Zhuozhi Dai

Quantitative chemical exchange saturation transfer (qCEST) MRI – RF spillover effect‐corrected omega plot for simultaneous determination of labile proton fraction ratio and exchange rate

Chemical exchange saturation transfer (CEST) MRI is sensitive to dilute proteins and peptides as well as microenvironmental properties. However, the complexity of the CEST MRI effect, which varies with the labile proton content, exchange rate and experimental conditions, underscores the need for developing quantitative CEST (qCEST) analysis. Towards this goal, it has been shown that omega plot is capable of quantifying paramagnetic CEST MRI. However, the use of the omega plot is somewhat limited for diamagnetic CEST (DIACEST) MRI because it is more susceptible to direct radio frequency (RF) saturation (spillover) owing to the relatively small chemical shift. Recently, it has been found that, for dilute DIACEST agents that undergo slow to intermediate chemical exchange, the spillover effect varies little with the labile proton ratio and exchange rate. Therefore, we postulated that the omega plot analysis can be improved if RF spillover effect could be estimated and taken into account. Specifically, simulation showed that both labile proton ratio and exchange rate derived using the spillover effect-corrected omega plot were in good agreement with simulated values. In addition, the modified omega plot was confirmed experimentally, and we showed that the derived labile proton ratio increased linearly with creatine concentration (p < 0.01), with little difference in their exchange rate (p = 0.32). In summary, our study extends the conventional omega plot for quantitative analysis of DIACEST MRI.

Early metabolic changes following ischemia onset in rats: An in vivo diffusion-weighted imaging and 1H-magnetic resonance spectroscopy study at 7.0 T

Despite improvements in imaging techniques, it remains challenging to quantitatively assess the time of ischemic onset of an acute ischemic stroke. It is crucial to evaluate the early signs of infarction, which are predictive of responses to recombinant tissue plasminogen activator within a treatment window of 4.5 h after stroke induction. The aim of the present study was to assess and quantify the onset time for hyperacute middle cerebral artery occlusion (MCAO) ischemic stroke by measuring the apparent diffusion coefficient (ADC) of diffusion-weighted imaging (DWI) and 1H-magnetic resonance spectroscopy (MRS) at 7.0 T. DWI, conventional T2-weighted imaging (T2WI) and subsequent focal ADCs were employed to evaluate ischemic brain lesions in a rat model of MCAO (n=20) at different time-points following a stroke. A quantitation of local changes in metabolite concentrations within the lesions was performed using MRS. Proton metabolites were quantified automatically using LCModel software. At 30 min after MCAO, intense signals were observed in the DWI spectra of all animals. No abnormal signal was observed within 3 h by T2WI. ADC images of the central area, peripheral striping and on the fringes of the infarction demonstrated a lower signal than that of the normal side. The ADC decreased significantly within 30 min after infarction, followed by a gradual elevation in volatility levels and then becoming relatively stable at a lower level 3 h later. MRS exhibited a consistent elevation of lactate and reduced N-acetyl aspartic acid. Glutamate and taurine reached a maximum 2 h after MCAO and began to decrease 1 h later. In conclusion, the present study demonstrated that hyperacute ischemic stroke can be quantitatively detected with the application of ADC, DWI and MRS. These methods may also be used to quantitatively assess the ischemic onset time of a hyperacute stroke.

Magnetization Transfer Prepared Gradient Echo MRI for CEST Imaging

Chemical exchange saturation transfer (CEST) is an emerging MRI contrast mechanism that is capable of noninvasively imaging dilute CEST agents and local properties such as pH and temperature, augmenting the routine MRI methods. However, the routine CEST MRI includes a long RF saturation pulse followed by fast image readout, which is associated with high specific absorption rate and limited spatial resolution. In addition, echo planar imaging (EPI)-based fast image readout is prone to image distortion, particularly severe at high field. To address these limitations, we evaluated magnetization transfer (MT) prepared gradient echo (GRE) MRI for CEST imaging. We proved the feasibility using numerical simulations and experiments in vitro and in vivo. Then we optimized the sequence by serially evaluating the effects of the number of saturation steps, MT saturation power (B1), GRE readout flip angle (FA), and repetition time (TR) upon the CEST MRI, and further demonstrated the endogenous amide proton CEST imaging in rats brains (n = 5) that underwent permanent middle cerebral artery occlusion. The CEST images can identify ischemic lesions in the first 3 hours after occlusion. In summary, our study demonstrated that the readily available MT-prepared GRE MRI, if optimized, is CEST-sensitive and remains promising for translational CEST imaging.

Novel gradient echo sequence‑based amide proton transfer magnetic resonance imaging in hyperacute cerebral infarction.

In the progression of ischemia, pH is important and is essential in elucidating the association between metabolic disruption, lactate formation, acidosis and tissue damage. Chemical exchange-dependent saturation transfer (CEST) imaging can be used to detect tissue pH and, in particular, a specific form of CEST magnetic resonance imaging (MRI), termed amide proton transfer (APT) MRI, which is sensitive to pH and can detect ischemic lesions, even prior to diffusion abnormalities. The critical parameter governing the ability of CEST to detect pH is the sequence. In the present study, a novel strategy was used, based on the gradient echo sequence (GRE), which involved the insertion of a magnetization transfer pulse in each repetition time (TR) and minimizing the TR for in vivo APT imaging. The proposed GRE-APT MRI method was initially verified using a tissue-like pH phantom and optimized MRI parameters for APT imaging. In order to assess the range of acute cerebral infarction, rats (n=4) were subjected to middle cerebral artery occlusion (MCAO) and MRI scanning at 7 telsa (T). Hyperacute ischemic tissue damage was characterized using multiparametric imaging techniques, including diffusion, APT and T2-Weighted MRI. By using a magnetization transfer pulse and minimizing TR, GRE-APT provided high spatial resolution and a homogeneous signal, with clearly distinguished cerebral anatomy. The GRE-APT and diffusion MRI were significantly correlated with lactate content and the area of cerebral infarction in the APT and apparent diffusion coefficient (ADC) maps matched consistently during the hyperacute period. In addition, compared with the infarction area observed on the ADC MRI map, the APT map contained tissue, which had not yet been irreversibly damaged. Therefore, GRE-APT MRI waa able to detect ischemic lactic acidosis with sensitivity and spatiotemporal resolution, suggesting the potential use of pH MRI as a surrogate imaging marker of impaired tissue metabolism for the diagnosis and prognosis of hyperacute stroke.

Evolution of blood-brain barrier damage associated with changes in brain metabolites following acute ischemia.

Stroke is a serious medical condition that requires emergency care. In the case of ischemic stroke, ischemia may lead to damage to the blood–brain barrier (BBB); the damage in turn may exacerbate the condition. Therefore, noninvasive detection of BBB damage represents a challenge for experimental and clinical researchers. In this study, we assessed the onset of BBB disruption by means of T1-weighted images with administration of the contrast enhancement agent gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and related BBB breakdown to brain metabolite changes in proton magnetic resonance spectrum (1H-MRS) in the infarcted site following middle cerebral artery occlusion (MCAO) in rats. It was shown that MCAO for 30 min and 1.5 h caused no Gd-DTPA signal change in the T1-weighted images, whereas MCAO for 1 h significantly altered some of 1H-MRS brain metabolites, suggesting that brain metabolite changes occurred earlier than BBB damage after ischemic stroke. MCAO for 2 h caused BBB breakdown, which was related to changes in the levels of some brain metabolites detected by 1H-MRS. Between the second and the third hour after MCAO, brain metabolite changes continued as the result of BBB breakdown and the concurrent overperfusion to the infarcted site, which may ameliorate the metabolite changes, thus compensating for the functional failures of the brain after stroke.

A Potential Magnetic Resonance Imaging Technique Based on Chemical Exchange Saturation Transfer for In Vivo γ-Aminobutyric Acid Imaging

Purpose We developed a novel magnetic resonance imaging (MRI) technique based on chemical exchange saturation transfer (CEST) for GABA imaging and investigated the concentration-dependent CEST effect ofGABA in a rat model of brain tumor with blood—brain barrier (BBB) disruption. Materials and Methods All MRI studies were performed using a 7.0-T Agilent MRI scanner. Z-spectra for GABA were acquired at 7.0 T, 37°C, and a pH of 7.0 using varying B1 amplitudes. CEST images of phantoms with different concentrations of GABA solutions (pH, 7.0) and other metabolites (glutamine, myoinositol, creatinine, and choline) were collected to investigate the concentration-dependent CEST effect of GABA and the potential contribution from other brain metabolites. CEST maps for GABA in rat brains with tumors were collected at baseline and 50 min, 1.5 h, and 2.0 h after the injection of GABA solution. Results The CEST effect of GABA was observed at approximately 2.75 parts per million(ppm) downfield from bulk water, and this effect increased with an increase in the B1 amplitude and remained steady after the B1 amplitude reached 6.0 μT (255 Hz). The CEST effect of GABA was proportional to the GABA concentration in vitro. CEST imaging of GABA in a rat brain with a tumor and compromised BBB showed a gradual increase in the CEST effect after GABA injection. Conclusion The findings of this study demonstrate the feasibility and potential of CEST MRI with the optimal B1 amplitude, which exhibits excellent spatial and temporal resolutions, to map changes in GABA.

Mapping the Changes of Glutamate Using Glutamate Chemical Exchange Saturation Transfer (GluCEST) Technique in a Traumatic Brain Injury Model: A Longitudinal Pilot Study

Glutamate excitoxicity plays a crucial role in the pathophysiology of traumatic brain injury (TBI) through the initiation of secondary injuries. Glutamate chemical exchange saturation transfer (GluCEST) MRI is a newly developed technique to noninvasively image glutamate in vivo with high sensitivity and spatial resolution. The aim of the present study was to use a rat model of TBI to map changes in brain glutamate distribution and explore the capability of GluCEST imaging for detecting secondary injuries. Sequential GluCEST imaging scans were performed in adult male Sprague-Dawley rats before TBI and at 1, 3, 7, and 14 days after TBI. GluCEST% increased and peaked on day 1 after TBI in the core lesion of injured cortex and peaked on day 3 in the ipsilateral hippocampus, as compared to baseline and controls. GluCEST% gradually declined to baseline by day 14 after TBI. A negative correlation between the GluCEST% of the ipsilateral hippocampus on day 3 and the time in the correct quadrant was observed in injured rats. Immunolabeling for glial fibrillary acidic protein showed significant astrocyte activation in the ipsilateral hippocampus of TBI rats. IL-6 and TNF-α in the core lesion peaked on day 1 postinjury, while those in the ipsilateral hippocampus peaked on day 3. These subsequently gradually declined to sham levels by day 14. It was concluded that GluCEST imaging has potential to be a novel neuroimaging approach for predicting cognitive outcome and to better understand neuroinflammation following TBI.

Nanoparticles in Magnetic Resonance Imaging

View Online Nano-Micro Conf., 2017, 1, 01055 | 1 Published by Nature Research Society http://nrs.org Nanoparticles in Magnetic Resonance Imaging Renhua Wu,* Zhiwei Shen, Zhuozhi Dai Department of Medical Imaging, Shantou University Medical College, 22 Xinling Road, Shantou 515041, China Corresponding Author. Email: rhwu@stu.edu.cn Received: 28 May 2017, Accepted: 16 June 2017, Published Online: 29 October 2017 Citation Information: Renhua Wu, Zhiwei Shen, Zhuozhi Dai, Nano-Micro Conference, 2017, 1, 01055 doi: 10.11605/cp.nmc2017.01055 Abstract Magnetic resonance imaging (MRI) provides crucial roles in diagnosis and treatment of human diseases. More and more new MRI techniques have been developed recently. Among them, chemical exchange saturation transfer (CEST) imaging (Figure 1) has shown its promising for noninvasive pH imaging and metabolic imaging [1]. Nanoparticles have also been studied widely in the field of magnetic resonance imaging, including disease detection and stem cell migration. For example, superparamagnetic iron oxide nanoparticles (SPIONs) have been intensively studied for their biomedical applications as T2 contrast agents in MRI. We collaborated with Zhang BL group [2] and found that compared with other nanoparticles, SPIONs exhibit highmagnetic responsivity which can reduce the amount of the contrast agents needed for calcium-responsive MRI, low cytotoxicity, higher biocompatibility and chemical stability. The assessment of changes in the extracellular calcium concentration by magnetic resonance imaging would be a valuable biomedical research tool to monitor brain neuronal activity. The nanoparticles, EGTA-SPIONs, have potential as smart contrast agents for Ca-sensitive MRI. We also collaborated with Bu WB group [3] and found that both T1-weighted imaging and in vivo pH mapping can be successfully acquired on the kidney and glioblastoma (GBM) of the mouse after intravenous injection of the T1/CEST NaGdF4@PLL nanodots (NDs), demonstrating the feasibility of such an anatomical and functional dual-mode imaging technique on one magnetic resonance machine by the rational design of MRI contrast agents. Meanwhile, the PLL shell exhibits a sensitive CEST effect that depends on the pH value of the lesions. Attractively, these ultrasmall nanoagents could be excreted through urine with negligible toxicity to body tissues, which has been demonstrated by the blood biochemistry, hematology, and tissue H&E staining analysis.Magnetic resonance imaging (MRI) provides crucial roles in diagnosis and treatment of human diseases. More and more new MRI techniques have been developed recently. Among them, chemical exchange saturation transfer (CEST) imaging (Figure 1) has shown its promising for noninvasive pH imaging and metabolic imaging [1]. Nanoparticles have also been studied widely in the field of magnetic resonance imaging, including disease detection and stem cell migration. For example, superparamagnetic iron oxide nanoparticles (SPIONs) have been intensively studied for their biomedical applications as T2 contrast agents in MRI. We collaborated with Zhang BL group [2] and found that compared with other nanoparticles, SPIONs exhibit highmagnetic responsivity which can reduce the amount of the contrast agents needed for calcium-responsive MRI, low cytotoxicity, higher biocompatibility and chemical stability. The assessment of changes in the extracellular calcium concentration by magnetic resonance imaging would be a valuable biomedical research tool to monitor brain neuronal activity. The nanoparticles, EGTA-SPIONs, have potential as smart contrast agents for Ca-sensitive MRI. We also collaborated with Bu WB group [3] and found that both T1-weighted imaging and in vivo pH mapping can be successfully acquired on the kidney and glioblastoma (GBM) of the mouse after intravenous injection of the T1/CEST NaGdF4@PLL nanodots (NDs), demonstrating the feasibility of such an anatomical and functional dual-mode imaging technique on one magnetic resonance machine by the rational design of MRI contrast agents. Meanwhile, the PLL shell exhibits a sensitive CEST effect that depends on the pH value of the lesions. Attractively, these ultrasmall nanoagents could be excreted through urine with negligible toxicity to body tissues, which has been demonstrated by the blood biochemistry, hematology, and tissue H&E staining analysis.

Nuclear Overhauser Enhancement-Mediated Magnetization Transfer Imaging in Glioma with Different Progression at 7 T

Glioma is a malignant neoplasm affecting the central nervous system. The conventional approaches to diagnosis, such as T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and contrast-enhanced T1WI, give an oversimplified representation of anatomic structures. Nuclear Overhauser enhancement (NOE) imaging is a special form of magnetization transfer (MT) that provides a new way to detect small solute pools through indirect measurement of attenuated water signals, and makes it possible to probe semisolid macromolecular protons. In this study, we investigated the correlation between the effect of NOE-mediated imaging and progression of glioma in a rat tumor model. We found that the NOE signal decreased in tumor region, and signal of tumor center and peritumoral normal tissue markedly decreased with growth of the glioma. At the same time, NOE signal in contralateral normal tissue dropped relatively late (at about day 16-20 after implanting the glioma cells). NOE imaging is a new contrast method that may provide helpful insights into the pathophysiology of glioma with regard to mobile proteins, lipids, and other metabolites. Further, NOE images differentiate normal brain tissue from glioma tissue at a molecular level. Our study indicates that NOE-mediated imaging is a new and promising approach for estimation of tumor progression.

Optimized amide proton transfer imaging of ischemic stroke

WCN 2013 No: 617 Topic: 3 — Stroke Optimized amide proton transfer imaging of ischemic stroke Z. Dai, G. Yan, S. Li, G. Xiao, Z. Shen, G. Zhang, R. Wu. 2nd Affiliated Hospital of Shantou University Medical College, Shantou, China; Hanshan Normal University, Chaozhou, China Objective: The identification of ischemic penumbra is very important to guide the treatment in ischemic stroke. Amide proton transfer (APT) imaging, a new MRI technology, is expected to detect the ischemic penumbra more precise than PWI–DWI mismatch in hyperacute cerebral infarction. But APT effect is typically small and sensitive to pre-saturation power, which needs to be optimized in the first 3 h after stroke. Material and methods: Twelve adult male Sprague Dawley rats underwent permanent middle cerebral artery occlusion by thread embolism. MRI experiments were conducted under an Agilent 7T animal MRI system in the first 3 h after ischemic stroke. APT imaging was obtained by the home-made APT sequence. Parameters were used: Offset at 3.5 ppm and −3.5 ppm, TR/TE = 26/2.5 ms, FA = 5°, slice thickness = 2 mm, FOV= 34 × 34 mm, NEX= 64, matrix = 64 × 64 and bandwidth = 50 kHz. APT MRI was optimized as functions of pre-saturation power. The pulse power (Gauss pulse, 15 ms) was serially set from 0.4 μT to 1.6 μT with intervals of 0.2 μT. Amide proton transfer imaging and contrast to noise rate (CNR) were processed in Matlab. Results: The optimized pre-saturation power in the first 3 h was 0.6 μT, which had better spatiotemporal resolution and contrast than others. The best CNR was about 4. Moreover, the APT effect almost disappeared when the pre-saturation power was varied more than 0.4 μT. Conclusion:Our study demonstrates the optimized APT imaging in the first 3 h of ischemic stroke, which showed the ischemic lesion precisely and be promising for an accurate gauge of ischemic penumbra. doi:10.1016/j.jns.2013.07.914 Abstract — WCN 2013 No: 2248 Topic: 3 — Stroke Endovascular treatment of acute basilar artery occlusion WCN 2013 No: 2248 Topic: 3 — Stroke Endovascular treatment of acute basilar artery occlusion T. Dorňak, R. Herzig, D. Skoloudik, D. Saňak, M. Kuliha, M. Roubec, M. Kocher, V. Prochazka, M. Kral, T. Veverka, M. Heřman, J. Zapletalova, P. Kaňovsky. Neurology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic; Neurology, Ostrava University and University Hospital, Ostrava, Czech Republic; Radiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic; Radiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Ostrava, Ostrava, Czech Republic; Medical Biophysics, Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University Olomouc, Olomouc, Czech Republic Background: Acute ischemic stroke (AIS) caused by basilar artery occlusion (BAO) is often associated with a severe and persistent neurological deficit and a high mortality rate. Nevertheless, the most effective therapeutic approach has not been established yet. Objective: To evaluate safety and efficacy of multimodal endovascular treatment (ET) of acute BAO, including bridging therapy (intravenous thrombolysis [IVT] with subsequent ET). Patients and methods: In the retrospective, bicenter study, the set consisted of 37 AIS patients (29 males; mean age 60.8 ± 9.2 years) with radiologically confirmed BAO. Following data was collected: baseline characteristics, risk factors, pre-event antithrombotic treatment, neurological deficit at time of treatment, time to therapy, recanalization rate (with successful recanalization defined as Thrombolysis in Cerebral Infarction score 2–3), post-treatment imaging findings. 90-Day outcome was assessed using modified Rankin scale (mRS) with good clinical outcome defined as 0–3 points. Results: The mean National Institutes of Health Stroke Scale score at presentation was 21.3 ± 8.3 points. The mean time to treatment was 5.31 ± 0.13 h. In 17 bridging group patients, mean time from IVT to ET 1.39 ± 0.05 h. Successful recanalizationwas achieved in 89.2% patients. In patients with BAO recanalization versus those without recanalization, good 90-day clinical outcome was observed in 36.4% versus 0% (p N 0.05), 90-day mortality was 30.3% versus 75.0% (p N 0.05) and mean 90-day mRS was 3.80 versus 5.75 points (p N 0.05). Conclusion: Data in this series showed that multimodal ET was an effective recanalization method of acute BAO. BAO recanalization was associated with lower mortality, but not necessarily with good clinical outcome. doi:10.1016/j.jns.2013.07.915 Abstract — WCN 2013 No: 2234 Topic: 3 — Stroke Influence of acute aneurysmal subarachnoid hemorrhage on subpopulations of mononuclear cells WCN 2013 No: 2234 Topic: 3 — Stroke Influence of acute aneurysmal subarachnoid hemorrhage on subpopulations of mononuclear cells J. Pera, R. Morga, E. Grzywna, T. Dziedzic, M. Moskala, A. Szczudlik, A. Slowik. Neurology, Jagiellonian University Medical College, Poland; Neurosurgery and Neurotraumatology, University Hospital, Poland; Neurosurgery and Neurotraumatology, Jagiellonian University Medical College, Krakow, Poland Background: Aneurysmal subarachnoid hemorrhage (aSAH) causes specific changes in transcription profiles of peripheral blood cells with a downregulation of transcripts related to T lymphocytes and an upregulation of transcripts related to monocytes and neutrophils. However, it is uncertain whether those changes reflect changes in cell count or in their activities. Objective: To analyze changes in subpopulations of mononuclear cells in the acute phase of aSAH. Patients and methods: Nine patients with acute nontraumatic aSAH (7 females) and 10 control subjects (8 females) were recruited into the study. Flow cytometry method was used to analyze following subpopulations of leukocytes: T lymphocytes (CD3+, CD4+, CD8+, invariant natural killer t cells [iNKT]) and monocytes (classical CD14++CD16-, intermediate CD14++CD16+, nonclassical CD14+CD16++). Results: Significant changes in leukocyte composition with an increase of granulocyte percentage (85.3% vs 63.3%) and a decrease of monocyte (4.9% vs 6.2%) and T lymphocyte (10.0% vs 26.5%) percentages were noted in aSAH patients comparing with controls (p b 0.05). Among monocytes a significant decrease only of nonclassical monocyte count was observed in aSAH patients (p b 0.05). Analysis of subsets of T lymphocytes revealed significantly lower count of CD3+, CD4+, and iNKT in aSAH patients comparing with controls. Abstracts / Journal of the Neurological Sciences 333 (2013) e215–e278 e234