The long and winding road to translation for imaging biomarker development: the case for arterial spin labelling (ASL)

Radiology is facing many challenges nowadays, and certainly needs to keep up with the fast pace of developments taking place in this field. This editorial aims at drawing the attention of the reader to the current establishment of quantitative imaging biomarkers, in particular through the efforts of the Quantitative Imaging Biomarker Alliance (QIBA) from the Radiological Society of North America (RSNA), as well as the European Imaging Biomarker Alliance (EIBALL) from the European Society of Radiology (ESR). The case of arterial spin labelling (ASL) is used as an example of the long and winding road to translate a good imaging technique into a clinically relevant imaging biomarker

Pulse sequences for measuring exchange rates between proton species: From unlocalised NMR spectroscopy to chemical exchange saturation transfer imaging

Within the field of NMR spectroscopy, the study of chemical exchange processes through saturation transfer techniques has a long history. In the context of MRI, chemical exchange techniques have been adapted to increase the sensitivity of imaging to small fractions of exchangeable protons, including the labile protons of amines, amides and hydroxyls. The MR contrast is generated by frequency-selective irradiation of the labile protons, which results in a reduction of the water signal associated with transfer of the labile protons’ saturated magnetization to the protons of the surrounding free water. The signal intensity depends on the rate of chemical exchange and the concentration of labile protons as well as on the properties of the irradiation field. This methodology is referred to as CEST (chemical exchange saturation transfer) imaging. Applications of CEST include imaging of molecules with short transverse relaxation times and mapping of physiological parameters such as pH, temperature, buffer concentration and chemical composition due to the dependency of this chemical exchange effect on all these parameters. This article aims to describe these effects both theoretically and experimentally. In depth analysis and mathematical modelling are provided for all pulse sequences designed to date to measure the chemical exchange rate. Importantly, it has become clear that the background signal from semi-solid protons and the presence of the Nuclear Overhauser Effect (NOE), either through direct dipole-dipole mechanisms or through exchange-relayed signals, complicates the analysis of CEST effects. Therefore, advanced methods to suppress these confounding factors have been developed, and these are also reviewed. Finally, the experimental work conducted both in vitro and in vivo is discussed and the progress of CEST imaging towards clinical practice is presented

SAS: Symmetric Analysis of Z-Spectra, a Method to Evaluate B0 Correction Techniques for CEST Data in Clinical Systems Using Non-Exchanging Phantoms

Presentation of a method for the comparison of B0 correction methods. This method is based on non-exchanging phantoms to remove CEST effects. SAS method proposed to inform studies

Endogenous chemical exchange saturation transfer (CEST) MR imaging for the diagnosis and therapy response assessment of brain tumors: A systematic review

Purpose: To generate a narrative synthesis of published data on the use of endogenous chemical exchange saturation transfer (CEST) MR imaging in brain tumors. Materials and Methods: A systematic database search (PubMed, Ovid Embase, Cochrane Library) was used to collate eligible studies. Two researchers independently screened publications according to predefined exclusion and inclusion criteria, followed by comprehensive data extraction. All included studies were subjected to a bias risk assessment using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Results: The electronic database search identified 430 studies, of which 36 studies fulfilled the inclusion criteria. The final selection of included studies was categorized into 5 groups as follows: grading gliomas, 19 studies (areas under the curve (AUC) 0.500-1.000); predicting molecular subtypes of gliomas, 5 studies (AUC 0.610-0.920); distinction of different brain tumor types, 7 studies (AUC 0.707-0.905); therapy response assessment, 3 studies (AUC not given) and differentiating recurrence from treatment-related changes, 5 studies (AUC 0.880- 0.980). A high bias risk was observed in a substantial proportion of studies. Conclusion: Endogenous CEST imaging offers valuable, potentially unique information in brain tumors, but its diagnostic accuracy remains incompletely known. Further research is required to assess the method’s role in support of molecular genetic diagnosis, to investigate its use in the post treatment phase, and to compare techniques with a view to standardization

Arterial Spin Labeling Perfusion of the Brain: Emerging Clinical Applications

Arterial spin labeling (ASL) is a magnetic resonance (MR) imaging technique used to assess cerebral blood flow noninvasively by magnetically labeling inflowing blood. In this article, the main labeling techniques, notably pulsed and pseudocontinuous ASL, as well as emerging clinical applications will be reviewed. In dementia, the pattern of hypoperfusion on ASL images closely matches the established patterns of hypometabolism on fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) images due to the close coupling of perfusion and metabolism in the brain. This suggests that ASL might be considered as an alternative for FDG, reserving PET to be used for the molecular disease-specific amyloid and tau tracers. In stroke, ASL can be used to assess perfusion alterations both in the acute and the chronic phase. In arteriovenous malformations and dural arteriovenous fistulas, ASL is very sensitive to detect even small degrees of shunting. In epilepsy, ASL can be used to assess the epileptogenic focus, both in peri- and interictal period. In neoplasms, ASL is of particular interest in cases in which gadolinium-based perfusion is contraindicated (eg, allergy, renal impairment) and holds promise in differentiating tumor progression from benign causes of enhancement. Finally, various neurologic and psychiatric diseases including mild traumatic brain injury or posttraumatic stress disorder display alterations on ASL images in the absence of visualized structural changes. In the final part, current limitations and future developments of ASL techniques to improve clinical applicability, such as multiple inversion time ASL sequences to assess alterations of transit time, reproducibility and quantification of cerebral blood flow, and to measure cerebrovascular reserve, will be reviewed

Sodium (Na) ultra-short echo time imaging in the human brain using a 3D-Cones trajectory

Object: Sodium magnetic resonance imaging (Na-MRI) of the brain has shown changes in Na signal as a hallmark of various neurological diseases such as stroke, Alzheimer's disease, Multiple Sclerosis and Huntington's disease. To improve scan times and image quality, we have implemented the 3D-Cones (CN) sequence for in vivo Na brain MRI. Materials and methods: Using signal-to-noise (SNR) as a measurement of sequence performance, CN is compared against more established 3D-radial k-space sampling schemes featuring cylindrical stack-of-stars (SOS) and 3D-spokes kooshball (KB) trajectories, on five healthy volunteers in a clinical setting. Resolution was evaluated by simulating the point-spread-functions (PSFs) and experimental measures on a phantom. Results: All sequences were shown to have a similar SNR arbitrary units (AU) of 6-6.5 in brain white matter, 7-9 in gray matter and 17-18 AU in cerebrospinal fluid. SNR between white and gray matter were significantly different for KB and CN (p = 0.046 and <0.001 respectively), but not for SOS (p = 0.1). Group mean standard deviations were significantly smaller for CN (p = 0.016). Theoretical full-width at half-maximum linewidth of the PSF for CN is broadened by only 0.1, compared to 0.3 and 0.8 pixels for SOS and KB respectively. Actual image resolution is estimated as 8, 9 and 6.3 mm for SOS, KB and CN respectively. Conclusion: The CN sequence provides stronger tissue contrast than both SOS and KB, with more reproducible SNR measurements compared to KB. For CN, a higher true resolution in the same amount of time with no significant trade-off in SNR is achieved. CN is therefore more suitable for Na-MRI in the brain. © 2013 The Author(s)

Sodium ((23)Na) ultra-short echo time imaging in the human brain using a 3D-Cones trajectory

Object: Sodium magnetic resonance imaging ((23)Na-MRI) of the brain has shown changes in (23)Na signal as a hallmark of various neurological diseases such as stroke, Alzheimer's disease, Multiple Sclerosis and Huntington's disease. To improve scan times and image quality, we have implemented the 3D-Cones (CN) sequence for in vivo (23)Na brain MRI. Materials and Methods: Using signal-to-noise (SNR) as a measurement of sequence performance, CN is compared against more established 3D-radial k-space sampling schemes featuring cylindrical stack-of-stars (SOS) and 3D-spokes kooshball (KB) trajectories, on five healthy volunteers in a clinical setting. Resolution was evaluated by simulating the point-spread-functions (PSFs) and experimental measures on a phantom. Results: All sequences were shown to have a similar SNR arbitrary units (AU) of 6–6.5 in brain white matter, 7–9 in gray matter and 17–18 AU in cerebrospinal fluid. SNR between white and gray matter were significantly different for KB and CN (p = 0.046 and\0.001 respectively), but not for SOS (p = 0.1). Group mean standard deviations were significantly smaller for CN (p = 0.016). Theoretical full-width at half-maximum linewidth of the PSF for CN is broadened by only 0.1, compared to 0.3 and 0.8 pixels for SOS and KB respectively. Actual image resolution is estimated as 8, 9 and 6.3 mm for SOS, KB and CN respectively. Conclusion: The CN sequence provides stronger tissue contrast than both SOS and KB, with more reproducible SNR measurements compared to KB. For CN, a higher true resolution in the same amount of time with no significant trade-off in SNR is achieved. CN is therefore more suitable for 23Na-MRI in the brain

Melatonin for neonatal encephalopathy: From bench to bedside

Neonatal encephalopathy is a leading cause of morbidity and mortality worldwide. Alt-hough therapeutic hypothermia (HT) is now standard practice in most neonatal intensive care units in high resource settings, some infants still develop long-term adverse neurological sequelae. In low resource settings, HT may not be safe or efficacious. Therefore, additional neuroprotective interventions are urgently needed. Melatonin’s diverse neuroprotective properties include antioxidant, anti-inflammatory, and anti-apoptotic effects. Its strong safety profile and compelling preclinical data suggests that melatonin is a promising agent to improve the outcomes of infants with NE. Over the past decade, the safety and efficacy of melatonin to augment HT has been studied in the neonatal piglet model of perinatal asphyxia. From this model, we have observed that the neuroprotective effects of melatonin are time-critical and dose dependent. Therapeutic melatonin levels are likely to be 15–30 mg/L and for optimal effect, these need to be achieved within the first 2–3 h after birth. This review summarises the neuroprotective properties of melatonin, the key findings from the piglet and other animal studies to date, and the challenges we face to translate melatonin from bench to bedside