Real-time fetal brain tracking for functional fetal MRI.

PURPOSE: To improve motion robustness of functional fetal MRI scans by developing an intrinsic real-time motion correction method. MRI provides an ideal tool to characterize fetal brain development and growth. It is, however, a relatively slow imaging technique and therefore extremely susceptible to subject motion, particularly in functional MRI experiments acquiring multiple Echo-Planar-Imaging-based repetitions, for example, diffusion MRI or blood-oxygen-level-dependency MRI. METHODS: A 3D UNet was trained on 125 fetal datasets to track the fetal brain position in each repetition of the scan in real time. This tracking, inserted into a Gadgetron pipeline on a clinical scanner, allows updating the position of the field of view in a modified echo-planar imaging sequence. The method was evaluated in real-time in controlled-motion phantom experiments and ten fetal MR studies (17 + 4-34 + 3 gestational weeks) at 3T. The localization network was additionally tested retrospectively on 29 low-field (0.55T) datasets. RESULTS: Our method achieved real-time fetal head tracking and prospective correction of the acquisition geometry. Localization performance achieved Dice scores of 84.4% and 82.3%, respectively for both the unseen 1.5T/3T and 0.55T fetal data, with values higher for cephalic fetuses and increasing with gestational age. CONCLUSIONS: Our technique was able to follow the fetal brain even for fetuses under 18 weeks GA in real-time at 3T and was successfully applied "offline" to new cohorts on 0.55T. Next, it will be deployed to other modalities such as fetal diffusion MRI and to cohorts of pregnant participants diagnosed with pregnancy complications, for example, pre-eclampsia and congenital heart disease.

Data-driven motion-corrected brain MRI incorporating pose-dependent B0 fields.

PURPOSE: To develop a fully data-driven retrospective intrascan motion-correction framework for volumetric brain MRI at ultrahigh field (7 Tesla) that includes modeling of pose-dependent changes in polarizing magnetic (B0 ) fields. THEORY AND METHODS: Tissue susceptibility induces spatially varying B0 distributions in the head, which change with pose. A physics-inspired B0 model has been deployed to model the B0 variations in the head and was validated in vivo. This model is integrated into a forward parallel imaging model for imaging in the presence of motion. Our proposal minimizes the number of added parameters, enabling the developed framework to estimate dynamic B0 variations from appropriately acquired data without requiring navigators. The effect on data-driven motion correction is validated in simulations and in vivo. RESULTS: The applicability of the physics-inspired B0 model was confirmed in vivo. Simulations show the need to include the pose-dependent B0 fields in the reconstruction to improve motion-correction performance and the feasibility of estimating B0 evolution from the acquired data. The proposed motion and B0 correction showed improved image quality for strongly corrupted data at 7 Tesla in simulations and in vivo. CONCLUSION: We have developed a motion-correction framework that accounts for and estimates pose-dependent B0 fields. The method improves current state-of-the-art data-driven motion-correction techniques when B0 dependencies cannot be neglected. The use of a compact physics-inspired B0 model together with leveraging the parallel imaging encoding redundancy and previously proposed optimized sampling patterns enables a purely data-driven approach.

CEST MRI provides amide/amine surrogate biomarkers for treatment-naïve glioma sub-typing.

PURPOSE: Accurate glioma classification affects patient management and is challenging on non- or low-enhancing gliomas. This study investigated the clinical value of different chemical exchange saturation transfer (CEST) metrics for glioma classification and assessed the diagnostic effect of the presence of abundant fluid in glioma subpopulations. METHODS: Forty-five treatment-naïve glioma patients with known isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion status received CEST MRI (B1rms = 2µT, Tsat = 3.5 s) at 3 T. Magnetization transfer ratio asymmetry and CEST metrics (amides: offset range 3-4 ppm, amines: 1.5-2.5 ppm, amide/amine ratio) were calculated with two models: 'asymmetry-based' (AB) and 'fluid-suppressed' (FS). The presence of T2/FLAIR mismatch was noted. RESULTS: IDH-wild type had higher amide/amine ratio than IDH-mutant_1p/19qcodel (p < 0.022). Amide/amine ratio and amine levels differentiated IDH-wild type from IDH-mutant (p < 0.0045) and from IDH-mutant_1p/19qret (p < 0.021). IDH-mutant_1p/19qret had higher amides and amines than IDH-mutant_1p/19qcodel (p < 0.035). IDH-mutant_1p/19qret with AB/FS mismatch had higher amines than IDH-mutant_1p/19qret without AB/FS mismatch ( < 0.016). In IDH-mutant_1p/19qret, the presence of AB/FS mismatch was closely related to the presence of T2/FLAIR mismatch (p = 0.014). CONCLUSIONS: CEST-derived biomarkers for amides, amines, and their ratio can help with histomolecular staging in gliomas without intense contrast enhancement. T2/FLAIR mismatch is reflected in the presence of AB/FS CEST mismatch. The AB/FS CEST mismatch identifies glioma subgroups that may have prognostic and clinical relevance.

Edited magnetic resonance spectroscopy in the neonatal brain.

J-difference-edited spectroscopy is a valuable approach for the detection of low-concentration metabolites with magnetic resonance spectroscopy (MRS). Currently, few edited MRS studies are performed in neonates due to suboptimal signal-to-noise ratio, relatively long acquisition times, and vulnerability to motion artifacts. Nonetheless, the technique presents an exciting opportunity in pediatric imaging research to study rapid maturational changes of neurotransmitter systems and other metabolic systems in early postnatal life. Studying these metabolic processes is vital to understanding the widespread and rapid structural and functional changes that occur in the first years of life. The overarching goal of this review is to provide an introduction to edited MRS for neonates, including the current state-of-the-art in editing methods and editable metabolites, as well as to review the current literature applying edited MRS to the neonatal brain. Existing challenges and future opportunities, including the lack of age-specific reference data, are also discussed.

Reproducibility of MRI-based white matter tract estimation using multi-fiber probabilistic tractography: effect of user-defined parameters and regions.

OBJECTIVE: There is a pressing need to assess user-dependent reproducibility of multi-fibre probabilistic tractography in order to encourage clinical implementation of these advanced and relevant approaches. The goal of this study was to evaluate both intrinsic and inter-user reproducibility of corticospinal tract estimation. MATERIALS AND METHODS: Six clinical datasets including motor functional and diffusion MRI were used. Three users performed an independent tractography analysis following identical instructions. Dice indices were calculated to quantify the reproducibility of seed region, fMRI-based end region, and streamline maps. RESULTS: The inter-user reproducibility ranged 41-93%, 29-94%, and 50-92%, for seed regions, end regions, and streamline maps, respectively. Differences in streamline maps correlated with differences in seed and end regions. Good inter-user agreement in seed and end regions, yielded inter-user reproducibility close to the intrinsic reproducibility (92-97%) and in most cases higher than 80%. DISCUSSION: Uncertainties related to user-dependent decisions and the probabilistic nature of the analysis should be considered when interpreting probabilistic tractography data. The standardization of the methods used to define seed and end regions is a necessary step to improve the accuracy and robustness of multi-fiber probabilistic tractography in a clinical setting. Clinical users should choose a feasible compromise between reproducibility and analysis duration.

Repeatability of perfusion measurements in adult gliomas using pulsed and pseudo-continuous arterial spin labelling MRI.

OBJECTIVES: To investigate the repeatability of perfusion measures in gliomas using pulsed- and pseudo-continuous-arterial spin labelling (PASL, PCASL) techniques, and evaluate different regions-of-interest (ROIs) for relative tumour blood flow (rTBF) normalisation. MATERIALS AND METHODS: Repeatability of cerebral blood flow (CBF) was measured in the Contralateral Normal Appearing Hemisphere (CNAH) and in brain tumours (aTBF). rTBF was normalised using both large/small ROIs from the CNAH. Repeatability was evaluated with intra-class-correlation-coefficient (ICC), Within-Coefficient-of-Variation (WCoV) and Coefficient-of-Repeatability (CR). RESULTS: PASL and PCASL demonstrated high reliability (ICC > 0.9) for CNAH-CBF, aTBF and rTBF. PCASL demonstrated a more stable signal-to-noise ratio (SNR) with a lower WCoV of the SNR than that of PASL (10.9-42.5% vs. 12.3-29.2%). PASL and PCASL showed higher WCoV in aTBF and rTBF than in CNAH CBF in WM and GM but not in the caudate, and higher WCoV for rTBF than for aTBF when normalised using a small ROI (PASL 8.1% vs. 4.7%, PCASL 10.9% vs. 7.9%, respectively). The lowest CR was observed for rTBF normalised with a large ROI. DISCUSSION: PASL and PCASL showed similar repeatability for the assessment of perfusion parameters in patients with primary brain tumours as previous studies based on volunteers. Both methods displayed reasonable WCoV in the tumour area and CNAH. PCASL's more stable SNR in small areas (caudate) is likely to be due to the longer post-labelling delays.

Planning of gamma knife radiosurgery (GKR) for brain arteriovenous malformations using triple magnetic resonance angiography (triple-MRA).

PURPOSE: Intra-arterial Digital Subtraction Angiography (DSA) is the gold standard technique for radiosurgery target delineation in brain Arterio-Venous Malformations (AVMs). This study aims to evaluate whether a combination of three Magnetic Resonance Angiography sequences (triple-MRA) could be used for delineation of brain AVMs for Gamma Knife Radiosurgery (GKR). METHODS: Fifteen patients undergoing DSA for GKR targeting of brain AVMs also underwent triple-MRA: 4D Arterial Spin Labelling based angiography (ASL-MRA), Contrast-Enhanced Time-Resolved MRA (CE-MRA) and High Definition post-contrast Time-Of-Flight angiography (HD-TOF). The arterial phase of the AVM nidus was delineated on triple-MRA by an interventional neuroradiologist and a consultant neurosurgeon (triple-MRA volume). Triple-MRA volumes were compared to AVM targets delineated by the clinical team for delivery of GKR using the current planning paradigm, i.e., stereotactic DSA and volumetric MRI (DSA volume). Difference in size, degree of inclusion (DI) and concordance index (CcI) between DSA and triple-MRA volumes are reported. RESULTS: AVM target volumes delineated on triple-MRA were on average 9.8% smaller than DSA volumes (95%CI:5.6-13.9%; SD:7.14%; p = .003). DI of DSA volume in triple-MRA volume was on average 73.5% (95%CI:71.2-76; range: 65-80%). The mean percentage of triple-MRA volume not included on DSA volume was 18% (95%CI:14.7-21.3; range: 7-30%). CONCLUSION: The technical feasibility of using triple-MRA for visualisation and delineation of brain AVMs for GKR planning has been demonstrated. Tighter and more precise delineation of AVM target volumes could be achieved by using triple-MRA for radiosurgery targeting. However, further research is required to ascertain the impact this may have in obliteration rates and side effects.

Simultaneous quantification of GABA, Glx and GSH in the neonatal human brain using magnetic resonance spectroscopy.

Balance between inhibitory and excitatory neurotransmitter systems and the protective role of the major antioxidant glutathione (GSH) are central to early healthy brain development. Disruption has been implicated in the early life pathophysiology of psychiatric disorders and neurodevelopmental conditions including Autism Spectrum Disorder. Edited magnetic resonance spectroscopy (MRS) methods such as HERMES have great potential for providing important new non-invasive insights into these crucial processes in human infancy. In this work, we describe a systematic approach to minimise the impact of specific technical challenges inherent to acquiring MRS data in a neonatal population, including automatic segmentation, full tissue-correction and optimised GABA+ fitting and consider the minimum requirements for a robust edited-MRS acquisition. With this approach we report for the first time simultaneous GABA+, Glx (glutamate + glutamine) and GSH concentrations in the neonatal brain (n = 18) in two distinct regions (thalamus and anterior cingulate cortex (ACC)) using edited MRS at 3T. The improved sensitivity provided by our method allows specific regional neurochemical differences to be identified including: significantly lower Glx and GSH ratios to total creatine in the thalamus compared to the ACC (p < 0.001 for both), and significantly higher GSH levels in the ACC following tissue-correction (p < 0.01). Furthermore, in contrast to adult GABA+ which can typically be accurately fitted with a single peak, all neonate spectra displayed a characteristic doublet GABA+ peak at 3 ppm, indicating a lower macromolecule (MM) contribution to the 3 ppm signal in neonates. Relatively high group-level variance shows the need to maximise voxel size/acquisition time in edited neonatal MRS acquisitions for robust estimation of metabolites. Application of this method to study how these levels and balance are altered by early-life brain injury or genetic risk can provide important new knowledge about the pathophysiology underlying neurodevelopmental disorders.

Uncertainty analysis of MR-PET image registration for precision neuro-PET imaging.

Accurate regional brain quantitative PET measurements, particularly when using partial volume correction, rely on robust image registration between PET and MR images. We argue here that the precision, and hence the uncertainty, of MR-PET image registration is mainly driven by the registration implementation and the quality of PET images due to their lower resolution and higher noise compared to the structural MR images. We propose a dedicated uncertainty analysis for quantifying the precision of MR-PET registration, centred around the bootstrap resampling of PET list-mode events to generate multiple PET image realisations with different noise (count) levels. The effects of PET image reconstruction parameters, such as the use of attenuation and scatter corrections and different number of iterations, on the precision and accuracy of MR-PET registration were investigated. In addition, the performance of four software packages with their default settings for rigid inter-modality image registration were considered: NiftyReg, Vinci, FSL and SPM. Four distinct PET image distributions made of two early time frames (similar to cortical FDG) and two late frames using two amyloid PET dynamic acquisitions of one amyloid positive and one amyloid negative participants were investigated. For the investigated four PET frames, the biggest impact on the uncertainty was observed between registration software packages (up to 10-fold difference in precision) followed by the reconstruction parameters. On average, the lowest uncertainty for different PET frames and brain regions was observed with SPM and two iterations of fully quantitative image reconstruction. The observed uncertainty for the varying PET count-level (from 5% to 60%) was slightly lower than for the reconstruction parameters. We also observed that the registration uncertainty in quantitative PET analysis depends on amyloid status of the considered PET frames, with increased uncertainty (up to three times) when using post-reconstruction partial volume correction. This analysis is applicable for PET data obtained from either PET/MR or PET/CT scanners.

Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease.

Converging lines of evidence from several models, and post-mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single-site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high-performance liquid-chromatography to measure the levels of KP metabolites-tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid-in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short-term stability, intergroup differences, associations with clinical and imaging measures and derived sample-size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient-derived biofluids.

Neurometabolite mapping highlights elevated myo-inositol profiles within the developing brain in down syndrome.

The neurodevelopmental phenotype in Down Syndrome (DS), or Trisomy 21, is variable including a wide spectrum of cognitive impairment and a high risk of early-onset Alzheimer's disease (AD). A key metabolite of interest within the brain in DS is Myo-inositol (mIns). The NA+/mIns co-transporter is located on human chromosome 21 and is overexpressed in DS. In adults with DS, elevated brain mIns was previously associated with cognitive impairment and proposed as a risk marker for progression to AD. However, it is unknown if brain mIns is increased earlier in development. The aim of this study was to estimate mIns concentration levels and key brain metabolites [N-acetylaspartate (NAA), Choline (Cho) and Creatine (Cr)] in the developing brain in DS and aged-matched controls. We used in vivo magnetic resonance spectroscopy (MRS) in neonates with DS (n = 12) and age-matched controls (n = 26) scanned just after birth (36-45 weeks postmenstrual age). Moreover, we used Mass Spectrometry in early (10-20 weeks post conception) ex vivo fetal brain tissue samples from DS (n = 14) and control (n = 30) cases. Relative to [Cho] and [Cr], we report elevated ratios of [mIns] in vivo in the basal ganglia/thalamus, in neonates with DS, when compared to age-matched typically developing controls. Glycine concentration ratios [Gly]/[Cr] and [Cho]/[Cr] also appear elevated. We observed elevated [mIns] in the ex vivo fetal cortical brain tissue in DS compared with controls. In conclusion, a higher level of brain mIns was evident as early as 10 weeks post conception and was measurable in vivo from 36 weeks post-menstrual age. Future work will determine if this early difference in metabolites is linked to cognitive outcomes in childhood or has utility as a potential treatment biomarker for early intervention.

ExploreASL: An image processing pipeline for multi-center ASL perfusion MRI studies.

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. To facilitate collaboration and data-exchange, the toolbox follows several standards and recommendations for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts which may increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

Motion-corrected and high-resolution anatomically assisted (MOCHA) reconstruction of arterial spin labeling MRI.

PURPOSE: A model-based reconstruction framework is proposed for motion-corrected and high-resolution anatomically assisted (MOCHA) reconstruction of arterial spin labeling (ASL) data. In this framework, all low-resolution ASL control-label pairs are used to reconstruct a single high-resolution cerebral blood flow (CBF) map, corrected for rigid-motion, point-spread-function blurring and partial volume effect. METHODS: Six volunteers were recruited for CBF imaging using pseudo-continuous ASL labeling, two-shot 3D gradient and spin-echo sequences and high-resolution T1 -weighted MRI. For 2 volunteers, high-resolution scans with double and triple resolution in the partition direction were additionally collected. Simulations were designed for evaluations against a high-resolution ground-truth CBF map, including a simulated hyperperfused lesion and hyperperfusion/hypoperfusion abnormalities. The MOCHA technique was compared with standard reconstruction and a 3D linear regression partial-volume effect correction method and was further evaluated for acquisitions with reduced control-label pairs and k-space undersampling. RESULTS: The MOCHA reconstructions of low-resolution ASL data showed enhanced image quality, particularly in the partition direction. In simulations, both MOCHA and 3D linear regression provided more accurate CBF maps than the standard reconstruction; however, MOCHA resulted in the lowest errors and well delineated the abnormalities. The MOCHA reconstruction of standard-resolution in vivo data showed good agreement with higher-resolution scans requiring 4-times and 9-times longer acquisitions. The MOCHA reconstruction was found to be robust for 4-times-accelerated ASL acquisitions, achieved by reduced control-label pairs or k-space undersampling. CONCLUSION: The MOCHA reconstruction reduces partial-volume effect by direct reconstruction of CBF maps in the high-resolution space of the corresponding anatomical image, incorporating motion correction and point spread function modeling. Following further evaluation, MOCHA should promote the clinical application of ASL.

Systematic evaluation of velocity-selective arterial spin labeling settings for placental perfusion measurement.

PURPOSE: Placental function is key for successful human pregnancies. Perfusion may be a sensitive marker for the in vivo assessment of placental function. Arterial spin labeling (ASL) MRI enables noninvasive measurement of tissue perfusion and it was recently suggested that ASL with velocity-selective (VS) labeling could be advantageous in the placenta. We systematically evaluated essential VS-ASL sequence parameters to determine optimal settings for efficient placental perfusion measurements. METHODS: Eleven pregnant women were scanned at 3T using VS-ASL with 2D multislice echo planar imaging (EPI)-readout. One reference VS-ASL scan was acquired in all subjects; within subgroups the following parameters were systematically varied: cutoff velocity, velocity encoding direction, and inflow time. Visual evaluation and region of interest analyses were performed to compare perfusion signal differences between acquisitions. RESULTS: In all subjects, a perfusion pattern with clear hyperintense focal regions was observed. Perfusion signal decreased with inflow time and cutoff velocity. Subject-specific dependence on velocity encoding direction was observed. High temporal signal-to-noise ratios with high contrast on the perfusion images between the hyperintense regions and placental tissue were seen at ~1.6 cm/s cutoff velocity and ~1000 ms inflow time. Evaluation of measurements at multiple inflow times revealed differences in blood flow dynamics between placental regions. CONCLUSION: Placental perfusion measurements are feasible at 3T using VS-ASL with 2D multislice EPI-readout. A clear dependence of perfusion signal on VS labeling parameters and inflow time was demonstrated. Whereas multiple parameter combinations may advance the interpretation of placental circulation dynamics, this study provides a basis to select an effective set of parameters for the observation of placenta perfusion natural history and its potential pathological changes.

Perfusion and apparent oxygenation in the human placenta (PERFOX).

PURPOSE: To study placental function-both perfusion and an oxygenation surrogate ( T2* )-simultaneously and quantitatively in-vivo. METHODS: Fifteen pregnant women were scanned on a 3T MR scanner. For perfusion measurements, a velocity selective arterial spin labeling preparation module was placed before a multi-echo gradient echo EPI readout to integrate T2* and perfusion measurements in 1 joint perfusion-oxygenation (PERFOX) acquisition. Joint motion correction and quantification were performed to evaluate changes in T2* and perfusion over GA. RESULTS: The optimized integrated PERFOX protocol and post-processing allowed successful visualization and quantification of perfusion and T2* in all subjects. Areas of high T2* and high perfusion appear to correspond to placental sub-units and show a systematic offset in location along the maternal-fetal axis. The areas of highest perfusion are consistently closer to the maternal basal plate and the areas of highest T2* closer to the fetal chorionic plate. Quantitative results show a strong negative correlation of gestational age with T2* and weak negative correlation with perfusion. CONCLUSIONS: A strength of the joint sequence is that it provides truly simultaneous and co-registered estimates of local T2* and perfusion, however, to achieve this, the time per slice is prolonged compared to a perfusion only scan which can potentially limit coverage. The achieved interlocking can be particularly useful when quantifying transient physiological effects such as uterine contractions. PERFOX opens a new avenue to elucidate the relationship between maternal supply and oxygen uptake, both of which are central to placental function and dysfunction.

Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study.

Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Cerebrospinal fluid flow dynamics in Huntington's disease evaluated by phase contrast MRI.

Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross-sectional study comparing people with early stage Huntington's disease with age- and gender-matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub-arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter-group differences with Wilcoxon rank-sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTTCAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics - that is, one that would justify dose-adjustments of intrathecal drugs - is unlikely to exist in Huntington's disease.

Robust kidney perfusion mapping in pediatric chronic kidney disease using single-shot 3D-GRASE ASL with optimized retrospective motion correction.

PURPOSE: To develop a robust renal arterial spin labeling (ASL) acquisition and processing strategy for mapping renal blood flow (RBF) in a pediatric cohort with severe kidney disease. METHODS: A single-shot background-suppressed 3D gradient and spin-echo (GRASE) flow-sensitive alternating inversion recovery (FAIR) ASL acquisition method was used to perform 2 studies. First, an evaluation of the feasibility of single-shot 3D-GRASE and retrospective noise reduction methods was performed in healthy volunteers. Second, a pediatric cohort with severe chronic kidney disease underwent single-shot 3D-GRASE FAIR ASL and RBF was quantified following several retrospective motion correction pipelines, including image registration and threshold-free weighted averaging. The effect of motion correction on the fit errors of saturation recovery (SR) images (required for RBF quantification) and on the perfusion-weighted image (PWI) temporal signal-to-noise ratio (tSNR) was evaluated, as well as the intra- and inter-session repeatability of renal longitudinal relaxation time (T1 ) and RBF. RESULTS: The mean cortical and/or functional renal parenchyma RBF in healthy volunteers and CKD patients was 295 ± 97 and 95 ± 47 mL/100 g/min, respectively. Motion-correction reduced image artefacts in both T1 and RBF maps, significantly reduced SR fit errors, significantly increased the PWI tSNR and improved the improved the repeatability of T1 and RBF in the pediatric patient cohort. CONCLUSION: Single-shot 3D-GRASE ASL combined with retrospective motion correction enabled repeatable non-invasive RBF mapping in the first pediatric cohort with severe kidney disease undergoing ASL scans.

Comparison of arterial spin labeling registration strategies in the multi-center GENetic frontotemporal dementia initiative (GENFI).

PURPOSE: To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. MATERIALS AND METHODS: Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. RESULTS: CBF-pGM outperformed M0-T1w (CC improvement 47.2% ± 22.0%; P < 0.001), and the non-rigid transformation outperformed rigid-body (20.6% ± 5.3%; P < 0.001). Masking only improved the M0-T1w rigid-body registration (14.5% ± 15.5%; P = 0.007). CONCLUSION: The choice of image registration strategy impacts ASL group analyses. The non-rigid transformation is promising but requires validation. CBF-pGM rigid-body registration without masking can be used as a default strategy. In patients with expansive perfusion deficits, M0-T1w may outperform CBF-pGM in sequences with high effective spatial resolution. BET-masking only improves M0-T1w registration when the M0 image has sufficient contrast. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:131-140.

Effects of systematic partial volume errors on the estimation of gray matter cerebral blood flow with arterial spin labeling MRI.

OBJECTIVE: Partial volume (PV) correction is an important step in arterial spin labeling (ASL) MRI that is used to separate perfusion from structural effects when computing the mean gray matter (GM) perfusion. There are three main methods for performing this correction: (1) GM-threshold, which includes only voxels with GM volume above a preset threshold; (2) GM-weighted, which uses voxel-wise GM contribution combined with thresholding; and (3) PVC, which applies a spatial linear regression algorithm to estimate the flow contribution of each tissue at a given voxel. In all cases, GM volume is obtained using PV maps extracted from the segmentation of the T1-weighted (T1w) image. As such, PV maps contain errors due to the difference in readout type and spatial resolution between ASL and T1w images. Here, we estimated these errors and evaluated their effect on the performance of each PV correction method in computing GM cerebral blood flow (CBF). MATERIALS AND METHODS: Twenty-two volunteers underwent scanning using 2D echo planar imaging (EPI) and 3D spiral ASL. For each PV correction method, GM CBF was computed using PV maps simulated to contain estimated errors due to spatial resolution mismatch and geometric distortions which are caused by the mismatch in readout between ASL and T1w images. Results were analyzed to assess the effect of each error on the estimation of GM CBF from ASL data. RESULTS: Geometric distortion had the largest effect on the 2D EPI data, whereas the 3D spiral was most affected by the resolution mismatch. The PVC method outperformed the GM-threshold even in the presence of combined errors from resolution mismatch and geometric distortions. The quantitative advantage of PVC was 16% without and 10% with the combined errors for both 2D and 3D ASL. Consistent with theoretical expectations, for error-free PV maps, the PVC method extracted the true GM CBF. In contrast, GM-weighted overestimated GM CBF by 5%, while GM-threshold underestimated it by 16%. The presence of PV map errors decreased the calculated GM CBF for all methods. CONCLUSION: The quality of PV maps presents no argument for the preferential use of the GM-threshold method over PVC in the clinical application of ASL.