Blake E. Dewey

Amide proton transfer imaging of the breast at 3 T: Establishing reproducibility and possible feasibility assessing chemotherapy response

Chemical exchange saturation transfer imaging can generate contrast that is sensitive to amide protons associated with proteins and peptides (termed amide proton transfer, APT). In breast cancer, APT contrast may report on underlying changes in microstructural tissue composition. However, to date, there have been no developments or applications of APT chemical exchange saturation transfer to breast cancer. As a result, the aims of this study were to (i) experimentally explore optimal scan parameters for breast chemical exchange saturation transfer near the amide resonance at 3 T, (ii) establish the reliability of APT imaging of healthy fibroglandular tissue, and (iii) demonstrate preliminary results on APT changes in locally advanced breast cancer observed during the course of neoadjuvant chemotherapy. Chemical exchange saturation transfer measurements were experimentally optimized on cross‐linked bovine serum albumin phantoms, and the reliability of APT imaging was assessed in 10 women with no history of breast disease. The mean difference between test–retest APT values was not significantly different from zero, and the individual difference values were not dependent on the average APT value. The 95% confidence interval limits were ±0.70% (α = 0.05), and the repeatability was 1.91. APT measurements were also performed in three women before and after one cycle of chemotherapy. Following therapy, APT increased in the one patient with progressive disease and decreased in the two patients with a partial or complete response. Together, these results suggest that APT imaging may report on treatment response in these patients. Magn Reson Med, 2013.

Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members

Importance Subclinical inflammatory demyelination and neurodegeneration often precede symptom onset in multiple sclerosis (MS). Objective To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS. Design, Setting, and Participants The Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant’s risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERSMS]) comprising an individual’s genetic burden and environmental exposures. The study dates were August 2012 to July 2015. Main Outcomes and Measures Participants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography. Results This study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P = .01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P = .008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population. Conclusions and Relevance Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals. Trial Registration clinicaltrials.gov Identifier: NCT01353547

Optimization of 7-T Chemical Exchange Saturation Transfer Parameters for Validation of Glycosaminoglycan and Amide Proton Transfer of Fibroglandular Breast Tissue

PURPOSE To (a) implement simulation-optimized chemical exchange saturation transfer (CEST) measurements sensitive to amide proton transfer (APT) and glycosaminoglycan (GAG) hydroxyl proton transfer effects in the human breast at 7 T and (b) determine the reliability of these techniques for evaluation of fibroglandular tissue in the healthy breast as a benchmark for future studies of pathologic findings. MATERIALS AND METHODS All human studies were institutional review board approved, were HIPAA compliant, and included informed consent. The CEST parameters of saturation duration (25 msec) and amplitude (1 μT) were chosen on the basis of simulation-driven optimization for APT contrast enhancement with the CEST effect quantified by using residuals of a Lorentzian fit. Optimized parameters were implemented at 7 T in 10 healthy women in two separate examinations to evaluate the reliability of CEST magnetic resonance (MR) imaging measurements in the breast. CEST z-spectra were acquired over saturation offset frequencies ranging between ±40 ppm by using a quadrature unilateral breast coil. The imaging-repeat imaging reliability was assessed in terms of the intraclass correlation coefficient, which indicates the ratio of between-subject variation to total variation. RESULTS Simulations were performed of the Bloch equations with chemical exchange-guided selection of optimal values for pulse duration and amplitude, 25 msec and 1 μT, respectively. Reliability was evaluated by using intraclass correlation coefficients (95% confidence intervals), with acceptable results: 0.963 (95% confidence interval: 0.852, 0.991) and 0.903 (95% confidence interval: 0.609, 0.976) for APT and GAG, respectively. CONCLUSION Simulations were used to derive optimal CEST preparation parameters to elicit maximal CEST contrast enhancement in healthy fibroglandular breast tissue due to APT at 7 T. By using these parameters, reproducible values were obtained for both the amide and hydroxyl protons from CEST MR imaging at 7 T and are feasible in the human breast.

Relating multi-sequence longitudinal intensity profiles and clinical covariates in incident multiple sclerosis lesions

The formation of multiple sclerosis (MS) lesions is a complex process involving inflammation, tissue damage, and tissue repair — all of which are visible on structural magnetic resonance imaging (MRI) and potentially modifiable by pharmacological therapy. In this paper, we introduce two statistical models for relating voxel-level, longitudinal, multi-sequence structural MRI intensities within MS lesions to clinical information and therapeutic interventions: (1) a principal component analysis (PCA) and regression model and (2) function-on-scalar regression models. To do so, we first characterize the post-lesion incidence repair process on longitudinal, multi-sequence structural MRI from 34 MS patients as voxel-level intensity profiles. For the PCA regression model, we perform PCA on the intensity profiles to develop a voxel-level biomarker for identifying slow and persistent, long-term intensity changes within lesion tissue voxels. The proposed biomarkers ability to identify such effects is validated by two experienced clinicians (a neuroradiologist and a neurologist). On a scale of 1 to 4, with 4 being the highest quality, the neuroradiologist gave the score on the first PC a median quality rating of 4 (95% CI: [4,4]), and the neurologist gave the score a median rating of 3 (95% CI: [3,3]). We then relate the biomarker to the clinical information in a mixed model framework. Treatment with disease-modifying therapies (p < 0.01), steroids (p < 0.01), and being closer to the boundary of abnormal signal intensity (p < 0.01) are all associated with return of a voxel to an intensity value closer to that of normal-appearing tissue. The function-on-scalar regression model allows for assessment of the post-incidence time points at which the covariates are associated with the profiles. In the function-on-scalar regression, both age and distance to the boundary were found to have a statistically significant association with the lesion intensities at some time point. The two models presented in this article show promise for understanding the mechanisms of tissue damage in MS and for evaluating the impact of treatments for the disease in clinical trials.

Statistical estimation of T1 relaxation times using conventional magnetic resonance imaging.

Quantitative T1 maps estimate T1 relaxation times and can be used to assess diffuse tissue abnormalities within normal-appearing tissue. T1 maps are popular for studying the progression and treatment of multiple sclerosis (MS). However, their inclusion in standard imaging protocols remains limited due to the additional scanning time and expert calibration required and susceptibility to bias and noise. Here, we propose a new method of estimating T1 maps using four conventional MR images, which are intensity-normalized using cerebellar gray matter as a reference tissue and related to T1 using a smooth regression model. Using cross-validation, we generate statistical T1 maps for 61 subjects with MS. The statistical maps are less noisy than the acquired maps and show similar reproducibility. Tests of group differences in normal-appearing white matter across MS subtypes give similar results using both methods.

Chemical exchange saturation transfer of the cervical spinal cord at 7 T

High‐magnetic‐field (7 T) chemical exchange saturation transfer (CEST) MRI provides information on the tissue biochemical environment. Multiple sclerosis (MS) affects the entire central nervous system, including the spinal cord. Optimal CEST saturation parameters found via simulation were implemented for CEST MRI in 10 healthy controls and 10 patients with MS, and the results were examined using traditional asymmetry analysis and a Lorentzian fitting method. In addition, T1‐ and T2*‐weighted images were acquired for lesion localization and the transmitted B1+ field was evaluated to guide imaging parameters. Distinct spectral features for all tissue types studied were found both up‐ and downfield from the water resonance. The z spectra in healthy subjects had the expected z spectral shape with CEST effects apparent from 2.0 to 4.5 ppm. The z spectra from patients with MS demonstrated deviations from this expected normal shape, indicating this methods sensitivity to known pathology as well as to tissues appearing normal on conventional MRI. Examination of the calculated CESTasym revealed increased asymmetry around the amide proton resonance (Δω = 3.5 ppm), but it was apparent that this measure is complicated by detail in the CEST spectrum upfield from water, which is expected to result from the nuclear Overhauser effect. The z spectra upfield (negative ppm range) were also distinct between healthy and diseased tissue, and could not be ignored, particularly when considering the conventional asymmetry analysis used to quantify the CEST effect. For all frequencies greater than +1 ppm, the Lorentzian differences (and z spectra) for lesions and normal‐appearing white matter were distinct from those for healthy white matter. The increased frequency separation and signal‐to‐noise ratio, in concert with prolonged T1 at 7 T, resulted in signal enhancements necessary to detect subtle tissue changes not possible at lower field strengths. This study presents CEST imaging metrics that may be sensitive to the extensive and temporally varying biochemical neuropathology of MS in the spinal cord. Copyright

Improved diffusion tensor imaging of the optic nerve using multishot two‐dimensional navigated acquisitions

A diffusion‐weighted multishot echo‐planar imaging approach combined with SENSE and a two‐dimensional (2D) navigated motion correction was investigated as an alternative to conventional single‐shot counterpart to obtain optic nerve images at higher spatial resolution with reduced artifacts.

Whole Brain Parcellation with Pathology: Validation on Ventriculomegaly Patients.

Numerous brain disorders are associated with ventriculomegaly; normal pressure hydrocephalus (NPH) is one example. NPH presents with dementia-like symptoms and is often misdiagnosed as Alzheimers due to its chronic nature and nonspecific presenting symptoms. However, unlike other forms of dementia NPH can be treated surgically with an over 80% success rate on appropriately selected patients. Accurate assessment of the ventricles, in particular its sub-compartments, is required to diagnose the condition. Existing segmentation algorithms fail to accurately identify the ventricles in patients with such extreme pathology. We present an improvement to a whole brain segmentation approach that accurately identifies the ventricles and parcellates them into four sub-compartments. Our work is a combination of patch-based tissue segmentation and multi-atlas registration-based labeling. We include a validation on NPH patients, demonstrating superior performance against state-of-the-art methods.

7T MRI Visualization of Cortical Lesions in Adolescents and Young Adults with Pediatric-Onset Multiple Sclerosis

Cortical pathology in multiple sclerosis (MS) has been associated with prolonged and progressive disease. 7T magnetic resonance imaging (MRI) provides enhanced visualization of cortical lesions (CLs). Hence, we conducted a pilot study to explore whether CLs occur early in MS, as evidenced by pediatric‐onset patients.

A lag functional linear model for prediction of magnetization transfer ratio in multiple sclerosis lesions

We propose a lag functional linear model to predict a response using multiple functional predictors observed at discrete grids with noise. Two procedures are proposed to estimate the regression parameter functions: 1) an approach that ensures smoothness for each value of time using generalized cross-validation; and 2) a global smoothing approach using a restricted maximum likelihood framework. Numerical studies are presented to analyze predictive accuracy in many realistic scenarios. The methods are employed to estimate a magnetic resonance imaging (MRI)-based measure of tissue damage (the magnetization transfer ratio, or MTR) in multiple sclerosis (MS) lesions, a disease that causes damage to the myelin sheaths around axons in the central nervous system. Our method of estimation of MTR within lesions is useful retrospectively in research applications where MTR was not acquired, as well as in clinical practice settings where acquiring MTR is not currently part of the standard of care. The model facilitates the use of commonly acquired imaging modalities to estimate MTR within lesions, and outperforms cross-sectional models that do not account for temporal patterns of lesion development and repair.