Vascular volume and blood-brain barrier permeability measured by dynamic contrast enhanced MRI in hippocampus and cerebellum of patients with MCI and normal controls

PURPOSE: To measure the cerebrovascular volume and blood-brain barrier (BBB) permeability indices in hippocampus and cerebellum of patients with mild cognitive impairment (MCI) using dynamic contrast-enhanced MRI (DCE-MRI), and compare to that of normal controls. MATERIALS AND METHODS: A total of 11 MCI subjects and 11 healthy elderly controls participated in this prospective study. DCE-MRI was performed to measure the contrast enhancement kinetics. The early enhancement percentage (at 50 seconds after injection) was defined as the vascular volume index, and the ratio between the four to five-minute enhancement relative to the 50-second enhancement was defined as the BBB permeability index. RESULTS: The enhancement kinetics measured from hippocampus of MCI individuals demonstrated a lower magnitude and slower decay than healthy controls, suggesting that they had a smaller vascular volume (significant in the right side; P <0.001) and a higher BBB permeability (not reaching significance level). The vascular volume index was significantly correlated with naming ability (P 0.05). CONCLUSION: These results suggest that changes in cerebrovasculature may occur in hippocampus of MCI. DCE-MRI may provide a noninvasive means to measure the subtle BBB leakage associated with the cerebrovascular pathology commonly found in Alzheimer's disease.     

Effect of vitreous fluidity on the measurement of blood-retinal barrier permeability using contrast-enhanced MRI

Breakdown of the blood-retinal barrier (BRB), frequently an early clinical sign in retinopathy, can be accurately determined using contrast-enhanced MRI. However, increased vitreous fluidity with age and disease may affect the accuracy of the MRI method. We compared the permeability surface area product per area of leaky retina in eyes with normal vitreous (5.42 ± 0.48 × 10^?4 cm/min, mean ± SEM, n = 5) to the contralateral gas-compressed vitrectomized eyes (5.41 ± 0.54 × 10^?4 cm/min, n = 5). The effect of vitrectomy was not significant (P = 0.325) using a Wilcoxon matched pairs signed rank test on the signed differences of the PS' values.     

高血糖大鼠血脑屏障的超微形态及免疫组化研究

目的探讨糖尿病的慢性高血糖对血脑屏障(BBB)超微形态及其内皮细胞ICAM-1表达的影响。方法采用SD大鼠建立高血糖模型。以透射电镜和免疫组化方法动态观察3天～8个月不同时程高血糖条件下,BBB超微结构的改变及其内皮细胞ICAM-1的表达。结果高血糖大鼠3天～2个月时,BBB改变不明显,有少量ICAM-1表达;3个月时出现明显的BBB改变,ICAM-1大量表达;6～8个月时改变继续加重,ICAM-1仍保持明显表达,范围更广。对照组BBB无改变及内皮细胞ICAM-1无表达。结论长期高血糖能导致大鼠BBB形态异常和内皮细胞ICAM-1表达增加。后者可能是高血糖导致脑组织毛细血管结构及功能异常的重要病理学基础。     

聚乙二醇修饰对尿激酶原性质的影响

为了延长尿激酶原的半衰期，采用聚乙二醇５０００（ＰＥＧ５０００）对该酶进行了修饰，结果表明，尿激酶原经ＰＥＧ修饰后，在兔体内的半衰期延长了９￣１３倍，同时酶活性也有损失，溶酰胺活性保持６２％，溶纤活性保持３．８％￣１０％。     

Quantitative cartilage degeneration associated with spontaneous osteoarthritis in a guinea pig model

Purpose:

To determine (i) the feasibility and intra‐ and inter‐scan reproducibility of T_1ρ MRI in assessing cartilage degeneration in a guinea pig model with naturally occurring joint disease that closely mimics human osteoarthritis (OA), (ii) demonstrate the sensitivity of T_1ρ MRI in assessing the age dependent cartilage degeneration in OA progression as compared to histopathological changes.

Materials and Methods:

Duncan‐Hartley guinea pigs were obtained at various ages and maintained under an IACUC approved protocol. The left hind stifle joint was imaged using T_1ρ MRI on a 9.4 Tesla Varian horizontal 20 cm bore scanner using a custom surface coil. Reproducibility of T_1ρ MRI was assessed using 4‐month‐old guinea pigs (N = 3). Three age cohorts; 3 month (N = 8), 5 month (N = 6), and 9 month (N = 5), were used to determine the age‐dependent osteoarthritic changes as measured by T_1ρ MRI. Validation of age‐dependent cartilage degeneration was confirmed by histology and Safranin‐O staining.

Results:

T_1ρ values obtained in the cartilage of the stifle joint in guinea pigs were highly reproducible with an inter‐scan mean coefficient of variation (CV) of 6.57% and a maximum intra‐scan CV of 9.29%. Mean cartilage T_1ρ values in animals with late stage cartilage degeneration were 56.3–56.9 ms (5–9 month cohorts) were both significantly (P < 0.01) higher than that obtained from 3‐month‐old cohort (44 ms) demonstrating an age‐dependent variation. T_1ρ was shown to be significantly greater than T₂. T_1ρ dispersion was observed in this animal model for the first time showing an increase of 45% between 500 Hz and 1500 Hz spin‐locking frequency. Cartilage thickness measurements were calculated from single mid‐coronal histology sections from same animals used for T_1ρ MRI. Thickness calculations showed insignificant differences between 3‐ and 5‐month cohorts and was significantly decreased by 9 months of age (P < 0.01). A moderate correlation (R² = 0.45) existed between T_1ρ values and signal intensity of Safranin‐O stain.

Conclusion:

The data presented demonstrate that T_1ρ MRI is highly reproducible in this spontaneous model of OA and may serve as a noninvasive tool to characterize joint cartilage degeneration during OA. Age‐dependent changes, verified with histological measurements of proteoglycan loss, correlated with T_1ρ across different age groups. T_1ρ has adequate dynamic range and is sensitive to detect and track the progression of cartilage degeneration in the guinea pig model before gross anatomical changes such as cartilage thinning has occurred. This study presents a technological advancement that would permit longitudinal studies of evaluating disease‐modifying therapies useful for treating human OA. J. Magn. Reson. Imaging 2012;35:891–898. © 2011 Wiley Periodicals, Inc.     

Synchronized inversion recovery-spin echo sequences for precise in vivo T1 measurement of human myocardium: A pilot study on 22 healthy subjects

An ECG-triggered, two-sequence MRI technique is proposed for the precise measurement of proton T₁ relaxation times of the human myocardium at a field strength of 0.5 T. The combination of an inversion recovery (IR) sequence and a spin echo (SE) sequence is not new. It is, however, rarely used in quantitative in vivo cardiac studies. Our approach employs a synchronization of the 90° read pulse to the systolic period. In a study of 22 healthy volunteers, the globally measured T₁ value was estimated to be 714 ± 23 ms. Four of the volunteers also underwent additional imaging scans for the purposes of reproducibility assessment. The T₁ precision was found to be 3.9 ± 1.1% for the IR/SE combination and 16.9 ± 5.3% for a combination of SE sequences. Total imaging time for the IR and SE sequences was 19.2 ± 3.0 mins. The relative rapidity of this classic technique and the T₁ precision obtained give this technique an obvious application in the discrimination of normal and diseased myocardium. In the same study, valuable supplementary tissue characterization is provided by T₂, calculated from the SE sequence. T₂ was evaluated to be 50 ± 3 ms.     

MRI measurement of change in vascular parameters in the 9L rat cerebral tumor after dexamethasone administration

PURPOSE: To demonstrate in the rat 9L cerebral tumor model that repeated MRI measurements can quantitate acute changes in the blood-brain distribution of Gadomer after dexamethasone administration. MATERIALS AND METHODS: A total of 16 Fischer 344 rats were studied at 7T, 15 days after cerebral implantation of a 9L tumor. MRI procedures employed a T-One by Multiple Read Out Pulses (TOMROP) sequence to estimate R(1) (R(1) = 1/T(1)) at 145-second intervals before and after administration of Gadomer (Bayer), a macromolecular contrast agent (CA). Two baseline studies preceded Gadomer administration and 10 subsequent R(1) maps tracked CA concentration in blood and brain for 25 minutes. Thereafter, either dexamethasone (N = 10) or normal saline (N = 6) was administered intravenously. A total of 90 minutes later a second series of 12 TOMROP measurements of Gadomer distribution was performed. The influx constant, K(1), plasma distribution volume, v(D), backflux constant, k(b), and interstitial space, v(e), were determined, and the test-retest differences of each of four vascular parameters were calculated. RESULTS: Dexamethasone decreased K(1) approximately 60% (P = 0.02), lowered k(b) and v(D) (P = 0.03 and P < 0.01, respectively), and marginally but insignificantly decreased v(e). CONCLUSION: This noninvasive MRI technique can detect drug effects on blood-brain transfer constants of CAs within two hours of administration.     

A MRI spatial mapping technique for microvascular permeability and tissue blood volume based on macromolecular contrast agent distribution

A rapid and automated method for two-dimensional spatial depiction (mapping) of quantitative physiological tissue characteristics derived from contrast enhanced MR imaging was developed and tested in disease models of cancer, inflammation, and myocardial reperfusion injury. Specifically, an established two-compartment kinetic model of unidirectional mass transport was implemented on a pixel-by-pixel basis to generate maps of tissue permeability surface area product (PS) and fractional blood volume (BV) based on dynamic MRI intensity data after administration of albumin-(Gd-DTPA)₃₀, a prototype macromolecular contrast medium (MMCM) designed for blood pool enhancement. Maps of PS and BV in disease models of adenocarcinoma, intramuscular abscess inflammation, and myocardial reperfusion injury clearly depicted zones of increased permeability (up to approximately 500.μl/cc/h-compared to <25 μl/cc/h in normal tissues). As revealed on PS maps, the rank ordering of studied permeability abnormalities was reperfusion injury > inflammation > tumors. A rapid, automated mapping technique derived from dynamic contrast-enhanced MRI data can be used to facilitate the identification and characterization of pathophysiologic abnormalities, specifically relative increases in blood volume and/or microvascular permeability.     

Precision in measurements of perfusion and microvascular permeability with T1-weighted dynamic contrast-enhanced MRI.

Dynamic contrast-enhanced MRI is used to estimate microvascular parameters by tracer kinetics analysis. The time for the contrast agent to travel from the artery to the tissue of interest (bolus arrival time (BAT)) is an important parameter that must be measured in such studies because inaccurate estimates or neglect of BAT contribute to inaccuracy in model fitting. Furthermore, although the precision with which these parameters are estimated is very important, it is rarely reported. To address these issues, two investigations were undertaken. First, simulated data were used to validate an independent method for estimation of BAT. Second, the adiabatic approximation to the tissue homogeneity model was fitted to experimental data acquired in prostate and muscle tissue of 22 patients with prostate cancer. A bootstrap error analysis was performed to estimate the precision of parameter estimates. The independent method of estimating BAT was found to be more accurate and precise than a model-fitting approach. Estimated precisions for parameters measured in the prostate gland were 14% for extraction fraction (median coefficient of variation), 19% for blood flow, 28% for permeability-surface area product, 35% for volume of the extravascular-extracellular space, and 36% for blood volume. Techniques to further reduce uncertainty are discussed.     

Small bowel MRI: comparison of a polyethylene glycol preparation and water as oral contrast media

PURPOSE: To compare water and a polyethylene glycol (PEG) preparation as potential oral contrast media for magnetic resonance imaging (MRI) of the small bowel. MATERIALS AND METHODS: Twenty-two healthy volunteers underwent separate MRI examinations after drinking up to two liters of water or PEG preparation. Small bowel images were obtained every 10 minutes for at least two hours using breath-hold single shot half-Fourier imaging, including both thick section projection and thin section images. Examinations were evaluated by two radiologists in consensus, blinded to the volunteer and contrast details, for arrival at the terminal ileum, transit time, and demonstration of small bowel segments. RESULTS: The PEG preparation was significantly better than water at reaching the terminal ileum (PEG 21/22 volunteers [95.45%], water 14/22 volunteers [63.6%], P = 0.04). There was no significant difference in the mean transit time (water 51 +/- 48 minutes, PEG 37.7 +/- 22 minutes) or in the demonstration of the stomach, duodenum, and jejunum, but the PEG preparation was significantly better at demonstrating the ileum (P = 0.005) and terminal ileum (P = 0.002). CONCLUSION: A PEG preparation is significantly better than water as an oral contrast medium for demonstrating the distal small bowel during breath-hold T2-weighted MRI.     

Positive effects of polyethylene glycol conjugation to generation-4 polyamidoamine dendrimers as macromolecular MR contrast agents.

Macromolecules conjugated with polyethylene glycol (PEG) acquire more hydrophilicity, resulting in a longer half-life in circulation and lower immunogenicity. Two novel conjugates for MRI contrast agents were synthesized from a generation-4 polyamidoamine dendrimer (G4D), 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), and one or two PEG molecules with a molecular weight of 20000 Da (PEG(2)-G4D-(1B4M-Gd)(62) (MW: 96 kD), PEG(1)-G4D-(1B4M-Gd)(63) (MW: 77 kD)). Their pharmacokinetics, excretion, and properties as vascular MRI contrast agents were evaluated and compared with those of G4D-(1B4M-Gd)(64) (MW: 57 kD). PEG(2)-G4D-(1B4M-Gd)(62) remained in the blood significantly longer and accumulated significantly less in the liver and kidney than the other two preparations (P < 0.01). Although the blood clearance was slower, PEG(2)-G4D-(1B4M-Gd)(62) was excreted more readily without renal retention than the other two preparations. In conclusion, the positive effects of PEG conjugation on a macromolecular MRI contrast agent were found to be prolonged retention in the circulation, increased excretion, and decreased accumulation in the organs.     

7 Tesla MR imaging of the human eye in vivo

Purpose:

To develop a protocol which optimizes contrast, resolution and scan time for three‐dimensional (3D) imaging of the human eye in vivo using a 7 Tesla (T) scanner and custom radio frequency (RF) coil.

Materials and Methods:

Initial testing was conducted to reduce motion and susceptibility artifacts. Three‐dimensional FFE and IR‐TFE images were obtained with variable flip angles and TI times. T₁ measurements were made and numerical simulations were performed to determine the ideal contrast of certain ocular structures. Studies were performed to optimize resolution and signal‐to‐noise ratio (SNR) with scan times from 20 s to 5 min.

Results:

Motion and susceptibility artifacts were reduced through careful subject preparation. T₁ values of the ocular structures are in line with previous work at 1.5T. A voxel size of 0.15 × 0.25 × 1.0 mm³ was obtained with a scan time of approximately 35 s for both 3D FFE and IR‐TFE sequences. Multiple images were registered in 3D to produce final SNRs over 40.

Conclusion:

Optimization of pulse sequences and avoidance of susceptibility and motion artifacts led to high quality images with spatial resolution and SNR exceeding prior work. Ocular imaging at 7T with a dedicated coil improves the ability to make measurements of the fine structures of the eye. J. Magn. Reson. Imaging 2009;30:924–932. © 2009 Wiley‐Liss, Inc.     

Quantitative regional blood volume studies in rat myocardium in Vivo

Many pathophysiological processes in the myocardium are in close relation to changes of the regional blood volume and regional myocardial blood flow or perfusion. Only few methods exist to obtain quantitative values for these parameters. Quantitative regional blood volume (RBV) studies in rat myocardium are presented using snapshot fast low angle shot (FLASH) inversion recovery T₁ measurements with two different blood pool contrast agents, gadolinium diethylenetriamin-opentaacetic acid (Gd-DTPA) albumin and Gd-DTPA polyly-sine. In contrast to previous attempts, each snapshot FLASH image acquisition was ECG-triggered under breathhold conditions. To measure relaxation times shorter than a heart cycle, each T₁ sequence was repeated two times with different delays between inversion pulse and first image acquisition. The experiments were performed on a Bruker Biospec 70/21 using a homogeneous transmitter coil and a circularly polarized surface receiver coil, a special ECG trigger unit, and a respirator that is controlled by the pulse program. Based on a fast exchange model RBV_m maps were calculated from the relaxation time maps for different concentrations of the two blood pool contrast agents. A significant dependence of the RBV, values on blood T₁ was found. This is in accordance with a model that has been developed recently relating the dependence of RBV_m on T₁ of blood to perfusion. For Gd-DTPA albumin, the application of the model to the experimental data yields realistic values for RBV and perfusion. The values, which are in accordance with literature data, were obtained at highest contrast agent concentrations i.e., lowest relaxation times of blood (ca. 200 ms).     

Cellular‐interstitial water exchange and its effect on the determination of contrast agent concentration in vivo: Dynamic contrast‐enhanced MRI of human internal obturator muscle

The purpose of this study was to assess the effects of cellular‐interstitial water exchange on estimates of tracer kinetics parameters obtained using rapid dynamic contrast‐enhanced (DCE) MRI. Data from the internal obturator muscle of six patients were examined using three models of water exchange: no exchange (NX), fast exchange limit (FXL), and intermediate rate (shutter‐speed [SS]). In combination with additional multiple flip angle (FA) data, a full two‐pool exchange model was also used. The results obtained using the NX model (transfer constant, K^trans = 0.049 ± 0.027 min^–1, apparent interstitial volume, v_e = 0.14 ± 0.04) were marginally higher than those obtained using the FXL model (K^trans = 0.045 ± 0.025 min^–1, v_e = 0.13 ± 0.04), but the error bars overlapped in two‐thirds of these parameter estimate pairs. Estimates of K^trans and v_e obtained using the SS model exceeded those obtained using the NX model in half the patients, and many estimates, including all those of intracellular residence time of water, t_i, were imprecise. Results obtained using the full two‐pool model fell between those obtained using FXL and NX models, and estimates of t_i were also imprecise. The results suggest that data obtained using clinically relevant DCE‐MRI are exchange‐insensitive and unsuitable for the assessment of cellular‐interstitial water exchange. Magn Reson Med 60:1011–1019, 2008. © 2008 Wiley‐Liss, Inc.