Velocity-selective arterial spin labeling perfusion measurements in 2nd trimester human placenta with varying BMI.

INTRODUCTION: Proper placental development is crucial to fetal health but is challenging to functionally assess non-invasively and is thus poorly characterized in populations. Body mass index (BMI) has been linked with adverse outcomes, but the causative mechanism is uncertain. Velocity-selective arterial spin labeling (VS-ASL) MRI provides a method to non-invasively measure placental perfusion with robustness to confounding transit time delays. In this study, we report on the measurement of perfusion in the human placenta in early pregnancy using velocity-selective arterial spin labeling (VS-ASL) MRI, comparing non-obese and obese participants. METHODS: Participants (N = 97) undergoing routine prenatal care were recruited and imaged with structural and VS-ASL perfusion MRI at 15 and 21 weeks gestation. Resulting perfusion images were analyzed with respect to obesity based on BMI, gestational age, and the presence of adverse outcomes. RESULTS: At 15 weeks gestation BMI was not associated with placental perfusion or perfusion heterogeneity. However, at 21 weeks gestation BMI was associated with higher placental perfusion (p < 0.01) and a decrease in perfusion heterogeneity (p < 0.05). In alignment with past studies, perfusion values were also higher at 21 weeks compared to 15 weeks gestation. In a small cohort of participants with adverse outcomes, at 21 weeks lower perfusion was observed compared to participants with uncomplicated pregnancies. DISCUSSION: These results suggest low placental perfusion in the early second trimester may not be the culpable factor driving associations of obesity with adverse outcomes.

Unraveling diurnal and technical variability in cerebral hemodynamics from neurovascular 4D-Flow MRI.

Neurovascular 4D-Flow MRI enables non-invasive evaluation of cerebral hemodynamics including measures of cerebral blood flow (CBF), vessel pulsatility index (PI), and cerebral pulse wave velocity (PWV). 4D-Flow measures have been linked to various neurovascular disorders including small vessel disease and Alzheimer's disease; however, physiological and technical sources of variability are not well established. Here, we characterized sources of diurnal physiological and technical variability in cerebral hemodynamics using 4D-Flow in a retrospective study of cognitively unimpaired older adults (N = 750) and a prospective study of younger adults (N = 10). Younger participants underwent repeated MRI sessions at 7am, 4 pm, and 10 pm. In the older cohort, having an MRI earlier on the day was significantly associated with higher CBF and lower PI. In prospective experiments, time of day significantly explained variability in CBF and PI; however, not in PWV. Test-retest experiments showed high CBF intra-session repeatability (repeatability coefficient (RPC) =7.2%), compared to lower diurnal repeatability (RPC = 40%). PI and PWV displayed similar intra-session and diurnal variability (PI intra-session RPC = 22%, RPC = 24% 7am vs 4 pm; PWV intra-session RPC = 17%, RPC = 21% 7am vs 4 pm). Overall, CBF measures showed low technical variability, supporting diurnal variability is from physiology. PI and PWV showed higher technical variability but less diurnal variability.

Cotyledon-Specific Flow Evaluation of Rhesus Macaque Placental Injury Using Ferumoxytol Dynamic Contrast-Enhanced MRI.

BACKGROUND: Recently, dynamic contrast-enhanced (DCE) MRI with ferumoxytol as contrast agent has recently been introduced for the noninvasive assessment of placental structure and function throughout. However, it has not been demonstrated under pathological conditions. PURPOSE: To measure cotyledon-specific rhesus macaque maternal placental blood flow using ferumoxytol DCE MRI in a novel animal model for local placental injury. STUDY TYPE: Prospective animal model. SUBJECTS: Placental injections of Tisseel (three with 0.5 mL and two with 1.5 mL), monocyte chemoattractant protein 1 (three with 100 µg), and three with saline as controls were performed in a total of 11 rhesus macaque pregnancies at approximate gestational day (GD 101). DCE MRI scans were performed prior (GD 100) and after (GD 115 and GD 145) the injection (term = GD 165). FIELD STRENGTH/SEQUENCE: 3 T, T1-weighted spoiled gradient echo sequence (product sequence, DISCO). ASSESSMENT: Source images were inspected for motion artefacts from the mother or fetus. Placenta segmentation and DCE processing were performed for the dynamic image series to measure cotyledon specific volume, flow, and normalized flow. Overall placental histopathology was conducted for controls, Tisseel, and MCP-1 animals and regions of tissue infarctions and necrosis were documented. Visual inspections for potential necrotic tissue were conducted for the two Tisseelx3 animals. STATISTICAL TESTS: Wilcoxon rank sum test, significance level P < 0.05. RESULTS: No motion artefacts were observed. For the group treated with 1.5 mL of Tisseel, significantly lower cotyledon volume, flow, and normalized flow per cotyledon were observed for the third gestational time point of imaging (day ~145), with mean normalized flow of 0.53 minute-1 . Preliminary histopathological analysis shows areas of tissue necrosis from a selected cotyledon in one Tisseel-treated (single dose) animal and both Tisseelx3 (triple dose) animals. DATA CONCLUSION: This study demonstrates the feasibility of cotyledon-specific functional analysis at multiple gestational time points and injury detection in a placental rhesus macaque model through ferumoxytol-enhanced DCE MRI. LEVEL OF EVIDENCE: NA TECHNICAL EFFICACY: Stage 2.

False lumen hemodynamics and partial thrombosis in chronic aortic dissection of the descending aorta.

OBJECTIVES: Partial thrombosis of the false lumen (FL) in patients with chronic aortic dissection (AD) of the descending aorta has been associated with poor outcomes. Meanwhile, the fluid dynamic and biomechanical characteristics associated with partial thrombosis remain to be elucidated. This retrospective, single-center study tested the association between FL fluid dynamics and biomechanics and the presence and extent of FL thrombus. METHODS: Patients with chronic non-thrombosed or partially thrombosed FLs in the descending aorta after an aortic dissection underwent computed tomography angiography, cardiovascular magnetic resonance (CMR) angiography, and a 4D flow CMR study. A comprehensive quantitative analysis was performed to test the association between FL thrombus presence and extent (percentage of FL with thrombus) and FL anatomy (diameter, entry tear location and size), fluid dynamics (inflow, rotational flow, wall shear stress, kinetic energy, and flow acceleration and stasis), and biomechanics (pulse wave velocity). RESULTS: Sixty-eight patients were included. In multivariate logistic regression FL kinetic energy (p = 0.038) discriminated the 33 patients with partial FL thrombosis from the 35 patients with no thrombosis. Similarly, in separated multivariate linear correlations kinetic energy (p = 0.006) and FL inflow (p = 0.002) were independently related to the extent of the thrombus. FL vortexes, flow acceleration and stasis, wall shear stress, and pulse wave velocity showed limited associations with thrombus presence and extent. CONCLUSION: In patients with chronic descending aorta dissection, false lumen kinetic energy is related to the presence and extent of false lumen thrombus. CLINICAL RELEVANCE STATEMENT: In patients with chronic aortic dissection of the descending aorta, false lumen hemodynamic parameters are closely linked with the presence and extent of false lumen thrombosis, and these non-invasive measures might be important in patient management. KEY POINTS: • Partial false lumen thrombosis has been associated with aortic growth in patients with chronic descending aortic dissection; therefore, the identification of prothrombotic flow conditions is desirable. • The presence of partial false lumen thrombosis as well as its extent was related with false lumen kinetic energy. • The assessment of false lumen hemodynamics may be important in the management of patients with chronic aortic dissection of the descending aorta.

Four-dimensional flow MRI for quantitative assessment of cerebrospinal fluid dynamics: Status and opportunities.

Neurological disorders can manifest with altered neurofluid dynamics in different compartments of the central nervous system. These include alterations in cerebral blood flow, cerebrospinal fluid (CSF) flow, and tissue biomechanics. Noninvasive quantitative assessment of neurofluid flow and tissue motion is feasible with phase contrast magnetic resonance imaging (PC MRI). While two-dimensional (2D) PC MRI is routinely utilized in research and clinical settings to assess flow dynamics through a single imaging slice, comprehensive neurofluid dynamic assessment can be limited or impractical. Recently, four-dimensional (4D) flow MRI (or time-resolved three-dimensional PC with three-directional velocity encoding) has emerged as a powerful extension of 2D PC, allowing for large volumetric coverage of fluid velocities at high spatiotemporal resolution within clinically reasonable scan times. Yet, most 4D flow studies have focused on blood flow imaging. Characterizing CSF flow dynamics with 4D flow (i.e., 4D CSF flow) is of high interest to understand normal brain and spine physiology, but also to study neurological disorders such as dysfunctional brain metabolite waste clearance, where CSF dynamics appear to play an important role. However, 4D CSF flow imaging is challenged by the long T1 time of CSF and slower velocities compared with blood flow, which can result in longer scan times from low flip angles and extended motion-sensitive gradients, hindering clinical adoption. In this work, we review the state of 4D CSF flow MRI including challenges, novel solutions from current research and ongoing needs, examples of clinical and research applications, and discuss an outlook on the future of 4D CSF flow.

Time-Resolved 3D cardiopulmonary MRI reconstruction using spatial transformer network.

The accurate visualization and assessment of the complex cardiac and pulmonary structures in 3D is critical for the diagnosis and treatment of cardiovascular and respiratory disorders. Conventional 3D cardiac magnetic resonance imaging (MRI) techniques suffer from long acquisition times, motion artifacts, and limited spatiotemporal resolution. This study proposes a novel time-resolved 3D cardiopulmonary MRI reconstruction method based on spatial transformer networks (STNs) to reconstruct the 3D cardiopulmonary MRI acquired using 3D center-out radial ultra-short echo time (UTE) sequences. The proposed reconstruction method employed an STN-based deep learning framework, which used a combination of data-processing, grid generator, and sampler. The reconstructed 3D images were compared against the start-of-the-art time-resolved reconstruction method. The results showed that the proposed time-resolved 3D cardiopulmonary MRI reconstruction using STNs offers a robust and efficient approach to obtain high-quality images. This method effectively overcomes the limitations of conventional 3D cardiac MRI techniques and has the potential to improve the diagnosis and treatment planning of cardiopulmonary disorders.

Biotransformation research advances - 2022 year in review.

This annual review is the eighth of its kind since 2016 (Baillie et al. 2016, Khojasteh et al. 2017, Khojasteh et al. 2018, Khojasteh et al. 2019, Khojasteh et al. 2020, Khojasteh et al. 2021, Khojasteh et al. 2022). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation.

Bioactivation and reactivity research advances - 2022 year in review‡.

With the 50th year mark since the launch of Drug Metabolism and Disposition journal, the field of drug metabolism and bioactivation has advanced exponentially in the past decades (Guengerich 2023).This has, in a major part, been due to the continued advances across the whole spectrum of applied technologies in hardware, software, machine learning (ML), and artificial intelligence (AI). LC-MS platforms continue to evolve to support key applications in the field, and automation is also improving the accuracy, precision, and throughput of these supporting assays. In addition, sample generation and processing is being aided by increased diversity and quality of reagents and bio-matrices so that what is being analyzed is more relevant and translatable. The application of in silico platforms (applied software, ML, and AI) is also making great strides, and in tandem with the more traditional approaches mentioned previously, is significantly advancing our understanding of bioactivation pathways and how these play a role in toxicity. All of this continues to allow the area of bioactivation to evolve in parallel with associated fields to help bring novel or improved medicines to patients with urgent or unmet needs.Shuai Wang and Cyrus Khojasteh, on behalf of the authors.

MR Angiography of Extracranial Carotid Disease.

Magnetic resonance angiography sequences, such as time-of-flight and contrast-enhanced angiography, provide clear depiction of vessel lumen, traditionally used to evaluate carotid pathologic conditions such as stenosis, dissection, and occlusion; however, atherosclerotic plaques with a similar degree of stenosis may vary tremendously from a histopathological standpoint. MR vessel wall imaging is a promising noninvasive method to evaluate the content of the vessel wall at high spatial resolution. This is particularly interesting in the case of atherosclerosis as vessel wall imaging can identify higher risk, vulnerable plaques as well as has potential applications in the evaluation of other carotid pathologic conditions.

Four-Dimensional Flow MR Imaging: Technique and Advances.

4D Flow MRI is an advanced imaging technique for comprehensive non-invasive assessment of the cardiovascular system. The capture of the blood velocity vector field throughout the cardiac cycle enables measures of flow, pulse wave velocity, kinetic energy, wall shear stress, and more. Advances in hardware, MRI data acquisition and reconstruction methodology allow for clinically feasible scan times. The availability of 4D Flow analysis packages allows for more widespread use in research and the clinic and will facilitate much needed multi-center, multi-vendor studies in order to establish consistency across scanner platforms and to enable larger scale studies to demonstrate clinical value.

MR Imaging for Intracranial Vessel Wall Imaging: Pearls and Pitfalls.

Conventional vascular imaging methods have primarily focused on evaluating the vascular lumen. However, these techniques are not intended to evaluate vessel wall abnormalities where many cerebrovascular pathologies reside. With increased interest for the visualization and study of the vessel wall, high-resolution vessel wall imaging (VWI) has gained traction.Over the past two decades, there has been a rapid increase in number of VWI publications with improvements in imaging techniques and expansion on clinical applications. With increasing utility and interest in VWI, application of proper protocols and understanding imaging characteristics of vasculopathies are important for the interpreting radiologists to understand.

Cerebral hemodynamics comparison using transcranial doppler ultrasound and 4D flow MRI.

Introduction: Age-related changes in cerebral hemodynamics are controversial and discrepancies may be due to experimental techniques. As such, the purpose of this study was to compare cerebral hemodynamics measurements of the middle cerebral artery (MCA) between transcranial Doppler ultrasound (TCD) and four-dimensional flow MRI (4D flow MRI). Methods: Twenty young (25 ± 3 years) and 19 older (62 ± 6 years) participants underwent two randomized study visits to evaluate hemodynamics at baseline (normocapnia) and in response to stepped hypercapnia (4% CO2, and 6% CO2) using TCD and 4D flow MRI. Cerebral hemodynamic measures included MCA velocity, MCA flow, cerebral pulsatility index (PI) and cerebrovascular reactivity to hypercapnia. MCA flow was only assessed using 4D flow MRI. Results: MCA velocity between the TCD and 4D flow MRI methods was positively correlated across the normocapnia and hypercapnia conditions (r = 0.262; p = 0.004). Additionally, cerebral PI was significantly correlated between TCD and 4D flow MRI across the conditions (r = 0.236; p = 0.010). However, there was no significant association between MCA velocity using TCD and MCA flow using 4D flow MRI across the conditions (r = 0.079; p = 0.397). When age-associated differences in cerebrovascular reactivity using conductance were compared using both methodologies, cerebrovascular reactivity was greater in young adults compared to older adults when using 4D flow MRI (2.11 ± 1.68 mL/min/mmHg/mmHg vs. 0.78 ± 1.68 mL/min/mmHg/mmHg; p = 0.019), but not with TCD (0.88 ± 1.01 cm/s/mmHg/mmHg vs. 0.68 ± 0.94 cm/s/mmHg/mmHg; p = 0.513). Conclusion: Our results demonstrated good agreement between the methods at measuring MCA velocity during normocapnia and in response to hypercapnia, but MCA velocity and MCA flow were not related. In addition, measurements using 4D flow MRI revealed effects of aging on cerebral hemodynamics that were not apparent using TCD.

Fat mitigation strategies to improve image quality of radial 4D flow MRI in obese subjects.

PURPOSE: This study addresses the challenges in obtaining abdominal 4D flow MRI of obese patients. We aimed to evaluate spectral saturation and inner volume excitation as methods to mitigating artifacts originating from adipose signals, with the goal of enhancing image quality and improving quantification. METHODS: Radial 4D flow MRI acquisitions with fat mitigation (inner volume excitation [IVE] and intermittent fat saturation [FS]) were compared to a standard slab selective excitation (SSE) in a test-retest study of 15 obese participants. IVE selectively excited a cylindrical region of interest, avoiding contamination from peripheral adipose tissue, while FS globally suppressed fat based on spectral selection. Acquisitions were evaluated qualitatively based on expert ratings and quantitatively based on conservation of mass, test-retest repeatability, and a divergence free quality metric. Errors were evaluated statistically using the absolute and relative errors, regression, and Bland-Altman analysis. RESULTS: IVE demonstrated superior performance quantitatively in the conservation of mass analysis in the portal vein, with higher correlation and lower bias in regression analysis. IVE also produced flow fields with the lowest divergence error and was rated best in overall image quality, delineating small vessels, and producing the least streaking artifacts. Evaluation results did not differ significantly between FS and SSE. Test-retest reproducibility was similarly high for all sequences, with data suggesting biological variations dominate the technical variability. CONCLUSION: IVE improved hemodynamic assessment of radial 4D flow MRI in the abdomen of obese participants while FS did not lead to significant improvements in image quality or flow metrics.

Longitudinal Lung Function Assessment of Patients Hospitalized With COVID-19 Using 1H and 129Xe Lung MRI.

BACKGROUND: Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear. RESEARCH QUESTION: Do patients hospitalized with COVID-19 without evidence of architectural distortion on structural imaging exhibit longitudinal improvements in lung function measured by using 1H and 129Xe MRI between 6 and 52 weeks following hospitalization? STUDY DESIGN AND METHODS: Patients who were hospitalized with COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25, and 51 weeks following hospital admission in a prospective cohort study between November 2020 and February 2022. The imaging protocol was as follows: 1H ultra-short echo time, contrast-enhanced lung perfusion, 129Xe ventilation, 129Xe diffusion-weighted, and 129Xe spectroscopic imaging of gas exchange. RESULTS: Nine patients were recruited (age 57 ± 14 [median ± interquartile range] years; six of nine patients were male). Patients underwent MRI at 6 (n = 9), 12 (n = 9), 25 (n = 6), and 51 (n = 8) weeks following hospital admission. Patients with signs of interstitial lung damage were excluded. At 6 weeks, patients exhibited impaired 129Xe gas transfer (RBC to membrane fraction), but lung microstructure was not increased (apparent diffusion coefficient and mean acinar airway dimensions). Minor ventilation abnormalities present in four patients were largely resolved in the 6- to 25-week period. At 12 weeks, all patients with lung perfusion data (n = 6) showed an increase in both pulmonary blood volume and flow compared with 6 weeks, although this was not statistically significant. At 12 weeks, significant improvements in 129Xe gas transfer were observed compared with 6-week examinations; however, 129Xe gas transfer remained abnormally low at weeks 12, 25, and 51. INTERPRETATION: 129Xe gas transfer was impaired up to 1 year following hospitalization in patients who were hospitalized with COVID-19 pneumonia, without evidence of architectural distortion on structural imaging, whereas lung ventilation was normal at 52 weeks.

Normative Cerebral Hemodynamics in Middle-aged and Older Adults Using 4D Flow MRI: Initial Analysis of Vascular Aging.

Background Characterizing cerebrovascular hemodynamics in older adults is important for identifying disease and understanding normal neurovascular aging. Four-dimensional (4D) flow MRI allows for a comprehensive assessment of cerebral hemodynamics in a single acquisition. Purpose To establish reference intracranial blood flow and pulsatility index values in a large cross-sectional sample of middle-aged (45-65 years) and older (>65 years) adults and characterize the effect of age and sex on blood flow and pulsatility. Materials and Methods In this retrospective study, patients aged 45-93 years (cognitively unimpaired) underwent cranial 4D flow MRI between March 2010 and March 2020. Blood flow rates and pulsatility indexes from 13 major arteries and four venous sinuses and total cerebral blood flow were collected. Intraobserver and interobserver reproducibility of flow and pulsatility measures was assessed in 30 patients. Descriptive statistics (mean ± SD) of blood flow and pulsatility were tabulated for the entire group and by age and sex. Multiple linear regression and linear mixed-effects models were used to assess the effect of age and sex on total cerebral blood flow and vessel-specific flow and pulsatility, respectively. Results There were 759 patients (mean age, 65 years ± 8 [SD]; 506 female patients) analyzed. For intra- and interobserver reproducibility, median intraclass correlation coefficients were greater than 0.90 for flow and pulsatility measures across all vessels. Regression coefficients ß ± standard error from multiple linear regression showed a 4 mL/min decrease in total cerebral blood flow each year (age ß = -3.94 mL/min per year ± 0.44; P < .001). Mixed effects showed a 1 mL/min average annual decrease in blood flow (age ß = -0.95 mL/min per year ± 0.16; P < .001) and 0.01 arbitrary unit (au) average annual increase in pulsatility over all vessels (age ß = 0.011 au per year ± 0.001; P < .001). No evidence of sex differences was observed for flow (ß = -1.60 mL/min per male patient ± 1.77; P = .37), but pulsatility was higher in female patients (sex ß = -0.018 au per male patient ± 0.008; P = .02). Conclusion Normal reference values for blood flow and pulsatility obtained using four-dimensional flow MRI showed correlations with age. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Steinman in this issue.

Motion compensated self supervised deep learning for highly accelerated 3D ultrashort Echo time pulmonary MRI.

PURPOSE: To investigate motion compensated, self-supervised, model based deep learning (MBDL) as a method to reconstruct free breathing, 3D pulmonary UTE acquisitions. THEORY AND METHODS: A self-supervised eXtra dimension MBDL architecture (XD-MBDL) was developed that combined respiratory states to reconstruct a single high-quality 3D image. Non-rigid motion fields were incorporated into this architecture by estimating motion fields from a lower resolution motion resolved (XD-GRASP) reconstruction. Motion compensated XD-MBDL was evaluated on lung UTE datasets with and without contrast and compared to constrained reconstructions and variants of self-supervised MBDL that do not account for dynamic respiratory states or leverage motion correction. RESULTS: Images reconstructed using XD-MBDL demonstrate improved image quality as measured by apparent SNR (aSNR), contrast to noise ratio (CNR), and visual assessment relative to self-supervised MBDL approaches that do not account for dynamic respiratory states, XD-GRASP and a recently proposed motion compensated iterative reconstruction strategy (iMoCo). Additionally, XD-MBDL reduced reconstruction time relative to both XD-GRASP and iMoCo. CONCLUSION: A method was developed to allow self-supervised MBDL to combine multiple respiratory states to reconstruct a single image. This method was combined with graphics processing unit (GPU)-based image registration to further improve reconstruction quality. This approach showed promising results reconstructing a user-selected respiratory phase from free breathing 3D pulmonary UTE acquisitions.

Memory efficient model based deep learning reconstructions for high spatial resolution 3D non-cartesian acquisitions.

Objective. Model based deep learning (MBDL) has been challenging to apply to the reconstruction of 3D non-Cartesian MRI due to GPU memory demand because the entire volume is needed for data-consistency steps embedded in the model. This requirement makes holding even a single unroll in GPU memory difficult meaning memory efficient techniques used to increase unroll number like gradient checkpointing and deep equilibrium learning will not work well for high spatial resolution 3D non-Cartesian reconstructions without modification. Here we develop a memory efficient method called block-wise learning that combines gradient checkpointing with patch-wise training to overcome this obstacle and allow for fast and high-quality 3D non-Cartesian reconstructions using MBDL.Approach. Block-wise learning applied to a single unroll decomposes the input volume into smaller patches, gradient checkpoints each patch, passes each patch iteratively through a neural network regularizer, and then rebuilds the full volume from these output patches for data-consistency. This method is applied across unrolls during training. Block-wise learning significantly reduces memory requirements by tying GPU memory for a single unroll to user selected patch size instead of the full volume. This algorithm was used to train a MBDL architecture to reconstruct highly undersampled, 1.25 mm isotropic, pulmonary magnetic resonance angiography volumes with matrix sizes varying from 300-450 × 200-300 × 300-450 on a single GPU. We compared block-wise learning reconstructions against L1 wavelet compressed reconstructions and proxy ground truth images.Main results. MBDL with block-wise learning significantly improved image quality relative to L1 wavelet compressed sensing while simultaneously reducing average reconstruction time 38x.Significance. Block-wise learning allows for MBDL to be applied to high spatial resolution, 3D non-Cartesian datasets with improved image quality and significant reductions in reconstruction time relative to traditional iterative methods.

Vascular contributions to Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by progressive neurodegeneration and cognitive decline. Understanding the pathophysiology underlying AD is paramount for the management of individuals at risk of and suffering from AD. The vascular hypothesis stipulates a relationship between cardiovascular disease and AD-related changes although the nature of this relationship remains unknown. In this review, we discuss several potential pathological pathways of vascular involvement in AD that have been described including dysregulation of neurovascular coupling, disruption of the blood brain barrier, and reduced clearance of metabolite waste such as beta-amyloid, a toxic peptide considered the hallmark of AD. We will also discuss the two-hit hypothesis which proposes a 2-step positive feedback loop in which microvascular insults precede the accumulation of Aß and are thought to be at the origin of the disease development. At neuroimaging, signs of vascular dysfunction such as chronic cerebral hypoperfusion have been demonstrated, appearing early in AD, even before cognitive decline and alteration of traditional biomarkers. Cerebral small vessel disease such as cerebral amyloid angiopathy, characterized by the aggregation of Aß in the vessel wall, is highly prevalent in vascular dementia and AD patients. Current data is unclear whether cardiovascular disease causes, precipitates, amplifies, precedes, or simply coincides with AD. Targeted imaging tools to quantitatively evaluate the intracranial vasculature and longitudinal studies in individuals at risk for or in the early stages of the AD continuum could be critical in disentangling this complex relationship between vascular disease and AD.

Accelerated 4D-flow MRI with 3-point encoding enabled by machine learning.

PURPOSE: To investigate the acceleration of 4D-flow MRI using a convolutional neural network (CNN) that produces three directional velocities from three flow encodings, without requiring a fourth reference scan measuring background phase. METHODS: A fully 3D CNN using a U-net architecture was trained in a block-wise fashion to take complex images from three flow encodings and to produce three real-valued images for each velocity component. Using neurovascular 4D-flow scans (n = 144), the CNN was trained to predict velocities computed from four flow encodings by standard reconstruction including correction for residual background phase offsets. Methods to optimize loss functions were investigated, including magnitude, complex difference, and uniform velocity weightings. Subsequently, 3-point encoding was evaluated using cross validation of pixelwise correlation, flow measurements in major arteries, and in experiments with data at differing acceleration rates than the training data. RESULTS: The CNN-produced 3-point velocities showed excellent agreements with the 4-point velocities, both qualitatively in velocity images, in flow rate measures, and quantitatively in regression analysis (slope = 0.96, R2  = 0.992). Optimizing the training to focus on vessel velocities rather than the global velocity error and improved the correlation of velocity within vessels themselves. The lowest error was observed when the loss function used uniform velocity weighting, in which the magnitude-weighted inverse of the velocity frequency uniformly distributed weighting across all velocity ranges. When applied to highly accelerated data, the 3-point network maintained a high correlation with ground truth data and demonstrated a denoising effect. CONCLUSION: The 4D-flow MRI can be accelerated using machine learning requiring only three flow encodings to produce three-directional velocity maps with small errors.

Effects of Local Sequence, Reaction Conditions, and Various Additives on the Formation and Stability of Interstrand Cross-Links Derived from the Reaction of an Abasic Site with an Adenine Residue in Duplex DNA.

The experiments described here examined the effects of reaction conditions, various additives, and local sequence on the formation and stability interstrand cross-links (ICLs) derived from the reaction of an apurinic/apyrimidinic (AP) site with the exocyclic amino group of an adenine residue on the opposing strand in duplex DNA. Cross-link formation was observed in a range of different buffers, with faster formation rates observed at pH 5. Inclusion of the base excision repair enzyme alkyladenine DNA glycosylase (hAAG) which binds tightly to AP-containing duplexes decreased, but did not completely prevent, formation of the dA-AP ICL. Formation of the dA-AP ICL was not altered by the presence of the biological metal ion Mg2+ or the biological thiol, glutathione. Several organocatalysts of imine formation did not enhance the rate of dA-AP ICL formation. Duplex length did not have a large effect on dA-AP yield, so long as the melting temperature of the duplex was not significantly below the reaction temperature (the duplex must remain hybridized for efficient ICL formation). Formation of the dA-AP ICL was examined in over 40 different sequences that varied the neighboring and opposing bases at the cross-linking site. The results indicate that ICL formation can occur in a wide variety of sequence contexts under physiological conditions. Formation of the dA-AP ICL was strongly inhibited by the aldehyde-trapping agents methoxyamine and hydralazine, by NaBH3CN, by the intercalator ethidium bromide, and by the minor groove-binding agent netropsin. ICL formation was inhibited to some extent in bicarbonate and Tris buffers. The dA-AP ICL showed substantial inherent stability under a variety of conditions and was not a substrate for AP-processing enzymes APE1 or Endo IV. Finally, we characterized cross-link formation in a small (11 bp) stem-loop (hairpin) structure and in DNA-RNA hybrid duplexes.