The Impact of MRI-Based Advanced Neuroimaging on Neurooncologists' Clinical Decision-Making in Patients With Posttreatment High-Grade Glioma: A Prospective Survey-Based Study.

Background: Advanced MRI-based neuroimaging techniques, such as perfusion and spectroscopy, have been increasingly incorporated into routine follow-up protocols in patients treated for high-grade glioma (HGG), to help differentiate tumor progression from treatment effect. However, these techniques' influence on clinical management remains poorly understood. Objective: To evaluate the impact of MRI-based advanced neuroimaging on clinical decision-making in patients with HGG in the posttreatment setting. Methods: This prospective study, performed at a comprehensive cancer center from March 1, 2017, to October 31, 2020, included adult patients treated by chemoradiation for WHO grade 4 diffuse glioma who underwent MRIbased advanced neuroimaging (comprising multiple perfusion imaging sequences and spectroscopy) to further evaluate findings on conventional MRI equivocal for tumor progression versus treatment effect. The ordering neuro-oncologists completed surveys before and after each advanced neuroimaging session. The percent of care episodes with a change between the intended and actual management plan on the surveys conducted before and after advanced neuroimaging, respectively, was computed and compared with a previously published percent using the Wald test for independent samples proportions. Results: The study included 63 patients (mean age, 55±13 years; 36 women, 27 men) who underwent 70 advanced neuroimaging sessions. Ordering neuro-oncologists' intended and actual management plans on the surveys completed before and after advanced neuroimaging, respectively, differed in 44% (31/70, [95% CI: 33-56%]) of episodes, which differed from the previously published frequency of 8.5% (5/59) (p<.001). These management plan changes included selection of a different plan for 6/8 episodes with an intended plan to enroll patients in a clinical trial, 12/19 episodes with an intended plan to change chemotherapeutic agents, 4/8 episodes with an intended plan of surgical intervention, and 1/2 episodes with an intended plan of re-irradiation. The ordering neuro-oncologists found advanced neuroimaging to be helpful in 93% (95% CI: 87%-99%) (65/70) of episodes. Conclusion: Neuro-oncologists' management plans changed in a substantial fraction of adult patients with HGG who underwent advanced neuroimaging to further evaluate conventional MRI findings equivocal for tumor progression versus treatment effect. Clinical Impact: The findings support incorporation of advanced neuroimaging into HGG posttreatment monitoring protocols.

Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition.

BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

Quantification of volumetric thigh and paravertebral muscle fat content: comparison of quantitative Dixon (Q-Dixon) magnetic resonance imaging (MRI) with high-speed T2-corrected multiecho MR spectroscopy.

Background: Muscle fat infiltration (MFI) is increasingly recognized as a critical factor influencing muscle function and metabolic health. Accurate quantification of MFI is essential for diagnosing and monitoring various muscular and metabolic disorders. Quantitative Dixon (Q-Dixon) magnetic resonance imaging (MRI) and high-speed T2-corrected multi-echo (HISTO) magnetic resonance spectroscopy (MRS) are both advanced imaging techniques that offer potential for detailed assessment of MFI. However, the validity and reliability of these methods in measuring volumetric changes in muscle composition, particularly in both thigh and paravertebral muscles, have not been thoroughly compared. This study aims to validate volumetric measurements using Q-Dixon MRI against HISTO MRS in thigh and paravertebral muscles, taking into account the heterogeneity of MFI. Methods: A retrospective study was conducted with 54 subjects [mean age, 60 years; 38 male (M)/16 female (F)] for thigh muscle and 56 subjects (mean age, 50 years; 22 M/34 F) for paravertebral muscle assessment using a 3-Tesla MRI. The proton density fat fraction (PDFF) was measured with Q-Dixon MRI and HISTO MRS within the upper-middle part of quadriceps femoris and paravertebral muscles at L4/5 level in volumes-of-interest (VOIs). The corresponding volumetric Q-Dixon freehand VOI PDFF was measured. Scatterplots, Bland-Altman plots, Spearman correlation coefficients, and Wilcoxon signed rank test with Bonferroni correction were employed. The Kruskal-Wallis H tests followed by Bonferroni-corrected post hoc tests were analyzed to compare parameter differences with visual MFI grades. Results: Q-Dixon cubic VOI PDFF correlated positively with HISTO MRS PDFF in thigh (r=0.96, P<0.001) and paravertebral groups (r=0.98, P<0.001), with insignificant differences (P=0.29, 0.82, respectively). Both PDFF values from cubic VOIs in Q-Dixon and HISTO MRS differed from the freehand Q-Dixon PDFF (all P<0.001). Only for <5% HISTO MRS PDFF, there was a difference between HISTO MRS PDFF and Q-Dixon cubic VOI PDFF (P=0.002). Conclusions: Volumetric Q-Dixon cubic VOI PDFF exhibited good correlation and consistency with HISTO MRS PDFF for quantitative fat assessment in thigh and paravertebral muscles except for muscles with fat fraction <5%, and the Q-Dixon freehand VOI PDFF offers a more comprehensive assessment of the actual MFI compared to cubic VOI.

Magnetic Resonance Spectroscopy of Intra-axial Gliomas With Histopathological Correlation in a Tertiary Care Center of Eastern Nepal.

Background and objective Magnetic resonance spectroscopy (MRS) is a magnetic resonance imaging technique used to identify in vivo metabolites non-invasively within the tissue of interest. It plays an important role in diagnosing brain lesions, particularly tumors and infections. There are certain metabolites whose levels are increased or decreased in brain tumors, the ratios of which can also be used to grade the tumors as high- or low-grade. This study aimed to assess the spectrum of different metabolites in intraaxial gliomas using magnetic resonance spectroscopy and to assess the usefulness of their ratios for grading gliomas into high-grade and low-grade. Methods This descriptive cross-sectional study was performed in the radiology department of Nobel Medical College and Teaching Hospital, Biratnagar, Nepal over one year (September 2019 to September 2020). Thirty-five patients diagnosed as having intra-axial tumors were enrolled. After taking informed consent the examination findings were recorded in structured proforma. Siemens' 3 Tesla open magnet MAGNETOM Skyra (Siemens Healthineers AG, Munich, Germany) MR scanner was used to evaluate each patient. Data was analyzed using the software Statistical Package for Social Sciences (SPSS), version 26.0 (IBM Corp., Armonk, NY). Results Out of 35 patients scanned, 18 had high-grade glioma and 17 had low-grade glioma. High-grade glioma had a choline/creatine (Cho/Cr) ratio of 2.44 ± 0.78 and a choline/N-acetyl-aspartate (Cho/NAA) ratio of 2.05 ± 0.84. Low-grade glioma had a Cho/Cr ratio of 1.48 ± 0.50 and a Cho/NAA ratio of 1.41 ± 0.19. Fourteen out of eighteen high-grade gliomas had raised lipid/lactate peaks. The sensitivity, specificity, positive and negative predictive values (PPV and NPV), and accuracy for diagnosing high-grade glioma with a Cho/Cr ratio cut-off of 1.5 was 83.3 %, 82.4%, 83.3%,82.4 %, and 82.85% respectively. Conclusion MRS metabolite ratios can be used to diagnose and grade gliomas. Cho/Cr, Cho/NAA, and the presence or absence of lipid/lactate peak can significantly improve the sensitivity, specificity, predictive values, and accuracy of preoperative glioma grading when used in conjunction with conventional MRI.

State of the art in the diagnostic evaluation of osteomyelitis: exploring the role of advanced MRI sequences-a narrative review.

Background and Objective: Osteomyelitis, a severe bone infection caused mainly by pyogenic organisms, poses diagnostic challenges due to its non-specific magnetic resonance imaging (MRI) manifestations. Conventional MRI, though the imaging modality of choice, often exhibits signal abnormalities with overlapping differential diagnoses, potentially leading to overestimation of infection extent and duration. To address these limitations, advanced MRI sequences, including dynamic contrast-enhanced (DCE) MRI, 1H magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), and Dixon techniques have emerged as promising alternatives. This narrative review explores the potential role of these sequences in aiding the differential diagnosis of osteomyelitis. Methods: We used the PubMed database to search for relevant articles using the MeSH keywords: (osteomyelitis) AND (advanced MRI sequences) and we manually selected the most suitable studies to include in our review. Articles outside of original studies were also included. Only records in English or French were considered. Key Content and Findings: In particular, DWI is useful for characterizing fluid collections, distinguishing bone infarcts, and bacterial skull base osteomyelitis from neoplastic lesions. Moreover, DWI assists in differentiating diabetic foot osteomyelitis (DFO) from Charcot neuro-osteoarthropathy, facilitates the diagnosis of pediatric acute osteoarticular infections, and aids in distinguishing osteomyelitis from Modic I degenerative changes. Additionally, DWI proves valuable in monitoring spinal infections and distinguishing pedal osteomyelitis from other conditions, even in patients with renal impairment. DCE-MRI enhances MRI specificity by assessing contrast uptake over time, providing valuable insights into inflammatory microenvironments. It aids in detecting DFO, differentiating it from acute Charcot arthropathy, and distinguishing osteomyelitis from neuropathic arthropathy. Moreover, DCE-MRI shows potential in assessing response to antibiotic therapy in spinal infections. Dixon acquisition improves image quality and facilitates the detection of bone marrow abnormalities, aiding in the differentiation of diabetic foot from osteomyelitis. It also assists in distinguishing osteomyelitis from neuropathic arthropathy and provides valuable information in evaluating the diabetic foot. Proton MR spectroscopy, a well-established modality, offers metabolic information that can differentiate malignant from benign lesions. Conclusions: The role of advanced MRI techniques in evaluating osteomyelitis remains to be fully defined, and further research is required to explore its potential utility in this context. In conclusion, the incorporation of advanced MRI sequences has shown promise in improving the differential diagnosis of osteomyelitis. Future investigations exploring combinations of these techniques and their clinical applications hold significant potential to enhance diagnostic accuracy and patient outcomes.

An exploratory study on the association between blood-based biomarkers and subacute neurometabolic changes following mild traumatic brain injury.

BACKGROUND AND OBJECTIVES: Blood-based biomarkers and advanced neuroimaging modalities such as magnetic resonance spectroscopy (MRS) or diffusion tensor imaging (DTI) have enhanced our understanding of the pathophysiology of mild traumatic brain injury (mTBI). However, there is limited published data on how blood biomarkers relate to neuroimaging biomarkers post-mTBI. METHODS: To investigate this, 30 patients with mTBI and 21 healthy controls were enrolled. Data was collected at two timepoints postinjury: acute, < 24 h, (blood) and subacute, four-to-six weeks, (blood and imaging). Interleukin (IL) 6 and 10 (inflammation), free thiols (systemic oxidative stress) and neurofilament light (NF-L) (axonal injury) were quantified in plasma. The neurometabolites total N-acetyl aspartate (tNAA) (neuronal energetics), Myo-Inositol (Ins) and total Choline (tCh) (inflammation) and, Glutathione (GSH, oxidative stress) were quantified using MRS. RESULTS: Concentrations of IL-6 and IL-10 were significantly elevated in the acute phase post-mTBI, while NF-L was elevated only in the subacute phase. Total NAA was lowered in patients with mTBI, although this difference was only nominally significant (uncorrected P < 0.05). Within the patient group, acute IL-6 and subacute tNAA levels were negatively associated (r = - 0.46, uncorrected-P = 0.01), albeit not at a threshold corrected for multiple testing (corrected-P = 0.17). When age was added as a covariate a significant increase in correlation magnitude was observed (ρ = - 0.54, corrected-P = 0.03). CONCLUSION: This study demonstrates potential associations between the intensity of the inflammatory response in the acute phase post-mTBI and neurometabolic perturbations in the subacute phase. Future studies should assess the longitudinal dynamics of blood-based and imaging biomarkers after injury.

Alteration of intracerebral metabolites and subjective sleepiness by acute caffeine administration in adults.

Background: Caffeine is the most widely consumed psychostimulant. Despite this, the effects of acute caffeine intake on brain metabolite levels remain largely unknown. We aimed to investigate the effect of acute caffeine intake on brain metabolite concentrations in different caffeine consumption habit groups and to explore the association between metabolite changes and sleepiness. Methods: Forty-five healthy adults were divided into groups based on their daily caffeine consumption: ≥1 cup/day, <1 cup/day, and no consumption. The exclusion criteria were the presence of neurological disorder, habitual consumption of mind-altering substances, and individuals who were unable to undergo magnetic resonance imaging. Mescher-Garwood point resolved spectroscopy and conventional spectroscopy data were acquired at 3 Tesla from voxels in the thalamus and posterior cingulate cortex (PCC). Subjective sleepiness was measured with the Karolinska Sleepiness Scale. Results: The results of two-way repeated measures analysis of variance indicated a significant interaction effect between time and group for glutamate, glycerylphosphocholine and phosphocholine (GPC + PCH), myo-inositol, glutamate + glutamine (Glx), and creatine and phosphocreatine (Cr + PCr) of the thalamus (all P<0.01), and glutamate (P<0.0001), GPC + PCH (P=0.016), and Glx (P<0.0001) of the PCC. The change between pre- and post-caffeine intake results with significant reductions in γ-aminobutyric acid-positive macromolecule (GABA+) (thalamus, P=0.011), Glx (thalamus, P=0.002), glutamate (PCC, P<0.0001), and significant increments in GPC + PCH (thalamus, P=0.012 and PCC, P<0.0001), myo-inositol (thalamus, P=0.009), and Glx (PCC, P<0.0001). The change among the groups, with the ≥1 cup/day was significantly higher than the <1 cup/day or no consumption for glutamate (PCC, P=0.028), GPC (thalamus, P=0.001; PCC, P=0.026), and Cr + PCr (PCC, P=0.035); ≥1 cup/day was significantly lower than <1 cup/day and no consumption for glutamate (thalamus, P<0.0001), Cr + PCr (thalamus, P=0.003), Glx (thalamus, P=0.014), and myo-inositol (PCC, P=0.009). Bivariate correlation analysis revealed that GABA+ in the thalamus voxel (r=-0.7676; P<0.0001) was negatively correlated with subjective sleepiness. Conclusions: Higher caffeine consumption had a significant impact on brain metabolites. Magnetic resonance spectroscopy was sensitive in measuring brain metabolite fluctuations after caffeine intake, particularly the levels of GABA+ in the thalamus, which was significantly correlated with sleepiness.

A rare case of tumefactive demyelination of brain: A case report and literature review.

This case report highlights the diagnostic challenges encountered in a 30-year-old female presenting with fever followed by Wernicke's aphasia without right-sided weakness, ultimately diagnosed as tumefactive demyelination (TD). TD is a rare neurological condition often misidentified as brain tumors or inflammatory disorders. The case emphasizes the importance of precise differentiation through advanced magnetic resonance imaging, showing restricted diffusion at lesion edges and the absence of gadolinium enhancement. Accurate diagnosis is crucial for tailored treatment and prognostic assessment. This case contributes to our understanding of TD and underscores the need for continued research and collaboration in the field of rare neurological disorders.

Denoising magnetic resonance spectroscopy (MRS) data using stacked autoencoder for improving signal-to-noise ratio and speed of MRS.

BACKGROUND: While magnetic resonance imaging (MRI) provides high resolution anatomical images with sharp soft tissue contrast, magnetic resonance spectroscopy (MRS) enables non-invasive detection and measurement of biochemicals and metabolites. However, MRS has low signal-to-noise ratio (SNR) when concentrations of metabolites are in the range of millimolar. Standard approach of using a high number of signal averaging (NSA) to achieve sufficient SNR comes at the cost of a long acquisition time. PURPOSE: We propose to use deep-learning approaches to denoise MRS data without increasing NSA. This method has potential to reduce the acquisition time as well as improve SNR and quality of spectra, which could enhance the diagnostic value and broaden the clinical applications of MRS. METHODS: The study was conducted using data collected from the brain spectroscopy phantom and human subjects. We utilized a stack auto-encoder (SAE) network to train deep learning models for denoising low NSA data (NSA = 1, 2, 4, 8, and 16) randomly truncated from high SNR data collected with high NSA (NSA = 192), which were also used to obtain the ground truth. We applied both self-supervised and fully-supervised training approaches and compared their performance of denoising low NSA data based on improvement in SNR. To prevent overfitting, the SAE network was trained in a patch-based manner. We then tested the denoising methods on noise-containing data collected from the phantom and human subjects, including data from brain tumor patients. We evaluated their performance by comparing the SNR levels and mean squared errors (MSEs) calculated for the whole spectra against high SNR "ground truth", as well as the value of chemical shift of N-acetyl-aspartate (NAA) before and after denoising. RESULTS: With the SAE model, the SNR of low NSA data (NSA = 1) obtained from the phantom increased by 28.5% and the MSE decreased by 42.9%. For low NSA data of the human parietal and temporal lobes, the SNR increased by 32.9% and the MSE decreased by 63.1%. In all cases, the chemical shift of NAA in the denoised spectra closely matched with the high SNR spectra without significant distortion to the spectra after denoising. Furthermore, the denoising performance of the SAE model was more effective in denoising spectra with higher noise levels. CONCLUSIONS: The reported SAE denoising method is a model-free approach to enhance the SNR of MRS data collected with low NSA. With the denoising capability, it is possible to acquire MRS data with a few NSA, shortening the scan time while maintaining adequate spectroscopic information for detecting and quantifying the metabolites of interest. This approach has the potential to improve the efficiency and effectiveness of clinical MRS data acquisition by reducing the scan time and increasing the quality of spectroscopic data.

Assessment of bone marrow fat by 3-Tesla magnetic resonance spectroscopy in patients with chronic kidney disease.

Background: Proton magnetic resonance spectroscopy (1H MRS) is an imaging method for quantification of bone marrow fat. It has been used for evaluation of bone marrow changes in patients with chronic disorders, such as chronic kidney disease (CKD). In these patients, there is a high turnover state, with an excessive amount of non-mineralized component of bone, leading to skeletal fragility and subsequent increased fracture risk. Methods: Thirty CKD patients underwent magnetic resonance spectroscopy (MRS) and quantitative computed tomography (QCT), and eight healthy controls underwent MRS at lumbar spine. Proton density fat fraction (PDFF) and volumetric bone mineral density (vBMD) of L1-L3 were determined from MRS and QCT respectively. CKD patients were divided into three groups according to glomerular filtration rate (GFR); for each patient, blood levels of parathyroid hormone (PTH) were also reported. Paired t-tests, Pearson's correlation coefficients and analysis of variance were applied. Results: The mean age of patients was 59.6±11.5 years, mean GFR value was 21.5±8.8 mL/min and mean PTH value was 149.2±53.1 pg/mL. PDFF at L1-L3 levels was significantly higher in CKD patients compared to controls (71.4±8.7 vs. 55.5±7.6; P<0.001) and showed an inverse correlation with vBMD (r=-0.71; P<0.001). PDFF significantly increased from CKD group 1 to CKD group 3 (P=0.002) and was inversely correlated with GFR (r=-0.53; P=0.003). There was no significant association between PDFF and PTH values (P>0.05). Conclusions: In CKD patients, PDFF assessed by MRS at lumbar spine is higher than in healthy population, correlates with bone loss assessed by QCT and significantly increases with the worsening of renal function. MRS is a reliable and highly repeatable tool for PDFF quantification in CKD patients.

Gliomatosis cerebri with blindness: A case report with literature review.

Cerebral gliomatosis (GC) is a rare diffuse infiltrative growth pattern of glioma with nonspecific clinical manifestations like visual impairment that may involve bilateral temporal lobes. Herpes simplex encephalitis (HSE) and limbic encephalitis (LE) can also lead to temporal lobe involvement. Differentiating these entities is necessary for patients with misleading presentations and imaging findings. To the best of our knowledge, this is the third case of GC presenting with blindness. The patient was a 35 years-old male in a drug rehabilitation center for heroin addiction. He presented with a headache, a single episode of seizure, and a 2-month history of bilateral decrease in visual acuity, which had acutely worsened. Magnetic resonance imaging (MRI) and computed tomography (CT) showed bilateral temporal lobe involvement. Ophthalmological studies showed bilateral papilledema, absence of visual evoked potential, and thickening of the retinal nerve fiber layer. Due to this clinical presentation, normal laboratory data, and suspicious MRI findings, further investigation with magnetic resonance spectroscopy (MRS) was performed. Results showed a greatly increased ratio of choline to creatinine(Cr) or N-acetyl aspartate (NAA), suggesting a neoplastic nature of the disease. Subsequently, the patient was referred for a brain tissue biopsy with a suspicion of malignancy. The pathology results revealed adult-type diffuse glioma with isocitrate dehydrogenase (IDH) mutation. Bilateral blindness, as well as bilateral temporal lobe involvement, each has many different causes. However, as demonstrated in this study, adult-type diffuse glioma must be considered a rare cause of concomitant bilateral temporal lobe involvement and blindness.

Characterizing Various Posterior Fossa Tumors in Children and Adults With Diffusion-Weighted Imaging and Spectroscopy.

Background The posterior fossa is situated between the tentorium cerebelli above and the foramen magnum below. Vital structures like the cerebellum, the pons, and the medulla are situated within it; hence, tumors within the posterior fossa are considered one of the most critical brain lesions. Children are more likely to develop posterior fossa tumors than adults. Diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS) sequences along with the conventional MRI help in providing additional information in the characterization of the various posterior fossa tumors. We hereby present a series of 30 patients with clinically suspected posterior fossa masses who underwent preoperative MRI. Objectives This study aims to differentiate the neoplastic from non-neoplastic posterior fossa mass by evaluating the diffusion restriction pattern on DWI, quantifying the apparent diffusion coefficient (ADC) map in various posterior fossa tumors, and comparing the different metabolites of various posterior fossa tumors on MRS. Results Out of the 30 patients with posterior fossa lesions, 18 were males and 12 were females. Eight of them were in the pediatric age group, while twenty-two of them were adults. Metastasis was the most common posterior fossa lesion in our study sample and was found in six patients (20%), followed by vestibular schwannomas (17%) and arachnoid cysts (13%), meningiomas, medulloblastoma, and pilocytic astrocytoma (10% each) and epidermoid, ependymoma, and hemangioblastoma (7% each). The mean ADC value of benign tumors was higher than that of malignant tumors, and this difference was found to be significant (p = 0.012). The cut-off ADC value 1.21x 10-3mm2/s had a sensitivity of 81.82% and specificity of 80.47%. MRS metabolites played an additional role in differentiating benign from malignant tumors. Conclusion A combination of conventional MRI, DWI, ADC values, and MRS metabolites showed good diagnostic accuracy to differentiate between the various posterior fossa neoplastic tumors both in adults and children.

Real-Time Semi-Automated and Automated Voxel Placement using fMRI Targets for Repeated Acquisition Magnetic Resonance Spectroscopy.

BACKGROUND: Currently, magnetic resonance spectroscopy (MRS) is dependent on the investigative team to manually prescribe, or demarcate, the desired tissue volume-of-interest. The need for a new method to automate precise voxel placements is warranted to improve the utility and interpretability of MRS data. NEW METHOD: We propose and validate robust and real-time methods to automate MRS voxel placement using functionally defined coordinates within the prefrontal cortex. Data were collected and analyzed using two independent prospective studies: 1) two independent imaging days with each consisting of a multi-session sandwich design (MRS data only collected on one of the days determined based on scan time) and 2) a longitudinal design. Participants with fibromyalgia syndrome (N = 50) and major depressive disorder (N = 35) underwent neuroimaging. MRS acquisitions were acquired at 3-tesla. Evaluation of the reproducibility of spatial location and tissue segmentation was assessed for: 1) manual, 2) semi-automated, and 3) automated voxel prescription approaches RESULTS: Variability of voxel grey and white matter tissue composition was reduced using automated placement protocols. Spatially, post- to pre-voxel center-of-gravity distance was reduced and voxel overlap increased significantly across datasets using automated compared to manual procedures COMPARISON WITH EXISTING METHODS: Manual prescription, the current standard in the field, can produce inconsistent data across repeated acquisitions. Using automated voxel placement, we found reduced variability and more consistent voxel placement across multiple acquisitions CONCLUSIONS: These results demonstrate the within subject reliability and reproducibility of a method for reducing variability introduced by spatial inconsistencies during MRS acquisitions. The proposed method is a meaningful advance toward improved consistency of MRS data in neuroscience and can be utilized for multi-session and longitudinal studies.

Exceptionally rare IDH1-mutant adult medulloblastoma with concurrent GNAS mutation revealed by in vivo magnetic resonance spectroscopy and deep sequencing.

Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adults. Based on transcriptome profile, MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) mutations have been described in several tumors, including gliomas, while in MB are rarely reported and not routinely investigated. By means of magnetic resonance spectroscopy (MRS), we unequivocally assessed the presence the oncometabolite D-2-hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutations, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also rarely described in MB. To the best of our knowledge, this is the first reported case of MB simultaneously harboring both mutations. Of note, tumor exhibited a heterogeneous phenotype with a tumor component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting co-existence of two different major tumor subclones. These findings drew attention to the need for a deeper genetic characterization of MB, in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, our results underlined the importance of performing MRS for the identification of IDH mutations in non-glial tumors. The use of throughput molecular profiling analysis and advanced medical imaging will certainly increase the frequency with which tumor entities with rare molecular alterations will be identified. Whether these findings have any specific therapeutic implications or prognostic relevance requires further investigations.

Molecular MRI-Based Monitoring of Cancer Immunotherapy Treatment Response.

Immunotherapy constitutes a paradigm shift in cancer treatment. Its FDA approval for several indications has yielded improved prognosis for cases where traditional therapy has shown limited efficiency. However, many patients still fail to benefit from this treatment modality, and the exact mechanisms responsible for tumor response are unknown. Noninvasive treatment monitoring is crucial for longitudinal tumor characterization and the early detection of non-responders. While various medical imaging techniques can provide a morphological picture of the lesion and its surrounding tissue, a molecular-oriented imaging approach holds the key to unraveling biological effects that occur much earlier in the immunotherapy timeline. Magnetic resonance imaging (MRI) is a highly versatile imaging modality, where the image contrast can be tailored to emphasize a particular biophysical property of interest using advanced engineering of the imaging pipeline. In this review, recent advances in molecular-MRI based cancer immunotherapy monitoring are described. Next, the presentation of the underlying physics, computational, and biological features are complemented by a critical analysis of the results obtained in preclinical and clinical studies. Finally, emerging artificial intelligence (AI)-based strategies to further distill, quantify, and interpret the image-based molecular MRI information are discussed in terms of perspectives for the future.

The spectrum of magnetic resonance imaging proton density fat fraction (MRI-PDFF), magnetic resonance spectroscopy (MRS), and two different histopathologic methods (artificial intelligence vs. pathologist) in quantifying hepatic steatosis.

Background: The grade of hepatic steatosis is assessed semi-quantitatively and graded as a discrete value. However, the proton density fat fraction (PDFF) measured by magnetic resonance imaging (MRI) and FF measured by MR spectroscopy (FFMRS) are continuous values. Therefore, a quantitative histopathologic method may be needed. This study aimed to (I) provide a spectrum of values of MRI-PDFF, FFMRS, and FFs measured by two different histopathologic methods [artificial intelligence (AI) and pathologist], (II) to evaluate the correlation among them, and (III) to evaluate the diagnostic performance of MRI-PDFF and MRS for grading hepatic steatosis. Methods: Forty-seven patients who underwent liver biopsy and MRI for nonalcoholic steatohepatitis (NASH) evaluation were included. The agreement between MRI-PDFF and MRS was evaluated through Bland-Altman analysis. Correlations among MRI-PDFF, MRS, and two different histopathologic methods were assessed using Pearson correlation coefficient (r). The diagnostic performance of MRI-PDFF and MRS was assessed using receiver operating characteristic curve analyses and the area under the curve (AUC) were obtained. Results: The means±standard deviation of MRI-PDFF, FFMRS, FF measured by pathologist (FFpathologist), and FF measured by AI (FFAI) were 12.04±6.37, 14.01±6.16, 34.26±19.69, and 6.79±4.37 (%), respectively. Bland-Altman bias [mean of MRS - (MRI-PDFF) differences] was 2.06%. MRI-PDFF and MRS had a very strong correlation (r=0.983, P<0.001). The two different histopathologic methods also showed a very strong correlation (r=0.872, P<0.001). Both MRI-PDFF and MRS demonstrated a strong correlation with FFpathologist (r=0.701, P<0.001 and r=0.709, P<0.001, respectively) and with FFAI (r=0.700, P<0.001 and r=0.690, P<0.001, respectively). The AUCs of MRI-PDFF for grading ≥S2 and ≥S3 were 0.846 and 0.855, respectively. The AUCs of MRS for grading ≥S2 and ≥S3 were 0.860 and 0.878, respectively. Conclusions: Since MRS and MRI-PDFF demonstrated a strong correlation with each other and with the two different histopathologic methods, they can be used as an alternative noninvasive reference standard in nonalcoholic fatty liver disease (NAFLD) patients. However, these preliminary results should be interpreted with caution until they are validated in further studies.

A Rare Case of Type B Neonatal Pyruvate Carboxylase Enzyme Deficiency Presenting With Refractory Lactic Acidosis in the Early Neonatal Period.

Pyruvate carboxylase (PC) enzyme deficiency is a rare genetic disorder inherited in an autosomal recessive (AR) manner. PC, a mitochondrial enzyme, converts pyruvate to oxaloacetate (OAA), which enters the tricarboxylic acid (TCA) cycle. Based on the tissue type, intermediate metabolites of the TCA cycle play a vital role in gluconeogenesis, lipogenesis, synthesis of nicotinamide adenine dinucleotide phosphate (NADPH), and neurotransmitter glutamate in the astrocytes. The severity of clinical presentation depends on the type of PC deficiency and on the residual enzyme activity. We present a term female infant admitted with refractory lactic acidosis that developed soon after birth. On biochemical evaluation, serum ammonia was 125 µmol/L; plasma amino acid analysis showed elevated citrulline, lysine, proline, decreased glutamine, and aspartic acid; urine organic acid analysis showed markedly increased lactic acid, and moderately elevated 3-hydroxy-butyric and acetoacetic acid. MRI brain demonstrated abnormal diffuse white matter edema, loculated and septate large cysts along the caudothalamic notch as well as lateral aspect of the frontal horn bilaterally. Magnetic resonance (MR) spectroscopy showed large amounts of lactate peak. Molecular genetic analysis showed two pathogenic variants in the PC gene confirming the diagnosis of PC enzyme deficiency. The infant was discharged home on palliative and hospice care, and she died on the 22nd day after birth.

Milk intake enhances cerebral antioxidant (glutathione) concentration in older adults: A randomized controlled intervention study.

Background: A major antioxidant, glutathione (GSH), is a key factor in the antioxidant defense mechanism against oxidative stress and aging-related functional declines. Our previous observational study showed positive correlations between brain GSH concentrations and dairy food consumption, particularly milk (p < 0.001), in older adults. Objective: To investigate whether a recommended amount of milk intake (3 cups/day) in low dairy consumers enhances brain GSH concentrations through an intervention trial. Methods: Seventy-three older adults (60-89 years) with a low dairy intake (≤1.5 servings/day) were randomized (5:2 ratio) in this 3-month randomized clinical trial. The intervention group was provided 1% milk weekly and instructed to consume 3 cups of milk/day for 3 months while the control group continued their habitual intake of total dairy ≤ 1.5 servings/day (<1 cup of milk/day). Brain GSH concentrations were measured in the fronto-parietal region using our unique 3 T magnetic resonance chemical shift imaging technique at baseline and 3 months. Results: Among 73 randomized participants, 66 participants (49 intervention; 17 controls) completed the study. Milk intake in the intervention group increased from 0.2 ± 0.3 cups/day to 3.0 ± 0.6 cups/day (p < 0.001) between baseline and the end of the study, while milk intake in the control group did not differ throughout the study duration (0.4 ± 0.4 cups/day). The intervention group showed increases in brain GSH concentrations by 7.4 ± 11.7% (p < 0.001) in parietal and 4.7 ± 9.8% (p = 0.003) in fronto-parietal regions, and 4.6 ± 8.7% (p < 0.001) in overall brain concentration after the intervention compared with baseline, while the control group showed no changes. Conclusion: This study provides evidence that milk serves as a good dietary source to increase and/or restore brain GSH concentrations in older adults. Identifying dietary sources that effectively enhance antioxidant defenses and neuroprotection could lead to the development of new strategies to promote brain health in the aging population. Clinical trial registration: [https://ClinicalTrials.gov], identifier [NCT02957422].

Two-dimensional correlated spectroscopy distinguishes clear cell renal cell carcinoma from other kidney neoplasms and non-cancer kidney.

Background: Routinely used clinical scanners, such as computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US), are unable to distinguish between aggressive and indolent tumor subtypes in masses localized to the kidney, often leading to surgical overtreatment. The results of the current investigation demonstrate that chemical differences, detected in human kidney biopsies using two-dimensional COrrelated SpectroscopY (2D L-COSY) and evaluated using multivariate statistical analysis, can distinguish these subtypes. Methods: One hundred and twenty-six biopsy samples from patients with a confirmed enhancing kidney mass on abdominal imaging were analyzed as part of the training set. A further forty-three samples were used for model validation. In patients undergoing radical nephrectomy, biopsies of non-cancer kidney cortical tissue were also collected as a non-cancer control group. Spectroscopy data were analyzed using multivariate statistical analysis, including principal component analysis (PCA) and orthogonal projection to latent structures with discriminant analysis (OPLS-DA), to identify biomarkers in kidney cancer tissue that was also classified using the gold-standard of histopathology. Results: The data analysis methodology showed good separation between clear cell renal cell carcinoma (ccRCC) versus non-clear cell RCC (non-ccRCC) and non-cancer cortical tissue from the kidneys of tumor-bearing patients. Variable Importance for the Projection (VIP) values, and OPLS-DA loadings plots were used to identify chemical species that correlated significantly with the histopathological classification. Model validation resulted in the correct classification of 37/43 biopsy samples, which included the correct classification of 15/17 ccRCC biopsies, achieving an overall predictive accuracy of 86%, Those chemical markers with a VIP value >1.2 were further analyzed using univariate statistical analysis. A subgroup analysis of 47 tumor tissues arising from T1 tumors revealed distinct separation between ccRCC and non-ccRCC tissues. Conclusions: This study provides metabolic insights that could have future diagnostic and/or clinical value. The results of this work demonstrate a clear separation between clear cell and non-ccRCC and non-cancer kidney tissue from tumor-bearing patients. The clinical translation of these results will now require the development of a one-dimensional (1D) magnetic resonance spectroscopy (MRS) protocol, for the kidney, using an in vivo clinical MRI scanner.