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.

Classifying intracranial stenosis disease severity from functional MRI data using machine learning.

Translation of many non-invasive hemodynamic MRI methods to cerebrovascular disease patients has been hampered by well-known artifacts associated with delayed blood arrival times and reduced microvascular compliance. Using machine learning and support vector machine (SVM) algorithms, we investigated whether arrival time-related artifacts in these methods could be exploited as novel contrast sources to discriminate angiographically confirmed stenotic flow territories. Intracranial steno-occlusive moyamoya patients (n = 53; age = 45 ± 14.2 years; sex = 43 F) underwent (i) catheter angiography, (ii) anatomical MRI, (iii) cerebral blood flow (CBF)-weighted arterial spin labeling, and (iv) cerebrovascular reactivity (CVR)-weighted hypercapnic blood-oxygenation-level-dependent MRI. Mean, standard deviation (std), and 99th percentile of CBF, CVR, CVRDelay, and CVRMax were calculated in major anterior and posterior flow territories perfused by vessels with vs. without stenosis (≥70%) confirmed by catheter angiography. These and demographic variables were input into SVMs to evaluate discriminatory capacity for stenotic flow territories using k-fold cross-validation and receiver-operating-characteristic-area-under-the-curve to quantify variable combination relevance. Anterior circulation CBF-std, attributable to heterogeneous endovascular signal and prolonged arterial transit times, was the best performing single variable and CVRDelay-mean and CBF-std, both reflective of delayed vascular compliance, were a high-performing two-variable combination (specificity = 0.67; sensitivity = 0.75). Findings highlight the relevance of hemodynamic imaging and machine learning for identifying cerebrovascular impairment.

Vessel Wall and Lumen Features in North American Moyamoya Patients.

PURPOSE: To apply intracranial vessel wall imaging (VWI) to determine changes in vessel wall characteristics between North American moyamoya patients and controls, as well as with standard clinical measures of moyamoya disease severity. METHODS: North American moyamoya patients and controls underwent intracranial 3.0 T VWI. Moyamoya patients also underwent digital subtraction angiography (DSA), from which modified Suzuki scores (mSS) were calculated. Lumen and outer vessel wall diameters of the supraclinoid internal carotid arteries (ICAs) and basilar artery on VWI were measured by two readers from which wall thickness was calculated. Controls and moyamoya patients were compared in logistic regression using disease category (moyamoya or none) as the dependent variable and wall thickness, age, gender, and side as the explanatory variables (significance: two-sided p < 0.05). In moyamoya patients, regression was performed with mSS as the dependent variable and wall thickness, age, gender, and side as the explanatory variables. Analyses were repeated for each lumen diameter and outer vessel wall diameter in place of wall thickness. RESULTS: Patients with moyamoya (n = 23, gender = 3/20 male/female; age = 43 ± 12 years) and controls (n = 23, gender = 3/20 male/female, age = 43 ± 13 years) were included. Moyamoya patients showed a significantly smaller ICA lumen and outer vessel wall diameter compared to controls (p < 0.05) but no significant change in vessel wall thickness. Similarly, ICA lumen and outer vessel wall diameters decreased with increasing mSS (p < 0.05). CONCLUSION: Findings suggest decreased ICA lumen and outer vessel wall diameters, but no significant difference in wall thickness, between patients and controls. Lumen and outer vessel wall diameters also decreased with disease severity.

CEST MRI quantification procedures for breast cancer treatment-related lymphedema therapy evaluation.

PURPOSE: To quantify chemical exchange saturation transfer contrast in upper extremities of participants with lymphedema before and after standardized lymphatic mobilization therapy using correction procedures for B0 and B1 heterogeneity, and T1 relaxation. METHODS: Females with (n = 12) and without (n = 17) breast cancer treatment-related lymphedema (BCRL) matched for age and body mass index were scanned at 3.0T MRI. B1 efficiency and T1 were calculated in series with chemical exchange saturation transfer in bilateral axilla (B1 amplitude = 2µT, Δω = ±5.5 ppm, slices = 9, spatial resolution = 1.8 × 1.47 × 5.5 mm3 ). B1 dispersion measurements (B1 = 1-3 µT; increment = 0.5 µT) were performed in controls (n = 6 arms in 3 subjects). BCRL participants were scanned pre- and post-manual lymphatic drainage (MLD) therapy. Chemical exchange saturation transfer amide proton transfer (APT) and nuclear Overhauser effect (NOE) metrics corrected for B1 efficiency were calculated, including proton transfer ratio (PTR'), magnetization transfer ratio asymmetry (MTRasymmetry') , and apparent exchange-dependent relaxation (AREX'). Nonparametric tests were used to evaluate relationships between metrics in BCRL participants pre- versus post-MLD (two-sided P < 0.05 required for significance). RESULTS: B1 dispersion experiments showed nonlinear dependence of Z-values on B1 efficiency in the upper extremities; PTR' showed < 1% mean fractional difference between subject-specific and group-level correction procedures. PTR'APT significantly correlated with T1 (Spearman's rho = 0.57, P < 0.001) and body mass index (Spearman's rho = -0.37, P = 0.029) in controls and with lymphedema stage (Spearman's rho = 0.48, P = 0.017) in BCRL participants. Following MLD therapy, PTR'APT significantly increased in the affected arm of BCRL participants (pre- vs. post-MLD: 0.41 ± 0.05 vs. 0.43 ± 0.03, P = 0.02), consistent with treatment effects from mobilized lymphatic fluid. CONCLUSION: Chemical exchange saturation transfer metrics, following appropriate correction procedures, respond to lymphatic mobilization therapies and may have potential for evaluating treatments in participants with secondary lymphedema.

Choroid plexus perfusion and intracranial cerebrospinal fluid changes after angiogenesis.

Recent studies have provided evidence that cortical brain ischemia may influence choroid plexus function, and such communication may be mediated by either traditional CSF circulation pathways and/or a possible glymphatic pathway. Here we investigated the hypothesis that improvements in arterial health following neoangiogenesis alter (i) intracranial CSF volume and (ii) choroid plexus perfusion in humans. CSF and tissue volume measurements were obtained from T1-weighted MRI, and cortical and choroid plexus perfusion were obtained from perfusion-weighted arterial spin labeling MRI, in patients with non-atherosclerotic intracranial stenosis (e.g. Moyamoya). Measurements were repeated after indirect surgical revascularization, which elicits cortical neoangiogenesis near the revascularization site (n = 23; age = 41.8 ± 13.4 years), or in a cohort of participants at two time points without interval surgeries (n = 10; age = 41.7 ± 10.7 years). Regression analyses were used to evaluate dependence of perfusion and volume on state (time 1 vs. 2). Post-surgery, neither CSF nor tissue volumes changed significantly. In surgical patients, cortical perfusion increased and choroid plexus perfusion decreased after surgery; in participants without surgeries, cortical perfusion reduced and choroid plexus perfusion increased between time points. Findings are discussed in the context of a homeostatic mechanism, whereby arterial health, paravascular flow, and/or ischemia can affect choroid plexus perfusion.

Vessel wall and lumen characteristics with age in healthy participants using 3T intracranial vessel wall magnetic resonance imaging.

BACKGROUND: Intracranial vessel wall imaging (VWI) at a clinical field strength of 3T has become more widely available. However, how vessel measurements change with age and sex, over an age range spanning a typical lifespan, are needed. PURPOSE/HYPOTHESIS: To assess for identifiable changes in arterial wall thickness, outer vessel wall diameter, and lumen diameter with age cross-sectionally in healthy controls without cerebrovascular disease risk factors at the spatial resolution afforded by currently recommended 3T VWI approaches. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Healthy subjects (n = 82; age = 8-79 years). FIELD STRENGTH/SEQUENCE: 3T intracranial VWI, angiography, and T1 -weighted anatomical imaging. ASSESSMENT: Two readers measured lumen and outer wall diameters of the supraclinoid internal carotid artery (ICA) and distal basilar artery. Wall thickness and intraclass correlation coefficients (ICCs) were calculated. STATISTICAL TESTS: Separate linear regressions were performed to understand the relationship between wall measurements (lumen diameter, outer vessel wall diameter, and wall thickness) and age, gender, side (left or right); significance: two-sided P < 0.05. RESULTS: Readers showed excellent agreement for lumen and outer wall diameters (ICC 0.83-094). Linear regression of supraclinoid ICA wall measurements showed a statistically significant increase in wall thickness (P = 0.00051) and outer vessel wall diameter (P = 0.030) with age. ICA lumen and outer vessel wall diameters were statistically greater in males vs. females (lumen diameter 3.69 ± 0.41 vs. 3.54 ± 0.35 mm, P = 0.026; outer wall diameter 5.78 ± 0.52 vs. 5.56 ± 0.44 mm, P = 0.0089) with a trend toward increase in wall thickness (1.05 ± 0.12 vs. 1.01 ± 0.10 mm, P = 0.055). No significant difference was found in basilar artery wall thickness (P = 0.45, P = 0.72), lumen diameter (P = 0.15, P = 0.42), or outer vessel wall diameter (P = 0.34, P = 0.41) with age or gender, respectively. DATA CONCLUSION: Intracranial vessel wall measurements were shown to be consistent between readers. At the available spatial resolution of 3T intracranial VWI sequences, supraclinoid ICA vessel wall thickness and outer vessel wall diameter appear to mildly increase with age. There was no detectable change in basilar artery vessel wall characteristics with age. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1452-1460.

Clinical Use of Cerebrovascular Compliance Imaging to Evaluate Revascularization in Patients With Moyamoya.

BACKGROUND: Surgical revascularization is often performed in patients with moyamoya, however routine tools for efficacy evaluation are underdeveloped. The gold standard is digital subtraction angiography (DSA); however, DSA requires ionizing radiation and procedural risk, and therefore is suboptimal for routine surveillance of parenchymal health. OBJECTIVE: To determine whether parenchymal vascular compliance measures, obtained noninvasively using magnetic resonance imaging (MRI), provide surrogates to revascularization success by comparing measures with DSA before and after surgical revascularization. METHODS: Twenty surgical hemispheres with DSA and MRI performed before and after revascularization were evaluated. Cerebrovascular reactivity (CVR)-weighted images were acquired using hypercapnic 3-Tesla gradient echo blood oxygenation level-dependent MRI. Standard and novel analysis algorithms were applied (i) to quantify relative CVR (rCVRRAW), and decompose this response into (ii) relative maximum CVR (rCVRMAX) and (iii) a surrogate measure of the time for parenchyma to respond maximally to the stimulus, CVRDELAY. Measures between time points in patients with good and poor surgical outcomes based on DSA-visualized neoangiogenesis were contrasted (signed-rank test; significance: 2-sided P < .050). RESULTS: rCVRRAW increases (P = .010) and CVRDELAY decreases (P = .001) were observed pre- vs post-revascularization in hemispheres with DSA-confirmed collateral formation; no difference was found pre- vs post-revascularization in hemispheres with poor revascularization. No significant change in rCVRMAX post-revascularization was observed in either group, or between any of the MRI measures, in the nonsurgical hemisphere. CONCLUSION: Improvement in parenchymal compliance measures post-revascularization, primarily attributed to reductions in microvascular response time, is concurrent with collateral formation visualized on DSA, and may be useful for longitudinal monitoring of surgical outcomes.

3.0 T relaxation time measurements of human lymph nodes in adults with and without lymphatic insufficiency: Implications for magnetic resonance lymphatic imaging.

The purpose of this work was to quantify 3.0 T (i) T1 and T2 relaxation times of in vivo human lymph nodes (LNs) and (ii) LN relaxometry differences between healthy LNs and LNs from patients with lymphatic insufficiency secondary to breast cancer treatment-related lymphedema (BCRL). MR relaxometry was performed over bilateral axillary regions at 3.0 T in healthy female controls (105 LNs from 20 participants) and patients with BCRL (108 LNs from 20 participants). Quantitative T1 maps were calculated using a multi-flip-angle (20, 40, 60°) method with B1 correction (dual-TR method, TR1 /TR2  = 30/130 ms), and T2 maps using a multi-echo (TE  = 9-189 ms; 12 ms intervals) method. T1 and T2 were quantified in the LN cortex and hilum. A Mann-Whitney U-test was applied to compare LN relaxometry values between patients and controls (significance, two sided, p < 0.05). Linear regression was applied to evaluate how LN relaxometry varied with age, BMI, and clinical indicators of disease. LN substructure relaxation times (mean ± standard deviation) in healthy controls were T1 cortex, 1435 ± 391 ms; T1 hilum, 714 ± 123 ms; T2 cortex, 102 ± 12 ms, and T2 hilum, 119 ± 21 ms. T1 of the LN cortex was significantly reduced in the contralateral axilla of BCRL patients compared with the axilla on the surgical side (p < 0.001) and compared with bilateral control values (p < 0.01). The LN cortex T1 asymmetry discriminated cases from controls (p = 0.004) in a multiple linear regression, accounting for age and BMI. Human 3.0 T T1 and T2 relaxation times in axillary LNs were quantified for the first time in vivo. Measured values are relevant for optimizing acquisition parameters in anatomical lymphatic imaging sequences, and can serve as a reference for novel functional and molecular LN imaging methods that require quantitative knowledge of LN relaxation times.

Variable impact of CSF flow suppression on quantitative 3.0T intracranial vessel wall measurements.

BACKGROUND: Flow suppression techniques have been developed for intracranial (IC) vessel wall imaging (VWI) and optimized using simulations; however, simulation results may not translate in vivo. PURPOSE: To evaluate experimentally how IC vessel wall and lumen measurements change in identical subjects when evaluated using the most commonly available blood and cerebrospinal fluid (CSF) flow suppression modules and VWI sequences. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Healthy adults (n = 13; age = 37 ± 15 years) were enrolled. FIELD STRENGTH/SEQUENCE: A 3.0T 3D T1 /proton density (PD)-weighted turbo-spin-echo (TSE) acquisition with post-readout anti-driven equilibrium module, with and without Delay-Alternating-with-Nutation-for-Tailored-Excitation (DANTE) was applied. DANTE flip angle (8-12°) and TSE refocusing angle (sweep = 40-120° or 50-120°) were varied. ASSESSMENT: Basilar artery and internal carotid artery (ICA) wall thicknesses, CSF signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and signal ratio (SR) were assessed. Measurements were made by two readers (radiology resident and board-certified neuroradiologist). STATISTICAL TESTS: A Wilcoxon signed-rank test was applied with corrected two-sided P < 0.05 required for significance (critical P = 0.008, 0.005, and 0.05 for SNR/CNR, SR, and wall thickness, respectively). RESULTS: A TSE pulse sweep = 40-120° and sweep = 50-120° provided similar (P = 0.55) CSF suppression. Addition of the DANTE preparation reduced CSF SNR from 17.4 to 6.7, thereby providing significant (P < 0.008) improvement in CSF suppression. The DANTE preparation also resulted in a significant (P < 0.008) reduction in vessel wall SNR, but variable vessel wall to CSF CNR improvement (P = 0.87). There was a trend for a difference in blood SNR with vs. without DANTE (P = 0.05). The outer vessel wall diameter and wall thickness values were lower (P < 0.05) with (basilar artery 4.45 mm, 0.81 mm, respectively) vs. without (basilar artery 4.88 mm, 0.97 mm, respectively) DANTE 8°. DATA CONCLUSION: IC VWI with TSE sweep = 40-120° and with DANTE flip angle = 8° provides the best CSF suppression and CNR of the approaches evaluated. However, improvements are heterogeneous, likely owing to intersubject vessel pulsatility and CSF flow variations, which can lead to variable flow suppression efficacy in these velocity-dependent modules. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1120-1128.

Tissue Sodium Content is Elevated in the Skin and Subcutaneous Adipose Tissue in Women with Lipedema.

OBJECTIVE: To test the hypothesis that tissue sodium and adipose content are elevated in patients with lipedema; if confirmed, this could establish precedence for tissue sodium and adipose content representing a discriminatory biomarker for lipedema. METHODS: Participants with lipedema (n = 10) and control (n = 11) volunteers matched for biological sex, age, BMI, and calf circumference were scanned with 3.0-T sodium and conventional proton magnetic resonance imaging (MRI). Standardized tissue sodium content was quantified in the calf skin, subcutaneous adipose tissue (SAT), and muscle. Dixon MRI was employed to quantify tissue fat and water volumes of the calf. Nonparametric statistical tests were applied to compare regional sodium content and fat-to-water volume between groups (significance: two-sided P ≤ 0.05). RESULTS: Skin (P = 0.01) and SAT (P = 0.04) sodium content were elevated in lipedema (skin: 14.9 ± 2.9 mmol/L; SAT: 11.9 ± 3.1 mmol/L) relative to control participants (skin: 11.9 ± 2.0 mmol/L; SAT: 9.4 ± 1.6 mmol/L). Relative fat-to-water volume in the calf was elevated in lipedema (1.2 ± 0.48 ratio) relative to control participants (0.63 ± 0.26 ratio; P < 0.001). Skin sodium content was directly correlated with fat-to-water volume (Spearman's rho = 0.54; P = 0.01). CONCLUSIONS: Internal metrics of tissue sodium and adipose content are elevated in patients with lipedema, potentially providing objective imaging-based biomarkers for differentially diagnosing the under-recognized condition of lipedema from obesity.

Treatment of Progressive Herpes Zoster-Induced Vasculopathy with Surgical Revascularization: Effects on Cerebral Hemodynamics.

BACKGROUND: Herpes zoster ophthalmicus (HZO) is caused by reactivation of the herpes simplex virus in the trigeminal nerve. HZO-initiated cerebral vasculopathy is well characterized; however, there are no documented cases that report the efficacy of surgical revascularization for improving cerebral hemodynamics following progressive HZO-induced vasculopathy. We present a case in which quantitative anatomic and hemodynamic imaging were performed longitudinally before and after surgical revascularization in a patient with HZO and vasculopathic changes. CASE DESCRIPTION: A 57-year-old female with history of right-sided HZO presented with left-sided hemiparesis and dysarthria and multiple acute infarcts. Angiography performed serially over a 2-month duration revealed progressive middle cerebral artery stenosis, development of new moyamoya-like lenticulostriate collaterals, and evidence of fibromuscular dysplasia in cervical portions of the internal carotid artery. Hemodynamic imaging revealed right hemisphere decreased blood flow and cerebrovascular reserve capacity. In addition to medical therapy, right-sided surgical revascularization was performed with the intent to reestablish blood flow. Follow-up imaging 13 months post revascularization demonstrated improved blood flow and vascular reserve capacity in the operative hemisphere, which paralleled symptom resolution. CONCLUSIONS: HZO can lead to progressive, symptomatic intracranial stenoses. This report suggests that surgical revascularization techniques can improve cerebral hemodynamics and symptomatology in patients with aggressive disease when medical management is unsuccessful; similar procedures could be considered in managing HZO patients with advanced or progressive vasculopathy.

Lymphedema evaluation using noninvasive 3T MR lymphangiography.

PURPOSE: To exploit the long 3.0T relaxation times and low flow velocity of lymphatic fluid to develop a noninvasive 3.0T lymphangiography sequence and evaluate its relevance in patients with lymphedema. MATERIALS AND METHODS: A 3.0T turbo-spin-echo (TSE) pulse train with long echo time (TEeffective = 600 msec; shot-duration = 13.2 msec) and TSE-factor (TSE-factor = 90) was developed and signal evolution simulated. The method was evaluated in healthy adults (n = 11) and patients with unilateral breast cancer treatment-related lymphedema (BCRL; n = 25), with a subgroup (n = 5) of BCRL participants scanned before and after manual lymphatic drainage (MLD) therapy. Maximal lymphatic vessel cross-sectional area, signal-to-noise-ratio (SNR), and results from a five-point categorical scoring system were recorded. Nonparametric tests were applied to evaluate study parameter differences between controls and patients, as well as between affected and contralateral sides in patients (significance criteria: two-sided P < 0.05). RESULTS: Patient volunteers demonstrated larger lymphatic cross-sectional areas in the affected (arm = 12.9 ± 6.3 mm2 ; torso = 17.2 ± 15.6 mm2 ) vs. contralateral (arm = 9.4 ± 3.9 mm2 ; torso = 9.1 ± 4.6 mm2 ) side; this difference was significant both for the arm (P = 0.014) and torso (P = 0.025). Affected (arm: P = 0.010; torso: P = 0.016) but not contralateral (arm: P = 0.42; torso: P = 0.71) vessel areas were significantly elevated compared with control values. Lymphatic cross-sectional areas reduced following MLD on the affected side (pre-MLD: arm = 8.8 ± 1.8 mm2 ; torso = 31.4 ± 26.0 mm2 ; post-MLD: arm = 6.6 ± 1.8 mm2 ; torso = 23.1 ± 24.3 mm2 ). This change was significant in the torso (P = 0.036). The categorical scoring was found to be less specific for detecting lateralizing disease compared to lymphatic-vessel areas. CONCLUSION: A 3.0T lymphangiography sequence is proposed, which allows for upper extremity lymph stasis to be detected in ∼10 minutes without exogenous contrast agents. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1349-1360.