A 3D-printed phantom for quality-controlled reproducibility measurements of arterial spin labeled perfusion.

PURPOSE: To develop a portable MR perfusion phantom for quality-controlled assessment and reproducibility of arterial spin labeled (ASL) perfusion measurement. METHODS: A 3D-printed perfusion phantom was developed that mimics the branching of arterial vessels, capillaries, and a chamber containing cellulose sponge representing tissue characteristics. A peristaltic pump circulated distilled water through the phantom, and was first evaluated at 300, 400, and 500 mL/min. Longitudinal reproducibility of perfusion was performed using 2D pseudo-continuous ASL at 20 post-label delays (PLDs, ranging between 0.2 and 7.8 s at 0.4-s intervals) over a period of 16 weeks, with three repetitions each week. Multi-PLD data were fitted into a general kinetic model for perfusion quantification (f) and arterial transit time (ATT). Intraclass correlation coefficient was used to assess intersession reproducibility. RESULTS: MR perfusion signals acquired in the 3D-printed perfusion phantom agreed well with the experimental conditions, with progressively increasing signal intensities and decreasing ATT for pump flow rates from 300 to 500 mL/min. The perfusion signal at 400 mL/min and the general kinetic model-derived f and ATT maps were similar across all PLDs for both intrasession and intersession reproducibility. Across all 48 experimental time points, the average f was 75.55 ± 3.83 × 10-3 mL/mL/s, the corresponding ATT was 2.10 ± 0.20 s, and the T1 was 1.84 ± 0.102 s. Intraclass correlation coefficient was 0.92 (95% confidence interval 0.83-0.97) for f, 0.96 (0.91-0.99) for ATT, and 0.94 (0.88-0.98) for T1 , demonstrating excellent reproducibility. CONCLUSION: A simple, portable 3D-printed perfusion phantom with excellent reproducibility of 2D pseudo-continuous ASL measurements was demonstrated that can serve for quality-controlled and reliable measurements of ASL perfusion.

In vivo MRS measurement of 2-hydroxyglutarate in patient-derived IDH-mutant xenograft mouse models versus glioma patients.

PURPOSE: To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS: Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS: The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION: The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.

Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma.

Purpose Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. Results Quantitative 2HG MRS was technically and biologically reproducible. 2HG concentration > 1 mM could be reliably detected with high confidence. During the period of indolent disease, 2HG concentration varied by less than ± 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively correlated with tumor cellularity and significantly differed between high- and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. The magnitude and time course of the decrease in 2HG concentration and magnitude of the decrease in tumor volume did not differ between oligodendrogliomas treated with temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. Conclusion 2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas.

¹H MRS characterization of neurochemical profiles in orthotopic mouse models of human brain tumors.

Glioblastoma (GBM), the most common primary brain tumor, is resistant to currently available treatments. The development of mouse models of human GBM has provided a tool for studying mechanisms involved in tumor initiation and growth as well as a platform for preclinical investigation of new drugs. In this study we used (1) H MR spectroscopy to study the neurochemical profile of a human orthotopic tumor (HOT) mouse model of human GBM. The goal of this study was to evaluate differences in metabolite concentrations in the GBM HOT mice when compared with normal mouse brain in order to determine if MRS could reliably differentiate tumor from normal brain. A TE =19 ms PRESS sequence at 9.4 T was used for measuring metabolite levels in 12 GBM mice and 8 healthy mice. Levels for 12 metabolites and for lipids/macromolecules at 0.9 ppm and at 1.3 ppm were reliably detected in all mouse spectra. The tumors had significantly lower concentrations of total creatine, GABA, glutamate, total N-acetylaspartate, aspartate, lipids/macromolecules at 0.9 ppm, and lipids/macromolecules at 1.3 ppm than did the brains of normal mice. The concentrations of glycine and lactate, however, were significantly higher in tumors than in normal brain.

Measurement of regional variation of GABA in the human brain by optimized point-resolved spectroscopy at 7 T in vivo.

The (1)H resonances of γ-aminobutyric acid (GABA) in the human brain in vivo are extensively overlapped with the neighboring abundant resonances of other metabolites and remain indiscernible in short-TE MRS at 7 T. Here we report that the GABA resonance at 2.28 ppm can be fully resolved by means of echo time optimization of a point-resolved spectroscopy (PRESS) scheme. Following numerical simulations and phantom validation, the subecho times of PRESS were optimized at (TE, TE2) = (31, 61) ms for detection of GABA, glutamate (Glu), glutamine (Gln), and glutathione (GSH). The in vivo feasibility of the method was tested in several brain regions in nine healthy subjects. Spectra were acquired from the medial prefrontal, left frontal, medial occipital, and left occipital brain and analyzed with LCModel. Following the gray and white matter (GM and WM) segmentation of T1 -weighted images, linear regression of metabolite estimates was performed against the fractional GM contents. The GABA concentration was estimated to be about seven times higher in GM than in WM. GABA was overall higher in frontal than in occipital brain. Glu was about twice as high in GM as in WM in both frontal and occipital brain. Gln was significantly different between frontal GM and WM while being similar between occipital GM and WM. GSH did not show significant dependence on tissue content. The signals from N-acetylaspartylglutamate were clearly resolved, giving the concentration more than 10 times higher in WM than in GM. Our data indicate that the PRESS TE = 92 ms method provides an effective means for measuring GABA and several challenging J-coupled spin metabolites in human brain at 7 T.

Urinary albumin to creatinine ratio as potential biomarker for cerebral microvascular disease.

Elevated urinary albumin to creatinine ratio (ACR) and white matter hyperintensity (WMH) volume seen on brain MRI are measures of microvascular disease which may have shared susceptibility to metabolic and vascular insults. We hypothesized that elevated ACR may be useful as inexpensive biomarker to predict presence of cerebral microvascular disease. We assessed the association between ACR at study entry and subsequent WMH volume. We evaluated pulse pressure, mean arterial pressure, hypertension duration, waist circumference, fasting glucose, glomerular filtration rate (GFR) and C-reactive protein (CRP) as potential mediators and diabetes as a moderator of the association between ACR and WMH. Data were collected at study entry and at follow-up approximately 7 years later in a multiethnic population sample of 1281 participants (mean age = 51, SD = 9.5) from Dallas County. Overall, ACR differences were only marginally (p = 0.05) associated with subsequent WMH. In mediator analysis, however, ACR differences related specifically to arterial pulsatility(ß = 0.010, bootstrap 95% Confidence Interval (CI): 0.002 to 0.021) and waist circumference (ß = -0.004, bootstrap 95% CI: -0.011 to -0.001) were significantly associated with WMH. ACR differences related to serum glucose and CRP were not associated with WMH. ACR evaluated at the same time as WMH had a higher level of significance (p < 0.001) indicating greater utility in predicting current cerebrovascular insults.

Effect of normal aging versus hypertension, abnormal body mass index, and diabetes mellitus on white matter hyperintensity volume.

BACKGROUND AND PURPOSE: The natural history of white matter hyperintensity (WMH) progression resulting from normal aging versus comorbid vascular insults remains unclear. Therefore we investigated age-related differences in WMH volumes among a group with comorbid hypertension, abnormal body mass index, and diabetes mellitus to a normal aging group drawn from the same population lacking any of these comorbidities. METHODS: WMH volumes were acquired using 3T MRI for 2011 Dallas Heart Study participants. The slope of the WMH versus age regression was compared between normal and comorbidity groups<50 and ≥50 years of age where a change in slope was demonstrated. RESULTS: Aging was linearly associated with greater log WMH volume for both normal (P=0.02) and comorbidity (P<0.0001) groups. Beyond 50 years of age, more rapid increases in WMH volumes for age were seen in the group with comorbidities (P<0.0001) but not in the normal group (P=0.173). The between-group difference in slope of expected WMH for age was significantly greater in the comorbidity groups≥50 years of age (P=0.0008) but not <50 years of age (P=0.752). CONCLUSIONS: After 50 years of age, but not before, comorbid hypertension, obesity, and diabetes mellitus were associated with significantly larger WMH volumes for age compared with a normal aging group lacking these conditions. These results support the assertion that age-related differences in WMH volumes are significantly increased in the presence of comorbidities, but the effect is only detectable after 50 years of age.

In vivo detection of citrate in brain tumors by 1H magnetic resonance spectroscopy at 3T.

PURPOSE: To test whether citrate is elevated in adult patients with gliomas using (1)H magnetic resonance spectroscopy (MRS) at 3T in vivo. METHODS: Thirty-four adult patients were enrolled in the study, including six subjects with glioblastomas, eight subjects with astrocytomas (World Health Organization grade 3, n = 5; grade 2, n = 3), and 20 subjects with oligodendrogliomas (grade 3, n = 5; grade 2, n = 15). Five healthy volunteers were studied for baseline citrate data. Single-voxel localized spectra were collected with point-resolved spectroscopy (PRESS) echo times of 35 and 97 ms and were analyzed with LCModel software using numerically calculated basis spectra that included the effects of the PRESS radiofrequency and gradient pulses. RESULTS: Citrate was not measurable by MRS in healthy brain but was detected in tumor patients at both echo times. The citrate concentration was estimated to be as high as 1.8 mM with reference to water at 42 M, with Cramér-Rao lower bounds (CRLB) as low as 5%. The mean citrate level was 0.7 ± 0.4 mM (mean ± SD, n = 32) with a median CRLB of ∼12%. No correlation was identified between citrate concentration and tumor grade or histological type. CONCLUSION: Citrate was increased in the majority of gliomas in adult patients. The elevated citrate in our data indicates an altered metabolic state of tumor relative to healthy brain.

White matter hyperintensities: use of aortic arch pulse wave velocity to predict volume independent of other cardiovascular risk factors.

PURPOSE: To evaluate the relationship between pulse wave velocity (PWV) from the aortic arch and subsequent cerebral microvascular disease independent of other baseline cardiovascular risk factors among the participants in the multiethnic Dallas Heart Study. MATERIALS AND METHODS: Each subject gave written consent to participate in this HIPAA-compliant, institutional review board-approved prospective study. Aortic arch PWV was measured with phase-contrast magnetic resonance (MR) imaging in a population sample (n = 1270) drawn from the probability-based Dallas Heart Study. Seven years later, the volume of white matter hyperintensities (WMHs) was determined from brain MR images. Linear regression was conducted with aortic arch PWV, 15 other cardiovascular risk factors, and age, sex, and ethnicity included as predictors of WMH. The authors implemented a smoothly clipped absolute deviation-penalized variable selection method to evaluate an optimal predictive risk factor model. RESULTS: Aortic arch PWV helped predict WMH volume independent of the other demographic and cardiovascular risk factors (regression coefficient: 0.29; standard error: 0.06; 95% confidence interval: 0.17, 0.42; P < .0001). The optimal predictor variables of subsequent WMH volume adjusted for sex and ethnicity included aortic arch PWV, age, systolic blood pressure, hypertension treatment, and congestive heart failure. The authors estimated that a 1% increase in aortic arch PWV (in meters per second) is related to a 0.3% increase in subsequent WMH volume (in milliliters) when all other variables in the model are held constant. CONCLUSION: Aortic arch PWV measured with phase-contrast MR imaging is a highly significant independent predictor of subsequent WMH volume, with a higher standardized effect than any other cardiovascular risk factor assessed except for age. In an optimal predictive model of subsequent WMH burden, aortic arch PWV provides a distinct contribution along with systolic blood pressure, hypertension treatment, congestive heart failure, and age.

Automated quantification of white matter disease extent at 3 T: comparison with volumetric readings.

PURPOSE: To develop and validate an algorithm to automatically quantify white matter hyperintensity (WMH) volume. MATERIALS AND METHODS: Images acquired as part of the Dallas Heart Study, a multiethnic, population-based study of cardiovascular health, were used to develop and validate the algorithm. 3D magnetization prepared rapid acquisition gradient echo (MP-RAGE) and 2D fluid-attenuated inversion recovery (FLAIR) images were acquired from 2082 participants. Images from 161 participants (7.7% of the cohort) were used to set an intensity threshold to maximize the agreement between the algorithm and a qualitative rating made by a radiologist. The resulting algorithm was run on the entire cohort and outlier analyses were used to refine the WMH volume measurement. The refined, automatic WMH burden estimate was then compared to manual quantitative measurements of WMH volume in 28 participants distributed across the range of volumes seen in the entire cohort. RESULTS: The algorithm showed good agreement with the volumetric readings of a trained analyst: the Spearman's Rank Order Correlation coefficient was r = 0.87. Linear regression analysis showed a good correlation WMHml[automated] = 1.02 × WMHml[manual] - 0.48. Bland-Altman analysis showed a bias of 0.34 mL and a standard deviation of 2.8 mL over a range of 0.13 to 41 mL. CONCLUSION: We have developed an algorithm that automatically estimates the volume of WMH burden using an MP-RAGE and a FLAIR image. This provides a tool for evaluating the WMH burden of large populations to investigate the relationship between WMH burden and other health factors.