Quantification of Radiomics features of Peritumoral Vasogenic Edema extracted from fluid-attenuated inversion recovery images in glioblastoma and isolated brain metastasis, using T1-dynamic contrast-enhanced Perfusion analysis.

The peritumoral vasogenic edema (PVE) in brain tumors exhibits varied characteristics. Brain metastasis (BM) and meningioma barely have tumor cells in PVE, while glioblastoma (GB) show tumor cell infiltration in most subjects. The purpose of this study was to investigate the PVE of these three pathologies using radiomics features in FLAIR images, with the hypothesis that the tumor cells might influence textural variation. Ex vivo experimentation of radiomics analysis of T1-weighted images of the culture medium with and without suspended tumor cells was also attempted to infer the possible influence of increasing tumor cells on radiomics features. This retrospective study involved magnetic resonance (MR) images acquired using a 3.0-T MR machine from 83 patients with 48 GB, 21 BM, and 14 meningioma. The 93 radiomics features were extracted from each subject's PVE mask from three pathologies using T1-dynamic contrast-enhanced MR imaging. Statistically significant (< 0.05, independent samples T-test) features were considered. Features maps were also computed for qualitative investigation. The same was carried out for T1-weighted cell line images but group comparison was carried out using one-way analysis of variance. Further, a random forest (RF)-based machine learning model was designed to classify the PVE of GB and BM. Texture-based variations, especially higher nonuniformity values, were observed in the PVE of GB. No significance was observed between BM and meningioma PVE. In cell line images, the culture medium had higher nonuniformity and was considerably reduced with increasing cell densities in four features. The RF model implemented with highly significant features provided improved area under the curve results. The possible infiltrative tumor cells in the PVE of the GB are likely influencing the texture values and are higher in comparison with BM PVE and may be of value in the differentiation of solitary metastasis from GB. However, the robustness of the features needs to be investigated with a larger cohort and across different scanners in the future.

Acute metabolic alterations in the hippocampus are associated with decreased acetylation after blast induced TBI.

INTRODUCTION: Blast induced Traumatic brain injury (BI-TBI) is common among military personnels as well as war affected civilians. In the war zone, people can also encounter repeated exposure of blast wave, which may affect their cognition and metabolic alterations. OBJECTIVE: In this study we assess the metabolic and histological changes in the hippocampus of rats at 24 h post injury. METHOD: Rats were divided into four groups: (i) Sham; (ii) Mild TBI (mi); (iii) Moderate TBI (mo); and (iv) Repetitive mild TBI (rm TBI) and then subjected to different intensities of blast exposure. Hippocampal tissues were collected after 24 h of injury for proton nuclear magnetic resonance spectroscopy (1H NMR spectroscopy) and immunohistochemical (IHC) analysis. RESULTS: The metabolic alterations were found in the hippocampal tissue samples and these alterations showed significant change in glutamate, N-Acetylaspartic acid (NAA), acetate, creatine, phosphoethanolamine (PE), ethanolamine and PC/choline concentrations in rmTBI rats only. IHC studies revealed that AH3 (Acetyl histone) positive cells were decreased in rm TBI tissue samples in comparison to other TBI groups and sham rats. This might reflect an epigenetic alteration due to repeated blast exposure at 24 h post injury. Additionally, astrogliosis was observed in miTBI and moTBI hippocampal tissue while no change was observed in rmTBI tissues. CONCLUSION: The present study reports altered acetylation in the presence of altered metabolism in hippocampal tissue of blast induced rmTBI at 24 h post injury. Mechanistic understanding of these intertwined processes may help in the development of better therapeutic pathways and agents for blast induced TBI in near future.

Temporal profile of serum metabolites and inflammation following closed head injury in rats is associated with HPA axis hyperactivity.

INTRODUCTION: Closed head injury (CHI) causes neurological disability along with systemic alterations that can activate neuro-endocrine response through hypothalamic-pituitary-adrenal (HPA) axis activation. A dysregulated HPA axis function can lead to relocation of energy substrates and alteration in metabolic pathways and inflammation at the systemic level. OBJECTIVES: Assessment of time-dependent changes in serum metabolites and inflammation after both mild and moderate CHI. Along with this, serum corticosterone levels and hypothalamic microglial response were observed. METHODS: Rats underwent mild and moderate weight-drop injury and their serum and hypothalamus were assessed at acute, sub-acute and chronic timepoints. Changes in serum metabolomics were determined using high resolution NMR spectroscopy. Serum inflammatory cytokine, corticosterone levels and hypothalamic microglia were assessed at all timepoints. RESULTS: Metabolites including lactate, choline and branched chain amino acids were found as the classifiers that helped distinguish between control and injured rats during acute, sub-acute and chronic timepoints. While, increased αglucose: ßglucose and TMAO: choline ratios after acute and sub-acute timepoints of mild injury differentiated from moderate injured rats. The injured rats also showed distinct inflammatory profile where IL-1ß and TNF-α levels were upregulated in moderate injured rats while IL-10 levels were downregulated in mild injured rats. Furthermore, injury specific alterations in serum metabolic and immunologic profile were found to be associated with hyperactive HPA axis, with consistent increase in serum corticosterone concentration post injury. The hypothalamic microglia showed a characteristic activated de-ramified cellular morphology in both mild and moderate injured rats. CONCLUSION: The study suggests that HPA axis hyperactivity along with hypothalamic microglial activation led to temporal changes in the systemic metabolism and inflammation. These time dependent changes in the metabolite profile of rats can further strengthen the knowledge of diagnostic markers and help distinguish injury related outcomes after TBI.

Oxidative stress contributes to cerebral metabolomic profile changes in animal model of blast-induced traumatic brain injury.

INTRODUCTION: Blast-induced neurotrauma (BINT) has been recognized as the common mode of traumatic brain injury amongst military and civilian personnel due to an increased insurgent activity domestically and abroad. Previous studies from this laboratory have identified three major pathological events following BINT which include blood brain barrier disruption the earliest event, followed by oxidative stress and neuroinflammation as secondary events occurring a few hours following blast. OBJECTIVES: Our recent studies have also identified an increase in oxidative stress mediated by the activation of superoxide producing enzyme NADPH oxidase (NOX) in different brain regions at varying levels with neurons displaying higher oxidative stress (NOX activation) compared to any other neural cell. Since neurons have higher energy demands in brain and are more prone to oxidative damage, this study evaluated the effect of oxidative stress on blast-blast induced changes in metabolomics profiles in different brain regions. METHODS: Animals were exposed to mild/moderate blast injury (180 kPa) and examined the metabolites of energy metabolism, amino acid metabolism as well as the profiles of plasma membrane metabolites in different brain regions at different time points (24 h, 3 day and 7 day) after blast using 1H NMR spectroscopy. Effect of apocynin, an inhibitor of superoxide producing enzyme NADPH oxidase on cerebral metabalomics profiles was also examined. RESULTS: Several metabolomic profile changes were observed in frontal cortex and hippocampus with concomitant decrease in energy metabolism. In addition, glutamate/glutamine and other amino acid metabolism as well as metabolites involved in plasma membrane integrity were also altered. Hippocampus appears metabolically more vulnerable than the frontal cortex. A post-treatment of animals with apocynin, an inhibitor of NOX activation significantly prevented the changes in metabolite profiles. CONCLUSION: Together these studies indicate that blast injury reduces both cerebral energy and neurotransmitter amino acid metabolism and that oxidative stress contributes to these processes. Thus, strategies aimed at reducing oxidative stress can have a therapeutic benefit in mitigating metabolic changes following BINT.

Altered metabolites of the rat hippocampus after mild and moderate traumatic brain injury - a combined in vivo and in vitro 1 H-MRS study.

Traumatic brain injury (TBI) has been shown to affect hippocampus-associated learning, memory and higher cognitive functions, which may be a consequence of metabolic alterations. Hippocampus-associated disorders may vary depending on the severity of injury [mild TBI (miTBI) and moderate TBI (moTBI)] and time since injury. The underlying hippocampal metabolic irregularities may provide an insight into the pathological process following TBI. In this study, in vivo and in vitro proton magnetic resonance spectroscopy (1 H-MRS) data were acquired from the hippocampus region of controls and TBI groups (miTBI and moTBI) at D0 (pre-injury), 4 h, Day 1 and Day 5 post-injury (PI). In vitro MRS results indicated trauma-induced changes in both miTBI and moTBI; however, in vivo MRS showed metabolic alterations in moTBI only. miTBI and moTBI showed elevated levels of osmolytes indicating injury-induced edema. Altered levels of citric acid cycle intermediates, glutamine/glutamate and amino acid metabolism indicated injury-induced aberrant bioenergetics, excitotoxicity and oxidative stress. An overall similar pattern of pathological process was observed in both miTBI and moTBI, with the distinction of depleted N-acetylaspartate levels (indicating neuronal loss) at 4 h and Day 1 and enhanced lactate production (indicating heightened energy depletion leading to the commencement of the anaerobic pathway) at Day 5 in moTBI. To the best of our knowledge, this is the first study to investigate the hippocampus metabolic profile in miTBI and moTBI simultaneously using in vivo and in vitro MRS.

Study of neurometabolic and behavioral alterations in rodent model of mild traumatic brain injury: a pilot study.

Mild traumatic brain injury (mTBI) is the most common form of TBI (70-90%) with consequences of anxiety-like behavioral alterations in approximately 23% of mTBI cases. This study aimed to assess whether mTBI-induced anxiety-like behavior is a consequence of neurometabolic alterations. mTBI was induced using a weight drop model to simulate mild human brain injury in rodents. Based on injury induction and dosage of anesthesia, four animal groups were included in this study: (i) injury with anesthesia (IA); (ii) sham1 (injury only, IO); (iii) sham2 (only anesthesia, OA); and (iv) control rats. After mTBI, proton magnetic resonance spectroscopy (1 H-MRS) and neurobehavioral analysis were performed in these groups. At day 5, reduced taurine (Tau)/total creatine (tCr, creatine and phosphocreatine) levels in cortex were observed in the IA and IO groups relative to the control. These groups showed mTBI-induced anxiety-like behavior with normal cognition at day 5 post-injury. An anxiogenic effect of repeated dosage of anesthesia in OA rats was observed with normal Tau/tCr levels in rat cortex, which requires further examination. In conclusion, this mTBI model closely mimics human concussion injury with anxiety-like behavior and normal cognition. Reduced cortical Tau levels may provide a putative neurometabolic basis of anxiety-like behavior following mTBI.

Acute and sub-acute metabolic change in different brain regions induced by moderate blunt traumatic brain injury.

The objective of the study was to observe the effect of moderate closed-head injury on hippocampal, thalamic, and striatal tissue metabolism with time. Closed head injury is responsible for metabolic changes. These changes can be permanent or temporary, depending on the injury's impact. For the experiment, 20 rats were randomly divided into four groups, each containing five animals. Animals were subjected to injury using a modified Marmarou's weight drop device; hippocampal, thalamic, and striatal tissue samples were collected after 1 day, 3 days, and 7 days of injury. NMR spectra were acquired following sample processing. Changes in myo-inositol, creatine, glutamate, succinate, lactate, and N-acetyl aspartic acid in hippocampal tissues were observed at day 3 PI. The tyrosine level in the hippocampus was altered at day 7 PI. While thalamic and striatal tissue samples showed altered levels of branched-chain amino acids and myo-inositol at day 1PI. Taurine, gamma amino butyric acid (GABA), choline, and alpha keto-glutarate levels were found to be significantly altered in striatal tissues at days 1 and 3PI. Acetate and GABA levels were altered in the thalamus on day 1 PI. The choline level in the thalamus was found to alter at all-time points after injury. The alteration in these metabolites may be due to the alteration in their respective pathways. Neurotransmitter and energy metabolism pathways were found to be altered in all three brain regions after TBI. This study may help better understand the effect of injury on the metabolic balance of a specific brain region and recovery.

Mild Blast Exposure Dysregulates Metabolic Pathways and Correlation Networking as Evident from LC-MS-Based Plasma Profiling.

Blast-induced trauma is emerging as a serious threat due to its wide pathophysiology where not only the brain but also a spectrum of organs is being affected. In the present study, we aim to identify the plasma-based metabolic dysregulations along with the associated temporal changes at 5-6 h, day 1 and day 7 post-injury in a preclinical animal model for blast exposure, through liquid chromatography-mass spectrometry (LC-MS). Using significantly advanced metabolomic and statistical bioinformatic platforms, we were able to elucidate better and unravel the complex networks of blast-induced neurotrauma (BINT) and its interlinked systemic effects. Significant changes were evident at 5-6 h with maximal changes at day 1. Temporal analysis also depicted progressive changes which continued till day 7. Significant associations of metabolic markers belonging to the class of amino acids, energy-related molecules, lipids, vitamin, hormone, phenolic acid, keto and histidine derivatives, nucleic acid molecules, uremic toxins, and uronic acids were observed. Also, the present study is the first of its kind where comprehensive, detailed pathway dysregulations of amino acid metabolism and biosynthesis, perturbed nucleotides, lipid peroxidation, and nucleic acid damage followed by correlation networking and multiomics networking were explored on preclinical animal models exposed to mild blast trauma. In addition, markers for systemic changes (renal dysfunction) were also observed. Global pathway predictions of unannotated peaks also presented important insights into BINT pathophysiology. Conclusively, the present study depicts important findings that might help underpin the biological mechanisms of blast-induced brain or systemic trauma.

Altered DTI scalars in the hippocampus are associated with morphological and structural changes after traumatic brain injury.

Blunt and diffuse injury is a highly prevalent form of traumatic brain injury (TBI) which can result in microstructural alterations in the brain. The blunt impact on the brain can affect the immediate contact region but can also affect the vulnerable regions like hippocampus, leading to functional impairment and long-lasting cognitive deficits. The hippocampus of the moderate weight drop injured male rats was longitudinally assessed for microstructural changes using in vivo MR imaging from 4 h to Day 30 post-injury (PI). The DTI analysis found a prominent decline in the apparent diffusion coefficient (ADC), radial diffusivity (RD), and axial diffusivity (AD) values after injury. The perturbed DTI scalars accompanied histological changes in the hippocampus, wherein both the microglia and astrocytes showed changes in the morphometric parameters at all timepoints. Along with this, the hippocampus showed presence of Aß positive fibrils and neurite plaques after injury. Therefore, this study concludes that TBI can lead to a complex morphological, cellular, and structural alteration in the hippocampus which can be diagnosed using in vivo MR imaging techniques to prevent long-term functional deficits.

Lipidomic Analysis Reveals Systemic Alterations in Servicemen Exposed to Repeated Occupational Low-Level Blast Waves.

INTRODUCTION: Occupational exposure to blast is a prevalent risk experienced by military personnel. While low-level exposure may not manifest immediate signs of illness, prolonged and repetitive exposure may result in neurophysiological dysfunction. Such repeated exposure to occupational blasts has been linked to structural and functional modifications in the brain, adversely affecting the performance of servicemen in the field. These neurological changes can give rise to symptoms resembling concussion and contribute to the development of post-traumatic stress disorder. MATERIALS AND METHODS: To understand long-term effects of blast exposure, the study was conducted to assess memory function, serum circulatory protein and lipid biomarkers, and associated concussive symptomology in servicemen. Concussion-like symptoms were assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPSQ) along with memory function using PGI memory scale. The serum protein biomarkers were quantified using a sandwich ELISA assay, and the serum lipid profile was measured using liquid chromatography-mass spectrometer. RESULTS: The findings revealed that repeated low-level blast exposure resulted in impaired memory function, accompanied by elevated levels of serum neurofilament light chain (neuroaxonal injury) and C-reactive protein. Furthermore, alterations in the lipid profile were observed, with an increase in lipid species associated with immune activation. These changes collectively point to systemic inflammation, neuronal injury, and memory dysfunction as pathological characteristics of repeated low-level blast exposure. CONCLUSION: The results of our preliminary investigation offer valuable insights for further large-scale study and provide a guiding principle that necessitates a suitable mitigation approach to safeguard the health of personnel against blast overpressure.