Jun Hua

Practical data acquisition method for human brain tumor amide proton transfer (APT) imaging

Amide proton transfer (APT) imaging is a type of chemical exchange–dependent saturation transfer (CEST) magnetic resonance imaging (MRI) in which amide protons of endogenous mobile proteins and peptides in tissue are detected. Initial studies have shown promising results for distinguishing tumor from surrounding brain in patients, but these data were hampered by magnetic field inhomogeneity and a low signal‐to‐noise ratio (SNR). Here a practical six‐offset APT data acquisition scheme is presented that, together with a separately acquired CEST spectrum, can provide B0‐inhomogeneity corrected human brain APT images of sufficient SNR within a clinically relevant time frame. Data from nine brain tumor patients at 3T shows that APT intensities were significantly higher in the tumor core, as assigned by gadolinium‐enhancement, than in contralateral normal‐appearing white matter (CNAWM) in patients with high‐grade tumors. Conversely, APT intensities in tumor were indistinguishable from CNAWM in patients with low‐grade tumors. In high‐grade tumors, regions of increased APT extended outside of the core into peripheral zones, indicating the potential of this technique for more accurate delineation of the heterogeneous areas of brain cancers. Magn Reson Med 60:842–849, 2008.

Quantitative Description of the Asymmetry in Magnetization Transfer Effects around the Water Resonance in the Human Brain

Magnetization transfer (MT) imaging provides a unique method of tissue characterization by capitalizing on the interaction between solid‐like tissue components and bulk water. We used a continuous‐wave (CW) MT pulse sequence with low irradiation power to study healthy human brains in vivo at 3 T and quantified the asymmetry of the MT effects with respect to the water proton frequency. This asymmetry was found to be a difference of approximately a few percent from the water signal intensity, depending on both the RF irradiation power and the frequency offset. The experimental results could be quantitatively described by a modified two‐pool MT model extended with a shift contribution for the semisolid pool with respect to water. For white matter, this shift was fitted to be 2.34 ± 0.17 ppm (N = 5) upfield from the water signal. Magn Reson Med 58:786–793, 2007.

Nuclear Overhauser Enhancement (NOE) Imaging in the Human Brain at 7 T

Chemical exchange saturation transfer (CEST) is a magnetization transfer (MT) technique to indirectly detect pools of exchangeable protons through the water signal. CEST MRI has focused predominantly on signals from exchangeable protons downfield (higher frequency) from water in the CEST spectrum. Low power radiofrequency (RF) pulses can slowly saturate protons with minimal interference of conventional semi-solid based MT contrast (MTC). When doing so, saturation-transfer signals are revealed upfield from water, which is the frequency range of non-exchangeable aliphatic and olefinic protons. The visibility of such signals indicates the presence of a relayed transfer mechanism to the water signal, while their finite width reflects that these signals are likely due to mobile solutes. It is shown here in protein phantoms and the human brain that these signals build up slower than conventional CEST, at a rate typical for intramolecular nuclear Overhauser enhancement (NOE) effects in mobile macromolecules such as proteins/peptides and lipids. These NOE-based saturation transfer signals show a pH dependence, suggesting that this process is the inverse of the well-known exchange-relayed NOEs in high resolution NMR protein studies, thus a relayed-NOE CEST process. When studying 6 normal volunteers with a low-power pulsed CEST approach, the relayed-NOE CEST effect was about twice as large as the CEST effects downfield and larger in white matter than gray matter. This NOE contrast upfield from water provides a way to study mobile macromolecules in tissue. First data on a tumor patient show reduction in both relayed NOE and CEST amide proton signals leading to an increase in magnetization transfer ratio asymmetry, providing insight into previously reported amide proton transfer (APT) effects in tumors.

Multi-parametric neuroimaging reproducibility: A 3-T resource study

Modern MRI image processing methods have yielded quantitative, morphometric, functional, and structural assessments of the human brain. These analyses typically exploit carefully optimized protocols for specific imaging targets. Algorithm investigators have several excellent public data resources to use to test, develop, and optimize their methods. Recently, there has been an increasing focus on combining MRI protocols in multi-parametric studies. Notably, these have included innovative approaches for fusing connectivity inferences with functional and/or anatomical characterizations. Yet, validation of the reproducibility of these interesting and novel methods has been severely hampered by the limited availability of appropriate multi-parametric data. We present an imaging protocol optimized to include state-of-the-art assessment of brain function, structure, micro-architecture, and quantitative parameters within a clinically feasible 60-min protocol on a 3-T MRI scanner. We present scan-rescan reproducibility of these imaging contrasts based on 21 healthy volunteers (11 M/10 F, 22-61 years old). The cortical gray matter, cortical white matter, ventricular cerebrospinal fluid, thalamus, putamen, caudate, cerebellar gray matter, cerebellar white matter, and brainstem were identified with mean volume-wise reproducibility of 3.5%. We tabulate the mean intensity, variability, and reproducibility of each contrast in a region of interest approach, which is essential for prospective study planning and retrospective power analysis considerations. Anatomy was highly consistent on structural acquisition (~1-5% variability), while variation on diffusion and several other quantitative scans was higher (~<10%). Some sequences are particularly variable in specific structures (ASL exhibited variation of 28% in the cerebral white matter) or in thin structures (quantitative T2 varied by up to 73% in the caudate) due, in large part, to variability in automated ROI placement. The richness of the joint distribution of intensities across imaging methods can be best assessed within the context of a particular analysis approach as opposed to a summary table. As such, all imaging data and analysis routines have been made publicly and freely available. This effort provides the neuroimaging community with a resource for optimization of algorithms that exploit the diversity of modern MRI modalities. Additionally, it establishes a baseline for continuing development and optimization of multi-parametric imaging protocols.

In vivo three-dimensional whole-brain pulsed steady-state chemical exchange saturation transfer at 7 T

Chemical exchange saturation transfer (CEST) is a technique to indirectly detect pools of exchangeable protons through the water signal. To increase its applicability to human studies, it is needed to develop sensitive pulse sequences for rapidly acquiring whole‐organ images while adhering to stringent amplifier duty cycle limitations and specific absorption rate restrictions. In addition, the interfering effects of direct water saturation and conventional magnetization transfer contrast complicate CEST quantification and need to be reduced as much as possible. It is shown that for protons exchanging with rates of less than 50–100 Hz, such as imaged in amide proton transfer experiments, these problems can be addressed by using a three‐dimensional steady state pulsed acquisition of limited B1 strength (∼1 μT). Such an approach exploits the fact that the direct water saturation width, magnetization transfer contrast magnitude, and specific absorption rate increase strongly with B1, while the size of the CEST effect for such protons depends minimally on B1. A short repetition time (65 ms) steady‐state sequence consisting of a brief saturation pulse (25 ms) and a segmented echo‐planar imaging train allowed acquisition of a three‐dimensional whole‐brain volume in approximately 11 s per saturation frequency, while remaining well within specific absorption rate and duty cycle limits. Magnetization transfer contrast was strongly reduced, but substantial saturation effects were found at frequencies upfield from water, which still confound the use of magnetization transfer asymmetry analysis. Fortunately, the limited width of the direct water saturation signal could be exploited to fit it with a Lorentzian function allowing CEST quantification. Amide proton transfer effects ranged between 1.5% and 2.5% in selected white and grey matter regions. This power and time‐efficient 3D pulsed CEST acquisition scheme should aid endogenous CEST quantification at both high and low fields. Magn Reson Med, 2011.

The BOLD post-stimulus undershoot, one of the most debated issues in fMRI

This paper provides a brief overview of how we got involved in fMRI work and of our efforts to elucidate the mechanisms underlying BOLD signal changes. The phenomenon discussed here in particular is the post-stimulus undershoot (PSU), the interpretation of which has captivated many fMRI scientists and is still under debate to date. This controversy is caused both by the convoluted physiological origin of the BOLD effect, which allows many possible explanations, and the lack of comprehensive data in the early years. BOLD effects reflect changes in cerebral blood flow (CBF), volume (CBV), metabolic rate of oxygen (CMRO(2)), and hematocrit fraction (Hct). However, the size of such effects is modulated by vascular origin such as intravascular, extravascular, macro and microvascular, venular and capillary, the relative contributions of which depend not only on the spatial resolution of the measurements, but also on stimulus duration, on magnetic field strength and on whether spin echo (SE) or gradient echo (GRE) detection is used. The two most dominant explanations of the PSU have been delayed vascular compliance (first venular, later arteriolar, and recently capillary) and sustained increases in CMRO(2), while post-activation reduction in CBF is a distant third. MRI has the capability to independently measure CBF and arteriolar, venous, and total CBV contributions in humans and animals, which has been of great assistance in improving the understanding of BOLD phenomena. Using currently available MRI and optical data, we conclude that the predominant PSU origin is a sustained increase in CMRO(2). However, some contributions from delayed vascular compliance are likely, and small CBF undershoot contributions that are difficult to detect with current arterial spin labeling technology can also not be excluded. The relative contribution of these different processes, which are not mutually exclusive and can act together, is likely to vary with stimulus duration and type.

Dynamic Glucose-Enhanced (DGE) MRI: Translation to Human Scanning and First Results in Glioma Patients

Recent animal studies have shown that d-glucose is a potential biodegradable magnetic resonance imaging (MRI) contrast agent for imaging glucose uptake in tumors. We show herein the first translation of that use of d-glucose to human studies. Chemical exchange saturation transfer (CEST) MRI at a single frequency offset optimized for detecting hydroxyl protons in d-glucose was used to image dynamic signal changes in the human brain at 7 T during and after d-glucose infusion. Dynamic glucose enhanced (DGE) image data from 4 normal volunteers and 3 glioma patients showed a strong signal enhancement in blood vessels, while a spatially varying enhancement was found in tumors. Areas of enhancement differed spatially between DGE and conventional gadolinium-enhanced imaging, suggesting complementary image information content for these 2 types of agents. In addition, different tumor areas enhanced with d-glucose at different times after infusion, suggesting a sensitivity to perfusion-related properties such as substrate delivery and blood-brain barrier (BBB) permeability. These preliminary results suggest that DGE MRI is feasible for studying glucose uptake in humans, providing a time-dependent set of data that contains information regarding arterial input function, tissue perfusion, glucose transport across the BBB and cell membrane, and glucose metabolism.

Physiological origin for the BOLD poststimulus undershoot in human brain: vascular compliance versus oxygen metabolism

The poststimulus blood oxygenation level-dependent (BOLD) undershoot has been attributed to two main plausible origins: delayed vascular compliance based on delayed cerebral blood volume (CBV) recovery and a sustained increased oxygen metabolism after stimulus cessation. To investigate these contributions, multimodal functional magnetic resonance imaging was employed to monitor responses of BOLD, cerebral blood flow (CBF), total CBV, and arterial CBV (CBVa) in human visual cortex after brief breath hold and visual stimulation. In visual experiments, after stimulus cessation, CBVa was restored to baseline in 7.9 ± 3.4 seconds, and CBF and CBV in 14.8 ± 5.0 seconds and 16.1 ± 5.8 seconds, respectively, all significantly faster than BOLD signal recovery after undershoot (28.1 ± 5.5 seconds). During the BOLD undershoot, postarterial CBV (CBVpa, capillaries and venules) was slightly elevated (2.4 ± 1.8%), and cerebral metabolic rate of oxygen (CMRO2) was above baseline (10.6 ± 7.4%). Following breath hold, however, CBF, CBV, CBVa and BOLD signals all returned to baseline in ∼20 seconds. No significant BOLD undershoot, and residual CBVpa dilation were observed, and CMRO2 did not substantially differ from baseline. These data suggest that both delayed CBVpa recovery and enduring increased oxidative metabolism impact the BOLD undershoot. Using a biophysical model, their relative contributions were estimated to be 19.7 ± 15.9% and 78.7 ± 18.6%, respectively.

Inflow-based vascular-space-occupancy (iVASO) MRI.

Vascular‐space‐occupancy (VASO) MRI, a blood nulling approach for assessing changes in cerebral blood volume (CBV), is hampered by low signal‐to‐noise ratio (SNR) because only 10–20% of tissue signal is recovered when using nonselective inversion for blood nulling. A new approach, called inflow‐VASO (iVASO), is introduced in which only blood flowing into the slice has experienced inversion, thereby keeping tissue and cerebrospinal fluid (CSF) signal in the slice maximal and reducing CSF partial volume effects. SNR increases of 198% ± 12% and 334% ± 9% (mean ± SD, n = 7) with respect to VASO were found at TR values of 5s and 2s, respectively. When using inflow approaches, data interpretation is complicated by the fact that signal changes are affected by vascular transit times. An optimal TR‐range (1.5–2.5s) was derived in which the iVASO response during activation predominantly reflects arterial/arteriolar CBV (CBVa) changes. In this TR‐range, perfusion contributions to the signal change are negligible because arterial label has not yet undergone capillary exchange, and arterial and precapillary blood signals are nulled. For TR = 2s, the iVASO signal change upon visual stimulation corresponded to a CBVa increase of 58% ± 7%, in agreement with arteriolar CBV changes previously reported. The onset of the hemodynamic response for iVASO occurred 1.2 ± 0.5s (n = 7) faster than for conventional VASO. Magn Reson Med, 2010.

Colocalization of cerebral iron with amyloid beta in mild cognitive impairment

Quantitative Susceptibility Mapping (QSM) MRI at 7 Tesla and 11-Carbon Pittsburgh-Compound-B PET were used for investigating the relationship between brain iron and Amyloid beta (Aβ) plaque-load in a context of increased risk for Alzheimers disease (AD), as reflected by the Apolipoprotein E ε4 (APOE-e4) allele and mild cognitive impairment (MCI) in elderly subjects. Carriers of APOE-e4 with normal cognition had higher cortical Aβ-plaque-load than non-carriers. In MCI an association between APOE-e4 and higher Aβ-plaque-load was observable both for cortical and subcortical brain-regions. APOE-e4 and MCI was also associated with higher cortical iron. Moreover, cerebral iron significantly affected functional coupling, and was furthermore associated with increased Aβ-plaque-load (R2-adjusted = 0.80, p < 0.001) and APOE-e4 carrier status (p < 0.001) in MCI. This study confirms earlier reports on an association between increased brain iron-burden and risk for neurocognitive dysfunction due to AD, and indicates that disease-progression is conferred by spatial colocalization of brain iron deposits with Aβ-plaques.