Alina Tudorica

Behavioral and magnetic resonance spectroscopic studies in the rat hyperserotonemic model of autism

Autism is classified as a pervasive developmental disorder, with several cardinal features including sensory disturbances, obsessive-compulsive-like behavior, lack of bonding to caregivers and motor disturbances. To date, there is a lack of an animal model of the disease. The current work is aimed at producing such a model by treating developing rat pups with a serotonergic agonist, 5-methoxytryptamine (5-MT; 1 mg/kg) during development (from gestational age 12 days to postnatal day 20), thus mimicking one of the hallmark neurochemical features of the illness-increases in the neurotransmitter, serotonin. Animals were then tested in behavioral paradigms that may resemble the human illness. Treated rat pups were found to be overreactive to auditory or tactile sensory stimuli, to display changes in the negative geotaxic test of motor development, to show lack of separation-induced vocalizations when their dam was removed and to show decreased alternation in the spontaneous alternation task. As well, the animals showed metabolic abnormalities in the brain using in vivo proton magnetic resonance spectroscopy, which are consistent with those observed in autistic children. In summary, the model we are proposing shows some of the behavioral and metabolic features of autism, as well as being produced through alteration of a neurochemical system known to be altered in autism.

Shutter-speed analysis of contrast reagent bolus-tracking data: Preliminary observations in benign and malignant breast disease

The standard pharmacokinetic model applied to contrast reagent (CR) bolus‐tracking (B‐T) MRI (dynamic‐contrast‐enhanced) data makes the intrinsic assumption that equilibrium transcytolemmal water molecule exchange is effectively infinitely fast. Theory and simulation have suggested that this assumption can lead to significant errors. Recent analyses of animal model experimental data have confirmed two predicted signature inadequacies: a specific temporal mismatch with the B‐T time‐course and a CR dose‐dependent underestimation of model parameters. The most parsimonious adjustment to account for this aspect leads to the “shutter‐speed” pharmacokinetic model. Application of the latter to the animal model data mostly eliminates the two signature inadequacies. Here, the standard and shutter‐speed models are applied to B‐T data obtained from routine human breast examinations. The signature standard model temporal mismatch is found for each of the three invasive ductal carcinoma (IDC) cases and for each of the three fibroadenoma (FA) cases studied. It is effectively eliminated by use of the shutter‐speed model. The size of the mismatch is considerably greater for the IDC lesions than for the FA lesions, causing the shutter‐speed model to exhibit improved discrimination of malignant IDC tumors from the benign FA lesions compared with the standard model. Furthermore, the shutter‐speed model clearly reveals focal “hot spots” of elevated CR perfusion/permeation present in only the malignant tumors. Magn Reson Med 53:724–729, 2005.

1H-Magnetic Resonance Spectroscopy Markers of Cognitive and Language Ability in Clinical Subtypes of Autism Spectrum Disorders

This study assessed metabolic functioning of regional brain areas to address whether there is a neurometabolic profile reflecting the underlying neuropathology in individuals with autism spectrum disorders, and if varied profiles correlate with the clinical subtypes. Thirteen children (7-16 years) with autism spectrum disorders and 8 typically developing children were compared on 1H-magnetic resonance spectroscopy data collected from hippocampus-amygdala and cerebellar regions. The autism spectrum disorder group had significantly lower N-acetyl-aspartate/creatine ratios bilaterally in the hippocampus-amygdala but not cerebellum, whereas myo-inositol/creatine was significantly increased in all measured regions. Choline/creatine was also significantly elevated in the left hippocampus-amygdala and cerebellar regions of children with autism spectrum disorder. Comparisons within the autism spectrum disorder group when clinically subdivided by history of speech delay revealed significant metabolic ratio differences. Magnetic resonance spectroscopy can provide important information regarding abnormal brain metabolism and clinical classification in autism spectrum disorders.

Phase I Trial of Preoperative Chemoradiation Plus Sorafenib for High Risk Extremity Soft Tissue Sarcomas with Dynamic Contrast-Enhanced MRI Correlates

Purpose: We conducted a phase I trial of the addition of sorafenib to a chemoradiotherapy regimen in patients with high-risk (intermediate/high grade, >5 cm) extremity soft tissue sarcoma undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced MRI (DCE-MRI) to assess response to treatment. Experimental Design: Patients were treated at increasing dose levels of sorafenib (200 mg daily, 400 mg daily, 400 mg twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. Results: Eighteen subjects were enrolled, of which 16 were evaluable. The MTD of sorafenib was 400 mg daily. Common grade 3–4 adverse events included neutropenia (94%), hypophosphatemia (75%), anemia (69%), thrombocytopenia (50%), and neutropenic fever/infection (50%). Of note, 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker ΔKtrans after 2 weeks of sorafenib correlated with histologic response (R2 = 0.67, P = 0.012) at surgery. Conclusion: The addition of sorafenib to preoperative chemoradiotherapy is feasible and warrants further investigation in a larger trial. DCE-MRI detected changes in tumor perfusion after 2 weeks of sorafenib and may be a minimally invasive tool for rapid assessment of drug effect in soft tissue sarcoma. Clin Cancer Res; 19(24); 6902–11. ©2013 AACR.

In Vivo 1H Magnetic Resonance Spectroscopic Measurement of Brain Glycine Levels in Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder of glycine metabolism. Defective glycine cleavage causes elevated concentrations of glycine in plasma, urine, and cerebrospinal fluid. A longitudinal study using magnetic resonance imaging (MRI) and single‐voxel1H magnetic resonance spectroscopy (MRS) was performed on an infant with the typical clinical picture of NKH. He was examined twice during the course of treatment with sodium benzoate and dextromethorphan. At the age of 10 months, MRI showed normal brain structure, while MRS detected a prominent glycine peak in the brain. Repeat MRS at the age of 13 months showed a small increase in glycine peak and a prominent glutamate/glutamine peak not previously detected. The MRS measurements were consistent with the slight increase in blood glycine level and the elevation in glutamine level, indicating that1H MRS can be a valuable tool in the diagnosis and monitoring of treatment effects in patients with NKH.

Using dynamic contrast-enhanced MRI to quantitatively characterize maternal vascular organization in the primate placenta

The maternal microvasculature of the primate placenta is organized into 10–20 perfusion domains that are functionally optimized to facilitate nutrient exchange to support fetal growth. This study describes a dynamic contrast‐enhanced magnetic resonance imaging method for identifying vascular domains and quantifying maternal blood flow in them.

Early Prediction and Evaluation of Breast Cancer Response to Neoadjuvant Chemotherapy Using Quantitative DCE-MRI

The purpose is to compare quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) metrics with imaging tumor size for early prediction of breast cancer response to neoadjuvant chemotherapy (NACT) and evaluation of residual cancer burden (RCB). Twenty-eight patients with 29 primary breast tumors underwent DCE-MRI exams before, after one cycle of, at midpoint of, and after NACT. MRI tumor size in the longest diameter (LD) was measured according to the RECIST (Response Evaluation Criteria In Solid Tumors) guidelines. Pharmacokinetic analyses of DCE-MRI data were performed with the standard Tofts and Shutter-Speed models (TM and SSM). After one NACT cycle the percent changes of DCE-MRI parameters Ktrans (contrast agent plasma/interstitium transfer rate constant), ve (extravascular and extracellular volume fraction), kep (intravasation rate constant), and SSM-unique τi (mean intracellular water lifetime) are good to excellent early predictors of pathologic complete response (pCR) vs. non-pCR, with univariate logistic regression C statistics value in the range of 0.804 to 0.967. ve values after one cycle and at NACT midpoint are also good predictors of response, with C ranging 0.845 to 0.897. However, RECIST LD changes are poor predictors with C = 0.609 and 0.673, respectively. Post-NACT Ktrans, τi, and RECIST LD show statistically significant (P < .05) correlations with RCB. The performances of TM and SSM analyses for early prediction of response and RCB evaluation are comparable. In conclusion, quantitative DCE-MRI parameters are superior to imaging tumor size for early prediction of therapy response. Both TM and SSM analyses are effective for therapy response evaluation. However, the τi parameter derived only with SSM analysis allows the unique opportunity to potentially quantify therapy-induced changes in tumor energetic metabolism.

Demonstration of nonlinearity bias in the measurement of the apparent diffusion coefficient in multicenter trials.

Characterize system‐specific bias across common magnetic resonance imaging (MRI) platforms for quantitative diffusion measurements in multicenter trials.

Cerebral blood volume measurements by T*2-weighted MRI and contrast infusion.

A reliable, accurate, and accessible method for measuring cerebral blood volume (CBV) has been developed based on T  *2 ‐weighted MRI and a 1‐min infusion of gadolinium instead of a bolus. Computer simulations predict that this infusion CBV method will have a signal‐to‐noise ratio (SNR) 3–5 times greater than that obtained by area‐under‐the‐curve (AUC) methods, with high accuracy over a wide range of arterial, tissue, and MRI conditions. In six healthy controls, the CBV was 1.87 ± 0.44 in white matter (WM), 3.40 ± 0.44 in deep gray matter (DGM), and 3.84 ± 1.87 ml blood/100 g tissue in cortical GM (CGM). The mean GM/WM ratio was 1.94. In five patients with bilateral carotid disease, the corresponding values were 2.63 ± 0.33, 4.72 ± 0.33, and 5.27 ± 2.40 ml blood/100 g tissue, all of which were significantly different from controls. AUC values were generally higher and failed to demonstrate differences between controls and patients. The infusion method shows great potential for providing reliable, accurate, and accessible CBV values with the ability to discriminate physiologic or pathological volume changes under a wide range of conditions. Magn Reson Med 50:844–855, 2003.

The Impact of Arterial Input Function Determination Variations on Prostate Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacokinetic Modeling: A Multicenter Data Analysis Challenge

Pharmacokinetic analysis of dynamic contrast-enhanced (DCE) MRI data allows estimation of quantitative imaging biomarkers such as Ktrans (rate constant for plasma/interstitium contrast reagent (CR) transfer) and ve (extravascular and extracellular volume fraction). However, the use of quantitative DCE-MRI in clinical practice is limited with uncertainty in arterial input function (AIF) determination being one of the primary reasons. In this multicenter study to assess the effects of AIF variations on pharmacokinetic parameter estimation, DCE-MRI data acquired at one center from 11 prostate cancer patients were shared among nine centers. Individual AIF from each data set was determined by each center and submitted to the managing center. These AIFs, along with a literature population averaged AIF, and their reference-tissue-adjusted variants were used by the managing center to perform pharmacokinetic data analysis using the Tofts model (TM). All other variables, including tumor region of interest (ROI) definition and pre-contrast T1, were kept constant to evaluate parameter variations caused solely by AIF discrepancies. Considerable parameter variations were observed with the within-subject coefficient of variation (wCV) of Ktrans obtained with unadjusted AIFs being as high as 0.74. AIF-caused variations were larger in Ktrans than ve and both were reduced when reference-tissue-adjusted AIFs were used. These variations were largely systematic, resulting in nearly unchanged parametric map patterns. The intravasation rate constant, kep (= Ktrans/ve), was less sensitive to AIF variation than Ktrans (wCV for unadjusted AIFs: 0.45 vs. 0.74), suggesting that it might be a more robust imaging biomarker of prostate microvasculature than Ktrans.