Utility of quantitative susceptibility mapping and diffusion kurtosis imaging in the diagnosis of early Parkinson's disease.

OBJECTIVE: To investigate the utility of quantitative susceptibility mapping (QSM) and diffusion kurtosis imaging (DKI) as complementary tools in characterizing pathological changes in the deep grey nuclei in early Parkinson's disease (PD) and their clinical correlates to aid in diagnosis of PD. METHOD: Patients with a diagnosis of PD made within a year and age-matched healthy controls were recruited. All participants underwent clinical evaluation using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) and Hoehn & Yahr stage (H&Y), and brain 3 T MRI including QSM and DKI. Regions-of-interest (ROIs) in the caudate nucleus, putamen, globus pallidus, and medial and lateral substantia nigra (SN) were manually drawn to compare the mean susceptibility (representing iron deposition) and DKI indices (representing restricted water diffusion) between PD patients and healthy controls and in correlation with MDS-UPDRS III and H&Y, focusing on susceptibility value, mean diffusivity (MD) and mean kurtosis (MK). RESULTS: There were forty-seven PD patients (aged 68.7 years, 51% male, disease duration 0.78 years) and 16 healthy controls (aged 67.4 years, 63% male). Susceptibility value was increased in PD in all ROIs except the caudate, and was significantly different after multiple comparison correction in the putamen (PD: 64.75 ppb, HC: 44.61 ppb, p = 0.004). MD was significantly higher in PD in the lateral SN, putamen and caudate, the regions with the lowest susceptibility value. In PD patients, we found significant association between the MDS-UPDRS III score and susceptibility value in the putamen after correcting for age and sex (ß = 0.21, p = 0.003). A composite DKI-QSM diagnostic marker based on these findings successfully differentiated the groups (p < 0.0001) and had "good" classification performance (AUC = 0.88). CONCLUSIONS: QSM and DKI are complementary tools allowing a better understanding of the complex contribution of iron deposition and microstructural changes in the pathophysiology of PD.

Reduced regional cerebral venous oxygen saturation is a risk factor for the cognitive impairment in hemodialysis patients: a quantitative susceptibility mapping study.

The purpose of this study was to noninvasively evaluate the changes of regional cerebral venous oxygen saturation (rSvO2) in hemodialysis patients using quantitative susceptibility mapping (QSM) and investigate the relationship with clinical risk factors and neuropsychological testing. Fifty four (54) hemodialysis patients and 54 age, gender and education matched healthy controls (HCs) were recruited in this prospective study. QSM data were reconstructed from the original phase data of susceptibility weighted imaging to measure the susceptibility of cerebral regional major veins in all subjects and calculate their rSvO2. The differences in rSvO2 between hemodialysis patients and HCs were investigated using analysis of covariance adjusting for age and gender as covariates. Stepwise multiple regression and correlation analysis were performed between the cerebral rSvO2 and clinical factors including neuropsychological testing. The SvO2 of the bilateral cortical, thalamostriate, septal, cerebral internal and basal veins in hemodialysis patients was significantly lower than that in HCs (p < 0.001, Bonferroni corrected). The cerebral rSvO2 in all these veins was reduced by 1.67% to 2.30%. The hematocrit, iron, glucose, pre-and post-dialysis diastolic blood pressure (DBP) were independent predictive factors for the cerebral rSvO2 (all P < 0.05). The Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA) scores were both lower in patients than those in HCs (both P < 0.05). The SvO2 of the left cerebral internal vein correlated with MoCA scores (r = 0.492; P = 0.02, FDR corrected). In conclusion, our study indicated that the cerebral rSvO2 was reduced in hemodialysis patients, which was the risk factor for neurocognitive impairment. The hematocrit, iron, glucose, pre-and post-dialysis DBP were independent risk factors for the cerebral rSvO2.

Quantitative susceptibility mapping in the human fetus to measure blood oxygenation in the superior sagittal sinus.

OBJECTIVES: To present the feasibility of performing quantitative susceptibility mapping (QSM) in the human fetus to evaluate the oxygenation (SvO2) of cerebral venous blood in vivo. METHODS: Susceptibility weighted imaging (SWI) data were acquired from healthy pregnant subjects (n = 21, median = 31.3 weeks, interquartile range = 8.8 weeks). The susceptibility maps were generated from the SWI-phase images using a modified QSM processing pipeline, optimised for fetal applications. The processing pipeline is as follows: (1) mild high-pass filtering followed by quadratic fitting of the phase images to eliminate background phase variations; (2) manual creation of a fetal brain mask that includes the superior sagittal sinus (SSS); (3) inverse filtering of the resultant masked phase images using a truncated k-space approach with geometric constraint. Further, the magnetic susceptibility, ∆χv and corresponding putative SvO2 of the SSS were quantified from the generated susceptibility maps. Systematic error in the measured SvO2 due to the modified pipeline was also studied through simulations. RESULTS: Simulations showed that the systematic error in SvO2 when using a mask that includes a minimum of 5 voxels around the SSS and five slices remains < 3% for different orientations of the vessel relative to the main magnetic field. The average ∆χv in the SSS quantified across all gestations was 0.42 ± 0.03 ppm. Based on ∆χv, the average putative SvO2 in the SSS across all fetuses was 67% ± 7%, which is in good agreement with published studies. CONCLUSIONS: This in vivo study demonstrates the feasibility of using QSM in the human fetal brain to estimate ∆χv and SvO2. KEY POINTS: • A modified quantitative susceptibility mapping (QSM) processing pipeline is tested and presented for the human fetus. • QSM is feasible in the human fetus for measuring magnetic susceptibility and oxygenation of venous blood in vivo. • Blood magnetic susceptibility values from MR susceptometry and QSM agree with each other in the human fetus.

Iron quantification in Parkinson's disease using an age-based threshold on susceptibility maps: The advantage of local versus entire structure iron content measurements.

BACKGROUND: Elevated brain iron has been observed in Idiopathic Parkinson's disease (IPD) within the deep gray matter. Using quantitative susceptibility mapping (QSM) and a thresholded high-iron region, we quantified iron content in the midbrain of patients with Parkinson's disease as a function of age. METHODS: We used MRI to scan 24 IPD patients at 3-Tesla. Susceptibility-weighted images were collected with the following parameters, TE: 6 and 20 ms, TR: 30 ms, FA: 15°, and resolution: 0.5 × 0.5 × 2.0 mm3. QSM images were reconstructed from the source phase images. Whole-region and thresholded high-iron (RII) region boundaries for the Substantia Nigra (SN) and Red Nucleus (RN) were traced. Iron content was measured via mean susceptibilities and volumes, which were compared between the groups, as well as between right and left side of the structures within groups. RESULTS: Twenty patients with mild to moderate IPD were used in this study. For the SN, mean RII and whole-region iron and volumes were higher in the IPD group compared to HC, as well as mean RII for the RN, while no differences were seen between the groups when considering whole-region mean susceptibility bilaterally for the RN. CONCLUSION: Using a two-region of interest analysis on QSM, we showed that abnormal iron occurs in IPD patients in the SN and with greater volumes compared to HC. This method may have application as a biomarker for disease diagnosis and early intervention.

Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke.

OBJECTIVE: Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. METHODS: The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 µg/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. RESULTS: Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 µg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066). INTERPRETATION: RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 µg/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.

Susceptibility mapping of the dural sinuses and other superficial veins in the brain.

Quantitative susceptibility mapping (QSM) is a means to obtain direct measurements of local tissue susceptibility distribution. Usually the focus is on imaging tissues in the brain, and the region of the brain studied is dictated by an eroded skull stripped mask. Producing the pristine local phase behavior for regions at the edge of the brain has been difficult in the past. For structures such as the superior sagittal sinus (SSS) that run alongside the surface of the brain and under the skull bones, a considerable part of the external phase from the dipole effect is lost due to the short T2* of the bones. In this paper, we propose a method that seeks to reconstruct the susceptibility distribution inside the dural sinuses by ensuring that the entire geometry of the dural sinuses is preserved with the help of an MR angiogram and venogram (MRAV). Having a geometrical model of the vessels makes it possible to estimate the missing phase outside the brain as well, by using the forward phase model and, hence, allowing a complete phase map to be reconstructed. Fifteen healthy volunteers were scanned using a susceptibility weighted imaging (SWI) sequence with interleaved rephased-dephased echoes. QSM results were compared between the conventional techniques and the proposed method of phase preservation outside the brain and inside the dural sinuses. This method demonstrates the reconstruction of the SSS, whereas conventional methods are either unable to preserve this structure or unable to provide complete phase information. The mean and standard deviation inside the SSS for all volunteers was 435 ±â€¯5 ppb (this is the inter-subject error). To validate the proposed approach, the mean susceptibility inside the straight sinus showed good agreement between conventional approach and the proposed method. The results presented in this study indicate the potential of generating the susceptibility map for the whole brain, including the SSS (as well as potentially all the cortical veins).

Subcortical brain iron deposition and cognitive performance in older women with breast cancer receiving adjuvant chemotherapy: A pilot MRI study.

As the number of older adults in the U.S. increases, so too will the incidence of cancer and cancer-related cognitive impairment (CRCI). However, the exact underlying biological mechanism for CRCI is not yet well understood. We utilized susceptibility-weighted imaging with quantitative susceptibility mapping, a non-invasive MRI-based technique, to assess longitudinal iron deposition in subcortical gray matter structures and evaluate its association with cognitive performance in women age 60+ with breast cancer receiving adjuvant chemotherapy and age-matched women without breast cancer as controls. Brain MRI scans and neurocognitive scores from the NIH Toolbox for Cognition were obtained before chemotherapy (time point 1) and within one month after the last infusion of chemotherapy for the patients and at matched intervals for the controls (time point 2). There were 14 patients age 60+ with breast cancer (mean age 66.3 ±â€¯5.3 years) and 13 controls (mean age 68.2 ±â€¯6.1 years) included in this study. Brain iron increased as age increased. There were no significant between- or within- group differences in neurocognitive scores or iron deposition at time point 1 or between time points 1 and 2 (p > 0.01). However, there was a negative correlation between iron in the globus pallidus and the fluid cognition composite scores in the control group at time point 1 (r = -0.71; p < 0.01), but not in the chemotherapy group. Baseline iron in the putamen was negatively associated with changes in the oral reading recognition scores in the control group (r = 0.74, p < 0.01), but not in the chemotherapy group. Brain iron assessment did not indicate cancer or chemotherapy related short-term differences, yet some associations with cognition were observed. Studies with larger samples and longer follow-up intervals are warranted.

COnstrained Data Extrapolation (CODE): A new approach for high definition vascular imaging from low resolution data.

PURPOSE: To introduce a new approach to reconstruct high definition vascular images using COnstrained Data Extrapolation (CODE) and evaluate its capability in estimating vessel area and stenosis. MATERIALS AND METHODS: CODE is based on the constraint that the full width half maximum of a vessel can be accurately estimated and, since it represents the best estimate for the width of the object, higher k-space data can be generated from this information. To demonstrate the potential of extracting high definition vessel edges using low resolution data, both simulated and human data were analyzed to better visualize the vessels and to quantify both area and stenosis measurements. The results from CODE using one-fourth of the fully sampled k-space data were compared with a compressed sensing (CS) reconstruction approach using the same total amount of data but spread out between the center of k-space and the outer portions of the original k-space to accelerate data acquisition by a factor of four. RESULTS: For a sufficiently high signal-to-noise ratio (SNR) such as 16 (8), we found that objects as small as 3 voxels in the 25% under-sampled data (6 voxels when zero-filled) could be used for CODE and CS and provide an estimate of area with an error <5% (10%). For estimating up to a 70% stenosis with an SNR of 4, CODE was found to be more robust to noise than CS having a smaller variance albeit a larger bias. Reconstruction times were >200 (30) times faster for CODE compared to CS in the simulated (human) data. CONCLUSION: CODE was capable of producing sharp sub-voxel edges and accurately estimating stenosis to within 5% for clinically relevant studies of vessels with a width of at least 3pixels in the low resolution images.

Decreased susceptibility of major veins in mild traumatic brain injury is correlated with post-concussive symptoms: A quantitative susceptibility mapping study.

Cerebral venous oxygen saturation (SvO2) is an important biomarker of brain function. In this study, we aimed to explore the relative changes of regional cerebral SvO2 among axonal injury (AI) patients, non-AI patients and healthy controls (HCs) using quantitative susceptibility mapping (QSM). 48 patients and 32 HCs were enrolled. The patients were divided into two groups depending on the imaging based evidence of AI. QSM was used to measure the susceptibility of major cerebral veins. Nonparametric testing was performed for susceptibility differences among the non-AI patient group, AI patient group and healthy control group. Correlation was performed between the susceptibility of major cerebral veins, elapsed time post trauma (ETPT) and post-concussive symptom scores. The ROC analysis was performed for the diagnostic efficiency of susceptibility to discriminate mTBI patients from HCs. The susceptibility of the straight sinus in non-AI and AI patients was significantly lower than that in HCs (P < 0.001, P = 0.004, respectively, Bonferroni corrected), which may indicate an increased regional cerebral SvO2 in patients. The susceptibility of the straight sinus in non-AI patients positively correlated with ETPT (r = 0.573, P = 0.003, FDR corrected) while that in AI patients negatively correlated with the Rivermead Post Concussion Symptoms Questionnaire scores (r = - 0.582, P = 0.018, FDR corrected). The sensitivity, specificity and AUC values of susceptibility for the discrimination between mTBI patients and HCs were 88%, 69% and 0.84. In conclusion, the susceptibility of the straight sinus can be used as a biomarker to monitor the progress of mild TBI and to differentiate mTBI patients from healthy controls.

Increased Number and Distribution of Cerebral Microbleeds Is a Risk Factor for Cognitive Dysfunction in Hemodialysis Patients: A Longitudinal Study.

The aim of this study was to explore the risk factors associated with longitudinal changes in hemodialysis patients including the correlation between number and distribution of cerebral microbleeds (CMBs).Sixty-one hemodialysis patients were enrolled in this prospective study. Twenty-eight patients had follow-up examinations with a mean interval of 24.79 ±â€Š5.17 months. The number of CMBs was manually counted on susceptibility-weighted imaging. Subjects were divided into 2 groups with and without CMBs. In the CMB group, 8 of 33 patients did not have a mini-mental state examination (MMSE) because of blurred vision. Multiple logistic regression was used to investigate the risk factors for CMBs. Partial correlation was used to explore the correlation between the increased number of CMBs and the change of MMSE scores.CMBs were seen in 33 (54%) hemodialysis patients. Both age and pre/postdialysis systolic blood pressure (SBP) positively correlated with CMBs. Serum iron (SI), and high-density lipoprotein cholesterol (HDL-c) negatively correlated with CMBs (all P < 0.05). Among 25 patients with CMBs and MMSE, 9 patients had scores <27, which was considered as subnormal and most CMBs in these patients were located in the brainstem and basal ganglia. Considering age and follow-up time as the co-confounding factors, the number of new CMBs over the 2 imaging time points negatively correlated with the change of MMSE scores (r = -0.673, P = 0.023).The presence of new CMBs was a risk factor for cognitive dysfunction and the location of CMBs may be correlated with cognitive impairment. Both SI and HDL-c were protective factors for the CMBs. The risk factors for CMBs included age, pre- and postdialysis SBP.

Quantifying errors in flow measurement using phase contrast magnetic resonance imaging: comparison of several boundary detection methods.

Quantifying flow from phase-contrast MRI (PC-MRI) data requires that the vessels of interest be segmented. The estimate of the vessel area will dictate the type and magnitude of the error sources that affect the flow measurement. These sources of errors are well understood, and mathematical expressions have been derived for them in previous work. However, these expressions contain many parameters that render them difficult to use for making practical error estimates. In this work, some realistic assumptions were made that allow for the simplification of such expressions in order to make them more useful. These simplified expressions were then used to numerically simulate the effect of segmentation accuracy and provide some criteria that if met, would keep errors in flow quantification below 10% or 5%. Four different segmentation methods were used on simulated and phantom MRA data to verify the theoretical results. Numerical simulations showed that including partial volumed edge pixels in vessel segmentation provides less error than missing them. This was verified with MRA simulations, as the best performing segmentation method generally included such pixels. Further, it was found that to obtain a flow error of less than 10% (5%), the vessel should be at least 4 (5) pixels in diameter, have an SNR of at least 10:1 and have a peak velocity to saturation cut-off velocity ratio of at least 5:3.

Quantitative susceptibility mapping of small objects using volume constraints.

Microbleeds have been implicated to play a role in many neurovascular and neurodegenerative diseases. The diameter of each microbleed has been used previously as a possible quantitative measure for grading microbleeds. We propose that magnetic susceptibility provides a new quantitative measure of extravasated blood. Recently, a Fourier-based method has been used that allows susceptibility quantification from phase images for any arbitrarily shaped structures. However, when very small objects, such as microbleeds, are considered, the accuracy of this susceptibility mapping method still remains to be evaluated. In this article, air bubbles and glass beads are taken as microbleed surrogates to evaluate the quantitative accuracy of the susceptibility mapping method. We show that when an object occupies only a few voxels, an estimate of the true volume of the object is necessary for accurate susceptibility quantification. Remnant errors in the quantified susceptibilities and their sources are evaluated. We show that quantifying magnetic moment, rather than the susceptibility of these small structures, may be a better and more robust alternative.

Evaluation of polymer gels and MRI as a 3-D dosimeter for intensity-modulated radiation therapy.

BANG gel (MGS Research, Inc., Guilford, CT) has been evaluated for measuring intensity-modulated radiation therapy (IMRT) dose distributions. Treatment plans with target doses of 1500 cGy were generated by the Peacock IMRT system (NOMOS Corp., Sewickley, PA) using test target volumes. The gels were enclosed in 13 cm outer diameter cylindrical glass vessels. Dose calibration was conducted using seven smaller (4 cm diameter) cylindrical glass vessels irradiated to 0-1800 cGy in 300 cGy increments. Three-dimensional maps of the proton relaxation rate R2 were obtained using a 1.5 T magnetic resonance imaging (MRI) system (Siemens Medical Systems, Erlangen, Germany) and correlated with dose. A Hahn spin echo sequence was used with TR = 3 s, TE = 20 and 100 ms, NEX = 1, using 1 x 1 x 3 mm3 voxels. The MRI measurements were repeated weekly to identify the gel-aging characteristics. Ionization chamber, thermoluminescent dosimetry (TLD), and film dosimetry measurements of the IMRT dose distributions were obtained to compare against the gel results. The other dosimeters were used in a phantom with the same external cross-section as the gel phantom. The irradiated R2 values of the large vessels did not precisely track the smaller vessels, so the ionization chamber measurements were used to normalize the gel dose distributions. The point-to-point standard deviation of the gel dose measurements was 7.0 cGy. When compared with the ionization chamber measurements averaged over the chamber volume, 1% agreement was obtained. Comparisons against radiographic film dose distribution measurements and the treatment planning dose distribution calculation were used to determine the spatial localization accuracy of the gel and MRI. Spatial localization was better than 2 mm, and the dose was accurately determined by the gel both within and outside the target. The TLD chips were placed throughout the phantom to determine gel measurement precision in high- and low-dose regions. A multidimensional dose comparison tool that simultaneously examines the dose-difference and distance-to-agreement was used to evaluate the gel in both low-and high-dose gradient regions. When 3% and 3 mm criteria were used for the comparisons, more than 90% of the TLD measurements agreed with the gel, with the worst of 309 TLD chip measurements disagreeing by 40% of the criteria. All four MRI measurement session gel-measured dose distributions were compared to evaluate the time behavior of the gel. The low-dose regions were evaluated by comparison with TLD measurements at selected points, while high-dose regions were evaluated by directly comparing measured dose distributions. Tests using the multidimensional comparison tool showed detectable degradation beyond one week postirradiation, but all low-dose measurements passed relative to the test criteria and the dose distributions showed few regions that failed.