Jie Wen

On the role of physiological fluctuations in quantitative gradient echo MRI: implications for GEPCI, QSM, and SWI

Physiological fluctuations in biological tissues adversely affect MR images if present during signal acquisition. This problem is especially important for quantitative MRI. The goal of the studies reported in this study was to reduce the contributions of physiological fluctuations in quantitative MRI based on T2* tissue relaxation properties. Specifically, in this study we deal with GEPCI, QSM, and SWI techniques and propose methods allowing for substantial improvement of their results.

Sparsely sampled high-resolution 4-D experiments for efficient backbone resonance assignment of disordered proteins

Intrinsically disordered proteins (IDPs) play important roles in many critical cellular processes. Due to their limited chemical shift dispersion, IDPs often require four pairs of resonance connectivities (H(α), C(α), C(β) and CO) for establishing sequential backbone assignment. Because most conventional 4-D triple-resonance experiments share an overlapping C(α) evolution period, combining existing 4-D experiments does not offer an optimal solution for non-redundant collection of a complete set of backbone resonances. Using alternative chemical shift evolution schemes, we propose a new pair of 4-D triple-resonance experiments--HA(CA)CO(CA)NH/HA(CA)CONH--that complement the 4-D HNCACB/HN(CO)CACB experiments to provide complete backbone resonance information. Collection of high-resolution 4-D spectra with sparse sampling and FFT-CLEAN processing enables efficient acquisition and assignment of complete backbone resonances of IDPs. Importantly, because the CLEAN procedure iteratively identifies resonance signals and removes their associating aliasing artifacts, it greatly reduces the dependence of the reconstruction quality on sampling schemes and produces high-quality spectra even with less-than-optimal sampling schemes.

In vivo detection of microstructural correlates of brain pathology in preclinical and early Alzheimer Disease with magnetic resonance imaging

Background Alzheimer disease (AD) affects at least 5 million individuals in the USA alone stimulating an intense search for disease prevention and treatment therapies as well as for diagnostic techniques allowing early identification of AD during a long pre‐symptomatic period that can be used for the initiation of prevention trials of disease‐modifying therapies in asymptomatic individuals. Methods Our approach to developing such techniques is based on the Gradient Echo Plural Contrast Imaging (GEPCI) technique that provides quantitative in vivo measurements of several brain‐tissue‐specific characteristics of the gradient echo MRI signal (GEPCI metrics) that depend on the integrity of brain tissue cellular structure. Preliminary data were obtained from 34 participants selected from the studies of aging and dementia at the Knight Alzheimers Disease Research Center at Washington University in St. Louis. Cognitive status was operationalized with the Clinical Dementia Rating (CDR) scale. The participants, assessed as cognitively normal (CDR=0; n=23) or with mild AD dementia (CDR=0.5 or 1; n=11) underwent GEPCI MRI, a collection of cognitive performance tests and CSF amyloid (A&bgr;) biomarker A&bgr;42. A subset of 19 participants also underwent PET PiB studies to assess their brain A&bgr; burden. According to the A&bgr; status, cognitively normal participants were divided into normal (A&bgr; negative; n=13) and preclinical (A&bgr; positive; n=10) groups. Results GEPCI quantitative measurements demonstrated significant differences between all the groups: normal and preclinical, normal and mild AD, and preclinical and mild AD. GEPCI quantitative metrics characterizing tissue cellular integrity in the hippocampus demonstrated much stronger correlations with psychometric tests than the hippocampal atrophy. Importantly, GEPCI‐determined changes in the hippocampal tissue cellular integrity were detected even in the hippocampal areas not affected by the atrophy. Our studies also uncovered strong correlations between GEPCI brain tissue metrics and beta‐amyloid (A&bgr;) burden defined by positron emission tomography (PET) – the current in vivo gold standard for detection of cortical A&bgr;, thus supporting GEPCI as a potential surrogate marker for A&bgr; imaging – a known biomarker of early AD. Remarkably, the data show significant correlations not only in the areas of high A&bgr; accumulation (e.g. precuneus) but also in some areas of medial temporal lobe (e.g. parahippocampal cortex), where A&bgr; accumulation is relatively low. Conclusion We have demonstrated that GEPCI provides a new approach for the in vivo evaluation of AD‐related tissue pathology in the preclinical and early symptomatic stages of AD. Since MRI is a widely available technology, the GEPCI surrogate markers of AD pathology have a potential for improving the quality of AD diagnostic, and the evaluation of new disease‐modifying therapies. HighlightsAlzheimer disease (AD) affects at least 5 million individuals in the USA alone.GEPCI is a MRI‐based approach to the in vivo evaluation of AD pathology.GEPCI metrics are good correlates of amyloid accumulation and neurodegeneration.GEPCI metrics differentiate normal individuals and those with asymptomatic and early AD.

Efficient acquisition of high-resolution 4-D diagonal-suppressed methyl-methyl NOESY for large proteins

The methyl-methyl NOESY experiment plays an important role in determining the global folds of large proteins. Despite the high sensitivity of this experiment, the analysis of methyl-methyl NOEs is frequently hindered by the limited chemical shift dispersion of methyl groups, particularly methyl protons. This makes it difficult to unambiguously assign all of the methyl-methyl NOE crosspeaks using 3-D spectroscopy. The recent development of sparse sampling methods enables highly efficient acquisition of high-resolution 4-D spectra, which provides an excellent solution to resolving the degeneracy of methyl signals. However, many reconstruction algorithms for processing sparsely-sampled NMR data do not provide adequate suppression of aliasing artifacts in the presence of strong NOE diagonal signals. In order to overcome this limitation, we present a 4-D diagonal-suppressed methyl-methyl NOESY experiment specifically optimized for ultrasparse sampling and evaluate it using a deuterated, ILV methyl-protonated sample of the 42 kDa Escherichia coli maltose binding protein (MBP). Suppression of diagonal signals removes the dynamic range barrier of the methyl-methyl NOESY experiment such that residual aliasing artifacts in the CLEAN-reconstructed high-resolution 4-D spectrum can be further reduced. At an ultrasparse sampling rate of less than 1%, we were able to identify and unambiguously assign the vast majority of expected NOE crosspeaks between methyl groups separated by less than 5 Å and to detect very weak NOE crosspeaks from methyl groups that are over 7 Å apart.

On the relationship between cellular and hemodynamic properties of the human brain cortex throughout adult lifespan

Establishing baseline MRI biomarkers for normal brain aging is significant and valuable for separating normal changes in the brain structure and function from different neurological diseases. In this paper for the first time we have simultaneously measured a variety of tissue specific contributions defining R2* relaxation of the gradient recalled echo (GRE) MRI signal in human brains of healthy adults (ages 22 to 74years) and related these measurements to tissue structural and functional properties. This was accomplished by separating tissue (R2t(⁎)) and extravascular BOLD contributions to the total tissue specific GRE MRI signal decay (R2(⁎)) using an advanced version of previously developed Gradient Echo Plural Contrast Imaging (GEPCI) approach and the acquisition and post-processing methods that allowed the minimization of artifacts related to macroscopic magnetic field inhomogeneities, and physiological fluctuations. Our data (20 healthy subjects) show that in most cortical regions R2t(⁎) increases with age while tissue hemodynamic parameters, i.e. relative oxygen extraction fraction (OEFrel), deoxygenated cerebral blood volume (dCBV) and tissue concentration of deoxyhemoglobin (Cdeoxy) remain practically constant. We also found the important correlations characterizing the relationships between brain structural and hemodynamic properties in different brain regions. Specifically, thicker cortical regions have lower R2t(⁎) and these regions have lower OEF. The comparison between GEPCI-derived tissue specific structural and functional metrics and literature information suggests that (a) regions in a brain characterized by higher R2t(⁎) contain higher concentration of neurons with less developed cellular processes (dendrites, spines, etc.), (b) regions in a brain characterized by lower R2t(⁎) represent regions with lower concentration of neurons but more developed cellular processes, and (c) the age-related increases in the cortical R2t(⁎) mostly reflect the age-related increases in the cellular packing density. The baseline GEPCI-based biomarkers obtain herein could serve to help distinguish age-related changes in brain cellular and hemodynamic properties from changes which occur due to the neurodegenerative diseases.

Detection and quantification of regional cortical gray matter damage in multiple sclerosis utilizing gradient echo MRI

Cortical gray matter (GM) damage is now widely recognized in multiple sclerosis (MS). The standard MRI does not reliably detect cortical GM lesions, although cortical volume loss can be measured. In this study, we demonstrate that the gradient echo MRI can reliably and quantitatively assess cortical GM damage in MS patients using standard clinical scanners. High resolution multi-gradient echo MRI was used for regional mapping of tissue-specific MRI signal transverse relaxation rate values (R2*) in 10 each relapsing–remitting, primary-progressive and secondary-progressive MS subjects. A voxel spread function method was used to correct artifacts induced by background field gradients. R2* values from healthy controls (HCs) of varying ages were obtained to establish baseline data and calculate ΔR2* values – age-adjusted differences between MS patients and HC. Thickness of cortical regions was also measured in all subjects. In cortical regions, ΔR2* values of MS patients were also adjusted for changes in cortical thickness. Symbol digit modalities (SDMT) and paced auditory serial addition (PASAT) neurocognitive tests, as well as Expanded Disability Status Score, 25-foot timed walk and nine-hole peg test results were also obtained on all MS subjects. We found that ΔR2* values were lower in multiple cortical GM and normal appearing white matter (NAWM) regions in MS compared with HC. ΔR2* values of global cortical GM and several specific cortical regions showed significant (p < 0.05) correlations with SDMT and PASAT scores, and showed better correlations than volumetric measures of the same regions. Neurological tests not focused on cognition (Expanded Disability Status Score, 25-foot timed walk and nine-hole peg tests) showed no correlation with cortical GM ΔR2* values. The technique presented here is robust and reproducible. It requires less than 10 min and can be implemented on any MRI scanner. Our results show that quantitative tissue-specific R2* values can serve as biomarkers of tissue injury due to MS in the brain, including the cerebral cortex, an area that has been difficult to evaluate using standard MRI.

Subcomponents of brain T2* relaxation in schizophrenia, bipolar disorder and siblings: A Gradient Echo Plural Contrast Imaging (GEPCI) study

Investigating brain tissue T2* relaxation properties in vivo can potentially guide the uncovering of neuropathology in psychiatric illness, which is traditionally examined post mortem. We use an MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique that produces inherently co-registered images allowing quantitative assessment of tissue cellular and hemodynamic properties. Usually described as R2* (=1/T2*) relaxation rate constant, recent developments in GEPCI allow the separation of cellular-specific (R2*C) and hemodynamic (BOLD) contributions to the MRI signal decay. We characterize BOLD effect in terms of tissue concentration of deoxyhemoglobin, i.e. CDEOXY, which reflects brain activity. 17 control (CON), 17 bipolar disorder (BPD), 16 schizophrenia (SCZ), and 12 unaffected schizophrenia sibling (SIB) participants were scanned and post-processed using GEPCI protocols. A MANOVA of 38gray matter regions ROIs showed significant group effects for CDEOXY but not for R2*C. In the three non-control groups, 71-92% of brain regions had increased CDEOXY. Group effects were observed in the superior temporal cortex and the thalamus. Increased superior temporal cortex CDEOXY was found in SCZ (p=0.01), BPD (p=0.01) and SIB (p=0.02), with bilateral effects in SCZ and only left hemisphere effects in BPD and SIB. Thalamic CDEOXY abnormalities were observed in SCZ (p=0.003), BPD (p=0.03) and SIB (p=0.02). Our results suggest that increased activity in certain brain regions is part of the underlying pathophysiology of specific psychiatric disorders. High CDEOXY in the superior temporal cortex suggests abnormal activity with auditory, language and/or social cognitive processing. Larger studies are needed to clarify the clinical significance of relaxometric abnormalities.

Limbic system damage in MS: MRI assessment and correlations with clinical testing

Volume loss in some limbic region structures has been observed in multiple sclerosis (MS) patients. However, in vivo evaluation of existing tissue cellular microstructure integrity has received less attention. The goal of studies reported here was to quantitatively assess loss of limbic system volumes and tissue integrity, and to evaluate associations of these measures with cognitive and physical dysfunction in MS patients. Thirty-one healthy controls (HC) and 80 MS patients, including 32 relapsing remitting (RRMS), 32 secondary progressive (SPMS) and 16 primary progressive (PPMS), participated in this study. Tissue cellular integrity was evaluated by means of recently introduced tissue-specific parameter R2t* that was calculated from multi-gradient-echo MRI signals using a recently developed method that separates R2t* from BOLD (blood oxygen level dependent) contributions to GRE signal decay rate constant (R2*), and accounting for physiological fluctuations and artifacts from background gradients. Volumes in limbic system regions, normalized to skull size (NV), were measured from standard MPRAGE images. MS patients had lower R2t* and smaller normalized volumes in the hippocampus, amygdala, and several other limbic system regions, compared to HC. Alterations in R2t* of several limbic system regions correlated with clinical and neurocognitive test scores in MS patients. In contrast, smaller normalized volumes in MS were only correlated with neurocognitive test scores in the hippocampus and amygdala. This study reports the novel finding that R2t*, a measure that estimates tissue integrity, is more sensitive to tissue damage in limbic system structures than is atrophy. R2t* measurements can serve as a biomarker that is distinct from and complementary to volume measurements.

Simultaneous multi-angular relaxometry of tissue with MRI (SMART MRI): Theoretical background and proof of concept.

Accurate measurement of tissue‐specific relaxation parameters is an ultimate goal of quantitative MRI. The objective of this study is to introduce a new technique, simultaneous multiangular relaxometry of tissue with MRI (SMART MRI), which provides naturally coregistered quantitative spin density, longitudinal and transverse relaxation rate constant maps along with parameters characterizing magnetization transfer (MT) effects.

Genetically defined cellular correlates of the baseline brain MRI signal

Significance Understanding the structure and function of the human brain at a cellular level is a fundamental aim of neuroscience. Tremendous progress has been made in recent years based on different in vivo and ex vivo approaches, including major advances in brain MRI. However, uncertainties remain in determining how brain MRI measurements relate to the brain’s underlying cellular composition. In this paper we use a recently developed MRI technique, quantitative gradient recalled echo (qGRE), and information on gene profiles in the human brain available from the Allen Human Brain Atlas. We demonstrate that qGRE and related MRI techniques can be used to probe the underlying cellular composition of the human brain in vivo. fMRI revolutionized neuroscience by allowing in vivo real-time detection of human brain activity. While the nature of the fMRI signal is understood as resulting from variations in the MRI signal due to brain-activity-induced changes in the blood oxygenation level (BOLD effect), these variations constitute a very minor part of a baseline MRI signal. Hence, the fundamental (and not addressed) questions are how underlying brain cellular composition defines this baseline MRI signal and how a baseline MRI signal relates to fMRI. Herein we investigate these questions by using a multimodality approach that includes quantitative gradient recalled echo (qGRE), volumetric and functional connectivity MRI, and gene expression data from the Allen Human Brain Atlas. We demonstrate that in vivo measurement of the major baseline component of a GRE signal decay rate parameter (R2t*) provides a unique genetic perspective into the cellular constituents of the human cortex and serves as a previously unidentified link between cortical tissue composition and fMRI signal. Data show that areas of the brain cortex characterized by higher R2t* have high neuronal density and have stronger functional connections to other brain areas. Interestingly, these areas have a relatively smaller concentration of synapses and glial cells, suggesting that myelinated cortical axons are likely key cortical structures that contribute to functional connectivity. Given these associations, R2t* is expected to be a useful signal in assessing microstructural changes in the human brain during development and aging in health and disease.