in the ipsilateral striatum after interleukin-8 injection. Both neutrophil depletion and IFN-beta treatment downregulated matrix metalloproteinase-9. IFN-beta has already been approved for human use as a treatment for the chronic inflammatory disorder multiple sclerosis. The potential value of IFN-beta as a treatment that can attenuate acute brain inflammation is considered.

In vivo excitotoxicity induced by ouabain, a Na+/K+-ATPase inhibitor.

The susceptibility of immature rat brain to neurotoxicity of N-methyl-D-aspartate (NMDA) has provided a widely used paradigm to study excitotoxicity relevant to acute neurodegenerative diseases such as cerebral ischemia. In this study, excitotoxicity was induced via injection of ouabain (1 mM/0.5 microL), a Na+/K+ -ATPase-inhibitor, into neonatal rat brain and compared with NMDA injection. The aim of the study was to induce excitotoxicity secondary to cellular membrane depolarization, thereby more closely mimicking the pathophysiologic processes of ischemia-induced brain injury where NMDA-receptor overstimulation by glutamate follows, not precedes, membrane depolarization. Na+/K+ -ATPase-inhibition caused an acute, 40% +/- 8% decrease of the apparent diffusion coefficient (ADC) of water, as measured using diffusion-weighted magnetic resonance imaging (MRI), and resulted in infarctlike lesions as measured using T2-weighted MRI and histology up to 2 weeks later. Localized one- and two-dimensional 1H-magnetic resonance spectroscopy (MRS) demonstrated that the early excitotoxic diffusion changes were not accompanied by an overall metabolic disturbance. Furthermore, 31P-MRS demonstrated that energy depletion is not a prerequisite for ADC decrease or excitotoxic cell death. Treatment with the NMDA-antagonist MK-801 (1 mg/kg) attenuated the volume of tissue exhibiting a decreased ADC (P < 0.005), demonstrating that the ouabain-induced injury is indeed excitotoxic in nature. The authors argue that, compared with NMDA-injection, ouabain-induced excitotoxicity elicits more appropriate glutamate-receptor overstimulation and is better suited to detect relevant neuroprotection in that it is more sensitive to attenuation of synaptic glutamate levels.

Interferon-beta blocks infiltration of inflammatory cells and reduces infarct volume after ischemic stroke in the rat.

The inflammatory response that exacerbates cerebral injury after ischemia is an attractive therapeutic target: it progresses over days and strongly contributes to worsening of the neurologic outcome. The authors show that, after transient ischemic injury to the rat brain, systemic application of interferon-beta (IFN-beta), a cytokine with antiinflammatory properties, attenuated the development of brain infarction. Serial magnetic resonance imaging (MRI) showed that IFN-beta treatment reduced lesion volume on diffusion-weighted MRI by 70% (P < 0.01) at 1 day after stroke. IFN-beta attenuated the leakage of contrast agent through the blood-brain barrier (P < 0.005), indicating a better-preserved blood-brain barrier integrity. Both control and IFN-beta-treated animals showed a similar degree of relative hyperperfusion of the lesioned hemisphere, indicating that neuroprotection by IFN-beta was not mediated by improved cerebral perfusion as assessed 24 hours after stroke onset. IFN-beta treatment resulted in an 85% reduction (P < 0.0001) in infarct volume 3 weeks later, as determined from T2-weighted MRI and confirmed by histology. This effect was achieved even when treatment was started 6 hours after stroke onset. Quantitative immunohistochemistry at 24 hours after stroke onset showed that IFN-beta almost completely prevented the infiltration of neutrophils and monocytes into the brain. Gelatinase zymography showed that this effect was associated with a decrease in matrix metalloproteinase-9 expression. In conclusion, treatment with the antiinflammatory cytokine IFN-beta affords significant neuroprotection against ischemia/reperfusion injury, and within a relatively long treatment window. Because IFN-beta has been approved for clinical use, it may be rapidly tested in a clinical trial for its efficacy against human stroke.

Acute neuronal injury, excitotoxicity, and the endocannabinoid system.

The endocannabinoid system is a valuable target for drug discovery, because it is involved in the regulation of many cellular and physiological functions. The endocannabinoid system constitutes the endogenous lipids anandamide, 2-arachidonoylglycerol and noladin ether, and the cannabinoid CB1 and CB2 receptors as well as the proteins for their inactivation. It is thought that (endo)cannabinoid-based drugs may potentially be useful to reduce the effects of neurodegeneration. This paper reviews recent developments in the endocannabinoid system and its involvement in neuroprotection. Exogenous (endo)cannabinoids have been shown to exert neuroprotection in a variety of in vitro and in vivo models of neuronal injury via different mechanisms, such as prevention of excitotoxicity by CB1-mediated inhibition of glutamatergic transmission, reduction of calcium influx, and subsequent inhibition of deleterious cascades, TNF-alpha formation, and anti-oxidant activity. It has been suggested that the release of endogenous endocannabinoids during neuronal injury might be a protective response. However, several observations indicate that the role of the endocannabinoid system as a general endogenous protection system is questionable. The data are critically reviewed and possible explanations are given.

Cells over-expressing EAAT2 protect motoneurons from excitotoxic death in vitro.

Amyotrophic lateral sclerosis is an incurable disease in which cerebral and spinal motoneurons degenerate, causing paralysis and death within 2-5 years. One of the pathogenic factors of motoneuron death is a chronic excess of glutamate, which exceeds its removal by astrocytes, i.e. excitotoxicity. Extra glutamate uptake in the spinal cord may slow down or prevent motoneuron death. We have engineered cells over-expressing the main glutamate transporter and tested their potential to rescue motoneurons exposed to high levels of glutamate in vitro. The engineered cells protected motoneurons in a motoneuron-astrocyte co-culture at glutamate concentrations when astrocytes were no longer capable of removing glutamate. This suggests that engineered cells, introduced into the spinal column, can help remove glutamate, thereby preventing motoneuron death.

Biosynthesis of endocannabinoids and their modes of action in neurodegenerative diseases.

Endocannabinoids are thought to function as retrograde messengers, which modulate neurotransmitter release by activating presynaptic cannabinoid receptors. Anandamide and 2-arachidonoylglycerol (2-AG) are the two best studied endogenous lipids which can act as endocannabinoids. Together with the proteins responsible for their biosynthesis, inactivation and the cannabinoid receptors, these lipids constitute the endocannabinoid system. This system is proposed to be involved in various neurodegenerative diseases such as Parkinson's and Huntington's diseases as well as Multiple Sclerosis. It has been demonstrated that the endocannabinoid system can protect neurons against glutamate excitotoxicity and acute neuronal damage in both in vitro and in vivo models. In this paper we review the data concerning the involvement of the endocannabinoid system in neurodegenerative diseases in which neuronal cell death may be elicited by excitotoxicity. We focus on the biosynthesis of endocannabinoids and on their modes of action in animal models of these neurodegenerative diseases.

Interdisciplinary preoperative patient education in cardiac surgery.

Patient education in cardiac surgery is complicated by the fact that cardiac surgery patients meet a lot of different health care providers. Little is known about education processes in terms of interdisciplinary tuning. In this study, complete series of consecutive preoperative consultations of 51 cardiac surgery patients with different health care providers (physicians, nurses and health educators) were videotaped. The information exchange between patients and providers was analyzed directly from the video recordings by using an adaptation of the Roter Interaction Analysis System (RIAS) and a checklist of relevant informational topics. Results pointed to overlaps and gaps as well as to a lack of a patient-centered approach. The physicians were mostly overlapped by the nurses, who spent almost 30% of the time on talking about medical issues. Gaps were found in giving psycho-educational information and emotional support, needed to establish effective patient education. The findings provided a sound basis for developing guidelines and changes in the organization of the education process.

Comparison of 3T and 7T MRI clinical sequences for ankle imaging.

The purpose of this study was to compare 3T and 7T signal-to-noise and contrast-to noise ratios of clinical sequences for imaging of the ankles with optimized sequences and dedicated coils. Ten healthy volunteers were examined consecutively on both systems with three clinical sequences: (1) 3D gradient-echo, T(1)-weighted; (2) 2D fast spin-echo, PD-weighted; and (3) 2D spin-echo, T(1)-weighted. SNR was calculated for six regions: cartilage; bone; muscle; synovial fluid; Achilles tendon; and Kager's fat-pad. CNR was obtained for cartilage/bone, cartilage/fluid, cartilage/muscle, and muscle/fat-pad, and compared by a one-way ANOVA test for repeated measures. Mean SNR significantly increased at 7T compared to 3T for 3D GRE, and 2D TSE was 60.9% and 86.7%, respectively. In contrast, an average SNR decrease of almost 25% was observed in the 2D SE sequence. A CNR increase was observed in 2D TSE images, and in most 3D GRE images. There was a substantial benefit from ultra high-field MR imaging of ankles with routine clinical sequences at 7T compared to 3T. Higher SNR and CNR at ultra-high field MR scanners may be useful in clinical practice for ankle imaging. However, carefully optimized protocols and dedicated extremity coils are necessary to obtain optimal results.

The expression of the chemorepellent Semaphorin 3A is selectively induced in terminal Schwann cells of a subset of neuromuscular synapses that display limited anatomical plasticity and enhanced vulnerability in motor neuron disease.

Neuromuscular synapses differ markedly in their plasticity. Motor nerve terminals innervating slow muscle fibers sprout vigorously following synaptic blockage, while those innervating fast-fatigable muscle fibers fail to exhibit any sprouting. Here, we show that the axon repellent Semaphorin 3A is differentially expressed in terminal Schwann cells (TSCs) on different populations of muscle fibers: postnatal, regenerative and paralysis induced remodeling of neuromuscular connections is accompanied by increased expression of Sema3A selectively in TSCs on fast-fatigable muscle fibers. To our knowledge, this is the first demonstration of a molecular difference between TSCs on neuromuscular junctions of different subtypes of muscle fibers. Interestingly, also in a mouse model for amyotrophic lateral sclerosis (ALS), Sema3A is expressed at NMJs of fast-fatigable muscle fibers. We propose that expression of Sema3A by TSCs not only suppresses nerve terminal plasticity at specific neuromuscular synapses, but may also contribute to their early and selective loss in the motor neuron disease ALS.

Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice.

ALS (amyotrophic lateral sclerosis) is an adult-onset and deadly neurodegenerative disease characterized by a progressive and selective loss of motoneurons. Transgenic mice overexpressing a mutated human gene (G93A) coding for the enzyme SOD1 (Cu/Zn superoxide dismutase) develop a motoneuron disease resembling ALS in humans. In this generally accepted ALS model, we tested the electrophysiological properties of individual embryonic and neonatal spinal motoneurons in culture by measuring a wide range of electrical properties influencing motoneuron excitability during current clamp. There were no differences in the motoneuron resting potential, input conductance, action potential shape, or afterhyperpolarization between G93A and control motoneurons. The relationship between the motoneuron's firing frequency and injected current (f-I relation) was altered. The slope of the f-I relation and the maximal firing rate of the G93A motoneurons were much greater than in the control motoneurons. Differences in spontaneous synaptic input were excluded as a cause of increased excitability. This finding identifies a markedly elevated intrinsic electrical excitability in cultured embryonic and neonatal mutant G93A spinal motoneurons. We conclude that the observed intrinsic motoneuron hyperexcitability is induced by the SOD1 toxic gain-of-function through an aberration in the process of action potential generation. This hyperexcitability may play a crucial role in the pathogenesis of ALS as the motoneurons were cultured from presymptomatic mice.

CGP 3466B has no effect on disease course of (G93A) mSOD1 transgenic mice.

BACKGROUND: There is an accumulating body of evidence that apoptosis is involved in the motor neuron death that occurs in ALS, and in the (G93A) mSOD1 transgenic mouse model (mSOD1 mice). CGP 3466B, a tricyclic propargylamine structurally related to (-)-deprenyl, was found to inhibit apoptosis in a wide variety of in vitro and in vivo models. We therefore studied the effect of CGP 3466B in mSOD1 mice. METHODS: As the effect of CGP 3466B was previously reported to have a bell-shaped curve, we performed a dose-ranging study. High-copy G93A mSOD1 mice were treated subcutaneously from the age of 50 days until death with four concentrations of CGP 3466B (0.39 microg kg(-1), 3.9 microg kg(-1), 39 microg kg(-1), and 390 microg kg(-1)). Behavioural tests were performed daily to determine disease onset, disease progression and survival. At the age of 110 days, two mice per group were sacrificed for histopathological analysis of the lumbar ventral horn and for semiquantitative analysis of motor neuron number. RESULTS: We observed no effect on disease onset, disease progression, or survival of the mice. We also did not observe a significant effect on the number of motor neurons due to CGP 3466B. CONCLUSIONS: We conclude that in high-copy G93A mSOD1 mice, chronic subcutaneous treatment with CGP 3466B offers no clinical benefit.