In vivo lymph node CEST-Dixon MRI in breast cancer patients with metastatic lymph node involvement.

PURPOSE: Axillary lymph nodes (LNs) often present a reservoir for metastatic breast cancer, yet metastatic LN involvement cannot be discerned definitively using diagnostic imaging. This study investigated whether in vivo CEST may discriminate LNs with versus without metastatic involvement. METHODS: 3T MRI was performed in patients with breast cancer before clinically-indicated mastectomy or lumpectomy with LN removal, after which LN metastasic involvement was determined using histological evaluation. Non-contrast anatomical imaging, as well as B0 and B1 field maps, were acquired in sequence with three-point CEST-Dixon (3D turbo-gradient-echo; factor = 25; TR/TE1/ΔTE = 851/1.35/1.1 ms; spatial-resolution = 2.5 × 2.5 × 6 mm; slices = 10; four sinc-gauss pulses with duty-cycle = 0.5, total saturation duration = 701.7 ms; B1 = 1.5 µT; saturation offsets = -5.5 to +5.5 ppm; stepsize = 0.2 ppm; scan duration = 6 min 30 s). The mean z-spectrum from LNs with (n = 20) versus without (n = 22) metastatic involvement were analyzed and a Wilcoxon rank-sum test (significance: p < 0.05) was applied to evaluate differences in B0, B1 , and magnetization transfer ratio (MTR) in differing spectral regions of known proton exchange (nuclear Overhauser effect [NOE], amide, amine, and hydroxyl) between cohorts. RESULTS: No difference in axillary B1 (p = 0.634) or B0 (p = 0.689) was observed between cohorts. Elevated MTR was observed for the NOE (-1.7 ppm; MTR = 0.285 ± 0.075 vs. 0.248 ± 0.039; p = 0.048), amine (+2.5 ppm; MTR = 0.284 ± 0.067 vs. 0.234 ± 0.31; p = 0.005), and hydroxyl (+1 ppm; MTR = 0.394 ± 0.075 vs. 0.329 ± 0.055; p = 0.002) protons in LNs from participants with versus without metastatic involvement. CONCLUSIONS: Findings are consistent with a unique metastatic LN microenvironment detectable by CEST-Dixon and suggest that CEST MRI may have potential for mapping LN metastasis non-invasively in vivo.

Systemic proteome phenotypes reveal defective metabolic flexibility in Mecp2 mutants.

Genes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2. Transcriptomes and proteomes of organs and brain regions from Mecp2-null mice as well as diverse MECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2- and MECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2/MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.

Systemic Proteome Phenotypes Reveal Defective Metabolic Flexibility in Mecp2 Mutants.

Genes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2. Transcriptomes and proteomes of organs and brain regions from Mecp2-null mice as well as diverse MECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2- and MECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2/MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.

Red cell exchange transfusions increase cerebral capillary transit times and may alter oxygen extraction in sickle cell disease.

Persons with sickle cell disease (SCD) suffer from chronic hemolytic anemia, reduced blood oxygen content, and lifelong risk of silent and overt stroke. Major conventional stroke risk factors are absent in most individuals with SCD, yet nearly 50% have evidence of brain infarcts by the age of 30 years, indicating alternative etiologies for ischemia. We investigated whether radiological evidence of accelerated blood water transit through capillaries, visible on arterial spin labeling (ASL) magnetic resonance imaging, reduces following transfusion-induced increases in hemoglobin and relates to oxygen extraction fraction (OEF). Neurological evaluation along with anatomical and hemodynamic imaging with cerebral blood flow (CBF)-weighted pseudocontinuous ASL and OEF imaging with T2 -relaxation-under-spin-tagging were applied in sequence before and after blood transfusion therapy (n = 32) and in a comparator cohort of nontransfused SCD participants on hydroxyurea therapy scanned at two time points to assess stability without interim intervention (n = 13). OEF was calculated separately using models derived from human hemoglobin-F, hemoglobin-A, and hemoglobin-S. Gray matter CBF and dural sinus signal, indicative of rapid blood transit, were evaluated at each time point and compared with OEF using paired statistical tests (significance: two-sided p < 0.05). No significant change in sinus signal was observed in nontransfused participants (p = 0.650), but a reduction was observed in transfused participants (p = 0.034), consistent with slower red cell transit following transfusion. The dural sinus signal intensity was inversely associated with OEF pretransfusion (p = 0.011), but not posttransfusion. Study findings suggest that transfusion-induced increases in total hemoglobin may lengthen blood transit times through cerebral capillaries and alter cerebral OEF in SCD.

Subcutaneous Adipose Tissue Edema in Lipedema Revealed by Noninvasive 3T MR Lymphangiography.

BACKGROUND: Lipedema exhibits excessive lower-extremity subcutaneous adipose tissue (SAT) deposition, which is frequently misidentified as obesity until lymphedema presents. MR lymphangiography may have relevance to distinguish lipedema from obesity or lymphedema. HYPOTHESIS: Hyperintensity profiles on 3T MR lymphangiography can identify distinct features consistent with SAT edema in participants with lipedema. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Participants (48 females, matched for age [mean = 44.8 years]) with lipedema (n = 14), lipedema with lymphedema (LWL, n = 12), cancer treatment-related lymphedema (lymphedema, n = 8), and controls without these conditions (n = 14). FIELD STRENGTH/SEQUENCE: 3T MR lymphangiography (nontracer 3D turbo-spin-echo). ASSESSMENT: Review of lymphangiograms in lower extremities by three radiologists was performed independently. Spatial patterns of hyperintense signal within the SAT were scored for extravascular (focal, diffuse, or not apparent) and vascular (linear, dilated, or not apparent) image features. STATISTICAL TESTS: Interreader reliability was computed using Fleiss Kappa. Fisher's exact test was used to evaluate the proportion of image features between study groups. Multinomial logistic regression was used to assess the relationship between image features and study groups. The odds ratio (OR) and 95% confidence interval (CI) of SAT extravascular and vascular features was reported in groups compared to lipedema. The threshold of statistical significance was P < 0.05. RESULTS: Reliable agreement was demonstrated between three independent, blinded reviewers (P < 0.001). The frequency of SAT hyperintensities in participants with lipedema (36% focal, 36% diffuse), LWL (42% focal, 33% diffuse), lymphedema (62% focal, 38% diffuse), and controls (43% focal, 0% diffuse) was significantly distinct. Compared with lipedema, SAT hyperintensities were less frequent in controls (focal: OR = 0.63, CI = 0.11-3.41; diffuse: OR = 0.05, CI = 0.00-1.27), similar in LWL (focal: OR = 1.29, CI = 0.19-8.89; diffuse: OR = 1.05, CI = 0.15-7.61), and more frequent in lymphedema (focal: OR = 9.00, CI = 0.30-274.12; diffuse: OR = 5.73, CI = 0.18-186.84). DATA CONCLUSION: Noninvasive MR lymphangiography identifies distinct signal patterns indicating SAT edema and lymphatic load in participants with lipedema. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Multimodal neuroimaging in pediatric type 1 diabetes: a pilot multisite feasibility study of acquisition quality, motion, and variability.

Type 1 diabetes (T1D) affects over 200,000 children and is associated with an increased risk of cognitive dysfunction. Prior imaging studies suggest the neurological changes underlying this risk are multifactorial, including macrostructural, microstructural, and inflammatory changes. However, these studies have yet to be integrated, limiting investigation into how these phenomena interact. To better understand these complex mechanisms of brain injury, a well-powered, prospective, multisite, and multimodal neuroimaging study is needed. We take the first step in accomplishing this with a preliminary characterization of multisite, multimodal MRI quality, motion, and variability in pediatric T1D. We acquire structural T1 weighted (T1w) MRI, diffusion tensor MRI (DTI), functional MRI (fMRI), and magnetic resonance spectroscopy (MRS) of 5-7 participants from each of two sites. First, we assess the contrast-to-noise ratio of the T1w MRI and find no differences between sites. Second, we characterize intervolume motion in DTI and fMRI and find it to be on the subvoxel level. Third, we investigate variability in regional gray matter volumes and local gyrification indices, bundle-wise DTI microstructural measures, and N-acetylaspartate to creatine ratios. We find the T1-based measures to be comparable between sites before harmonization and the DTI and MRS-based measures to be comparable after. We find a 5-15% coefficient of variation for most measures, suggesting ~150-200 participants per group on average are needed to detect a 5% difference across these modalities at 0.9 power. We conclude that multisite, multimodal neuroimaging of pediatric T1D is feasible with low motion artifact after harmonization of DTI and MRS.

Presurgical Magnetic Resonance Imaging Indicators of Revascularization Response in Adults With Moyamoya Vasculopathy.

BACKGROUND: Moyamoya is a progressive intracranial vasculopathy, primarily affecting distal segments of the internal carotid and middle cerebral arteries. Treatment may comprise angiogenesis-inducing surgical revascularization; however, lack of randomized trials often results in subjective treatment decisions. HYPOTHESIS: Compensatory presurgical posterior vertebrobasilar artery (VBA) flow-territory reactivity, including greater cerebrovascular reactivity (CVR) and reduced vascular delay time, portends greater neoangiogenic response verified on digital subtraction angiography (DSA) at 1-year follow-up. STUDY TYPE: Prospective intervention cohort. SUBJECTS: Thirty-one patients with moyamoya (26 females; age = 45 ± 13 years; 41 revascularized hemispheres). METHODS: Anatomical MRI, hypercapnic CVR MRI, and DSA acquired presurgically in adult moyamoya participants scheduled for clinically indicated surgical revascularization. One-year postsurgery, DSA was repeated to evaluate collateralization. FIELD STRENGTH: 3 T. SEQUENCE: Hypercapnic T 2 * -weighted gradient-echo blood-oxygenation-level-dependent, T2 -weighted turbo-spin-echo fluid-attenuated-inversion-recovery, T1 -weighted magnetization-prepared-rapid-gradient-echo, and T2 -weighted diffusion-weighted-imaging. ASSESSMENT: Presurgical maximum CVR and response times were evaluated in VBA flow-territories. Revascularization success was determined using an ordinal scoring system of neoangiogenic collateralization from postsurgical DSA by two cerebrovascular neurosurgeons (R.V.C. with 8 years of experience; M.R.F. with 9 years of experience) and one neuroradiologist (L.T.D. with 8 years of experience). Stroke risk factors (age, sex, race, vasculopathy, and diabetes) were recorded. STATISTICAL TESTS: Fisher's exact and Wilcoxon rank-sum tests were applied to compare presurgical variables between cohorts with angiographically confirmed good (>1/3 middle cerebral artery [MCA] territory revascularized) vs. poor (<1/3 MCA territory revascularized) outcomes. SIGNIFICANCE: two-sided P < 0.05. Normalized odds ratios (ORs) were calculated. RESULTS: Criteria for good collateralization were met in 25 of the 41 revascularized hemispheres. Presurgical normalized VBA flow-territory CVR was significantly higher in those with good (1.12 ± 0.13 unitless) vs. poor (1.04 ± 0.05 unitless) outcomes. Younger (OR = -0.60 ± 0.67) and White (OR = -1.81 ± 1.40) participants had highest revascularization success (good outcomes: age = 42 ± 14 years, race = 84% White; poor outcomes: age = 49 ± 11 years, race = 44% White). DATA CONCLUSION: Presurgical MRI-measures of VBA flow-territory CVR are highest in moyamoya participants with better angiographic responses to surgical revascularization. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 4.

Heterozygous LMNA mutation-carrying iPSC lines from three cardiac laminopathy patients.

LMNA-related dilated cardiomyopathy (LMNA-DCM) is caused by pathogenic variants in the LMNA gene and is characterized by left ventricular chamber enlargement, reduced systolic function, and arrhythmia. Here, we generated three human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of three DCM patients carrying the same single heterozygous mutation, c.398 G > A, in LMNA. All lines exhibited normal iPSC morphology, expressed high levels of pluripotency markers, showed normal karyotypes, and could differentiate into the three germ layers. These patient-specific iPSC lines can serve as invaluable tools to model in vitro pathological mechanisms of LMNA-DCM.

Generation of three iPSC lines from dilated cardiomyopathy patients carrying a pathogenic LMNA variant.

LMNA-related dilated cardiomyopathy (DCM) is caused by pathogenic variants in LMNA and is characterized by left ventricular enlargement, reduced systolic function, and arrhythmia. Here, we generated three human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of three DCM patients carrying the same single heterozygous mutation, c.1129C > T, in LMNA. All lines expressed normal iPSC morphology, high levels of pluripotent markers, normal karyotypes, and could differentiate into the three germ layers. These iPSC lines can serve as invaluable tools to model pathological mechanisms of DCM in vitro caused by LMNA mutations.

Physical Therapy in Women with Early Stage Lipedema: Potential Impact of Multimodal Manual Therapy, Compression, Exercise, and Education Interventions.

Background: Lipedema is a distinct adipose disorder from obesity necessitating awareness as well as different management approaches to address pain and optimize quality of life (QoL). The purpose of this proof-of-principle study is to evaluate the therapeutic potential of physical therapy interventions in women with lipedema. Methods and Results: Participants with Stage 1-2 lipedema and early Stage 0-1 lymphedema (n = 5, age = 38.4 ± 13.4 years, body mass index = 27.2 ± 4.3 kg/m2) underwent nine visits of physical therapy in 6 weeks for management of symptoms impacting functional mobility and QoL. Pre- and post-therapy, participants were scanned with 3 Tesla sodium and water magnetic resonance imaging (MRI), underwent biophysical measurements, and completed questionnaires measuring function and QoL (patient-specific functional scale, PSFS, and RAND-36). Pain was measured at each visit using the 0-10 visual analog scale (VAS). Treatment effect was calculated for all study variables. The primary symptomatology measures of pain and function revealed clinically significant post-treatment improvements and large treatment effects (Cohen's d for pain VAS = -2.5 and PSFS = 4.4). The primary sodium MRI measures, leg skin sodium, and subcutaneous adipose tissue (SAT) sodium, reduced following treatment and revealed large treatment effects (Cohen's d for skin sodium = -1.2 and SAT sodium = -0.9). Conclusions: This proof-of-principle study provides support that persons with lipedema can benefit from physical therapy to manage characteristic symptoms of leg pain and improve QoL. Objective MRI measurement of reduced tissue sodium in the skin and SAT regions indicates reduced inflammation in the treated limbs. Further research is warranted to optimize the conservative therapy approach in lipedema, a condition for which curative and disease-modifying treatments are unavailable.

Elevated magnetic resonance imaging measures of adipose tissue deposition in women with breast cancer treatment-related lymphedema.

PURPOSE: Breast cancer treatment-related lymphedema (BCRL) is a common co-morbidity of breast cancer therapies, yet factors that contribute to BCRL progression remain incompletely characterized. We investigated whether magnetic resonance imaging (MRI) measures of subcutaneous adipose tissue were uniquely elevated in women with BCRL. METHODS: MRI at 3.0 T of upper extremity and torso anatomy, fat and muscle tissue composition, and T2 relaxometry were applied in left and right axillae of healthy control (n = 24) and symptomatic BCRL (n = 22) participants to test the primary hypothesis that fat-to-muscle volume fraction is elevated in symptomatic BCRL relative to healthy participants, and the secondary hypothesis that fat-to-muscle volume fraction is correlated with MR relaxometry of affected tissues and BCRL stage (significance criterion: two-sided p < 0.05). RESULTS: Fat-to-muscle volume fraction in healthy participants was symmetric in the right and left sides (p = 0.51); in BCRL participants matched for age, sex, and BMI, fat-to-muscle volume fraction was elevated on the affected side (fraction = 0.732 ± 0.184) versus right and left side in controls (fraction = 0.545 ± 0.221, p < 0.001). Fat-to-muscle volume fraction directly correlated with muscle T2 (p = 0.046) and increased with increasing level of BCRL stage (p = 0.041). CONCLUSION: Adiposity quantified by MRI is elevated in the affected upper extremity of women with BCRL and may provide a surrogate marker of condition onset or severity. CLINICAL TRIAL: NCT02611557.

Generation of three induced pluripotent stem cell lines from hypertrophic cardiomyopathy patients carrying TNNI3 mutations.

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with a prevalence of about 0.2%. HCM is typically caused by mutations in genes encoding sarcomere or sarcomere-associated proteins. Here, we characterized induced pluripotent stem cell (iPSC) lines generated from the peripheral blood mononuclear cells of three HCM patients each carrying c.433C > T, c.610C > T, or c.235C > T mutation in the TNNI3 gene by non-integrated Sendai virus. All of the three lines exhibited normal morphology, expression of pluripotent markers, stable karyotype, and the potential of trilineage differentiation. The cardiomyocytes differentiated from these iPSC lines can serve as useful tools to model HCM in vitro.

Generation of three induced pluripotent stem cell lines from hypertrophic cardiomyopathy patients carrying MYH7 mutations.

MYH7 heterozygous mutations are common genetic causes of hypertrophic cardiomyopathy (HCM). HCM is characterized by hypertrophy of the left ventricle and diastolic dysfunction. We generated three human induced pluripotent stem cell (iPSC) lines from three HCM patients each carrying a single heterozygous mutation in MYH7, c.2167C > T, c.4066G > A, and c.5135G > A, respectively. All lines expressed high levels of pluripotent markers, had normal karyotype, and possessed capability of differentiation into derivatives of the three germ layers, which can serve as valuable tools for modeling HCM in vitro and investigating the pathological mechanisms related to MYH7 mutations.

Preliminary Study of Coping, Perceived Control, and Depressive Symptoms in Youth with Sickle Cell Anemia.

OBJECTIVE: The primary objective of this study was to test perceived controllability of stressors as a moderator of the association between coping and depressive symptoms in children and adolescents with sickle cell anemia (SCA). METHOD: Twenty-eight children and adolescents (Mage = 11.71, SD = 4.31; 60.7% female) with SCA were enrolled. Caregivers provided reports of child and adolescent coping using the Response to Stress Questionnaire (RSQ), perceived control of stressors using the RSQ, and depressive symptoms using the Child Behavior Checklist. Children and adolescents also completed Wechsler assessments of working memory and verbal comprehension. RESULTS: Secondary control coping (i.e., cognitive reappraisal, positive thinking, acceptance, and distraction) was a significant predictor of depressive symptoms such that greater use of secondary control coping was related to fewer reported depressive symptoms when accounting for perceived control of stress and neurocognitive variables. Furthermore, perceived control of peer-related stress was a significant moderator of the association between secondary control coping and depressive symptoms such that there was a significant negative association of secondary control coping with depressive symptoms only for low perceived control. CONCLUSION: Secondary control coping may be particularly helpful for reducing depressive symptoms when adolescents' peer-related stressors are perceived as uncontrollable. Interventions to reduce internalizing problems in this population should consider teaching children and adolescents secondary control coping skills in addition to skills in identifying uncontrollable sources of stress.

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus.

Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders, such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a pathogenic mechanism for neurodevelopmental disorders.SIGNIFICANCE STATEMENT The balance between cytoplasmic protein synthesis and degradation, or cytoplasmic proteostasis, is required for normal synapse function and neurodevelopment. Cytoplasmic and mitochondrial ribosomes are necessary for two compartmentalized, yet interdependent, forms of proteostasis. Proteostasis dependent on cytoplasmic ribosomes is a well-established target of genetic defects that cause neurodevelopmental disorders, such as autism. Here we show that the mitochondrial ribosome is a neurodevelopmentally regulated organelle whose function is required for synapse development and function. We propose that defective mitochondrial proteostasis is a mechanism with the potential to contribute to neurodevelopmental disease.

Safety of 3 Tesla Magnetic Resonance Imaging in Patients with Sickle Cell Disease.

Sickle cell disease (SCD) is a well-characterized hemoglobinopathy affecting more than 20 million individuals worldwide and carries an increased risk of cerebral vasculopathy, cerebral infarct, and stroke. As mechanisms of cerebral infarction in SCD are partly attributable to microvascular vaso-occlusive crises, manifesting as altered cerebral blood flow and associated impaired oxygen delivery, magnetic resonance imaging (MRI) methods that can quickly provide a comprehensive perspective on structural and functional disease status, without exogenous contrast administration or ionizing radiation, have emerged as crucial clinical tools for surveillance. However, early ex vivo MRI work in suspended erythrocytes containing hemoglobin S at 0.35 Tesla (T) suggested that sickled erythrocytes can orient preferentially in the presence of an external magnetic field, and as such, it was suggested that MRI exams in sickle cell hemoglobinopathy could induce vaso-occlusion. While this observation has generally not impacted clinical imaging in individuals with SCD, it has led to resistance for some sickle cell studies within the engineering community among some imaging scientists as this early observation has never been rigorously shown to be unconcerning. Here, we performed MRI at the clinical field strength of 3 T in 172 patients with SCD, which included standard anatomical and angiographic assessments together with gold standard diffusion-weighted imaging (DWI; spatial resolution = 1.8 × 1.8 × 4 mm; b-value = 1000 s/mm2) for acute infarct assessment (performed approximately 20 min after patient introduction to the field isocenter). The presence of vasculopathy, as well as chronic and acute infarcts, was evaluated by two independent board-certified radiologists using standard clinical criteria. In these patients (52.3% female; mean age = 19.6 years; age range = 6-44 years), hematocrit (mean = 25.8%; range = 15-36%), hemoglobin phenotype (87.8% HbSS variant), presence of silent infarct (44.2%), and overt chronic infarct (13.4%) were consistent with a typical SCD population; however, no participants exhibited evidence of acute infarction. These findings are consistent with 3 T MRI not inducing acute infarction or vaso-occlusion in individuals with SCD and suggest that earlier low-field ex vivo work of erythrocytes in suspension is not a sufficient cause to discourage MRI scans in patients with SCD.

Cerebral Hemodynamics and Executive Function in Sickle Cell Anemia.

BACKGROUND AND PURPOSE: Individuals with sickle cell anemia experience cognitive deficits, even in the absence of cerebral infarcts or strokes. This study tested the hypothesis that elevated cerebral blood flow and oxygen extraction fraction are associated with lower executive function in individuals with sickle cell anemia. METHODS: Three-Tesla brain magnetic resonance imaging was performed, including anatomic, gray matter cerebral blood flow, and global oxygen extraction fraction imaging. Executive function was measured using the working memory index from an age-appropriate Wechsler battery and tasks from the National Institutes of Health Toolbox Cognition Battery. Bivariate and multivariate models were examined (significance: P<0.05). RESULTS: Fifty-four participants (age range=6-31 years) with sickle cell anemia were enrolled. Hematocrit was positively related to fluid cognition, cerebral blood flow was inversely related to working memory and inhibitory control, and oxygen extraction fraction was inversely related to processing speed. Associations remained significant in multivariate analyses controlling for age, income, and infarcts. CONCLUSIONS: Elevated cerebral blood flow and oxygen extraction fraction, markers of hemodynamic impairment, are associated with deficits in executive function in individuals with sickle cell anemia.

Choroid plexus perfusion in sickle cell disease and moyamoya vasculopathy: Implications for glymphatic flow.

Cerebrospinal fluid (CSF) and interstitial fluid exchange have been shown to increase following pharmacologically-manipulated increases in cerebral arterial pulsatility, consistent with arterial pulsatility improving CSF circulation along perivascular glymphatic pathways. The choroid plexus (CP) complexes produce CSF, and CP activity may provide a centralized indicator of perivascular flow. We tested the primary hypothesis that elevated cortical cerebral blood volume and flow, present in sickle cell disease (SCD), is associated with fractionally-reduced CP perfusion relative to healthy adults, and the supplementary hypothesis that reduced arterial patency, present in moyamoya vasculopathy, is associated with elevated fractional CP perfusion relative to healthy adults. Participants (n = 75) provided informed consent and were scanned using a 3-Tesla arterial-spin-labeling MRI sequence for CP and cerebral gray matter (GM) perfusion quantification. ANOVA was used to calculate differences in CP-to-GM perfusion ratios between groups, and regression analyses applied to evaluate the dependence of the CP-to-GM perfusion ratio on group after co-varying for age and sex. ANOVA yielded significant (p < 0.001) group differences, with CP-to-GM perfusion ratios increasing between SCD (ratio = 0.93 ± 0.28), healthy (ratio = 1.04 ± 0.32), and moyamoya (ratio = 1.29 ± 0.32) participants, which was also consistent with regression analyses. Findings are consistent with CP perfusion being inversely associated with cortical perfusion.

Reconstructing the heart using iPSCs: Engineering strategies and applications.

Induced pluripotent stem cells (iPSCs) have emerged as a key component of cardiac tissue engineering, enabling studies of cardiovascular disease mechanisms, drug responses, and developmental processes in human 3D tissue models assembled from isogenic cells. Since the very first engineered heart tissues were introduced more than two decades ago, a wide array of iPSC-derived cardiac spheroids, organoids, and heart-on-a-chip models have been developed incorporating the latest available technologies and materials. In this review, we will first outline the fundamental biological building blocks required to form a functional unit of cardiac muscle, including iPSC-derived cells differentiated by soluble factors (e.g., small molecules), extracellular matrix scaffolds, and exogenous biophysical maturation cues. We will then summarize the different fabrication approaches and strategies employed to reconstruct the heart in vitro at varying scales and geometries. Finally, we will discuss how these platforms, with continued improvements in scalability and tissue maturity, can contribute to both basic cardiovascular research and clinical applications in the future.

A Prospective, Longitudinal Magnetic Resonance Imaging Evaluation of Cerebrovascular Reactivity and Infarct Development in Patients With Intracranial Stenosis.

BACKGROUND: Patients with symptomatic atherosclerotic and non-atherosclerotic (i.e., moyamoya) intracranial steno-occlusive disease experience high 2-year infarct rates. PURPOSE: To investigate whether cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) measures may provide biomarkers of 1-to-2-year infarct risk. STUDY TYPE: Prospective, longitudinal study. SUBJECTS: Adult participants (age = 18-85 years) with symptomatic intracranial atherosclerotic disease (N = 26) or non-atherosclerotic (i.e., moyamoya; N = 43) and stenosis ≥50% of a major intracranial artery were initially scanned within 45 days of stroke. Follow-up imaging (target  = 1.5 years) was acquired for new infarct assessment. FIELD STRENGTH/SEQUENCE: 3.0 Tesla with normocapnic arterial spin labeling (ASL) and blood oxygenation level-dependent (BOLD) imaging acquired during an interleaved hypercapnic (3 minutes) and normocapnic (3 minutes) respiratory stimulus. ASSESSMENT: CBF, maximum CVR, and time-to-maximum CVR (i.e., CVRDELAY ) were calculated. Laterality indices (difference between infarcted and contralesional hemispheres divided by sum of absolute values) of metrics at enrollment were contrasted between participants with vs. without new infarcts on follow-up. STATISTICAL TESTS: Laterality indices were compared using non-parametric Wilcoxon tests (significance: two-sided P < 0.05) and effect sizes as Cohen's d. Continuous variables are presented as mean ± SD. RESULTS: New infarcts were observed on follow-up in 15.0% of participants. The laterality index of the CVRDELAY was elevated (P = 0.01) in participants with atherosclerosis with new infarcts (index = 0.13) compared to participants without new infarcts (index = 0.05). DATA CONCLUSION: Elevated CVRDELAY may indicate brain parenchyma at increased risk for new infarcts in patients with symptomatic intracranial atherosclerotic disease treated with standard-of-care medical management. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.