Publications by authors named "Peter van Zijl"

319 Publications

Huntingtin silencing delays onset and slows progression of Huntington's disease: a biomarker study.

Brain 2021 May 27. Epub 2021 May 27.

Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, Maryland, USA.

Huntington's disease is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene, coding for pathologic mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic etiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest stage, when clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of clinical manifest, it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we aim to develop noninvasive sensitive biomarkers that provide insight into therapeutic efficacy in premanifest stage of Huntington's disease. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI in the heterozygous zQ175 mice, a full-length mHTT expressing and slowly progressing model with a premanifest period as in human Huntington's disease. Significantly elevated CBVa was evident in premanifest zQ175 mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest Huntington's disease. CRISPR/Cas9-mediated nonallele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study for the first time shows that a noninvasive functional MRI measure detects therapeutic efficacy in the premanifest stage and demonstrates long-term benefits of a nonallele-selective HTT silencing treatment introduced in the premanifest Huntington's disease.
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http://dx.doi.org/10.1093/brain/awab190DOI Listing
May 2021

Deuterium oxide as a contrast medium for real-time MRI-guided endovascular neurointervention.

Theranostics 2021 15;11(13):6240-6250. Epub 2021 Apr 15.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Endovascular intervention plays an important role in the treatment of various diseases, in which MRI-guidance can potentially improve precision. However, the clinical applications of currently available contrast media, including Gadolinium-based contrast agents and superparamagnetic iron oxide particles (SPIO), are hindered by safety concerns. In the present study, we sought to develop DO as a novel contrast agent for guiding endovascular neurointervention. Animal studies were approved by institutional ACUC and conducted using an 11.7 T Bruker Biospec system and a 3T Siemens Trio clinical scanner for rodent and canine imaging, respectively. The locally selective blood brain barrier opening (BBBO) in rat brains was obtained by intraarterial (IA) injection of mannitol. The dynamic T* EPI MRI sequence was used to study the trans-catheter perfusion territory by IA administered SPIO before mannitol administration, whereas a dynamic T FLASH sequence was used to acquire Gd contrast-enhanced MRI for assessing BBBO after injection of mannitol. The contrast generated by DO assessed by either EPI or FLASH methods was compared with the corresponding results assessed by SPIO or Gd. The utility of DO MRI was also demonstrated to guide drug delivery to glioma in a mouse model. Finally, the clinical utility of DO-MRI was demonstrated in a canine model. Our study has shown that the contrast generated by DO can be used to precisely delineate trans-catheter perfusion territory in both small and large animals. The perfusion territories determined by DO-MRI show moderate correlation with those by SPIO-MRI (Spearman coefficient r = 0.5234, P < 0.001). Moreover, our results show that the perfusion territory determined by DO-MRI can successfully predict the areas with BBBO after mannitol treatment similar to that assessed by Gd-MRI (Spearman coefficient r = 0.6923, P < 0.001). Using DO-MRI as imaging guidance, the optimal infusion rate in the mouse brain was determined to be 150 µL/min to maximize the delivery efficacy to the tumor without serious off-target delivery to the brain parenchyma. The enhanced drug delivery of antibodies to the brain tumor was confirmed by fluorescence imaging. Our study demonstrated that DO can be used as a negative MRI contrast medium to guide endovascular neurointervention. The established DO -MRI method is safe and quantitative, without the concern of contrast accumulation. These qualities make it an attempting approach for a variety of endovascular procedures.
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http://dx.doi.org/10.7150/thno.55953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120199PMC
April 2021

Pulseq-CEST: Towards multi-site multi-vendor compatibility and reproducibility of CEST experiments using an open-source sequence standard.

Magn Reson Med 2021 Oct 7;86(4):1845-1858. Epub 2021 May 7.

Magnetic Resonance Center, Max Planck Institute for Biological Cybernetics, Tuebingen, Germany.

Purpose: As the field of CEST grows, various novel preparation periods using different parameters are being introduced. At the same time, large, multisite clinical studies require clearly defined protocols, especially across different vendors. Here, we propose a CEST definition standard using the open Pulseq format for a shareable, simple, and exact definition of CEST protocols.

Methods: We present the benefits of such a standard in three ways: (1) an open database on GitHub, where fully defined, human-readable CEST protocols can be shared; (2) an open-source Bloch-McConnell simulation to test and optimize CEST preparation periods in silico; and (3) a hybrid MR sequence that plays out the CEST preparation period and can be combined with any existing readout module.

Results: The exact definition of the CEST preparation period, in combination with the flexible simulation, leads to a good match between simulations and measurements. The standard allowed finding consensus on three amide proton transfer-weighted protocols that could be compared in healthy subjects and a tumor patient. In addition, we could show coherent multisite results for a sophisticated CEST method, highlighting the benefits regarding protocol sharing and reproducibility.

Conclusion: With Pulseq-CEST, we provide a straightforward approach to standardize, share, simulate, and measure different CEST preparation schemes, which are inherently completely defined.
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http://dx.doi.org/10.1002/mrm.28825DOI Listing
October 2021

Three-dimensional whole-brain mapping of cerebral blood volume and venous cerebral blood volume using Fourier transform-based velocity-selective pulse trains.

Magn Reson Med 2021 09 6;86(3):1420-1433. Epub 2021 May 6.

The Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Purpose: To develop 3D MRI methods for cerebral blood volume (CBV) and venous cerebral blood volume (vCBV) estimation with whole-brain coverage using Fourier transform-based velocity-selective (FT-VS) pulse trains.

Methods: For CBV measurement, FT-VS saturation pulse trains were used to suppress static tissue, whereas CSF contamination was corrected voxel-by-voxel using a multi-readout acquisition and a fast CSF T scan. The vCBV mapping was achieved by inserting an arterial-nulling module that included a FT-VS inversion pulse train. Using these methods, CBV and vCBV maps were obtained on 6 healthy volunteers at 3 T.

Results: The mean CBV and vCBV values in gray matter and white matter in different areas of the brain showed high correlation (r = 0.95 and P < .0001). The averaged CBV and vCBV values of the whole brain were 5.4 ± 0.6 mL/100 g and 2.5 ± 0.3 mL/100 g in gray matter, and 2.6 ± 0.5 mL/100 g and 1.5 ± 0.2 mL/100 g in white matter, respectively, comparable to the literature.

Conclusion: The feasibility of FT-VS-based CBV and vCBV estimation was demonstrated for 3D acquisition with large spatial coverage.
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http://dx.doi.org/10.1002/mrm.28815DOI Listing
September 2021

Early detection of Alzheimer's disease using creatine chemical exchange saturation transfer magnetic resonance imaging.

Neuroimage 2021 08 18;236:118071. Epub 2021 Apr 18.

F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, USA; Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Detecting Alzheimer's disease (AD) at an early stage brings a lot of benefits including disease management and actions to slow the progression of the disease. Here, we demonstrate that reduced creatine chemical exchange saturation transfer (CrCEST) contrast has the potential to serve as a new biomarker for early detection of AD. The results on wild type (WT) mice and two age-matched AD models, namely tauopathy (Tau) and Aβ amyloidosis (APP), indicated that CrCEST contrasts of the cortex and corpus callosum in the APP and Tau mice were significantly reduced compared to WT counterpart at an early stage (6-7 months) (p < 0.011). Two main causes of the reduced CrCEST contrast, i.e. cerebral pH and creatine concentration, were investigated. From phantom and hypercapnia experiments, CrCEST showed excellent sensitivity to pH variations. From MRS results, the creatine concentration in WT and AD mouse brain was equivalent, which suggests that the reduced CrCEST contrast was dominated by cerebral pH change involved in the progression of AD. Immunohistochemical analysis revealed that the abnormal cerebral pH in AD mice may relate to neuroinflammation, a known factor that can cause pH reduction.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118071DOI Listing
August 2021

Single-step calculation of susceptibility through multiple orientation sampling.

NMR Biomed 2021 Jul 6;34(7):e4517. Epub 2021 Apr 6.

F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA.

Quantitative susceptibility mapping (QSM) was developed to estimate the spatial distribution of magnetic susceptibility from MR signal phase acquired using a gradient echo (GRE) sequence. The field-to-susceptibility inversion in QSM is known to be ill-posed and needs numerical stabilization through either regularization or data oversampling. The calculation of susceptibility through the multiple orientation sampling (COSMOS) method uses phase data acquired at three or more head orientations to achieve a well-conditioned field-to-susceptibility inversion and is often considered the gold standard for in vivo QSM. However, the conventional COSMOS approach, here named multistep COSMOS (MSCOSMOS), solves the dipole inversion from the local field derived from raw GRE phase through multiple steps of phase preprocessing. Error propagations between these consecutive phase processing steps can thus affect the final susceptibility quantification. On the other hand, recently proposed single-step QSM (SSQSM) methods aim to solve an integrated inversion from unprocessed or total phase to mitigate such error propagations but have been limited to single orientation QSM. This study therefore aimed to test the feasibility of using single-step COSMOS (SSCOSMOS) to jointly perform background field removal and dipole inversion with multiple orientation sampling, which could serve as a better standard for gauging SSQSM methods. We incorporated multiple spherical mean value (SMV) kernels of various radii with the dipole inversion in SSCOSMOS. QSM reconstructions with SSCOSMOS and MSCOSMOS were compared using both simulations with a numerical head phantom and in vivo human brain data. SSCOSMOS permitted integrated background removal and dipole inversion without the need to adjust any regularization parameters. In addition, with sufficiently large SMV kernels, SSCOSMOS performed consistently better than MSCOSMOS in all the tested error metrics in our simulations, giving better susceptibility quantification and smaller reconstruction error. Consistent tissue susceptibility values were obtained between SSCOSMOS and MSCOSMOS.
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http://dx.doi.org/10.1002/nbm.4517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184590PMC
July 2021

Whole-brain amide CEST imaging at 3T with a steady-state radial MRI acquisition.

Magn Reson Med 2021 08 27;86(2):893-906. Epub 2021 Mar 27.

F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, Maryland, USA.

Purpose: To develop a steady-state saturation with radial readout chemical exchange saturation transfer (starCEST) for acquiring CEST images at 3 Tesla (T). The polynomial Lorentzian line-shape fitting approach was further developed for extracting amideCEST intensities at this field.

Method: StarCEST MRI using periodically rotated overlapping parallel lines with enhanced reconstruction-based spatial sampling was implemented to acquire Z-spectra that are robust to brain motion. Multi-linear singular value decomposition postprocessing was applied to enhance the CEST SNR. The egg white phantom studies were performed at 3T to reveal the contributions to the 3.5 ppm CEST signal. Based on the phantom validation, the amideCEST peak was quantified using the polynomial Lorentzian line-shape fitting, which exploits the inverse relationship between Z-spectral intensity and the longitudinal relaxation rate in the rotating frame. The 3D turbo spin echo CEST was also performed to compare with the starCEST method.

Results: The amideCEST peak showed a negligible peak B dependence between 1.2 µT and 2.4 µT. The amideCEST images acquired with starCEST showed much improved image quality, SNR, and motion robustness compared to the conventional 3D turbo spin echo CEST method with the same scan time. The amideCEST contrast extracted by the polynomial Lorentzian line-shape fitting method trended toward a stronger gray matter signal (1.32% ± 0.30%) than white matter (0.92% ± 0.08%; P = .02, n = 5). When calculating the magnetization transfer contrast and T -corrected rotating frame relaxation rate maps, amideCEST again was not significantly different for white matter and gray matter.

Conclusion: Rapid multi-slice amideCEST mapping can be achieved by the starCEST method (< 5 min) at 3T by combing with the polynomial Lorentzian line-shape fitting method.
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http://dx.doi.org/10.1002/mrm.28770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076068PMC
August 2021

APT-weighted MRI Can Be an Early Marker for Demyelination.

Radiology 2021 05 16;299(2):435-437. Epub 2021 Mar 16.

From the Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 720 Rutland Ave, 217 Traylor Bldg, Baltimore, MD 21205; and F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, Md.

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http://dx.doi.org/10.1148/radiol.2021210041DOI Listing
May 2021

Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition.

Brain 2021 Jun;144(5):1396-1408

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identifying this process in multiple sclerosis patients using post-contrast fluid-attenuated inversion recovery imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 T) MRI to perform post-contrast imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced via immunization with proteolipid protein peptide (PLP139-151) and complete Freund's adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which revealed dense cellular infiltrates corresponding to areas of contrast enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas, namely the presence of peripheral node addressin-positive structures, C-X-C motif chemokine ligand-13 (CXCL13)-producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib [a Bruton tyrosine kinase (BTK) inhibitor] for a period of 4 weeks. These mice underwent serial imaging; we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We used ultra-high field MRI to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis, and then used this model to identify BTK inhibition as a novel therapeutic approach to target meningeal inflammation. The results of this study provide support for future studies in multiple sclerosis patients with imaging evidence of meningeal inflammation.
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http://dx.doi.org/10.1093/brain/awab045DOI Listing
June 2021

Highly efficient magnetic labelling allows MRI tracking of the homing of stem cell-derived extracellular vesicles following systemic delivery.

J Extracell Vesicles 2021 Jan 15;10(3):e12054. Epub 2021 Jan 15.

Russell H. Morgan Department of Radiology Johns Hopkins University School of Medicine Baltimore Maryland USA.

Human stem-cell-derived extracellular vesicles (EVs) are currently being investigated for cell-free therapy in regenerative medicine applications, but the lack of noninvasive imaging methods to track EV homing and uptake in injured tissues has limited the refinement and optimization of the approach. Here, we developed a new labelling strategy to prepare magnetic EVs (magneto-EVs) allowing sensitive yet specific MRI tracking of systemically injected therapeutic EVs. This new labelling strategy relies on the use of 'sticky' magnetic particles, namely superparamagnetic iron oxide (SPIO) nanoparticles coated with polyhistidine tags, to efficiently separate magneto-EVs from unencapsulated SPIO particles. Using this method, we prepared pluripotent stem cell (iPSC)-derived magneto-EVs and subsequently used MRI to track their homing in different animal models of kidney injury and myocardial ischemia. Our results showed that iPSC-derived EVs preferentially accumulated in the injury sites and conferred substantial protection. Our study paves a new pathway for preparing highly purified magnetic EVs and tracking them using MRI towards optimized, systemically administered EV-based cell-free therapies.
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http://dx.doi.org/10.1002/jev2.12054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809601PMC
January 2021

Assessment of Amide proton transfer weighted (APTw) MRI for pre-surgical prediction of final diagnosis in gliomas.

PLoS One 2020 29;15(12):e0244003. Epub 2020 Dec 29.

Division of Radiology, Department of Clinical Sciences, Lund University, Lund, Sweden.

Purpose: Radiological assessment of primary brain neoplasms, both high (HGG) and low grade tumors (LGG), based on contrast-enhancement alone can be inaccurate. We evaluated the radiological value of amide proton transfer weighted (APTw) MRI as an imaging complement for pre-surgical radiological diagnosis of brain tumors.

Methods: Twenty-six patients were evaluated prospectively; (22 males, 4 females, mean age 55 years, range 26-76 years) underwent MRI at 3T using T1-MPRAGE pre- and post-contrast administration, conventional T2w, FLAIR, and APTw imaging pre-surgically for suspected primary/secondary brain tumor. Assessment of the additional value of APTw imaging compared to conventional MRI for correct pre-surgical brain tumor diagnosis. The initial radiological pre-operative diagnosis was based on the conventional contrast-enhanced MR images. The range, minimum, maximum, and mean APTw signals were evaluated. Conventional normality testing was performed; with boxplots/outliers/skewness/kurtosis and a Shapiro-Wilk's test. Mann-Whitney U for analysis of significance for mean/max/min and range APTw signal. A logistic regression model was constructed for mean, max, range and Receiver Operating Characteristic (ROC) curves calculated for individual and combined APTw signals.

Results: Conventional radiological diagnosis prior to surgery/biopsy was HGG (8 patients), LGG (12 patients), and metastasis (6 patients). Using the mean and maximum: APTw signal would have changed the pre-operative evaluation the diagnosis in 8 of 22 patients (two LGGs excluded, two METs excluded). Using a cut off value of >2.0% for mean APTw signal integral, 4 of the 12 radiologically suspected LGG would have been diagnosed as high grade glioma, which was confirmed by histopathological diagnosis. APTw mean of >2.0% and max >2.48% outperformed four separate clinical radiological assessments of tumor type, P-values = .004 and = .002, respectively.

Conclusions: Using APTw-images as part of the daily clinical pre-operative radiological evaluation may improve diagnostic precision in differentiating LGGs from HGGs, with potential improvement of patient management and treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244003PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771875PMC
February 2021

Quantitative Susceptibility Mapping of Brain Iron and β-Amyloid in MRI and PET Relating to Cognitive Performance in Cognitively Normal Older Adults.

Radiology 2021 02 24;298(2):353-362. Epub 2020 Nov 24.

From the F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, 707 N Broadway, Room G-25, Baltimore, MD 21205 (L.C., P.C.M.v.Z., X.L.); Department of Radiology and Radiological Sciences (L.C., K.O., A.F., P.C.M.v.Z., X.L.) and Department of Neurology (A.S., M.A.), Johns Hopkins University School of Medicine, Baltimore, Md; and Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, Md (Y.Z.).

Background For individuals with mild cognitive impairment (MCI) or dementia, elevated brain iron together with β-amyloid is associated with lower cognitive functioning. But this needs further investigation among cognitively normal older adults. Purpose To investigate via quantitative susceptibility mapping (QSM) in MRI and PET how cerebral iron together with β-amyloid affects cognition among cognitively normal older adults. Materials and Methods In this secondary analysis of a prospective study, cognitively normal older adults underwent QSM MRI to measure brain iron. A majority underwent PET to measure cerebral β-amyloid within 30 days of MRI. Multiple linear regression analyses were performed for 12 cortical and subcortical gray matter regions to assess the effect of brain iron on cognitive functions. Voxel-based analyses investigated the associations between tissue iron and β-amyloid load and their relationship to cognitive performance. Results Evaluated were 150 cognitively normal older adults (mean age, 69 years ± 8 [standard deviation]; 93 women). Of 150, 97 underwent PET; 22 of the 97 (mean age, 71 years ± 6; 13 women) were positive for β-amyloid. In all participants, brain iron content in the hippocampus negatively correlated with global cognitive composite score (standardized β = -0.24; 95% CI: -0.40, -0.07; = .005). In the PET subgroup, brain iron in the hippocampus negatively correlated with episodic memory (β = -0.24; 95% CI: -0.40, -0.08; = .004) and visuospatial score (β = -0.34; 95% CI: -0.56, -0.12; = .003) independent of β-amyloid burden. Both negative and positive correlations between brain iron and β-amyloid were observed in the PET subgroup, revealing clusters where brain iron content negatively correlated with β-amyloid and global cognitive scores (eg, in the frontal cortex: β = -0.13; 95% CI: -0.23, -0.02; = .02). No clusters showed associations between β-amyloid and global cognition. Conclusion Among cognitively normal older adults, quantitative susceptibility mapping in MRI and PET indicated that elevated cerebral iron load was related to lower cognitive performance independent of β-amyloid. © RSNA, 2020 See also the editorial by Chiang in this issue.
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http://dx.doi.org/10.1148/radiol.2020201603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850239PMC
February 2021

Diffusion-regularized susceptibility tensor imaging (DRSTI) of tissue microstructures in the human brain.

Med Image Anal 2021 01 20;67:101827. Epub 2020 Oct 20.

Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205, USA.

Susceptibility tensor imaging (STI) has been proposed as an alternative to diffusion tensor imaging (DTI) for non-invasive in vivo characterization of brain tissue microstructure and white matter fiber architecture, potentially benefitting from its high spatial resolution. In spite of different biophysical mechanisms, animal studies have demonstrated white matter fiber directions measured using STI to be reasonably consistent with those from diffusion tensor imaging (DTI). However, human brain STI is hampered by its requirement of acquiring data at more than 10 head rotations and a complicated processing pipeline. In this paper, we propose a diffusion-regularized STI method (DRSTI) that employs a tensor spectral decomposition constraint to regularize the STI solution using the fiber directions estimated by DTI as a priori. We then explore the high-resolution DRSTI with MR phase images acquired at only 6 head orientations. Compared to other STI approaches, the DRSTI generated susceptibility tensor components, mean magnetic susceptibility (MMS), magnetic susceptibility anisotropy (MSA) and fiber direction maps with fewer artifacts, especially in regions with large susceptibility variations, and with less erroneous quantifications. In addition, the DRSTI method allows us to distinguish more structural features that could not be identified in DTI, especially in deep gray matters. DRSTI enables a more accurate susceptibility tensor estimation with a reduced number of sampling orientations, and achieves better tracking of fiber pathways than previous STI attempts on in vivo human brain.
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http://dx.doi.org/10.1016/j.media.2020.101827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725957PMC
January 2021

Learned Proximal Networks for Quantitative Susceptibility Mapping.

Med Image Comput Comput Assist Interv 2020 Oct 29;12262:125-135. Epub 2020 Sep 29.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.

Quantitative Susceptibility Mapping (QSM) estimates tissue magnetic susceptibility distributions from Magnetic Resonance (MR) phase measurements by solving an ill-posed dipole inversion problem. Conventional single orientation QSM methods usually employ regularization strategies to stabilize such inversion, but may suffer from streaking artifacts or over-smoothing. Multiple orientation QSM such as calculation of susceptibility through multiple orientation sampling (COSMOS) can give well-conditioned inversion and an artifact free solution but has expensive acquisition costs. On the other hand, Convolutional Neural Networks (CNN) show great potential for medical image reconstruction, albeit often with limited interpretability. Here, we present a Learned Proximal Convolutional Neural Network (LP-CNN) for solving the ill-posed QSM dipole inversion problem in an iterative proximal gradient descent fashion. This approach combines the strengths of data-driven restoration priors and the clear interpretability of iterative solvers that can take into account the physical model of dipole convolution. During training, our LP-CNN learns an implicit regularizer via its proximal, enabling the decoupling between the forward operator and the data-driven parameters in the reconstruction algorithm. More importantly, this framework is believed to be the first deep learning QSM approach that can naturally handle an arbitrary number of phase input measurements without the need for any ad-hoc rotation or re-training. We demonstrate that the LP-CNN provides state-of-the-art reconstruction results compared to both traditional and deep learning methods while allowing for more flexibility in the reconstruction process.
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http://dx.doi.org/10.1007/978-3-030-59713-9_13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647124PMC
October 2020

Mutant G2019S-LRRK2 Induces Abnormalities in Arteriolar Cerebral Blood Volume in Mouse Brains: An MRI Study.

Neurodegener Dis 2020 5;20(2-3):65-72. Epub 2020 Nov 5.

Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease and the most common movement disorder characterized by motor impairments resulting from midbrain dopamine neuron loss. Abnormalities in small pial arteries and arterioles, which are the primary pathways of local delivery of nutrients and oxygen in brain tissue, have been reported in many neurodegenerative diseases including PD. Mutations in LRRK2 cause genetic PD and contribute to sporadic PD. The most common PD-linked mutation LRRK2 G2019S contributes 20-47% of genetic forms of PD in Caucasian populations. The human LRRK2 G2019S transgenic mouse model displays PD-like movement impairment and was used to identify novel LRRK2 inhibitors, which provides a useful model for studying microvascular abnormalities in PD.

Objectives: To investigate abnormalities in arteriolar cerebral blood volume (CBVa) in various brain regions using the inflow-based vascular-space occupancy (iVASO) MRI technique in LRRK2 mouse models of PD.

Methods: Anatomical and iVASO MRI scans were performed in 5 female and 7 male nontransgenic (nTg), 3 female and 4 male wild-type (WT) LRRK2, and 5 female and 7 male G2019S-LRRK2 mice of 9 months of age. CBVa was calculated and compared in the substantia nigra (SN), olfactory cortex, and prefrontal cortex.

Results: Compared to nTg mice, G2019S-LRRK2 mice showed decreased CBVa in the SN, but increased CBVa in the olfactory and prefrontal cortex in both male and female groups, whereas WT-LRRK2 mice showed no change in CBVa in the SN (male and female), the olfactory (female), and prefrontal (female) cortex, but a slight increase in CBVa in the olfactory and prefrontal cortex in the male group only.

Conclusions: Alterations in the blood volume of small arteries and arterioles (CBVa) were detected in the G2019S-LRRK2 mouse model of PD. The opposite changes in CBVa in the SN and the cortex indicate that PD pathology may have differential effects in different brain regions. Our results suggest the potential value of CBVa as a marker for clinical PD studies.
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http://dx.doi.org/10.1159/000510387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864856PMC
November 2020

Mechanism and quantitative assessment of saturation transfer for water-based detection of the aliphatic protons in carbohydrate polymers.

Magn Reson Med 2021 03 24;85(3):1643-1654. Epub 2020 Sep 24.

The Russell H. Morgan Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Purpose: CEST MRI experiments of mobile macromolecules, for example, proteins, carbohydrates, and phospholipids, often show signals due to saturation transfer from aliphatic protons to water. Currently, the mechanism of this nuclear Overhauser effect (NOE)-based transfer pathway is not completely understood and could be due either to NOEs directly to bound water or NOEs relayed intramolecularly via exchangeable protons. We used glycogen as a model system to investigate this saturation transfer pathway in sugar polymer solution.

Methods: To determine whether proton exchange affected saturation transfer, saturation spectra (Z-spectra) were measured for glycogen solutions of different pH, D O/H O ratio, and glycogen particle size. A theoretical model was derived to analytically describe the NOE-based signals in these spectra. Numerical simulations were performed to verify this theory, which was further tested by fitting experimental data for different exchange regimes.

Results: Signal intensities of aliphatic NOEs in Z-spectra of glycogen in D O solution were influenced by hydroxyl proton exchange rates, whereas those in H O were not. This indicates that the primary transfer pathway is an exchange-relayed NOE from these aliphatic protons to neighboring hydroxyl protons, followed by the exchange to water protons. Experimental data for glycogen solutions in D O and H O could be analyzed successfully using an analytical theory derived for such relayed NOE transfer, which was further validated using numerical simulations with the Bloch equations.

Conclusion: The predominant mechanism underlying aliphatic signals in Z-spectra of mobile carbohydrate polymers is intramolecular relayed NOE transfer followed by proton exchange.
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http://dx.doi.org/10.1002/mrm.28503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718412PMC
March 2021

D-Glucose uptake and clearance in the tauopathy Alzheimer's disease mouse brain detected by on-resonance variable delay multiple pulse MRI.

J Cereb Blood Flow Metab 2021 05 16;41(5):1013-1025. Epub 2020 Jul 16.

F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, USA.

In this study, we applied on-resonance variable delay multiple pulse (onVDMP) MRI to study D-glucose uptake in a mouse model of Alzheimer's disease (AD) tauopathy and demonstrated its feasibility in discriminating AD mice from wild-type mice. The D-glucose uptake in the cortex of AD mice (1.70 ± 1.33%) was significantly reduced compared to that of wild-type mice (5.42 ± 0.70%,  = 0.0051). Also, a slower D-glucose uptake rate was found in the cerebrospinal fluid (CSF) of AD mice (0.08 ± 0.01 min) compared to their wild-type counterpart (0.56 ± 0.1 min,  < 0.001), which suggests the presence of an impaired glucose transporter on both blood-brain and blood-CSF barriers of these AD mice. Clearance of D-glucose was observed in the CSF of wild-type mice but not AD mice, which suggests dysfunction of the glymphatic system in the AD mice. The results in this study indicate that onVDMP MRI could be a cost-effective and widely available method for simultaneously evaluating glucose transporter and glymphatic function of AD. This study also suggests that tau protein affects the D-glucose uptake and glymphatic impairment in AD at a time point preceding neurofibrillary tangle pathology.
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http://dx.doi.org/10.1177/0271678X20941264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054725PMC
May 2021

Association of cerebrovascular reactivity and Alzheimer pathologic markers with cognitive performance.

Neurology 2020 08 13;95(8):e962-e972. Epub 2020 Jul 13.

From the Departments of Radiology (S.S., Z.L., Y.L., X.H., K.H., G.P., C.X., P.v.Z., J.P., P.L., H.L.), Biomedical Engineering (Z.L., X.H., H.L.), Medicine (S.Y., R.K.), Psychiatry and Behavioral Sciences (P.R.), Neurology (A.M., M.A.), and Neurosurgery (J.P.), Johns Hopkins University, School of Medicine; and F.M. Kirby Research Center (P.v.Z., H.L.), Kennedy Krieger Institute, Baltimore, MD.

Objective: To determine whether MRI-based cerebrovascular reactivity (CVR) can predict cognitive performance independently of Alzheimer pathologic markers, we studied the relationship between cognition, CVR, and CSF-derived β-amyloid (Aβ) and tau in a group of elderly individuals with mixed Alzheimer and vascular cognitive impairment and dementia.

Methods: This was a cross-sectional study of 72 participants 69 ± 8 years of age consisting of individuals with normal cognition (n = 28) and cognitive impairment (n = 44) (including 36 with mild cognitive impairment [MCI] and 8 with mild dementia). CVR was measured with hypercapnia-MRI. Whole-brain CVR (percent blood oxygen level-dependent per 1 mm Hg Etco) was used to estimate vasodilatory capacity. Montreal Cognitive Assessment (MoCA) scores, cognitive domains scores, and a global composite cognitive score were obtained. AD biomarkers included CSF assays of Aβ and tau.

Results: Whole-brain CVR was lower in the impaired (mean ± SE, 0.132 ± 0.006%/mm Hg) compared to the normal (0.151 ± 0.007%/mm Hg) group (β = -0.02%/mm Hg; 95% confidence interval [CI] -0.038 to -0.001). After adjustment for CSF Aβ and tau, higher whole-brain CVR was associated with better performance on the MoCA (β = 29.64, 95% CI 9.94-49.34) and with a global composite cognitive score (β = 4.32, 95% CI 0.05-8.58). When the CVR marker was compared with the Fazekas score based on white matter hyperintensities and vascular risk-score in a single regression model predicting the MoCA score, only CVR revealed a significant effect (β = 28.09, 95% CI 6.14-50.04), while the other 2 measures were not significant.

Conclusions: CVR was significantly associated with cognitive performance independently of AD pathology. Whole-brain CVR may be a useful biomarker for evaluating cognitive impairment related to vascular disease in older individuals.

Classification Of Evidence: This study provides Class II evidence that CVR was significantly associated with cognitive performance independent of AD pathology.
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http://dx.doi.org/10.1212/WNL.0000000000010133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668551PMC
August 2020

Fast whole brain MR imaging of dynamic susceptibility contrast changes in the cerebrospinal fluid (cDSC MRI).

Magn Reson Med 2020 12 3;84(6):3256-3270. Epub 2020 Jul 3.

F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA.

Purpose: The circulation of cerebrospinal fluid (CSF) is closely associated with many aspects of brain physiology. When gadolinium(Gd)-based contrast is administered intravenously, pre- and post-contrast MR signal changes can often be observed in the CSF at certain locations within the intra-cranial space, mainly due to the lack of a blood-brain barrier in the dural blood vessels. This study aims to develop and systemically optimize MRI sequences that can detect dynamic signal changes in the CSF after Gd administration with a sub-millimeter spatial resolution, a temporal resolution of <10 s, and whole brain coverage.

Methods: Bloch simulations were performed to determine optimal imaging parameters for maximum CSF contrast before and after Gd injection. Simulations were validated with phantom scans. An optimized turbo-spin-echo (TSE) sequence was performed on healthy volunteers on 3T and 7T.

Results: Simulation results agreed well with phantom scans. In human scans, dynamic signal changes after Gd injection in the CSF were detected at several locations where cerebral lymphatic vessels were identified in previous studies. The concentration of Gd in CSF in these regions was estimated to be approximately 0.2 mmol/L.

Conclusion: Dynamic signal changes induced by the distribution of Gd in the CSF can be detected in healthy human subjects with an optimized TSE sequence. The proposed methodology does not rely on any particular theory on CSF circulation. We expect it to be useful for studies on CSF circulation and cerebral lymphatic vessels in the brain.
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http://dx.doi.org/10.1002/mrm.28389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113983PMC
December 2020

High-sensitivity CEST mapping using a spatiotemporal correlation-enhanced method.

Magn Reson Med 2020 12 29;84(6):3342-3350. Epub 2020 Jun 29.

F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, Maryland, USA.

Purpose: To obtain high-sensitivity CEST maps by exploiting the spatiotemporal correlation between CEST images.

Methods: A postprocessing method accomplished by multilinear singular value decomposition (MLSVD) was used to enhance the CEST SNR by exploiting the correlation between the Z-spectrum for each voxel and the low-rank property of the overall CEST data. The performance of this method was evaluated using CrCEST in ischemic mouse brain at 11.7 tesla. Then, MLSVD CEST was applied to obtain Cr, amide, and amine CEST maps of the ischemic mouse brain to demonstrate its general applications.

Results: Complex-valued Gaussian noise was added to CEST k-space data to mimic a low SNR situation. MLSVD CEST analysis was able to suppress the noise, recover the degraded CEST peak, and provide better CrCEST quality compared to the smoothing and singular value decomposition (SVD)-based denoising methods. High-resolution Cr, amide, and amine CEST maps of an ischemic stroke using MLSVD CEST suggest that CrCEST is also a sensitive pH mapping method, and a wide range of pH changes can be detected by combing CrCEST with amine CEST at high magnetic fields.

Conclusion: MLSVD CEST provides a simple and efficient way to improve the SNR of CEST images.
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http://dx.doi.org/10.1002/mrm.28380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722217PMC
December 2020

Age-Related Alterations in Brain Perfusion, Venous Oxygenation, and Oxygen Metabolic Rate of Mice: A 17-Month Longitudinal MRI Study.

Front Neurol 2020 12;11:559. Epub 2020 Jun 12.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MA, United States.

Characterization of physiological parameters of the aging brain, such as perfusion and brain metabolism, is important for understanding brain function and diseases. Aging studies on human brain have mostly been based on the cross-sectional design, while the few longitudinal studies used relatively short follow-up time compared to the lifespan. To determine the longitudinal time courses of cerebral physiological parameters across the adult lifespan in mice. The present work examined longitudinal changes in cerebral blood flow (CBF), cerebral venous oxygenation (Y), and cerebral metabolic rate of oxygen (CMRO) using MRI in healthy C57BL/6 mice from 3 to 20 months of age. Each mouse received 16 imaging sessions at an ~1-month interval. Significant increases with age were observed in CBF ( = 0.017) and CMRO ( < 0.001). Meanwhile, Y revealed a significant decrease ( = 0.002) with a non-linear pattern ( = 0.013). The rate of change was 0.87, 2.26, and -0.24% per month for CBF, CMRO2, and Y, respectively. On the other hand, systemic parameters such as heart rate did not show a significant age dependence ( = 0.47). No white-matter-hyperintensities (WMH) were observed on the T-weighted image at any age of the mice. With age, the mouse brain revealed an increase in oxygen consumption. This observation is consistent with previous findings in humans using a cross-sectional design and suggests a degradation of the brain's energy production or utilization machinery. Cerebral perfusion remains relatively intact in aged mice, at least until 20 months of age, consistent with the absence of WMH in mice.
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http://dx.doi.org/10.3389/fneur.2020.00559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304368PMC
June 2020

Five-year longitudinal changes in quantitative spinal cord MRI in multiple sclerosis.

Mult Scler 2021 04 1;27(4):549-558. Epub 2020 Jun 1.

Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

Background: The spinal cord (SC) is highly relevant to disability in multiple sclerosis (MS), but few studies have evaluated longitudinal changes in quantitative spinal cord magnetic resonance imaging (SC-MRI).

Objectives: The aim of this study was to characterize the relationships between 5-year changes in SC-MRI with disability in MS.

Methods: In total, 75 MS patients underwent 3 T SC-MRI and clinical assessment (expanded disability status scale (EDSS) and MS functional composite (MSFC)) at baseline, 2 and 5 years. SC-cross-sectional area (CSA) and diffusion-tensor indices (fractional anisotropy (FA), mean, perpendicular, parallel diffusivity (MD, λ, λ) and magnetization transfer ratio (MTR)) were extracted at C3-C4. Mixed-effects regression incorporating subject-specific slopes assessed longitudinal change in SC-MRI measures.

Results: SC-CSA and MTR decreased ( = 0.009,  = 0.03) over 5.1 years. There were moderate correlations between 2- and 5-year subject-specific slopes of SC-MRI indices and follow-up EDSS scores (Pearson's with FA = -0.23 ( < 0.001); MD = 0.31 ( < 0.001); λ = 0.34 ( < 0.001); λ = -0.12 ( = 0.05), MTR = -0.37 ( < 0.001); SC-CSA = -0.47 ( < 0.001) at 5 years); MSFC showed similar trends. The 2- and 5-year subject-specific slopes were robustly correlated ( = 0.93-0.97 for FA, λ, SC-CSA and MTR, all s < 0.001).

Conclusion: In MS, certain quantitative SC-MRI indices change over 5 years, reflecting ongoing tissue changes. Subject-specific trajectories of SC-MRI index change at 2 and 5 years are strongly correlated and highly relevant to follow-up disability. These findings suggest that individual dynamics of change should be accounted for when interpreting longitudinal SC-MRI measures and that measuring short-term change is predictive of long-term clinical disability.
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http://dx.doi.org/10.1177/1352458520923970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704828PMC
April 2021

Altered d-glucose in brain parenchyma and cerebrospinal fluid of early Alzheimer's disease detected by dynamic glucose-enhanced MRI.

Sci Adv 2020 May 13;6(20):eaba3884. Epub 2020 May 13.

Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China.

Altered cerebral glucose uptake is one of the hallmarks of Alzheimer's disease (AD). A dynamic glucose-enhanced (DGE) magnetic resonance imaging (MRI) approach was developed to simultaneously monitor d-glucose uptake and clearance in both brain parenchyma and cerebrospinal fluid (CSF). We observed substantially higher uptake in parenchyma of young (6 months) transgenic AD mice compared to age-matched wild-type (WT) mice. Notably lower uptakes were observed in parenchyma and CSF of old (16 months) AD mice. Both young and old AD mice had an obviously slower CSF clearance than age-matched WT mice. This resembles recent reports of the hampered CSF clearance that leads to protein accumulation in the brain. These findings suggest that DGE MRI can identify altered glucose uptake and clearance in young AD mice upon the emergence of amyloid plaques. DGE MRI of brain parenchyma and CSF has potential for early AD stratification, especially at 3T clinical field strength MRI.
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http://dx.doi.org/10.1126/sciadv.aba3884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220384PMC
May 2020

Improved velocity-selective-inversion arterial spin labeling for cerebral blood flow mapping with 3D acquisition.

Magn Reson Med 2020 11 13;84(5):2512-2522. Epub 2020 May 13.

The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Purpose: To further optimize the velocity-selective arterial spin labeling (VSASL) sequence utilizing a Fourier-transform based velocity-selective inversion (FT-VSI) pulse train, and to evaluate its utility for 3D mapping of cerebral blood flow (CBF) with a gradient- and spin-echo (GRASE) readout.

Methods: First, numerical simulations and phantom experiments were done to test the susceptibility to eddy currents and B field inhomogeneities for FT-VSI pulse trains with block and composite refocusing pulses. Second, the choices of the post-labeling delay (PLD) for FT-VSI prepared 3D VSASL were evaluated for the sensitivity to perfusion signal. The study was conducted among a young-age and a middle-age group at 3T. Both signal-to-noise ratio (SNR) and CBF were quantitatively compared with pseudo-continuous ASL (PCASL). The optimized 3D VSI-ASL was also qualitatively compared with PCASL in a whole-brain coverage among two healthy volunteers and a brain tumor patient.

Results: The simulations and phantom test showed that composite refocusing pulses are more robust to both eddy-currents and B field inhomogeneities than block pulses. 3D VSASL images with FT-VSI preparation were acquired over a range of PLDs and PLD = 1.2 s was selected for its higher perfusion signal. FT-VSI labeling produced quantitative CBF maps with 27% higher SNR in gray matter compared to PCASL. 3D whole-brain CBF mapping using VSI-ASL were comparable to the corresponding PCASL results.

Conclusion: FT-VSI with 3D-GRASE readout was successfully implemented and showed higher sensitivity to perfusion signal than PCASL for both young and middle-aged healthy volunteers.
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http://dx.doi.org/10.1002/mrm.28310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402012PMC
November 2020

APOE4 moderates effects of cortical iron on synchronized default mode network activity in cognitively healthy old-aged adults.

Alzheimers Dement (Amst) 2020 7;12(1):e12002. Epub 2020 Feb 7.

Institute for Regenerative Medicine University of Zurich Zurich Switzerland.

Introduction: Apolipoprotein E ε4 (APOE4)-related genetic risk for sporadic Alzheimer's disease is associated with an early impairment of cognitive brain networks. The current study determines relationships between APOE4 carrier status, cortical iron, and cortical network-functionality.

Methods: Sixty-nine cognitively healthy old-aged individuals (mean age [SD] 66.1 [± 7.2] years; Mini-Mental State Exam [MMSE] 29.3 ± 1.1) were genotyped for APOE4 carrier-status and received 3 Tesla magnetic resonance imaging (MRI) for blood oxygen level-dependent functional magnetic resonance imaging (MRI) at rest, three-dimensional (3D)-gradient echo (six echoes) for cortical gray-matter, non-heme iron by quantitative susceptibility mapping, and 18F-flutemetamol positron emission tomography for amyloid-β.

Results: A spatial pattern consistent with the default mode network (DMN) could be identified by independent component analysis. DMN activity was enhanced in APOE4 carriers and related to cortical iron burden. APOE4 and cortical iron synergistically interacted with DMN activity. Secondary analysis revealed a positive, APOE4 associated, relationship between cortical iron and DMN connectivity.

Discussion: Our findings suggest that APOE4 moderates effects of iron on brain functionality prior to manifestation of cognitive impairment.
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http://dx.doi.org/10.1002/dad2.12002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085281PMC
February 2020

Spectroscopic measurements of metabolic fluxes.

Nat Biomed Eng 2020 03;4(3):254-256

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1038/s41551-020-0535-8DOI Listing
March 2020

In vivo imaging of phosphocreatine with artificial neural networks.

Nat Commun 2020 02 26;11(1):1072. Epub 2020 Feb 26.

F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, USA.

Phosphocreatine (PCr) plays a vital role in neuron and myocyte energy homeostasis. Currently, there are no routine diagnostic tests to noninvasively map PCr distribution with clinically relevant spatial resolution and scan time. Here, we demonstrate that artificial neural network-based chemical exchange saturation transfer (ANNCEST) can be used to rapidly quantify PCr concentration with robust immunity to commonly seen MRI interferences. High-quality PCr mapping of human skeletal muscle, as well as the information of exchange rate, magnetic field and radio-frequency transmission inhomogeneities, can be obtained within 1.5 min on a 3 T standard MRI scanner using ANNCEST. For further validation, we apply ANNCEST to measure the PCr concentrations in exercised skeletal muscle. The ANNCEST outcomes strongly correlate with those from P magnetic resonance spectroscopy (R = 0.813, p < 0.001, t test). These results suggest that ANNCEST has potential as a cost-effective and widely available method for measuring PCr and diagnosing related diseases.
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http://dx.doi.org/10.1038/s41467-020-14874-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044432PMC
February 2020

Quantitative theory for the transverse relaxation time of blood water.

NMR Biomed 2020 05 5;33(5):e4207. Epub 2020 Feb 5.

Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

An integrative model is proposed to describe the dependence of the transverse relaxation rate of blood water protons (R = 1/T ) on hematocrit fraction and oxygenation fraction (Y). This unified model takes into account (a) the diamagnetic effects of albumin, hemoglobin and the cell membrane; (b) the paramagnetic effect of hemoglobin; (c) the effect of compartmental exchange between plasma and erythrocytes under both fast and slow exchange conditions that vary depending on field strength and compartmental relaxation rates and (d) the effect of diffusion through field gradients near the erythrocyte membrane. To validate the model, whole-blood and lysed-blood R data acquired previously using Carr-Purcell-Meiboom-Gill measurements as a function of inter-echo spacing τ at magnetic fields of 3.0, 7.0, 9.4 and 11.7 T were fitted to determine the lifetimes (field-independent physiological constants) for water diffusion and exchange, as well as several physical constants, some of which are field-independent (magnetic susceptibilities) and some are field-dependent (relaxation rates for water protons in solutions of albumin and oxygenated and deoxygenated hemoglobin, ie, blood plasma and erythrocytes, respectively). This combined exchange-diffusion model allowed excellent fitting of the curve of the τ -dependent relaxation rate dispersion at all four fields using a single average erythrocyte water lifetime, τ = 9.1 ± 1.4 ms, and an averaged diffusional correlation time, τ = 3.15 ± 0.43 ms. Using this model and the determined physiological time constants and relaxation parameters, blood T values published by multiple groups based on measurements at magnetic field strengths of 1.5 T and higher could be predicted correctly within error. Establishment of this theory is a fundamental step for quantitative modeling of the BOLD effect underlying functional MRI.
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http://dx.doi.org/10.1002/nbm.4207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322972PMC
May 2020

Magnetic resonance imaging of glycogen using its magnetic coupling with water.

Proc Natl Acad Sci U S A 2020 02 30;117(6):3144-3149. Epub 2020 Jan 30.

Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;

Glycogen plays a central role in glucose homeostasis and is abundant in several types of tissue. We report an MRI method for imaging glycogen noninvasively with enhanced detection sensitivity and high specificity, using the magnetic coupling between glycogen and water protons through the nuclear Overhauser enhancement (NOE). We show in vitro that the glycogen NOE (glycoNOE) signal is correlated linearly with glycogen concentration, while pH and temperature have little effect on its intensity. For validation, we imaged glycoNOE signal changes in mouse liver, both before and after fasting and during glucagon infusion. The glycoNOE signal was reduced by 88 ± 16% ( = 5) after 24 h of fasting and by 76 ± 22% ( = 5) at 1 h after intraperitoneal (i.p.) injection of glucagon, which is known to rapidly deplete hepatic glycogen. The ability to noninvasively image glycogen should allow assessment of diseases in which glucose metabolism or storage is altered, for instance, diabetes, cardiac disease, muscular disorders, cancer, and glycogen storage diseases.
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http://dx.doi.org/10.1073/pnas.1909921117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022182PMC
February 2020

d-glucose weighted chemical exchange saturation transfer (glucoCEST)-based dynamic glucose enhanced (DGE) MRI at 3T: early experience in healthy volunteers and brain tumor patients.

Magn Reson Med 2020 07 24;84(1):247-262. Epub 2019 Dec 24.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: Dynamic glucose enhanced (DGE) MRI has shown potential for imaging glucose delivery and blood-brain barrier permeability at fields of 7T and higher. Here, we evaluated issues involved with translating d-glucose weighted chemical exchange saturation transfer (glucoCEST) experiments to the clinical field strength of 3T.

Methods: Exchange rates of the different hydroxyl proton pools and the field-dependent T relaxivity of water in d-glucose solution were used to simulate the water saturation spectra (Z-spectra) and DGE signal differences as a function of static field strength B , radiofrequency field strength B , and saturation time t . Multislice DGE experiments were performed at 3T on 5 healthy volunteers and 3 glioma patients.

Results: Simulations showed that DGE signal decreases with B , because of decreased contributions of glucoCEST and transverse relaxivity, as well as coalescence of the hydroxyl and water proton signals in the Z-spectrum. At 3T, because of this coalescence and increased interference of direct water saturation and magnetization transfer contrast, the DGE effect can be assessed over a broad range of saturation frequencies. Multislice DGE experiments were performed in vivo using a B of 1.6 µT and a t of 1 second, leading to a small glucoCEST DGE effect at an offset frequency of 2 ppm from the water resonance. Motion correction was essential to detect DGE effects reliably.

Conclusion: Multislice glucoCEST-based DGE experiments can be performed at 3T with sufficient temporal resolution. However, the effects are small and prone to motion influence. Therefore, motion correction should be used when performing DGE experiments at clinical field strengths.
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http://dx.doi.org/10.1002/mrm.28124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083699PMC
July 2020