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Academic Appointments


  • Instructor, Radiology

Publications

All Publications


  • Assessment of acute bone loading in humans using [18F]NaF PET/MRI. European journal of nuclear medicine and molecular imaging Haddock, B., Fan, A. P., Uhlrich, S. D., Jorgensen, N. R., Suetta, C., Gold, G. E., Kogan, F. 2019

    Abstract

    PURPOSE: The acute effect of loading on bone tissue and physiology can offer important information with regard to joint function in diseases such as osteoarthritis. Imaging studies using [18F]-sodium fluoride ([18F]NaF) have found changes in tracer kinetics in animals after subjecting bones to strain, indicating an acute physiological response. The aim of this study is to measure acute changes in NaF uptake in human bone due to exercise-induced loading.METHODS: Twelve healthy subjects underwent two consecutive 50-min [18F]NaF PET/MRI examinations of the knees, one baseline followed by one post-exercise scan. Quantification of tracer kinetics was performed using an image-derived input function from the popliteal artery. For both scans, kinetic parameters of KiNLR, K1, k2, k3, and blood volume were mapped parametrically using nonlinear regression with the Hawkins model. The kinetic parameters along with mean SUV and SUVmax were compared between the pre- and post-exercise examinations. Differences in response to exercise were analysed between bone tissue types (subchondral, cortical, and trabecular bone) and between regional subsections of knee subchondral bone.RESULTS: Exercise induced a significant (p<<0.001) increase in [18F]NaF uptake in all bone tissues in both knees, with mean SUV increases ranging from 47% in trabecular bone tissue to 131% in subchondral bone tissue. Kinetic parameters involving vascularization (K1 and blood volume) increased, whereas the NaF extraction fraction [k3/(k2+k3)] was reduced.CONCLUSIONS: Bone loading induces an acute response in bone physiology as quantified by [18F]NaF PET kinetics. Dynamic imaging after bone loading using [18F]NaF PET is a promising diagnostic tool in bone physiology and imaging of biomechanics.

    View details for DOI 10.1007/s00259-019-04424-2

    View details for PubMedID 31385012

  • High resolution atlas of the venous brain vasculature from 7 T quantitative susceptibility maps. Brain structure & function Huck, J., Wanner, Y., Fan, A. P., Jager, A., Grahl, S., Schneider, U., Villringer, A., Steele, C. J., Tardif, C. L., Bazin, P., Gauthier, C. J. 2019

    Abstract

    The vascular organization of the human brain can determine neurological and neurophysiological functions, yet thus far it has not been comprehensively mapped. Aging and diseases such as dementia are known to be associated with changes to the vasculature and normative data could help detect these vascular changes in neuroimaging studies. Furthermore, given the well-known impact of venous vessels on the blood oxygen level dependent (BOLD) signal, information about the common location of veins could help detect biases in existing datasets. In this work, a quantitative atlas of the venous vasculature using quantitative susceptibility maps (QSM) acquired with a 0.6-mm isotropic resolution is presented. The Venous Neuroanatomy (VENAT) atlas was created from 5 repeated 7 Tesla MRI measurements in young and healthy volunteers (n=20, 10 females, mean age=25.1±2.5years) using a two-step registration method on 3D segmentations of the venous vasculature. This cerebral vein atlas includes the average vessel location, diameter (mean: 0.84±0.33mm) and curvature (0.11±0.05mm-1) from all participants and provides an in vivo measure of the angio-architectonic organization of the human brain and its variability. This atlas can be used as a basis to understand changes in the vasculature during aging and neurodegeneration, as well as vascular and physiological effects in neuroimaging.

    View details for DOI 10.1007/s00429-019-01919-4

    View details for PubMedID 31278570

  • Kinetic [F-18]-Fluoride of the Knee in Normal Volunteers CLINICAL NUCLEAR MEDICINE Haddock, B., Fan, A. P., Jorgensen, N. R., Suetta, C., Gold, G., Kogan, F. 2019; 44 (5): 377–85
  • Impact of attenuation correction on image-derived input functions and cerebral blood flow quantification with simultaneous [O-15]-water PET/MRI Hjoernevik, T., Khalighi, M., Kaushik, S., Ishii, Y., Zaharchuk, G., Fan, A. SOC NUCLEAR MEDICINE INC. 2019
  • Elevated brain oxygen extraction fraction measured by MRI susceptibility relates to perfusion status in acute ischemic stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Fan, A. P., Khalil, A. A., Fiebach, J. B., Zaharchuk, G., Villringer, A., Villringer, K., Gauthier, C. J. 2019: 271678X19827944

    Abstract

    Recent clinical trials of new revascularization therapies in acute ischemic stroke have highlighted the importance of physiological imaging to identify optimal treatments for patients. Oxygen extraction fraction (OEF) is a hallmark of at-risk tissue in stroke, and can be quantified from the susceptibility effect of deoxyhemoglobin molecules in venous blood on MRI phase scans. We measured OEF within cerebral veins using advanced quantitative susceptibility mapping (QSM) MRI reconstructions in 20 acute stroke patients. Absolute OEF was elevated in the affected (29.3±3.4%) versus the contralateral hemisphere (25.5±3.1%) of patients with large diffusion-perfusion lesion mismatch ( P=0.032). In these patients, OEF negatively correlated with relative CBF measured by dynamic susceptibility contrast MRI ( P=0.004), suggesting compensation for reduced flow. Patients with perfusion-diffusion match or no hypo-perfusion showed less OEF difference between hemispheres. Nine patients received longitudinal assessment and showed OEF ratio (affected to contralateral) of 1.2±0.1 at baseline that normalized (decreased) to 1.0±0.1 at follow-up three days later ( P=0.03). Our feasibility study demonstrates that QSM MRI can non-invasively quantify OEF in stroke patients, relates to perfusion status, and is sensitive to OEF changes over time. Clinical trial registration: Longitudinal MRI examinations of patients with brain ischemia and blood brain barrier permeability; clinicaltrials.org : NCT02077582.

    View details for PubMedID 30732551

  • Identifying Hypoperfusion in Moyamoya Disease With Arterial Spin Labeling and an [O-15]-Water Positron Emission Tomography/Magnetic Resonance Imaging Normative Database STROKE Fan, A. P., Khalighi, M. M., Guo, J., Ishii, Y., Rosenberg, J., Wardak, M., Park, J., Shen, B., Holley, D., Gandhi, H., Haywood, T., Singh, P., Steinberg, G. K., Chin, F. T., Zaharchuk, G. 2019; 50 (2): 373–80
  • Simultaneous phase-contrast MRI and PET for noninvasive quantification of cerebral blood flow and reactivity in healthy subjects and patients with cerebrovascular disease. Journal of magnetic resonance imaging : JMRI Ishii, Y., Thamm, T., Guo, J., Khalighi, M. M., Wardak, M., Holley, D., Gandhi, H., Park, J. H., Shen, B., Steinberg, G. K., Chin, F. T., Zaharchuk, G., Fan, A. P. 2019

    Abstract

    H215 O-positron emission tomography (PET) is considered the reference standard for absolute cerebral blood flow (CBF). However, this technique requires an arterial input function measured through continuous sampling of arterial blood, which is invasive and has limitations with tracer delay and dispersion.To demonstrate a new noninvasive method to quantify absolute CBF with a PET/MRI hybrid scanner. This blood-free approach, called PC-PET, takes the spatial CBF distribution from a static H215 O-PET scan, and scales it to the whole-brain average CBF value measured by simultaneous phase-contrast MRI.Observational.Twelve healthy controls (HC) and 13 patients with Moyamoya disease (MM) as a model of chronic ischemic disease.3T/2D cardiac-gated phase-contrast MRI and H215 O-PET.PC-PET CBF values from whole brain (WB), gray matter (GM), and white matter (WM) in HCs were compared with literature values since 2000. CBF and cerebrovascular reactivity (CVR), which is defined as the percent CBF change between baseline and post-acetazolamide (vasodilator) scans, were measured by PC-PET in MM patients and HCs within cortical regions corresponding to major vascular territories. Statistical Tests: Linear, mixed effects models were created to compare CBF and CVR, respectively, between patients and controls, and between different degrees of stenosis.The mean CBF values in WB, GM, and WM in HC were 42 ± 7 ml/100 g/min, 50 ± 7 ml/100 g/min, and 23 ± 3 ml/100 g/min, respectively, which agree well with literature values. Compared with normal regions (57 ± 23%), patients showed significantly decreased CVR in areas with mild/moderate stenosis (47 ± 17%, P = 0.011) and in severe/occluded areas (40 ± 16%, P = 0.016). Data Conclusion: PC-PET identifies differences in cerebrovascular reactivity between healthy controls and cerebrovascular patients. PC-PET is suitable for CBF measurement when arterial blood sampling is not accessible, and warrants comparison to fully quantitative H215 O-PET in future studies.3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019.

    View details for PubMedID 31044459

  • Consensus statement on current and emerging methods for the diagnosis and evaluation of cerebrovascular disease JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Donahue, M. J., Achten, E., Cogswell, P. M., De Leeuw, F., Derdeyn, C. P., Dijkhuizen, R. M., Fan, A. P., Ghaznawi, R., Heit, J. J., Ikram, M., Jezzard, P., Jordan, L. C., Jouvent, E., Knutsson, L., Leigh, R., Liebeskind, D. S., Lin, W., Okell, T. W., Qureshi, A. I., Stagg, C. J., van Osch, M. P., van Zijl, P. M., Watchmaker, J. M., Wintermark, M., Wu, O., Zaharchuk, G., Zhou, J., Hendrikse, J. 2018; 38 (9): 1391–1417

    Abstract

    Cerebrovascular disease (CVD) remains a leading cause of death and the leading cause of adult disability in most developed countries. This work summarizes state-of-the-art, and possible future, diagnostic and evaluation approaches in multiple stages of CVD, including (i) visualization of sub-clinical disease processes, (ii) acute stroke theranostics, and (iii) characterization of post-stroke recovery mechanisms. Underlying pathophysiology as it relates to large vessel steno-occlusive disease and the impact of this macrovascular disease on tissue-level viability, hemodynamics (cerebral blood flow, cerebral blood volume, and mean transit time), and metabolism (cerebral metabolic rate of oxygen consumption and pH) are also discussed in the context of emerging neuroimaging protocols with sensitivity to these factors. The overall purpose is to highlight advancements in stroke care and diagnostics and to provide a general overview of emerging research topics that have potential for reducing morbidity in multiple areas of CVD.

    View details for PubMedID 28816594

  • Comparing accuracy and reproducibility of sequential and Hadamard-encoded multidelay pseudocontinuous arterial spin labeling for measuring cerebral blood flow and arterial transit time in healthy subjects: A simulation and in vivo study JOURNAL OF MAGNETIC RESONANCE IMAGING Guo, J., Holdsworth, S. J., Fan, A. P., Lebel, M. R., Zun, Z., Shankaranarayanan, A., Zaharchuk, G. 2018; 47 (4): 1119–32

    Abstract

    To compare performance of sequential and Hadamard-encoded pseudocontinuous arterial spin labeling (PCASL).Monte Carlo simulations and in vivo experiments were performed in 10 healthy subjects. Field strength and sequence: 5-delay sequential (5-del. Seq.), 7-delay Hadamard-encoded (7-del. Had.), and a single-delay (1-del.) PCASL, without and with vascular crushing at 3.0T. The errors and variations of cerebral blood flow (CBF) and arterial transit time (ATT) from simulations and the CBF and ATT estimates and variations in gray matter (GM) with different ATT ranges were compared. Pairwise t-tests with Bonferroni correction were used.The simulations and in vivo experiments showed that 1-del. PCASL underestimated GM CBF due to insufficient postlabeling delay (PLD) (37.2 ± 8.1 vs. 47.3 ± 8.5 and 47.3 ± 9.0 ml/100g/min, P ≤ 6.5 × 10-6 ), while 5-del. Seq. and 7-del. Had. yielded comparable GM CBF (P ≥ 0.49). 5-del. Seq. was more reproducible for CBF (P = 4.7 × 10-4 ), while 7-del. Had. was more reproducible for ATT (P = 0.033). 5-del. Seq. was more prone to intravascular artifacts and yielded lower GM ATTs compared to 7-del. Had. without crushing (1.13 ± 0.18 vs. 1.23 ± 0.13 seconds, P = 2.3 × 10-3 ), but they gave comparable ATTs with crushing (P = 0.12). ATTs measured with crushing were longer than those without crushing (P ≤ 6.7 × 10-4 ), but CBF was not affected (P ≥ 0.16).The theoretical signal-to-noise ratio (SNR) gain through Hadamard encoding was confirmed experimentally. For 1-del., a PLD of 1.8 seconds is recommended for healthy subjects. With current parameters, 5-del. Seq. was more reproducible for CBF, and 7-del. Had. for ATT. Vascular crushing may help reduce variations in multidelay experiments without compromising tissue CBF or ATT measurements.1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1119-1132.

    View details for PubMedID 28792653

    View details for PubMedCentralID PMC5807238

  • PET/MRI of Metabolic Activity in Osteoarthritis: A Feasibility Study JOURNAL OF MAGNETIC RESONANCE IMAGING Kogan, F., Fan, A. P., McWalter, E. J., Oei, E. H., Quon, A., Gold, G. E. 2017; 45 (6): 1736-1745

    Abstract

    To evaluate positron emission tomography / magnetic resonance imaging (PET/MRI) knee imaging to detect and characterize osseous metabolic abnormalities and correlate PET radiotracer uptake with osseous abnormalities and cartilage degeneration observed on MRI.Both knees of 22 subjects with knee pain or injury were scanned at one timepoint, without gadolinium, on a hybrid 3.0T PET-MRI system following injection of (18) F-fluoride or (18) F-fluorodeoxyglucose (FDG). A musculoskeletal radiologist identified volumes of interest (VOIs) around bone abnormalities on MR images and scored bone marrow lesions (BMLs) and osteophytes using a MOAKS scoring system. Cartilage appearance adjacent to bone abnormalities was graded with MRI-modified Outerbridge classifications. On PET standardized uptake values (SUV) maps, VOIs with SUV greater than 5 times the SUV in normal-appearing bone were identified as high-uptake VOI (VOIHigh ). Differences in (18) F-fluoride uptake between bone abnormalities, BML, and osteophyte grades and adjacent cartilage grades on MRI were identified using Mann-Whitney U-tests.SUVmax in all subchondral bone lesions (BML, osteophytes, sclerosis) was significantly higher than that of normal-appearing bone on MRI (P < 0.001 for all). Of the 172 high-uptake regions on (18) F-fluoride PET, 63 (37%) corresponded to normal-appearing subchondral bone on MRI. Furthermore, many small grade 1 osteophytes (40 of 82 [49%]), often described as the earliest signs of osteoarthritis (OA), did not show high uptake. Lastly, PET SUVmax in subchondral bone adjacent to grade 0 cartilage was significantly lower compared to that of grades 1-2 (P < 0.05) and grades 3-4 cartilage (P < 0.001).PET/MRI can simultaneously assess multiple early metabolic and morphologic markers of knee OA across multiple tissues in the joint. Our findings suggest that PET/MR may detect metabolic abnormalities in subchondral bone, which appear normal on MRI.2 J. Magn. Reson. Imaging 2016.

    View details for DOI 10.1002/jmri.25529

    View details for Web of Science ID 000401259900018

  • Mitigation of Partial Volume Effects in Susceptibility-Based Oxygenation Measurements by Joint Utilization of Magnitude and Phase (JUMP) MAGNETIC RESONANCE IN MEDICINE McDaniel, P., Bilgic, B., Fan, A. P., Stout, J. N., Adalsteinsson, E. 2017; 77 (4): 1713-1727

    View details for DOI 10.1002/mrm.26227

    View details for Web of Science ID 000398085200035

  • Improved Quantification of Cerebral Vein Oxygenation Using Partial Volume Correction FRONTIERS IN NEUROSCIENCE Ward, P. G., Fan, A. P., Raniga, P., Barnes, D. G., Dowe, D. L., Ng, A. C., Egan, G. F. 2017; 11

    Abstract

    Purpose: Quantitative susceptibility mapping (QSM) enables cerebral venous characterization and physiological measurements, such as oxygen extraction fraction (OEF). The exquisite sensitivity of QSM to deoxygenated blood makes it possible to image small veins; however partial volume effects must be addressed for accurate quantification. We present a new method, Iterative Cylindrical Fitting (ICF), to estimate voxel-based partial volume effects for susceptibility maps and use it to improve OEF quantification of small veins with diameters between 1.5 and 4 voxels. Materials and Methods: Simulated QSM maps were generated to assess the performance of the ICF method over a range of vein geometries with varying echo times and noise levels. The ICF method was also applied to in vivo human brain data to assess the feasibility and behavior of OEF measurements compared to the maximum intensity voxel (MIV) method. Results: Improved quantification of OEF measurements was achieved for vessels with contrast to noise greater than 3.0 and vein radii greater than 0.75 voxels. The ICF method produced improved quantitative accuracy of OEF measurement compared to the MIV approach (mean OEF error 7.7 vs. 12.4%). The ICF method provided estimates of vein radius (mean error <27%) and partial volume maps (root mean-squared error <13%). In vivo results demonstrated consistent estimates of OEF along vein segments. Conclusion: OEF quantification in small veins (1.5-4 voxels in diameter) had lower error when using partial volume estimates from the ICF method.

    View details for DOI 10.3389/fnins.2017.00089

    View details for PubMedID 28289372

  • Image-derived input function estimation on a TOF-enabled PET/MR for cerebral blood flow mapping. Journal of cerebral blood flow and metabolism Khalighi, M. M., Deller, T. W., Fan, A. P., Gulaka, P. K., Shen, B., Singh, P., Park, J., Chin, F. T., Zaharchuk, G. 2017: 271678X17691784-?

    Abstract

    (15)O-H2O PET imaging is an accurate method to measure cerebral blood flow (CBF) but it requires an arterial input function (AIF). Historically, image-derived AIF estimation suffers from low temporal resolution, spill-in, and spill-over problems. Here, we optimized tracer dose on a time-of-flight PET/MR according to the acquisition-specific noise-equivalent count rate curve. An optimized dose of 850 MBq of (15)O-H2O was determined, which allowed sufficient counts to reconstruct a short time-frame PET angiogram (PETA) during the arterial phase. This PETA enabled the measurement of the extent of spill-over, while an MR angiogram was used to measure the true arterial volume for AIF estimation. A segment of the high cervical arteries outside the brain was chosen, where the measured spill-in effects were minimal. CBF studies were performed twice with separate [15O]-H2O injections in 10 healthy subjects, yielding values of 88 ± 16, 44 ± 9, and 58 ± 11 mL/min/100 g for gray matter, white matter, and whole brain, with intra-subject CBF differences of 5.0 ± 4.0%, 4.1 ± 3.3%, and 4.5 ± 3.7%, respectively. A third CBF measurement after the administration of 1 g of acetazolamide showed 35 ± 23%, 29 ± 20%, and 33 ± 22% increase in gray matter, white matter, and whole brain, respectively. Based on these findings, the proposed noninvasive AIF method provides robust CBF measurement with (15)O-H2O PET.

    View details for DOI 10.1177/0271678X17691784

    View details for PubMedID 28155582

  • Long-Delay Arterial Spin Labeling Provides More Accurate Cerebral Blood Flow Measurements in Moyamoya Patients: A Simultaneous Positron Emission Tomography/MRI Study. Stroke Fan, A. P., Guo, J., Khalighi, M. M., Gulaka, P. K., Shen, B., Park, J. H., Gandhi, H., Holley, D., Rutledge, O., Singh, P., Haywood, T., Steinberg, G. K., Chin, F. T., Zaharchuk, G. 2017; 48 (9): 2441–49

    Abstract

    Arterial spin labeling (ASL) MRI is a promising, noninvasive technique to image cerebral blood flow (CBF) but is difficult to use in cerebrovascular patients with abnormal, long arterial transit times through collateral pathways. To be clinically adopted, ASL must first be optimized and validated against a reference standard in these challenging patient cases.We compared standard-delay ASL (post-label delay=2.025 seconds), multidelay ASL (post-label delay=0.7-3.0 seconds), and long-label long-delay ASL acquisitions (post-label delay=4.0 seconds) against simultaneous [15O]-positron emission tomography (PET) CBF maps in 15 Moyamoya patients on a hybrid PET/MRI scanner. Dynamic susceptibility contrast was performed in each patient to identify areas of mild, moderate, and severe time-to-maximum (Tmax) delays. Relative CBF measurements by each ASL scan in 20 cortical regions were compared with the PET reference standard, and correlations were calculated for areas with moderate and severe Tmax delays.Standard-delay ASL underestimated relative CBF by 20% in areas of severe Tmax delays, particularly in anterior and middle territories commonly affected by Moyamoya disease (P<0.001). Arterial transit times correction by multidelay acquisitions led to improved consistency with PET, but still underestimated CBF in the presence of long transit delays (P=0.02). Long-label long-delay ASL scans showed the strongest correlation relative to PET, and there was no difference in mean relative CBF between the modalities, even in areas of severe delays.Post-label delay times of ≥4 seconds are needed and may be combined with multidelay strategies for robust ASL assessment of CBF in Moyamoya disease.

    View details for PubMedID 28765286

  • Potential of PET-MRI for imaging of non-oncologic musculoskeletal disease. Quantitative imaging in medicine and surgery Kogan, F., Fan, A. P., Gold, G. E. 2016; 6 (6): 756-771

    Abstract

    Early detection of musculoskeletal disease leads to improved therapies and patient outcomes, and would benefit greatly from imaging at the cellular and molecular level. As it becomes clear that assessment of multiple tissues and functional processes are often necessary to study the complex pathogenesis of musculoskeletal disorders, the role of multi-modality molecular imaging becomes increasingly important. New positron emission tomography-magnetic resonance imaging (PET-MRI) systems offer to combine high-resolution MRI with simultaneous molecular information from PET to study the multifaceted processes involved in numerous musculoskeletal disorders. In this article, we aim to outline the potential clinical utility of hybrid PET-MRI to these non-oncologic musculoskeletal diseases. We summarize current applications of PET molecular imaging in osteoarthritis (OA), rheumatoid arthritis (RA), metabolic bone diseases and neuropathic peripheral pain. Advanced MRI approaches that reveal biochemical and functional information offer complementary assessment in soft tissues. Additionally, we discuss technical considerations for hybrid PET-MR imaging including MR attenuation correction, workflow, radiation dose, and quantification.

    View details for DOI 10.21037/qims.2016.12.16

    View details for PubMedID 28090451

  • PET/MRI of metabolic activity in osteoarthritis: A feasibility study. Journal of magnetic resonance imaging : JMRI Kogan, F., Fan, A. P., McWalter, E. J., Oei, E. H., Quon, A., Gold, G. E. 2016

    Abstract

    To evaluate positron emission tomography / magnetic resonance imaging (PET/MRI) knee imaging to detect and characterize osseous metabolic abnormalities and correlate PET radiotracer uptake with osseous abnormalities and cartilage degeneration observed on MRI.Both knees of 22 subjects with knee pain or injury were scanned at one timepoint, without gadolinium, on a hybrid 3.0T PET-MRI system following injection of (18) F-fluoride or (18) F-fluorodeoxyglucose (FDG). A musculoskeletal radiologist identified volumes of interest (VOIs) around bone abnormalities on MR images and scored bone marrow lesions (BMLs) and osteophytes using a MOAKS scoring system. Cartilage appearance adjacent to bone abnormalities was graded with MRI-modified Outerbridge classifications. On PET standardized uptake values (SUV) maps, VOIs with SUV greater than 5 times the SUV in normal-appearing bone were identified as high-uptake VOI (VOIHigh ). Differences in (18) F-fluoride uptake between bone abnormalities, BML, and osteophyte grades and adjacent cartilage grades on MRI were identified using Mann-Whitney U-tests.SUVmax in all subchondral bone lesions (BML, osteophytes, sclerosis) was significantly higher than that of normal-appearing bone on MRI (P < 0.001 for all). Of the 172 high-uptake regions on (18) F-fluoride PET, 63 (37%) corresponded to normal-appearing subchondral bone on MRI. Furthermore, many small grade 1 osteophytes (40 of 82 [49%]), often described as the earliest signs of osteoarthritis (OA), did not show high uptake. Lastly, PET SUVmax in subchondral bone adjacent to grade 0 cartilage was significantly lower compared to that of grades 1-2 (P < 0.05) and grades 3-4 cartilage (P < 0.001).PET/MRI can simultaneously assess multiple early metabolic and morphologic markers of knee OA across multiple tissues in the joint. Our findings suggest that PET/MR may detect metabolic abnormalities in subchondral bone, which appear normal on MRI.2 J. Magn. Reson. Imaging 2016.

    View details for DOI 10.1002/jmri.25529

    View details for PubMedID 27796082

  • Comparison of cerebral blood flow measurement with [O-15]-water positron emission tomography and arterial spin labeling magnetic resonance imaging: A systematic review JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Fan, A. P., Jahanian, H., Holdsworth, S. J., Zaharchuk, G. 2016; 36 (5): 842-861

    Abstract

    Noninvasive imaging of cerebral blood flow provides critical information to understand normal brain physiology as well as to identify and manage patients with neurological disorders. To date, the reference standard for cerebral blood flow measurements is considered to be positron emission tomography using injection of the [(15)O]-water radiotracer. Although [(15)O]-water has been used to study brain perfusion under normal and pathological conditions, it is not widely used in clinical settings due to the need for an on-site cyclotron, the invasive nature of arterial blood sampling, and experimental complexity. As an alternative, arterial spin labeling is a promising magnetic resonance imaging technique that magnetically labels arterial blood as it flows into the brain to map cerebral blood flow. As arterial spin labeling becomes more widely adopted in research and clinical settings, efforts have sought to standardize the method and validate its cerebral blood flow values against positron emission tomography-based cerebral blood flow measurements. The purpose of this work is to critically review studies that performed both [(15)O]-water positron emission tomography and arterial spin labeling to measure brain perfusion, with the aim of better understanding the accuracy and reproducibility of arterial spin labeling relative to the positron emission tomography reference standard.

    View details for DOI 10.1177/0271678X16636393

    View details for Web of Science ID 000375261800002

    View details for PubMedID 26945019

    View details for PubMedCentralID PMC4853843

  • Mitigation of partial volume effects in susceptibility-based oxygenation measurements by joint utilization of magnitude and phase (JUMP). Magnetic resonance in medicine McDaniel, P., Bilgic, B., Fan, A. P., Stout, J. N., Adalsteinsson, E. 2016: -?

    Abstract

    Susceptibility-based blood oxygenation measurements in small vessels of the brain derive from gradient echo (GRE) phase and can provide localized assessment of brain function and pathology. However, when vessel diameter becomes smaller than the acquisition voxel size, partial volume effects compromise these measurements. The purpose of this study was to develop a technique to improve the reliability of vessel oxygenation estimates in the presence of partial volume effects.Intravoxel susceptibility variations are present when a vessel and parenchyma experience partial volume effects, modifying the voxel's GRE phase signal and attenuating the GRE magnitude signal. Using joint utilization of magnitude and phase (JUMP), both vessel susceptibility and voxel partial volume fraction can be estimated, providing measurements of venous oxygen saturation ( Yv) in straight, nearly vertical vessels that have improved robustness to partial volume effects.JUMP was demonstrated by estimating vessel Yv in numerical and in vivo experiments. Deviations from ground truth of Yv measurements in vessels tilted up to 30° from B0 were reduced by over 50% when using JUMP compared with phase-only techniques.JUMP exploits both magnitude and phase data in GRE imaging to mitigate partial volume effects in estimation of vessel oxygenation. Magn Reson Med, 2016. © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/mrm.26227

    View details for PubMedID 27059521

    View details for PubMedCentralID PMC5052095

  • Susceptibility-based time-resolved whole-organ and regional tissue oximetry. NMR in biomedicine Wehrli, F. W., Fan, A. P., Rodgers, Z. B., Englund, E. K., Langham, M. C. 2016

    Abstract

    The magnetism of hemoglobin - being paramagnetic in its deoxy and diamagnetic in its oxy state - offers unique opportunities to probe oxygen metabolism in blood and tissues. The magnetic susceptibility χ of blood scales linearly with blood oxygen saturation, which can be obtained by measuring the magnetic field ΔB of the intravascular MR signal relative to tissue. In contrast to χ, the induced field ΔB is non-local. Therefore, to obtain the intravascular susceptibility Δχ relative to adjoining tissue from the measured ΔB demands solution of an inverse problem. Fortunately, for ellipsoidal structures, to which a straight, cylindrically shaped blood vessel segment conforms, the solution is trivial. The article reviews the principle of MR susceptometry-based blood oximetry. It then discusses applications for quantification of whole-brain oxygen extraction - typically on the basis of a measurement in the superior sagittal sinus - and, in conjunction with total cerebral blood flow, the cerebral metabolic rate of oxygen (CMRO2 ). By simultaneously measuring flow and venous oxygen saturation (SvO2 ) a temporal resolution of a few seconds can be achieved, allowing the study of the response to non-steady-state challenges such as volitional apnea. Extensions to regional measurements in smaller cerebral veins are also possible, as well as voxelwise quantification of venous blood saturation in cerebral veins accomplished by quantitative susceptibility mapping (QSM) techniques. Applications of susceptometry-based oximetry to studies of metabolic and degenerative disorders of the brain are reviewed. Lastly, the technique is shown to be applicable to other organ systems such as the extremities using SvO2 as a dynamic tracer to monitor the kinetics of the microvascular response to induced ischemia. Copyright © 2016 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/nbm.3495

    View details for PubMedID 26918319

    View details for PubMedCentralID PMC5001941

  • Baseline oxygenation in the brain: Correlation between respiratory-calibration and susceptibility methods NEUROIMAGE Fan, A. P., Schaefer, A., Huber, L., Lampe, L., von Smuda, S., Moeller, H. E., Villringer, A., Gauthier, C. J. 2016; 125: 920-931

    View details for DOI 10.1016/j.neuroimage.2015.11.007

    View details for PubMedID 26549301

  • Potential of PET-MRI for imaging of non-oncologic musculoskeletal disease Quantitative Imaging in Medicine and Surgery Kogan, F., Fan, A. P., Gold, G. E. 2016; 6 (6): 756-771

    Abstract

    Early detection of musculoskeletal disease leads to improved therapies and patient outcomes, and would benefit greatly from imaging at the cellular and molecular level. As it becomes clear that assessment of multiple tissues and functional processes are often necessary to study the complex pathogenesis of musculoskeletal disorders, the role of multi-modality molecular imaging becomes increasingly important. New positron emission tomography-magnetic resonance imaging (PET-MRI) systems offer to combine high-resolution MRI with simultaneous molecular information from PET to study the multifaceted processes involved in numerous musculoskeletal disorders. In this article, we aim to outline the potential clinical utility of hybrid PET-MRI to these non-oncologic musculoskeletal diseases. We summarize current applications of PET molecular imaging in osteoarthritis (OA), rheumatoid arthritis (RA), metabolic bone diseases and neuropathic peripheral pain. Advanced MRI approaches that reveal biochemical and functional information offer complementary assessment in soft tissues. Additionally, we discuss technical considerations for hybrid PET-MR imaging including MR attenuation correction, workflow, radiation dose, and quantification.

    View details for DOI 10.21037/qims.2016.12.16

    View details for PubMedCentralID PMC5219958

  • Fast quantitative susceptibility mapping using 3D EPI and total generalized variation NEUROIMAGE Langkammer, C., Bredies, K., Poser, B. A., Barth, M., Reishofer, G., Fan, A. P., Bilgic, B., Fazekas, F., Mainero, C., Ropele, S. 2015; 111: 622-630

    Abstract

    Quantitative susceptibility mapping (QSM) allows new insights into tissue composition and organization by assessing its magnetic property. Previous QSM studies have already demonstrated that magnetic susceptibility is highly sensitive to myelin density and fiber orientation as well as to para- and diamagnetic trace elements. Image resolution in QSM with current approaches is limited by the long acquisition time of 3D scans and the need for high signal to noise ratio (SNR) to solve the dipole inversion problem. We here propose a new total-generalized-variation (TGV) based method for QSM reconstruction, which incorporates individual steps of phase unwrapping, background field removal and dipole inversion in a single iteration, thus yielding a robust solution to the reconstruction problem. This approach has beneficial characteristics for low SNR data, allowing for phase data to be rapidly acquired with a 3D echo planar imaging (EPI) sequence. The proposed method was evaluated with a numerical phantom and in vivo at 3 and 7 T. Compared to total variation (TV), TGV-QSM enforced higher order smoothness which yielded solutions closer to the ground truth and prevented stair-casing artifacts. The acquisition time for images with 1mm isotropic resolution and whole brain coverage was 10s on a clinical 3 Tesla scanner. In conclusion, 3D EPI acquisition combined with single-step TGV reconstruction yields reliable QSM images of the entire brain with 1mm isotropic resolution in seconds. The short acquisition time combined with the robust reconstruction may enable new QSM applications in less compliant populations, clinical susceptibility tensor imaging, and functional resting state examinations.

    View details for DOI 10.1016/j.neuroimage.2015.02.041

    View details for Web of Science ID 000352224100054

    View details for PubMedID 25731991

  • Regional quantification of cerebral venous oxygenation from MRI susceptibility during hypercapnia NEUROIMAGE Fan, A. P., Evans, K. C., Stout, J. N., Rosen, B. R., Adalsteinsson, E. 2015; 104: 146-155

    Abstract

    There is an unmet medical need for noninvasive imaging of regional brain oxygenation to manage stroke, tumor, and neurodegenerative diseases. Oxygenation imaging from magnetic susceptibility in MRI is a promising new technique to measure local venous oxygen extraction fraction (OEF) along the cerebral venous vasculature. However, this approach has not been tested in vivo at different levels of oxygenation. The primary goal of this study was to test whether susceptibility imaging of oxygenation can detect OEF changes induced by hypercapnia, via CO2 inhalation, within selected a priori brain regions. Ten healthy subjects were scanned at 3T with a 32-channel head coil. The end-tidal CO2 (ETCO2) was monitored continuously and inspired gases were adjusted to achieve steady-state conditions of eucapnia (41±3mmHg) and hypercapnia (50±4mmHg). Gradient echo phase images and pseudo-continuous arterial spin labeling (pcASL) images were acquired to measure regional OEF and CBF respectively during eucapnia and hypercapnia. By assuming constant cerebral oxygen consumption throughout both gas states, regional CBF values were computed to predict the local change in OEF in each brain region. Hypercapnia induced a relative decrease in OEF of -42.3% in the straight sinus, -39.9% in the internal cerebral veins, and approximately -50% in pial vessels draining each of the occipital, parietal, and frontal cortical areas. Across volunteers, regional changes in OEF correlated with changes in ETCO2. The reductions in regional OEF (via phase images) were significantly correlated (P<0.05) with predicted reductions in OEF derived from CBF data (via pcASL images). These findings suggest that susceptibility imaging is a promising technique for OEF measurements, and may serve as a clinical biomarker for brain conditions with aberrant regional oxygenation.

    View details for DOI 10.1016/j.neuroimage.2014.09.068

    View details for Web of Science ID 000345393800015

    View details for PubMedID 25300201

  • Quantitative oxygen extraction fraction from 7-Tesla MRI phase: reproducibility and application in multiple sclerosis JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Fan, A. P., Govindarajan, S. T., Kinkel, R. P., Madigan, N. K., Nielsen, A. S., Benner, T., Tinelli, E., Rosen, B. R., Adalsteinsson, E., Mainero, C. 2015; 35 (1): 131-139

    Abstract

    Quantitative oxygen extraction fraction (OEF) in cortical veins was studied in patients with multiple sclerosis (MS) and healthy subjects via magnetic resonance imaging (MRI) phase images at 7 Tesla (7 T). Flow-compensated, three-dimensional gradient-echo scans were acquired for absolute OEF quantification in 23 patients with MS and 14 age-matched controls. In patients, we collected T2*-weighted images for characterization of white matter, deep gray matter, and cortical lesions, and also assessed cognitive function. Variability of OEF across readers and scan sessions was evaluated in a subset of volunteers. OEF was averaged from 2 to 3 pial veins in the sensorimotor, parietal, and prefrontal cortical regions for each subject (total of ~10 vessels). We observed good reproducibility of mean OEF, with intraobserver coefficient of variation (COV)=2.1%, interobserver COV=5.2%, and scan-rescan COV=5.9%. Patients exhibited a 3.4% reduction in cortical OEF relative to controls (P=0.0025), which was not different across brain regions. Although oxygenation did not relate with measures of structural tissue damage, mean OEF correlated with a global measure of information processing speed. These findings suggest that cortical OEF from 7-T MRI phase is a reproducible metabolic biomarker that may be sensitive to different pathologic processes than structural MRI in patients with MS.

    View details for DOI 10.1038/jcbfm.2014.187

    View details for Web of Science ID 000347392200016

    View details for PubMedID 25352043

  • Fast Quantitative Susceptibility Mapping with L1-Regularization and Automatic Parameter Selection MAGNETIC RESONANCE IN MEDICINE Bilgic, B., Fan, A. P., Polimeni, J. R., Cauley, S. F., Bianciardi, M., Adalsteinsson, E., Wald, L. L., Setsompop, K. 2014; 72 (5): 1444-1459

    Abstract

    To enable fast reconstruction of quantitative susceptibility maps with total variation penalty and automatic regularization parameter selection.ℓ(1) -Regularized susceptibility mapping is accelerated by variable splitting, which allows closed-form evaluation of each iteration of the algorithm by soft thresholding and fast Fourier transforms. This fast algorithm also renders automatic regularization parameter estimation practical. A weighting mask derived from the magnitude signal can be incorporated to allow edge-aware regularization.Compared with the nonlinear conjugate gradient (CG) solver, the proposed method is 20 times faster. A complete pipeline including Laplacian phase unwrapping, background phase removal with SHARP filtering, and ℓ(1) -regularized dipole inversion at 0.6 mm isotropic resolution is completed in 1.2 min using MATLAB on a standard workstation compared with 22 min using the CG solver. This fast reconstruction allows estimation of regularization parameters with the L-curve method in 13 min, which would have taken 4 h with the CG algorithm. The proposed method also permits magnitude-weighted regularization, which prevents smoothing across edges identified on the magnitude signal. This more complicated optimization problem is solved 5 times faster than the nonlinear CG approach. Utility of the proposed method is also demonstrated in functional blood oxygen level-dependent susceptibility mapping, where processing of the massive time series dataset would otherwise be prohibitive with the CG solver.Online reconstruction of regularized susceptibility maps may become feasible with the proposed dipole inversion.

    View details for DOI 10.1002/mrm.25029

    View details for Web of Science ID 000343873900026

    View details for PubMedID 24259479

  • Quantitative Oxygenation Venography from MRI Phase MAGNETIC RESONANCE IN MEDICINE Fan, A. P., Bilgic, B., Gagnon, L., Witzel, T., Bhat, H., Rosen, B. R., Adalsteinsson, E. 2014; 72 (1): 149-159

    Abstract

    To demonstrate acquisition and processing methods for quantitative oxygenation venograms that map in vivo oxygen saturation (SvO2 ) along cerebral venous vasculature.Regularized quantitative susceptibility mapping (QSM) is used to reconstruct susceptibility values and estimate SvO2 in veins. QSM with ℓ1 and ℓ2 regularization are compared in numerical simulations of vessel structures with known magnetic susceptibility. Dual-echo, flow-compensated phase images are collected in three healthy volunteers to create QSM images. Bright veins in the susceptibility maps are vectorized and used to form a three-dimensional vascular mesh, or venogram, along which to display SvO2 values from QSM.Quantitative oxygenation venograms that map SvO2 along brain vessels of arbitrary orientation and geometry are shown in vivo. SvO2 values in major cerebral veins lie within the normal physiological range reported by (15) O positron emission tomography. SvO2 from QSM is consistent with previous MR susceptometry methods for vessel segments oriented parallel to the main magnetic field. In vessel simulations, ℓ1 regularization results in less than 10% SvO2 absolute error across all vessel tilt orientations and provides more accurate SvO2 estimation than ℓ2 regularization.The proposed analysis of susceptibility images enables reliable mapping of quantitative SvO2 along venograms and may facilitate clinical use of venous oxygenation imaging.

    View details for DOI 10.1002/mrm.24918

    View details for Web of Science ID 000337624400017

    View details for PubMedID 24006229

  • Phase-based regional oxygen metabolism (PROM) using MRI MAGNETIC RESONANCE IN MEDICINE Fan, A. P., Benner, T., Bolar, D. S., Rosen, B. R., Adalsteinsson, E. 2012; 67 (3): 669-678

    Abstract

    Venous oxygen saturation (Y(v) ) in cerebral veins and the cerebral metabolic rate of oxygen (CMRO(2)) are important indicators for brain function and disease. Although MRI has been used for global measurements of these parameters, currently there is no recognized technique to quantify regional Y(v) and CMRO(2) using noninvasive imaging. This article proposes a technique to quantify CMRO(2) from independent MRI estimates of Y(v) and cerebral blood flow. The approach uses standard gradient-echo and arterial spin labeling acquisitions to make these measurements. Using MR susceptometry on gradient-echo phase images, Y(v) was quantified for candidate vein segments in gray matter that approximate a long cylinder parallel to the main magnetic field. Local cerebral blood flow for the identified vessel was determined from a corresponding region in the arterial spin labeling perfusion map. Fick's principle of arteriovenous difference was then used to quantify CMRO(2) locally around each vessel. Application of this method in young, healthy subjects provided gray matter averages of 59.6% ± 2.3% for Y(v), 51.7 ± 6.4 mL/100 g/min for cerebral blood flow, and 158 ± 18 μmol/100 g/min for CMRO(2) (mean ± SD, n = 12), which is consistent with values previously reported by positron emission tomography and MRI.

    View details for DOI 10.1002/mrm.23050

    View details for Web of Science ID 000300683900011

    View details for PubMedID 21713981

  • MicroRNA Processing Pathway Regulates Olfactory Neuron Morphogenesis CURRENT BIOLOGY Berdnik, D., Fan, A. P., Potter, C. J., Luo, L. 2008; 18 (22): 1754-1759

    Abstract

    The microRNA (miRNA) processing pathway produces miRNAs as posttranscriptional regulators of gene expression. The nuclear RNase III Drosha catalyzes the first processing step together with the dsRNA binding protein DGCR8/Pasha generating pre-miRNAs [1, 2]. The next cleavage employs the cytoplasmic RNase III Dicer producing miRNA duplexes [3, 4]. Finally, Argonautes are recruited with miRNAs into an RNA-induced silencing complex for mRNA recognition (Figure 1A). Here, we identify two members of the miRNA pathway, Pasha and Dicer-1, in a forward genetic screen for mutations that disrupt wiring specificity of Drosophila olfactory projection neurons (PNs). The olfactory system is built as discrete map of highly stereotyped neuronal connections [5, 6]. Each PN targets dendrites to a specific glomerulus in the antennal lobe and projects axons stereotypically into higher brain centers [7-9]. In selected PN classes, pasha and Dicer-1 mutants cause specific PN dendrite mistargeting in the antennal lobe and altered axonal terminations in higher brain centers. Furthermore, Pasha and Dicer-1 act cell autonomously in postmitotic neurons to regulate dendrite and axon targeting during development. However, Argonaute-1 and Argonaute-2 are dispensable for PN morphogenesis. Our findings suggest a role for the miRNA processing pathway in establishing wiring specificity in the nervous system.

    View details for DOI 10.1016/j.cub.2008.09.045

    View details for Web of Science ID 000261244800025

    View details for PubMedID 19013069

    View details for PubMedCentralID PMC2612040