Preliminary Assessment of Reference Region Quantification and Reduced Scanning Times for [18F]SynVesT-1 PET in Parkinson's Disease.

Synaptic density in the central nervous system can be measured in vivo using PET with [18F]SynVesT-1. While [18F]SynVesT-1 has been proven to be a powerful radiopharmaceutical for PET imaging of neurodegenerative disorders such as Parkinson's disease (PD), its currently validated acquisition and quantification protocols are invasive and technically challenging in these populations due to the arterial sampling and relatively long scanning times. The objectives of this work were to evaluate a noninvasive (reference tissue) quantification method for [18F]SynVesT-1 in PD patients and to determine the minimum scan time necessary for accurate quantification. [18F]SynVesT-1 PET scans were acquired in 5 patients with PD and 3 healthy control subjects for 120 min with arterial blood sampling. Quantification was performed using the one-tissue compartment model (1TCM) with arterial input function, as well as with the simplified reference tissue model (SRTM) to estimate binding potential (BPND) using centrum semiovale (CS) as a reference region. The SRTM2 method was used with k2' fixed to either a sample average value (0.037 min-1) or a value estimated first through coupled fitting across regions for each participant. Direct SRTM estimation and the Logan reference region graphical method were also evaluated. There were no significant group differences in CS volume, radiotracer uptake, or efflux (ps > 0.47). Each fitting method produced BPND estimates in close agreement with those derived from the 1TCM (subject R2s > 0.98, bias < 10%), with no difference in bias between the control and PD groups. With SRTM2, BPND estimates from truncated scan data as short as 80 min produced values in excellent agreement with the data from the full 120 min scans (bias < 6%). While these are preliminary results from a small sample of patients with PD (n = 5), this work suggests that accurate synaptic density quantification may be performed without blood sampling and with scan time under 90 minutes. If further validated, these simplified procedures for [18F]SynVesT-1 PET quantification can facilitate its application as a clinical research imaging technology and allow for larger study samples and include a broader scope of patients including those with neurodegenerative diseases.

First-in-Human PET Imaging of [18F]SDM-4MP3: A Cautionary Tale.

[18F]SynVesT-1 is a PET radiopharmaceutical that binds to the synaptic vesicle protein 2A (SV2A) and serves as a biomarker of synaptic density with widespread clinical research applications in psychiatry and neurodegeneration. The initial goal of this study was to concurrently conduct PET imaging studies with [18F]SynVesT-1 at our laboratories. However, the data in the first two human PET studies had anomalous biodistribution despite the injected product meeting all specifications during the prerelease quality control protocols. Further investigation, including imaging in rats as well as proton and carbon 2D-NMR spectroscopic studies, led to the discovery that a derivative of the precursor had been received from the manufacturer. Hence, we report our investigation and the first-in-human study of [18F]SDM-4MP3, a structural variant of [18F]SynVesT-1, which does not have the requisite characteristics as a PET radiopharmaceutical for imaging SV2A in the central nervous system.

Development, validation, qualification, and dissemination of quantitative MR methods: Overview and recommendations by the ISMRM quantitative MR study group.

On behalf of the International Society for Magnetic Resonance in Medicine (ISMRM) Quantitative MR Study Group, this article provides an overview of considerations for the development, validation, qualification, and dissemination of quantitative MR (qMR) methods. This process is framed in terms of two central technical performance properties, i.e., bias and precision. Although qMR is confounded by undesired effects, methods with low bias and high precision can be iteratively developed and validated. For illustration, two distinct qMR methods are discussed throughout the manuscript: quantification of liver proton-density fat fraction, and cardiac T1 . These examples demonstrate the expansion of qMR methods from research centers toward widespread clinical dissemination. The overall goal of this article is to provide trainees, researchers, and clinicians with essential guidelines for the development and validation of qMR methods, as well as an understanding of necessary steps and potential pitfalls for the dissemination of quantitative MR in research and in the clinic.

Chemical exchange saturation transfer for predicting response to stereotactic radiosurgery in human brain metastasis.

PURPOSE: The purpose of this work was to determine the predictive value of chemical exchange saturation transfer (CEST) metrics in brain metastases treated with stereotactic radiosurgery (SRS). METHODS: CEST spectra at a radiofrequency power of 0.52 µT were collected on a 3 Tesla (T) magnetic resonance imaging from 25 patients at three time points: pretreatment, 1 week, and 1 month post-treatment. Amide proton transfer-weighted images and maps of the amplitude and width of Lorentzian-shaped CEST peaks and the relaxation-compensated AREX metric were constructed at the offset frequencies of amide, amine, and relayed nuclear Overhauser effect (NOE) from aliphatic groups as well as the broad magnetization transfer effect. Pretreatment CEST metrics, as well as CEST metric changes at 1 week post-treatment, were compared to changes in tumor volume at 1 month. RESULTS: Significant (P < 0.05) 1-week predictive metrics included NOE peak amplitude (R = 0.69) in normal-appearing white matter (NAWM) and width (R = -0.55) in tumor. Baseline NOE in contralateral NAWM was negatively correlated (R = -0.69) with volume changes at 1 month. Metrics-defined outside tumor margins had higher correlation with volume changes than tumor regions of interest. CONCLUSION: CEST metrics, in particular, the NOE peak amplitude, can predict volume changes 1 month post-SRS. Magn Reson Med 78:1110-1120, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Differences in iron and manganese concentration may confound the measurement of myelin from R1 and R2 relaxation rates in studies of dysmyelination.

A model of dysmyelination, the Long Evans Shaker (les) rat, was used to study the contribution of myelin to MR tissue properties in white matter. A large region of white matter was identified in the deep cerebellum and was used for measurements of the MR relaxation rate constants, R1 = 1/T1 and R2 = 1/T2 , at 7 T. In this study, R1 of the les deep cerebellar white matter was found to be 0.55 ± 0.08 s (-1) and R2 was found to be 15 ± 1 s(-1) , revealing significantly lower R1 and R2 in les white matter relative to wild-type (wt: R1 = 0.69 ± 0.05 s(-1) and R2 = 18 ± 1 s(-1) ). These deviated from the expected ΔR1 and ΔR2 values, given a complete lack of myelin in the les white matter, derived from the literature using values of myelin relaxivity, and we suspect that metals could play a significant role. The absolute concentrations of the paramagnetic transition metals iron (Fe) and manganese (Mn) were measured by a micro-synchrotron radiation X-ray fluorescence (µSRXRF) technique, with significantly greater Fe and Mn in les white matter than in wt (in units of µg [metal]/g [wet weight tissue]: les: Fe concentration,19 ± 1; Mn concentration, 0.71 ± 0.04; wt: Fe concentration,10 ± 1; Mn concentration, 0.47 ± 0.04). These changes in Fe and Mn could explain the deviations in R1 and R2 from the expected values in white matter. Although it was found that the influence of myelin still dominates R1 and R2 in wt rats, there were non-negligible changes in the contribution of the metals to relaxation. Although there are already problems with the estimation of myelin from R1 and R2 changes in disease models with pathology that also affects the relaxation rate constants, this study points to a specific pitfall in the estimation of changes in myelin in diseases or models with disrupted concentrations of paramagnetic transition metals. Copyright © 2016 John Wiley & Sons, Ltd.

Mapping of amide, amine, and aliphatic peaks in the CEST spectra of murine xenografts at 7 T.

PURPOSE: To evaluate the performance of endogenous chemical exchange saturation transfer (CEST) spectra and derived maps in a longitudinal study of tumor xenografts to ascertain the role of CEST parameters in describing tumor progression and in distinguishing between tumor, muscle, and necrosis. METHODS: CEST spectra of 24 mice with tumor xenografts (20 LLC and 4 MDA) were acquired at three time-points. We employed a novel method of decomposing the CEST spectrum into a sum of four Lorentzian shapes, each with a corresponding measured amplitude, width and frequency offset. This semi-quantitative method is an improvement over techniques which simply assess the asymmetry in the spectrum for the presence of CEST, due to the fact that it is not confounded by CEST peaks on opposing sides of the direct effect. The CEST images were compared to several other commonly employed contrast mechanisms: T1 relaxation, T2 relaxation, diffusion (ADC), and magnetization transfer (MT). RESULTS: Tumor spectra had distinct CEST peaks corresponding to the presence of hydrogen exchange between free water and amide, amine, and aliphatic groups. All three CEST peaks (amide, amine, and aliphatic) were larger in the tumor tissue as compared with the adjacent healthy muscle. CONCLUSIONS: CEST contrast (particularly the amine peak amplitude) performed especially well in distinguishing areas of apoptosis and/or necrosis from actively progressing tumor, as validated by histology.

Understanding quantitative pulsed CEST in the presence of MT.

Phantom experiments in agar and ammonium chloride were performed to evaluate a three-pool model of magnetization transfer and chemical exchange saturation transfer (CEST) in a pulsed saturation transfer experiment. The utility of the pulsed CEST method was demonstrated by varying the pH of the phantoms and observing the effect upon the CEST spectra both with and without the solid agar (the magnetization transfer pool), while fitting the spectra to the Bloch equation model with exchange. Pulsed CEST could be used to robustly quantify parameters related to CEST, including the exchange rate constant describing proton exchange with free water and the concentration of exchanging protons. Furthermore, the exchange rate constant and the CEST pool offset frequency of the ammonium chloride remained unchanged in the presence of a magnetization transfer pool. The logarithm of the fitted exchange rate constant was linearly related to pH: this relationship was maintained in the presence of magnetization transfer.

Quantitative magnetization transfer studies of apoptotic cell death.

Magnetization transfer measurements were performed on samples of acute myeloid leukemia cells at early (36 h postcisplatin treatment) and late (48 h posttreatment) stages of apoptosis. Magnetization transfer ratio was calculated and a two-pool model was fitted to data at two powers and 16 offset frequencies of saturation pulse. No parameters changed significantly at early stages of apoptosis. At late stages, changes in magnetization transfer ratio were not significant, but quantitative model parameters showed a decrease in macromolecular proton fraction, M(0B), and an increase in the T(2) relaxation time of free water. Analysis also indicated an increase in the ratio R × M(0B)/R(1A), where R is the exchange rate between free water and macromolecular protons and R(1A) is the T(1) relaxation rate of free water. Changes in the magnetization transfer spectrum were largely attributable to differences in the free water pool and did not occur any earlier than changes in the average T(1) relaxation time, T(1obs).

A practical method for post-acquisition reduction of bias in fast, whole-brain B1-maps.

Large consistent differences have been observed between maps of the flip angle correction factor (commonly called "B1-maps") produced with different fast methods in the human brain. We present an empirical procedure for first-order multiplicative bias correction that can be applied when more than one B1-mapping method is available. We use a B1-map measurement in a calibration phantom as a reference and the voxel-wise histogram mode between ratios of B1-maps produced from different methods to calculate determine the bias as a multiplicative correcting scale factor. Institutional implementations of four common methods of B1-mapping were assessed: Method of Slopes, FSE and EPI double angle methods (DAM), and Bloch-Siegert. In human subjects, the multiplicative bias used to correct for each of the four methods was: Method of Slopes = 1.005, FSE-DAM = 0.956, EPI-DAM = 1.080, and Bloch-Siegert = 1.128. Scaling to remove this bias between methods produces more consistent B1-maps which enable more consistent values for any computations requiring flip angle correction. In addition, we present evidence that the corrected B1 maps, using our calibration method, are also more accurate.

Differentiation between Radiation Necrosis and Tumor Progression Using Chemical Exchange Saturation Transfer.

Purpose: Stereotactic radiosurgery (SRS) is a common treatment used in patients with brain metastases and is associated with high rates of local control, however, at the risk of radiation necrosis. It is difficult to differentiate radiation necrosis from tumor progression using conventional MRI, making it a major diagnostic dilemma for practitioners. This prospective study investigated whether chemical exchange saturation transfer (CEST) was able to differentiate these two conditions.Experimental Design: Sixteen patients with brain metastases who had been previously treated with SRS were included. Average time between SRS and evaluation was 12.6 months. Lesion type was determined by pathology in 9 patients and the other 7 were clinically followed. CEST imaging was performed on a 3T Philips scanner and the following CEST metrics were measured: amide proton transfer (APT), magnetization transfer (MT), magnetization transfer ratio (MTR), and area under the curve for CEST peaks corresponding to amide and nuclear Overhauser effect (NOE).Results: Five lesions were classified as progressing tumor and 11 were classified as radiation necrosis (using histopathologic confirmation and radiographic follow-up). The best separation was obtained by NOEMTR (NOEMTR,necrosis = 8.9 ± 0.9%, NOEMTR,progression = 12.6 ± 1.6%, P < 0.0001) and AmideMTR (AmideMTR,necrosis = 8.2 ± 1.0%, AmideMTR,progression = 12.0 ± 1.9%, P < 0.0001). MT (MTnecrosis = 4.7 ± 1.0%, MTprogression = 6.7 ± 1.7%, P = 0.009) and NOEAUC (NOEAUC,necrosis = 4.3 ± 2.0% Hz, NOEAUC,progression = 7.2 ± 1.9% Hz, P = 0.019) provided statistically significant separation but with higher P values.Conclusions: CEST was capable of differentiating radiation necrosis from tumor progression in brain metastases. Both NOEMTR and AmideMTR provided statistically significant separation of the two cohorts. However, APT was unable to differentiate the two groups. Clin Cancer Res; 23(14); 3667-75. ©2017 AACR.

Water Exchange Rate Constant as a Biomarker of Treatment Efficacy in Patients With Brain Metastases Undergoing Stereotactic Radiosurgery.

PURPOSE: This study was designed to evaluate whether changes in metastatic brain tumors after stereotactic radiosurgery (SRS) can be seen with quantitative MRI early after treatment. METHODS AND MATERIALS: Using contrast-enhanced MRI, a 3-water-compartment tissue model consisting of intracellular (I), extracellular-extravascular (E), and vascular (V) compartments was used to assess the intra-extracellular water exchange rate constant (kIE), efflux rate constant (kep), and water compartment volume fractions (M0,I, M0,E, M0,V). In this prospective study, 19 patients were MRI-scanned before treatment and 1 week and 1 month after SRS. The change in model parameters between the pretreatment and 1-week posttreatment scans was correlated to the change in tumor volume between pretreatment and 1-month posttreatment scans. RESULTS: At 1 week kIE differentiated (P<.001) tumors that had partial response from tumors with stable and progressive disease, and a high correlation (R=-0.76, P<.001) was observed between early changes in the kIE and tumor volume change 1 month after treatment. Other model parameters had lower correlation (M0,E) or no correlation (kep, M0,V). CONCLUSIONS: This is the first study that measured kIE early after SRS, and it found that early changes in kIE (1 week after treatment) highly correlated with long-term tumor response and could predict the extent of tumor shrinkage at 1 month after SRS.

Comparison of biphasic and reordered fat suppression for dynamic breast MRI.

PURPOSE: To optimize a reordered k-space acquisition that applies intermittent fat saturation (FS) pulses to allow for a time-efficient reduction of fat signal in breast MR images, and compare it with an elliptic-centric biphasic FS method in terms of the degree of fat suppression and speed. MATERIALS AND METHODS: The behavior of the fat and water signals under the influence of the reordered sequence was characterized. This allowed us to optimize the flip angle and visualize the expected artifacts by deriving the point spread function (PSF) of the fat signal. We compared the two sequences by acquiring images with a varying number of FS pulses, with a corresponding difference in scan time. The quality of the images was assessed by comparison with images obtained with full fat suppression as measured by a root-mean-square (RMS) error metric. RESULTS: The reordered sequence allowed for an approximately twofold reduction in error compared to the biphasic sequence for the same scan time. With the reordered sequence and optimized scan parameters, we were able to reduce the time spent on fat suppression by as much as 99% with no discernible reduction in image quality. CONCLUSION: This method will allow robust fat suppression with virtually no extension in imaging time for dynamic contrast-enhanced (DCE)-MRI.