Chloride Voltage-Gated Channel 2 (CLCN2)-Related Leukoencephalopathy Exhibiting Reduced Choline Levels on Magnetic Resonance Spectroscopy.

In this article, we report the third case of chloride voltage-gated channel 2 (CLCN2)-related leukoencephalopathy (CC2L) in Japan. The patient presented with headache, vertigo, and mild visual impairment. The CLCN2 variant of the patient, NM_004366.6:c.61dup, p.(Leu21Profs*27), was also found in two other Japanese patients as this variant is relatively common in the Japanese population. Magnetic resonance imaging (MRI) revealed T2 prolongation with reduced diffusion in the bilateral posterior limbs of the internal capsule, cerebral peduncles, and superior and middle cerebellar peduncles. Magnetic resonance spectroscopy (MRS) of normal-appearing white matter revealed decreased choline content. This represents the first evidence of decreased choline levels in CC2L, highlighting the superior sensitivity of MRS over MRI.

Applying chemical shift images (in-phase/opposed phased) for differentiating low-grade from high-grade glioma and comparison with magnetic resonance spectroscopy.

BACKGROUND: Grading gliomas is essential for treatment decisions and patient prognosis. In this study we evaluated the in-phase and out-of-phase sequences for distinguishing high-grade (HGG) from low-grade glioma (LGG) and the correlation with magnetic resonance spectroscopy (MRS) results. METHODS: This observational study comprised patients with brain tumors referred to our center for brain MRS. The gold standard for diagnosis was based on the World Health Organization (WHO) glioma classification. A standard tumor protocol was accomplished using a 1.5­T MRS scanner. Before contrast medium administration, extra in- and out-phase sequences were acquired. Three 20-30-mm2 oval regions of interest (ROIs) were placed in the solid component and the signal loss ratio (SLR) was calculated with the following formula: SLR tumor = (SI In phase - SI Opposed phase) / SI In phase Correlations and comparisons between groups were made using the Pearson, chi-square and, independent samples t tests. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic performance. Statistical significance was set at p < 0.05. RESULTS: In total, 20 patients were included in the LGG and 13 were included in the HGG group. The mean SLR in the HGG and LGG groups was 3.66 ± 2.12 and 1.63 ± 1.86, respectively (p = 0.01). There was a statistically significant correlation between lipid lactate (0.48, p = 0.004) and free lipid (0.44, p = 0.009) concentrations on MRS with SLR. CONCLUSIONS: The SLR is a simple, rapid, and noninvasive marker for differentiating between LGG and HGG. There is a significant correlation with both the concentration and presence of free lipid and lipid-lactate peaks in MRS.

Brain Metabolite Differences in Fetuses With Cytomegalovirus Infection: A Magnetic Resonance Spectroscopy Study.

BACKGROUND: Cytomegalovirus (CMV) is the most common intrauterine infection and may be associated with unfavorable outcomes. While some CMV-infected fetuses may show gross or subtle brain abnormalities on MRI, their clinical significance may be unclear. Conversely, normal development cannot be guaranteed in CMV-infected fetuses with normal MRI. PURPOSE: To assess brain metabolite differences in CMV-infected fetuses using magnetic resonance spectroscopy (MRS). STUDY TYPE: Retrospective. SUBJECTS: Out of a cohort of 149 cases, 44 with maternal CMV infection, amniocentesis results, and good-quality MRS were included. CMV-infected fetuses with positive polymerase chain reaction (PCR) (N = 35) were divided based on MRI results as follows: typical brain abnormalities (gross findings, N = 8), exclusive white matter hyperintense signal (WMHS) on T2-weighted images (subtle findings, N = 7), and normal MRI (N = 20). Uninfected fetuses (negative PCR) with normal MRI were included as controls (N = 9). FIELD STRENGTH: 3 T, T2-weighted half Fourier single-shot turbo spin-echo (HASTE), T2-weighted true fast imaging with steady-state free precession (TrueFISP), T1- and T2*-weighted fast low angle shot (FLASH), and 1H-MRS single-voxel point resolved spectroscopy (PRESS) sequences. ASSESSMENT: MRI findings were assessed by three radiologists, and metabolic ratios within the basal ganglia were calculated using LCModel. STATISTICAL TESTS: Analysis of covariance test with Bonferroni correction for multiple comparisons was used to compare metabolic ratios between groups while accounting for gestational age. A P-value <0.05 was deemed significant. RESULTS: MRS was successfully acquired in 63% of fetuses. Substantial agreement was observed between radiologists (Fleiss' kappa [k] = 0.8). Infected fetuses with gross MRI findings exhibited significantly reduced tNAA/tCr ratios (0.64 ± 0.08) compared with infected fetuses with subtle MRI findings (0.85 ± 0.19), infected fetuses with normal MRI (0.8 ± 0.14) and controls (0.81 ± 0.15). No other significant differences were detected (P ≥ 0.261). CONCLUSION: Reduced tNAA/tCr within the apparently normal brain tissue was detected in CMV-infected fetuses with gross brain abnormalities, suggesting extensive brain damage. In CMV-infected fetuses with isolated WMHS, no damage was detected by MRS. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Rate of abnormalities in quantitative MR neuroimaging of persons with chronic traumatic brain injury.

BACKGROUND: Mild traumatic brain injury (mTBI) can result in lasting brain damage that is often too subtle to detect by qualitative visual inspection on conventional MR imaging. Although a number of FDA-cleared MR neuroimaging tools have demonstrated changes associated with mTBI, they are still under-utilized in clinical practice. METHODS: We investigated a group of 65 individuals with predominantly mTBI (60 mTBI, 48 due to motor-vehicle collision, mean age 47 ± 13 years, 27 men and 38 women) with MR neuroimaging performed in a median of 37 months post-injury. We evaluated abnormalities in brain volumetry including analysis of left-right asymmetry by quantitative volumetric analysis, cerebral perfusion by pseudo-continuous arterial spin labeling (PCASL), white matter microstructure by diffusion tensor imaging (DTI), and neurometabolites via magnetic resonance spectroscopy (MRS). RESULTS: All participants demonstrated atrophy in at least one lobar structure or increased lateral ventricular volume. The globus pallidi and cerebellar grey matter were most likely to demonstrate atrophy and asymmetry. Perfusion imaging revealed significant reductions of cerebral blood flow in both occipital and right frontoparietal regions. Diffusion abnormalities were relatively less common though a subset analysis of participants with higher resolution DTI demonstrated additional abnormalities. All participants showed abnormal levels on at least one brain metabolite, most commonly in choline and N-acetylaspartate. CONCLUSION: We demonstrate the presence of coup-contrecoup perfusion injury patterns, widespread atrophy, regional brain volume asymmetry, and metabolic aberrations as sensitive markers of chronic mTBI sequelae. Our findings expand the historic focus on quantitative imaging of mTBI with DTI by highlighting the complementary importance of volumetry, arterial spin labeling perfusion and magnetic resonance spectroscopy neurometabolite analyses in the evaluation of chronic mTBI.

Study on the Relationship Between MRI Functional Imaging and Multiple Immunohistochemical Features of Glioma: A Noninvasive and More Precise Glioma Management.

Objective: To investigate the performance of diffusion-tensor imaging (DTI) and hydrogen proton magnetic resonance spectroscopy (1H-MRS) parameters in predicting the immunohistochemistry (IHC) biomarkers of glioma. Methods: Patients with glioma confirmed by pathology from March 2015 to September 2019 were analyzed, the preoperative DTI and 1H-MRS images were collected, apparent diffusion coefficient (ADC) and fractional anisotropy (FA), in the lesion area were measured, the relative values relative ADC (rADC) and relative FA (rFA) were obtained by the ratio of them in the lesion area to the contralateral normal area. The peak of each metabolite in the lesion area of 1H-MRS image: N-acetylaspartate (NAA), choline (Cho), and creatine (Cr), and metabolite ratio: NAA/Cho, NAA/(Cho + Cr) were selected and calculated. The preoperative IHC data were collected including CD34, Ki-67, p53, S-100, syn, vimentin, NeuN, Nestin, and glial fibrillary acidic protein. Results: One predicting parameter of DTI was screened, the rADC of the Ki-67 positive group was lower than that of the negative group. Two parameters of 1H-MRS were found to have significant reference values for glioma grades, the NAA and Cr decreased as the grade of glioma increased, moreover, Ki-67 Li was negatively correlated with NAA and Cr. Conclusion: NAA and Cr have potential application value in predicting glioma grades and tumor proliferation activity. Only rADC has predictive value for Ki-67 expression among DTI parameters.

Non-invasive hepatic fat quantification: Can multi-echo Dixon help?

Objective: To evaluate the diagnostic accuracy of multi-echo Dixon magnetic resonance imaging (MRI) in hepatic fat quantification, in comparison with that of magnetic resonance spectroscopy (MRS), on 3.0-T MRI. Materials and Methods: Fifty-five adults with no known liver disease underwent MRI in a 3.0-T scanner for determination of the hepatic fat fraction, with two techniques: multi-echo Dixon, in a manually drawn region of interest (ROI) and in the entire liver parenchyma (automated segmentation); and MRS. The diagnostic accuracy and cutoff value for multi-echo Dixon were determined, with MRS being used as the reference standard. Results: The mean fat fraction obtained by multi-echo Dixon in the manually drawn ROI and in the entire liver was 5.2 ± 5.8% and 6.6 ± 5.2%, respectively, whereas the mean hepatic fat fraction obtained by MRS was 5.7 ± 6.4%. A very strong positive correlation and good agreement were observed between MRS and multi-echo Dixon, for the ROI (r = 0.988, r2 = 0.978, p < 0.001) and for the entire liver parenchyma (r = 0.960, r2 = 0.922, p < 0.001). A moderate positive correlation was observed between the hepatic fat fraction and body mass index of the participants, regardless of the fat estimation technique employed. Conclusion: For hepatic fat quantification, multi-echo Dixon MRI demonstrated a very strong positive correlation and good agreement with MRS (often considered the gold-standard noninvasive technique). Because multi-echo Dixon MRI is more readily available than is MRS, it can be used as a rapid tool for hepatic fat quantification, especially when the hepatic fat distribution is not homogeneous.

Objetivo: Avaliar a acurácia diagnóstica da técnica multieco Dixon na quantificação da gordura hepática em comparação com a espectroscopia por ressonância magnética (ERM), em exames de RM 3.0-T. Materiais e Métodos: Cinquenta e cinco participantes adultos sem doença hepática conhecida foram submetidos a RM 3.0-T para determinação da fração de gordura hepática, usando duas técnicas: multieco Dixon (em ROI desenhada manualmente e em segmentação automatizada para todo o parênquima hepático) e ERM. A precisão diagnóstica e o valor de corte para multieco Dixon foram determinados usando a ERM como padrão de referência. Resultados: A fração de gordura média usando multieco Dixon na ROI desenhada manualmente e na segmentação automatizada do fígado inteiro foi 5,2 ± 5,8% e 6,6 ± 5,2%, respectivamente. A fração de gordura hepática média usando ERM foi 5,7 ± 6,4%. Correlação positiva muito alta e forte concordância foram observadas entre ERM e multieco Dixon, tanto para ROI (r = 0,988, r2 = 0,978, p < 0,001) quanto para todo o parênquima hepático (r = 0,960, r2 = 0,922, p < 0,001). Correlação positiva moderada foi observada entre a fração de gordura hepática e o índice de massa corpórea dos participantes usando ambas as técnicas de estimativa de gordura. Conclusão: Multieco Dixon demonstrou correlação positiva muito alta e concordância com a ERM (muitas vezes considerada padrão de referência não invasivo) para quantificação de gordura hepática. Uma vez que o multieco Dixon está mais prontamente disponível do que a ERM, pode ser usado como uma ferramenta rápida para a quantificação da gordura hepática, especialmente na distribuição não homogênea da gordura.

Dataset on sperm quality parameters and NMR-detected changes in metabolic profile of fresh and frozen turkey spermatozoa related to two different reproductive period ages.

Significant changes in the quality and metabolic profile of fresh turkey sperm as a result of both cryopreservation and reproductive age have already been individually confirmed in our previous studies. This new dataset adds a relevant piece to the tangled puzzle of changes in metabolite levels affecting cryopreserved turkey sperm quality, taking into consideration two different reproductive period ages. Fresh semen samples were collected at 44 and 56 weeks of age and exposed to the cryopreservation process. All fresh and frozen-thawed samples were subjected to analysis of mobility, viability and osmotic tolerance as parameters for evaluating the sperm quality, while NMR spectroscopy was used to assess the quantitative changes in water and lipid-soluble metabolites. Our results showed that the cryopreservation process significantly affected all of the measured qualitative parameters both at 44 and 56 weeks. Concerning the metabolic profile, a greater number of quantitative changes for both water and lipid-soluble components were found in frozen semen at 56 weeks than at 44 weeks of age. These data could contribute to identifying new strategies aimed at improving freezing procedures even as reproductive age increases.

Widespread correction of brain pathology in feline alpha-mannosidosis by dose escalation of intracisternal AAV vector injection.

Alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Enzyme replacement therapy is available but is not approved for treating the CNS, since the enzyme does not penetrate the blood-brain barrier. However, intellectual disability is a major manifestation of the disease; thus, a complimentary treatment is needed. While enzyme replacement therapy into the brain is technically feasible, it requires ports and frequent administration over time that are difficult to manage medically. Infusion of adeno-associated viral vectors into the cerebrospinal fluid is an attractive route for broadly targeting brain cells. We demonstrate here the widespread post-symptomatic correction of the globally distributed storage lesions by infusion of a high dose of AAV1-feline alpha-mannosidase (fMANB) into the CSF via the cisterna magna in the gyrencephalic alpha-mannosidosis cat brain. Significant improvements in clinical parameters occurred, and widespread global correction was documented pre-mortem by non-invasive magnetic resonance imaging. Postmortem analysis demonstrated high levels of MANB activity and reversal of lysosomal storage lesions throughout the brain. Thus, CSF treatment by adeno-associated viral vector gene therapy appears to be a suitable complement to systemic enzyme replacement therapy to potentially treat the whole patient.

Metabolite T2 relaxation times decrease across the adult lifespan in a large multi-site cohort.

Purpose: Relaxation correction is crucial for accurately estimating metabolite concentrations measured using in vivo magnetic resonance spectroscopy (MRS). However, the majority of MRS quantification routines assume that relaxation values remain constant across the lifespan, despite prior evidence of T2 changes with aging for multiple of the major metabolites. Here, we comprehensively investigate correlations between T2 and age in a large, multi-site cohort. Methods: We recruited approximately 10 male and 10 female participants from each decade of life: 18-29, 30-39, 40-49, 50-59, and 60+ years old (n=101 total). We collected PRESS data at 8 TEs (30, 50, 74, 101, 135, 179, 241, and 350 ms) from voxels placed in white-matter-rich centrum semiovale (CSO) and gray-matter-rich posterior cingulate cortex (PCC). We quantified metabolite amplitudes using Osprey and fit exponential decay curves to estimate T2. Results: Older age was correlated with shorter T2 for tNAA, tCr3.0, tCr3.9, tCho, Glx, and tissue water in CSO and PCC; rs = -0.21 to -0.65, all p<0.05, FDR-corrected for multiple comparisons. These associations remained statistically significant when controlling for cortical atrophy. T2 values did not differ across the adult lifespan for mI. By region, T2 values were longer in the CSO for tNAA, tCr3.0, tCr3.9, Glx, and tissue water and longer in the PCC for tCho and mI. Conclusion: These findings underscore the importance of considering metabolite T2 changes with aging in MRS quantification. We suggest that future 3T work utilize the equations presented here to estimate age-specific T2 values instead of relying on uniform default values.

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.

Whole-body hypothermia in mild neonatal encephalopathy: protocol for a multicentre phase III randomised controlled trial.

BACKGROUND: Mild hypoxic ischemic encephalopathy is associated with sub optimal cognition and learning difficulties at school age. Although whole-body hypothermia reduces death and disability after moderate or severe encephalopathy in high-income countries, the safety and efficacy of hypothermia in mild encephalopathy is not known. The cooling in mild encephalopathy (COMET) trial will examine if whole-body hypothermia improves cognitive development of neonates with mild encephalopathy. METHODS: The COMET trial is a phase III multicentre open label two-arm randomised controlled trial with masked outcome assessments. A total of 426 neonates with mild encephalopathy will be recruited from 50 to 60 NHS hospitals over 2 ½ years following parental consent. The neonates will be randomised to 72 h of whole-body hypothermia (33.5 ± 0.5 C) or normothermia (37.0 ± 0.5 C) within six hours or age. Prior to the recruitment front line clinical staff will be trained and certified on expanded modified Sarnat staging for encephalopathy. The neurological assessment of all screened and recruited cases will be video recorded and centrally assessed for quality assurance. If recruitment occurs at a non-cooling centre, neonates in both arms will be transferred to a cooling centre for continued care, after randomisation. All neonates will have continuous amplitude integrated electroencephalography (aEEG) at least for the first 48 h to monitor for seizures. Predefined safety outcomes will be documented, and data collected to assess resource utilization of health care. A central team masked to trial group allocation will assess neurodevelopmental outcomes at 2 years of age. The primary outcome is mean difference in composite cognitive scores on Bayley scales of Infant and Toddler development 4th Edition. DISCUSSION: The COMET trial will establish the safety and efficacy of whole-body hypothermia for mild hypoxic ischaemic encephalopathy and inform national and international guidelines in high income countries. It will also provide an economic assessment of whole-body hypothermia therapy for mild encephalopathy in the NHS on cost-effectiveness grounds. TRIAL REGISTRATION NUMBER: NCT05889507 June 5, 2023.

Correlation between cerebral neurotransmitters levels by proton magnetic resonance spectroscopy and HbA1c in patients with type 2 diabetes.

BACKGROUND: Cognitive dysfunction is the main manifestation of central neuropathy. Although cognitive impairments tend to be overlooked in patients with diabetes mellitus (DM), there is a growing body of evidence linking DM to cognitive dysfunction. Hyperglycemia is closely related to neurological abnormalities, while often disregarded in clinical practice. Changes in cerebral neurotransmitter levels are associated with a variety of neurological abnormalities and may be closely related to blood glucose control in patients with type 2 DM (T2DM). AIM: To evaluate the concentrations of cerebral neurotransmitters in T2DM patients exhibiting different hemoglobin A1c (HbA1c) levels. METHODS: A total of 130 T2DM patients were enrolled at the Department of Endocrinology of Shanghai East Hospital. The participants were divided into four groups according to their HbA1c levels using the interquartile method, namely Q1 (< 7.875%), Q2 (7.875%-9.050%), Q3 (9.050%-11.200%) and Q4 (≥ 11.200%). Clinical data were collected and measured, including age, height, weight, neck/waist/hip circumferences, blood pressure, comorbidities, duration of DM, and biochemical indicators. Meanwhile, neurotransmitters in the left hippocampus and left brainstem area were detected by proton magnetic resonance spectroscopy. RESULTS: The HbA1c level was significantly associated with urinary microalbumin (mALB), triglyceride, low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HOMA-IR), and beta cell function (HOMA-ß), N-acetylaspartate/creatine (NAA/Cr), and NAA/choline (NAA/Cho). Spearman correlation analysis showed that mALB, LDL-C, HOMA-IR and NAA/Cr in the left brainstem area were positively correlated with the level of HbA1c (P < 0.05), whereas HOMA-ß was negatively correlated with the HbA1c level (P < 0.05). Ordered multiple logistic regression analysis showed that NAA/Cho [Odds ratio (OR): 1.608, 95% confidence interval (95%CI): 1.004-2.578, P < 0.05], LDL-C (OR: 1.627, 95%CI: 1.119-2.370, P < 0.05), and HOMA-IR (OR: 1.107, 95%CI: 1.031-1.188, P < 0.01) were independent predictors of poor glycemic control. CONCLUSION: The cerebral neurotransmitter concentrations in the left brainstem area in patients with T2DM are closely related to glycemic control, which may be the basis for the changes in cognitive function in diabetic patients.

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.

Model-based frequency-and-phase correction of 1H MRS data with 2D linear-combination modeling.

PURPOSE: Retrospective frequency-and-phase correction (FPC) methods attempt to remove frequency-and-phase variations between transients to improve the quality of the averaged MR spectrum. However, traditional FPC methods like spectral registration struggle at low SNR. Here, we propose a method that directly integrates FPC into a 2D linear-combination model (2D-LCM) of individual transients ("model-based FPC"). We investigated how model-based FPC performs compared to the traditional approach, i.e., spectral registration followed by 1D-LCM in estimating frequency-and-phase drifts and, consequentially, metabolite level estimates. METHODS: We created synthetic in-vivo-like 64-transient short-TE sLASER datasets with 100 noise realizations at 5 SNR levels and added randomly sampled frequency and phase variations. We then used this synthetic dataset to compare the performance of 2D-LCM with the traditional approach (spectral registration, averaging, then 1D-LCM). Outcome measures were the frequency/phase/amplitude errors, the SD of those ground-truth errors, and amplitude Cramér Rao lower bounds (CRLBs). We further tested the proposed method on publicly available in-vivo short-TE PRESS data. RESULTS: 2D-LCM estimates (and accounts for) frequency-and-phase variations directly from uncorrected data with equivalent or better fidelity than the conventional approach. Furthermore, 2D-LCM metabolite amplitude estimates were at least as accurate, precise, and certain as the conventionally derived estimates. 2D-LCM estimation of FPC and amplitudes performed substantially better at low-to-very-low SNR. CONCLUSION: Model-based FPC with 2D linear-combination modeling is feasible and has great potential to improve metabolite level estimation for conventional and dynamic MRS data, especially for low-SNR conditions, for example, long TEs or strong diffusion weighting.

Altered brain metabolites in male nonhuman primate offspring exposed to maternal immune activation.

Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed.

Muscle mitochondrial function is impaired in adults with type 1 diabetes.

AIMS: Type 1 diabetes has been associated with mitochondrial dysfunction. However, the mechanism of this dysfunction in adults remains unclear. METHODS: A secondary analysis was conducted using data from several clinical trials measuring in-vivo and ex-vivo mitochondrial function in adults with type 1 diabetes (n = 34, age 38.8 ± 14.6 years) and similarly aged controls (n = 59, age 44.6 ± 13.9 years). In-vivo mitochondrial function was assessed before, during, and after isometric exercise with 31phosphorous magnetic resonance spectroscopy. High resolution respirometry of vastus lateralis muscle tissue was used to assess ex-vivo measures. RESULTS: In-vivo data showed higher rates of anaerobic glycolysis (p = 0.013), and a lower maximal mitochondrial oxidative capacity (p = 0.012) and mitochondrial efficiency (p = 0.024) in adults with type 1 diabetes. After adjustment for age and percent body fat maximal mitochondrial capacity (p = 0.014) continued to be lower and anaerobic glycolysis higher (p = 0.040) in adults with type 1 diabetes. Ex-vivo data did not demonstrate significant differences between the two groups. CONCLUSIONS: The in-vivo analysis demonstrates that adults with type 1 diabetes have mitochondrial dysfunction. This builds on previous research showing in-vivo mitochondrial dysfunction in youths with type 1 diabetes and suggests that defects in substrate or oxygen delivery may play a role in in-vivo dysfunction.

Technologies to Study Genetics and Molecular Pathways.

Over the last few decades, the study of congenital heart disease (CHD) has benefited from various model systems and the development of molecular biological techniques enabling the analysis of single gene as well as global effects. In this chapter, we first describe different models including CHD patients and their families, animal models ranging from invertebrates to mammals, and various cell culture systems. Moreover, techniques to experimentally manipulate these models are discussed. Second, we introduce cardiac phenotyping technologies comprising the analysis of mouse and cell culture models, live imaging of cardiogenesis, and histological methods for fixed hearts. Finally, the most important and latest molecular biotechniques are described. These include genotyping technologies, different applications of next-generation sequencing, and the analysis of transcriptome, epigenome, proteome, and metabolome. In summary, the models and technologies presented in this chapter are essential to study the function and development of the heart and to understand the molecular pathways underlying CHD.

Identification and Characterization of Cannabichromene's Major Metabolite Following Incubation with Human Liver Microsomes.

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC phase I-oxidized metabolite generated in vitro following incubation with human liver microsomes. The novel metabolite structure was identified as 2'-hydroxycannabicitran using gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. Following the identification, in silico molecular modeling experiments were conducted and predicted 2'-hydroxycannabicitran to fit in the orthosteric site of both the CB1 and CB2 receptors. When tested in vitro utilizing a competitive binding assay, the metabolite did not show significant binding to either the CB1 or CB2 receptors. Further work necessitates the determination of potential activity of CBC and the here-identified phase I metabolite in other non-cannabinoid receptors.

Analyzing the impact of T7L variants overexpression on the metabolic profile of Escherichia coli.

INTRODUCTION: Exploring metabolic changes within host E. coli through an untargeted metabolomic study of T7L variants overexpression to optimize engineered endolysins for clinical/therapeutic use. AIM AND OBJECTIVE: This study aims to assess the impact of overexpressing T7L variants on the metabolic profiles of E. coli. The two variants considered include T7L-H37A, which has enhanced lytic activity compared to its wild-type protein, and T7L-H48K, a dead mutant with no significant activity. METHODS: 1H NMR-based metabolomics was employed to compare the metabolic profiles of E. coli cells overexpressing T7L wild-type protein and its variants. RESULTS: Overexpression of the T7L wild-type (T7L-WT) protein and its variants (T7L-H48K and T7L-H37A) was compared to RNAP overexpression in E. coli cells using 1H NMR-based metabolomics, analyzing a total of 75 annotated metabolites, including organic acids, amino acids, sugars, and nucleic acids. The results showed distinct clustering patterns for the two T7L variant groups compared with the WT, in which the dead mutant (H48K) group showed clustering close to that of RNAP. Pathway impact analysis revealed different effects of T7L variants on E. coli metabolic profiles, with T7L-H48K showing minimal alterations in energy and amino acid pathways linked to osmotic stress compared to noticeable alterations in these pathways for both T7L-H37A and T7L-WT. CONCLUSIONS: This study uncovered distinct metabolic fingerprints when comparing the overexpression of active and inactive mutants of T7L lytic enzymes in E. coli cells. These findings could contribute to the optimization and enhancement of suitable endolysins as potential alternatives to antibiotics.

Neurochemical changes in the progression of Huntington's disease: A meta-analysis of in vivo1H-MRS studies.

Proton magnetic resonance spectroscopy (1H-MRS) allows measuring specific brain metabolic alterations in Huntington's disease (HD), and these metabolite profiles may serve as non-invasive biomarkers associated with disease progression. Despite this potential, previous findings are inconsistent. Accordingly, we performed a meta-analysis on available in vivo1H-MRS studies in premanifest (Pre-HD) and symptomatic HD stages (Symp-HD), and quantified neurometabolic changes relative to controls in 9 Pre-HD studies (227 controls and 188 mutation carriers) and 14 Symp-HD studies (326 controls and 306 patients). Our results indicated decreased N-acetylaspartate and creatine in the basal ganglia in both Pre-HD and Symp-HD. The overall level of myo-inositol was decreased in Pre-HD while increased in Symp-HD. Besides, Symp-HD patients showed more severe metabolism disruption than Pre-HD patients. Taken together, 1H-MRS is important for elucidating progressive metabolite changes from Pre-HD to clinical conversion; N-acetylaspartate and creatine in the basal ganglia are already sensitive at the preclinical stage and are promising biomarkers for tracking disease progression; overall myo-inositol is a possible characteristic metabolite for distinguishing HD stages.