Improved reproducibility of γ-aminobutyric acid measurement from short-echo-time proton MR spectroscopy by linewidth-matched basis sets in LCModel.

γ-Aminobutyric acid (GABA), as the primary inhibitory neurotransmitter, is extremely important for maintaining healthy brain function, and deviations from GABA homeostasis are related to various brain diseases. Short-echo-time (short-TE) proton MR spectroscopy (1 H-MRS) has been employed to measure GABA concentration from various human brain regions at high magnetic fields. The aim of this study was to investigate the effect of spectral linewidth on GABA quantification and explore the application of an optimized basis-set preparation approach using a spectral-linewidth-matched (LM) basis set in LCModel to improve the reproducibility of GABA quantification from short-TE 1 H-MRS. In contrast to the fixed-linewidth basis-set approach, the LM basis-set preparation approach, where all metabolite basis spectra were simulated with a linewidth 4 Hz narrower than that of water, showed a smaller standard deviation of estimated GABA concentration from synthetic spectra with varying linewidths and lineshapes. The test-retest reproducibility was assessed by the mean within-subject coefficient of variation, which improved from 19.2% to 12.0% in the thalamus, from 27.9% to 14.9% in the motor cortex, and from 9.7% to 2.8% in the medial prefrontal cortex using LM basis sets at 7 T. We conclude that spectral linewidth has a large effect on GABA quantification from short-TE 1 H-MRS data and that using LM basis sets in LCModel can improve the reproducibility of GABA quantification.

Regional sex differences in neurochemical profiles of healthy mice measured by magnetic resonance spectroscopy at 9.4 tesla.

Objective: To determine sex differences in the neurochemical concentrations measured by in vivo proton magnetic resonance spectroscopy (1H MRS) of healthy mice on a genetic background commonly used for neurodegenerative disease models. Methods: 1H MRS data collected from wild type mice with C57BL/6 or related genetic backgrounds in seven prior studies were used in this retrospective analysis. To be included, data had to be collected at 9.4 tesla magnetic field using advanced 1H MRS protocols, with isoflurane anesthesia and similar animal handling protocols, and a similar number of datasets from male and female mice had to be available for the brain regions analyzed. Overall, 155 spectra from female mice and 166 spectra from male mice (321 in total), collected from six brain regions (brainstem, cerebellum, cortex, hippocampus, hypothalamus, and striatum) at various ages were included. Results: Concentrations of taurine, total creatine (creatine + phosphocreatine), ascorbate, glucose and glutamate were consistently higher in male vs. female mice in most brain regions. Striatum was an exception with similar total creatine in male and female mice. The sex difference pattern in the hypothalamus was notably different from other regions. Interaction between sex and age was significant for total creatine and taurine in the cerebellum and hippocampus. Conclusion: Sex differences in regional neurochemical levels are small but significant and age-dependent, with consistent male-female differences across most brain regions. The neuroendocrine region hypothalamus displays a different pattern of sex differences in neurochemical levels. Differences in energy metabolism and cellular density may underlie the differences, with higher metabolic rates in females and higher osmoregulatory and antioxidant capacity in males.

Decreased 25-Hydroxy Vitamin D Level Is Associated with All-Cause Mortality in Patients with Type 2 Diabetes at High Cardiovascular Risk.

Cardiovascular diseases are among the leading causes of morbidity and mortality, particularly in individuals with type 2 diabetes. There is a need for new biomarkers to improve the prediction of cardiovascular events and overall mortality. We investigated the association of selected atherosclerosis related biomarkers, specifically osteoprotegerin (OPG), 25-hydroxy-vitamin D (25(OH)D), C-reactive protein (CRP), lipopolysaccharide-binding protein (LBP), and asymmetric dimethylarginine (ADMA), with the occurrence of any cardiovascular event or all-cause mortality (primary outcome) during a 5.6-year follow-up of 190 patients with type 2 diabetes. Data were analyzed using logistic regression to adjust for baseline cardiovascular status and cardiovascular risk factors. The primary outcome occurred in 89 participants (46.8%) during the study. When analyzed individually, 25(OH)D, CRP, and LBP significantly predicted the primary outcome in multivariable models. However, in a model that included all biomarkers, only a decreased level of 25(OH)D remained a significant predictor of the primary outcome. Moreover, the level of 25(OH)D significantly predicted all-cause mortality: a reduction of 10 ng/mL was associated with a two-fold increase in all-cause mortality. Our study thus demonstrates that vitamin D deficiency was the strongest factor associated with the primary outcome and all-cause mortality after a 5.6-year follow-up in patients with type 2 diabetes at high cardiovascular risk.

BDNF rs962369 Is Associated with Major Depressive Disorder.

This study enrolled 291 patients diagnosed with depression and schizophrenia (F32, F33, and F20 according to ICD-10) and 227 ethnicity-matched control subjects. We analyzed the distribution of BDNF rs6265 and BDNF rs962369 genotypes, finding no significant associations between these and schizophrenia. We revealed a significant increase in the risk of single-episode major depression disorder (MDD) for rs962369 minor allele homozygotes (CC vs. TT+TC), an association that persisted after adjusting for age and sex (OR 3.47; 95% CI 1.36-8.85; p = 0.009). Furthermore, rs962369 genotype was significantly associated with an increased risk of recurrent MDD in a log-additive model (OR per C-allele 1.65; 95% CI 1.11-2.45; p = 0.013). A comparative analysis between MDD subtypes and between MDD subtypes and schizophrenia showed no significant differences for BDNF rs6265. Notably, the frequency of minor allele C of BDNF rs962369 varied across subgroups, with the highest frequency in patients with recurrent MDD (0.32) and the lowest in schizophrenia patients (0.20). The presence of genotypes with at least one minor allele C was significantly higher in the recurrent MDD patient group compared to the schizophrenia group. In conclusion, the BDNF rs962369 variant was associated with MDD but not with schizophrenia.

Effect of a Disease Management Program on the Adherence to Guideline-Recommended HbA1c Monitoring in Patients with Diabetes in Slovakia.

INTRODUCTION: Glycated hemoglobin (HbA1c) is a crucial marker of glucose control that is widely utilized in the management of diabetes mellitus. The aim of this study was to evaluate the effect of a diabetes management program (DMP) offered by a health insurance company, together with the effects of other factors associated with patient and physician characteristics, on the frequency of HbA1c testing in outpatient diabetes clinics in Slovakia. METHODS: A retrospective analysis was conducted to compare the frequency of HbA1c measurements in patients under the care of physicians participating in the DMP with those who did not, spanning the years 2015 to 2019. In 2019, a total of 74,384 patients with diabetes were included in the analysis, of which 52% were men and 48% were women, with an average age of 64.1 years. RESULTS: At the end of the study period, the average annual number of HbA1c measurements was significantly higher in patients treated by physicians participating in the DMP than in patients treated by physicians who were not (2.50 vs. 1.91 per year, respectively; P < 0.001). There was a substantial increase in HbA1c testing at least twice yearly in both groups, but the growth rate was greater in the group with DMP-engaged diabetologists (14.3%) compared to the diabetes specialists who were not involved in the DMP (5.1%). In the multivariate analysis, participation in the DMP was correlated with an increase in HbA1c tests per year by 0.7. CONCLUSIONS: Physician participation in a DMP was found to significantly increase the number of HbA1c tests ordered by physicians, potentially leading to improved glycemic control.

Switching from Multiple Insulin Injections to a Fixed Combination of Degludec and Liraglutide in Patients with Type 2 Diabetes Mellitus: Results from the Simplify Study After 6 Months.

INTRODUCTION: This study aimed to evaluate the effectiveness and safety of switching from basal bolus insulin treatment (BBIT) to a fixed combination of insulin degludec and liraglutide (IDegLira) in patients with type 2 diabetes mellitus (T2DM) who had preserved insulin secretion but inadequate glucose control. The study also aimed to assess the feasibility of implementing this therapeutic approach in common clinical practice settings. METHODS: This was a non-randomized, open-label, multicenter, prospective, single-arm study involving 234 patients with T2DM who were receiving BBIT. Inclusion criteria were duration of diabetes mellitus > 60 months, stable total daily dose of insulin (TDDI) ranging from > 20 to < 70 IU/day (approx. > 0.3 to < 0.7 IU/kg body weight/day), C-peptide levels > 10% above the lower limit, HbA1c levels > 7% and < 10% (Diabetes Control and Complications Trial), and body mass index > 25 kg/m2. The primary endpoints were changes in glycated hemoglobin (HbA1c) and body weight at week 28 after treatment switching. Secondary endpoints included changes in the 7-point glycemic profile, hypoglycemia frequency, blood pressure, blood lipids, liver enzymes, insulin dose, and a patient questionnaire focusing on treatment satisfaction, concerns and impact on daily activities. A subgroup of 55 patients underwent continuous glucose monitoring (CGM) with the evaluation of CGM-derived parameters, such as time in range (TIR), time above range (TAR), time below range (TBR), hypoglycemia, and glucose variability. RESULTS: A significant decrease in HbA1c (8.6% vs. 7.6%; p < 0.0001) and body weight (97.8 vs. 94.0 kg; p < 0.0001) was observed at week 28 after treatment switching. Significant improvements were also seen in all measurements of the 7-point glycemic profile (p < 0.0001), reduction in the number of hypoglycemia episodes per patient, and the proportion of patients with at least one hypoglycemia event (p < 0.001). Furthermore, there was a significant decrease in daily insulin dose (55.6 vs. 32.7 IU/day; p < 0.0001), as well as improvements in blood pressure, blood lipids, and liver enzymes (gamma glutamyl transferase and alanine aminotransferase). The subgroup of patients who underwent CGM showed a significant increase in TIR (57.9% vs. 69.0%; p < 0.01) and a decrease in TAR (40.1% vs. 28.8%; p < 0.01), while TBR, hypoglycemia (number of episodes per patient and proportion of patients), and glucose variability did not change significantly. CONCLUSION: The results of this study suggest that switching from BBIT to IDegLira in patients with T2DM and preserved insulin secretion can simplify treatment without compromising glycemic control. The switch to IDegLira was associated with significant improvements in various glucose control parameters, including HbA1c, glycemic profile, hypoglycemia, insulin doses, and CGM-derived parameters TIR and TAR. Additionally, it led to significant reductions in body weight, blood pressure, lipid profile, and liver enzyme levels. Switching to IDegLira may be considered a safe and beneficial approach in clinical practice settings, offering metabolic and individual advantages.

Factors associated with all-cause mortality following endovascular abdominal aortic aneurysm repair.

Background: Knowledge of factors that influence all-cause mortality after endovascular abdominal aortic aneurysm repair (EVAR) could improve therapeutic strategies post-EVAR and thus patient prognosis. Our study aimed to evaluate the association between sociodemographic information, comorbidities, laboratory parameters, treatment, selected anatomical and genetic factors and all-cause mortality post-EVAR. Patients and methods: We reviewed all patients who had undergone elective EVAR for non-ruptured abdominal aortic aneurysm (AAA) between January 2010 and December 2019. AAA size (maximum diameter and volume) was measured using CT-angiography. Sac expansion was defined as at least 5 mm increase, sac regression as at least 5 mm decrease in the sac diameter determined at 36±3 months post-EVAR in relation to pre-EVAR AAA diameter. Adjustments were performed for age, hypertension, diabetes mellitus, dyslipidaemia, sex, smoking, number of lumbar arteries, patency of inferior mesenteric artery and number of reinterventions post-EVAR. Results: One hundred and sixty-two patients (150 men, 12 women) with a mean age of 72.6±7.3 years were included in the analysis. Pre-EVAR AAA diameter (HR 1.07; 95% CI 1.03 - 1.12; p=0.001), pre-EVAR AAA volume (HR 1.01; 95% CI 1.002 - 1.011; p=0.008), post-EVAR sac diameter (HR 1.06; 95% CI 1.03 - 1.10; p=0.000), post-EVAR sac volume (HR 1.01; 95% CI 1.002 - 1.011; p=0.006) and anticoagulation therapy (HR 2.46; 95% CI 1.18 - 5.14; p=0.019) were associated with higher mortality in multivariate analysis. Sac regression (HR 0.42; 95% CI 0.22 - 0.82; p=0.011), and treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) (HR 0.71; 95% CI 0.36 - 0.97; p=0.047) were associated with lower mortality. Conclusions: Greater pre- and post-EVAR diameter and volume, failure of sac regression and anticoagulation were associated with higher mortality post-EVAR. Reduced mortality was observed in patients treated with ACE inhibitors or ARBs, and in patients with AAA sac regression.

Association Study of BDNF, SLC6A4, and FTO Genetic Variants with Schizophrenia Spectrum Disorders.

Schizophrenia spectrum disorders (patients with a diagnosis of schizophrenia, schizotypal, and delusional disorders: F20-F29 according to International Classification of Diseases 10th revision (ICD-10)) are considered highly heritable heterogeneous psychiatric conditions. Their pathophysiology is multifactorial with involved dysregulated serotonergic neurotransmission and synaptic plasticity. The present study aimed to evaluate the association of SLC6A4 (5-HTTLPR), FTO (rs9939609), and BDNF (rs6265, rs962369) polymorphisms with schizophrenia spectrum disorders in Slovak patients. We analyzed the genotypes of 150 patients with schizophrenia, schizotypal, and delusional disorders and compared them with genotypes from 178 healthy volunteers. We have found a marginally protective effect of LS + SS genotypes of 5-HTTLPR variant of the serotonin transporter SLC6A4 gene against the development of schizophrenia spectrum disorders, but the result failed to remain significant after Bonferroni correction. Similarly, we have not proven any significant association between other selected genetic variants and schizophrenia and related disorders. Studies including a higher number of subjects are warranted to reliably confirm the presence or absence of the studied associations.

Neonatal hyperbilirubinemia differentially alters the neurochemical profiles of the developing cerebellum and hippocampus in a preterm Gunn rat model.

Neonatal hyperbilirubinemia (NHB) can lead to brain injury in newborn infants by affecting specific regions including the cerebellum and hippocampus. Extremely preterm infants are more vulnerable to bilirubin neurotoxicity, but the mechanism and extent of injury is not well understood. A preterm version of the Gunn rat model was utilized to investigate severe preterm NHB. Homozygous/jaundiced Gunn rat pups were injected (i.p.) on postnatal day (P) 5 with sulfadimethoxine, which increases serum free bilirubin capable of crossing the blood-brain barrier and causing brain injury. The neurochemical profiles of the cerebellum and hippocampus were determined using in vivo 1 H MRS at 9.4 T on P30 and compared with those of heterozygous/non-jaundiced control rats. Transcript expression of related genes was determined by real-time quantitative PCR. MRI revealed significant morphological changes in the cerebellum of jaundiced rats. The concentrations of myo-inositol (+54%), glucose (+51%), N-acetylaspartylglutamate (+21%), and the sum of glycerophosphocholine and phosphocholine (+17%) were significantly higher in the cerebellum of the jaundiced group compared with the control group. Despite the lack of morphologic changes in the hippocampus, the concentration of myo-inositol (+9%) was higher and the concentrations of creatine (-8%) and of total creatine (-3%) were lower in the jaundiced group. In the hippocampus, expression of calcium/calmodulin dependent protein kinase II alpha (Camk2a), glucose transporter 1 (Glut1), and Glut3 transcripts were downregulated in the jaundiced group. In the cerebellum, glial fibrillary acidic protein (Gfap), myelin basic protein (Mbp), and Glut1 transcript expression was upregulated in the jaundiced group. These results indicate osmotic imbalance, gliosis, and changes in energy utilization and myelination, and demonstrate that preterm NHB critically affects brain development in a region-specific manner, with the cerebellum more severely impacted than the hippocampus.

Association of HTTLPR, BDNF, and FTO Genetic Variants with Completed Suicide in Slovakia.

Since suicide and suicidal behavior are considered highly heritable phenotypes, the identification of genetic markers that can predict suicide risk is a clinically important topic. Several genes studied for possible associations between genetic polymorphisms and suicidal behaviors had mostly inconsistent and contradictory findings. The aim of this case-control study was to evaluate the associations between completed suicide and polymorphisms in genes BDNF (rs6265, rs962369), SLC6A4 (5-HTTLPR), and FTO (rs9939609) in relation to sex and BMI. We genotyped 119 completed suicide victims and 137 control subjects that were age, sex, and ethnicity matched. A significant association with completed suicide was found for BDNF rs962369. This variant could play a role in completed suicide, as individuals with the CC genotype were more often found among suicides than in control subjects. After sex stratification, the association remained significant only in males. A nominally significant association between the gene variant and BMI was observed for BDNF rs962369 under the overdominant model. Heterozygotes with the TC genotype showed a lower average BMI than homozygotes with TT or CC genotypes. FTO polymorphism (rs9939609) did not affect BMI in the group of Slovak suicide completers, but our findings follow an inverse association between BMI and completed suicide.

Female and male C57BL/6J offspring exposed to maternal obesogenic diet develop altered hypothalamic energy metabolism in adulthood.

Maternal obesity is exceedingly common and strongly linked to offspring obesity and metabolic disease. Hypothalamic function is critical to obesity development. Hypothalamic mechanisms causing obesity following exposure to maternal obesity have not been elucidated. Therefore, we studied a cohort of C57BL/6J dams, treated with a control or high-fat-high-sugar diet, and their adult offspring to explore potential hypothalamic mechanisms to explain the link between maternal and offspring obesity. Dams treated with obesogenic diet were heavier with mild insulin resistance, which is reflective of the most common metabolic disease in pregnancy. Adult offspring exposed to maternal obesogenic diet had no change in body weight but significant increase in fat mass, decreased glucose tolerance, decreased insulin sensitivity, elevated plasma leptin, and elevated plasma thyroid-stimulating hormone. In addition, offspring exposed to maternal obesity had decreased energy intake and activity without change in basal metabolic rate. Hypothalamic neurochemical profile and transcriptome demonstrated decreased neuronal activity and inhibition of oxidative phosphorylation. Collectively, these results indicate that maternal obesity without diabetes is associated with adiposity and decreased hypothalamic energy production in offspring. We hypothesize that altered hypothalamic function significantly contributes to obesity development. Future studies focused on neuroprotective strategies aimed to improve hypothalamic function may decrease obesity development.NEW & NOTEWORTHY Offspring exposed to maternal diet-induced obesity demonstrate a phenotype consistent with energy excess. Contrary to previous studies, the observed energy phenotype was not associated with hyperphagia or decreased basal metabolic rate but rather decreased hypothalamic neuronal activity and energy production. This was supported by neurochemical changes in the hypothalamus as well as inhibition of hypothalamic oxidative phosphorylation pathway. These results highlight the potential for neuroprotective interventions in the prevention of obesity with fetal origins.

Intranasal Insulin Attenuates the Long-Term Adverse Effects of Neonatal Hyperglycemia on the Hippocampus in Rats.

Hyperglycemia due to relative hypoinsulinism is common in extremely preterm infants and is associated with hippocampus-mediated long-term cognitive impairment. In neonatal rats, hypoinsulinemic hyperglycemia leads to oxidative stress, altered neurochemistry, microgliosis, and abnormal synaptogenesis in the hippocampus. Intranasal insulin (INS) bypasses the blood-brain barrier, targets the brain, and improves synaptogenesis in rodent models, and memory in adult humans with Alzheimer's disease or type 2 diabetes, without altering the blood levels of insulin or glucose. To test whether INS improves hippocampal development in neonatal hyperglycemia, rat pups were subjected to hypoinsulinemic hyperglycemia by injecting streptozotocin (STZ) at a dose of 80 mg/kg i.p. on postnatal day (P) 2 and randomized to INS, 0.3U twice daily from P3-P6 (STZ + INS group), or no treatment (STZ group). The acute effects on hippocampal neurochemical profile and transcript mRNA expression of insulin receptor (Insr), glucose transporters (Glut1, Glut4, and Glut8), and poly(ADP-ribose) polymerase-1 (Parp1, a marker of oxidative stress) were determined on P7 using in vivo 1H MR spectroscopy (MRS) and qPCR. The long-term effects on the neurochemical profile, microgliosis, and synaptogenesis were determined at adulthood using 1H MRS and histochemical analysis. Relative to the control (CONT) group, mean blood glucose concentration was higher from P3 to P6 in the STZ and STZ + INS groups. On P7, MRS showed 10% higher taurine concentration in both STZ groups. qPCR showed 3-folds higher Insr and 5-folds higher Glut8 expression in the two STZ groups. Parp1 expression was 18% higher in the STZ group and normal in the STZ + INS group. At adulthood, blood glucose concentration in the fed state was higher in the STZ and STZ + INS groups. MRS showed 59% higher brain glucose concentration and histochemistry showed microgliosis in the hippocampal subareas in the STZ group. Brain glucose was normal in the STZ + INS group. Compared with the STZ group, phosphocreatine and phosphocreatine/creatine ratio were higher, and microglia in the hippocampal subareas fewer in the STZ + INS group (p < 0.05 for all). Neonatal hyperglycemia was associated with abnormal glucose metabolism and microgliosis in the adult hippocampus. INS administration during hyperglycemia attenuated these adverse effects and improved energy metabolism in the hippocampus.

Positive association between calcium channel blocker treatment and persistent type II endoleak.

BACKGROUND: Type II endoleaks are the most common complication occurring after endovascular abdominal aortic aneurysm repair (EVAR). The aims of our study were to evaluate the impact of persistent type II endoleak on sac dynamics post-EVAR, and to study the association between non-anatomical factors including polymorphisms associated with abdominal aortic aneurysm (AAA) and persistent type II endoleak. METHODS: The cohort comprises 210 patients undergoing EVAR between January 2010 and December 2018. A persistent type II endoleak was defined as any type II endoleak lasting longer than six months and included also a type II endoleak diagnosed after six months or more post-EVAR during the 36-month follow-up period confirmed with CT-angiography. Anteroposterior AAA maximum diameter and AAA volume were measured pre-EVAR and 36 months post-EVAR using CT-angiographic pictures. Sac progression was defined as at least 5 mm increase, sac regression as at least 5 mm decrease in the sac diameter in relation to the preprocedural diameter. Sociodemographic information, comorbidities, treatment, laboratory parameters, selected anatomical and genetic factors were all analyzed to determine their impact on persistent type II endoleak. The adjustments included age, hypertension, diabetes mellitus, dyslipidemia, sex, smoking in multivariate analyses. When postprocedural diameter and volume were evaluated, adjustments included also preprocedural diameter/volume. RESULTS: After exclusion, 178 patients with mean age 72.4±7.60 years remained for analysis. Persistent type II endoleak was found in 27.5% of patients (N.=49) and 2.94-times increased risk of sac progression in multivariate analysis (P=0.033). In multivariate analysis, AAA diameter in patients with persistent type II endoleak was 4.31 mm greater than in patients without (B=4.31; P=0.014); and its presence was also associated with 22.0 cm3 greater sac volume (B=22.0; P=0.034) compared to patients without persistent type II endoleak. Treatment with calcium channel blockers increased risk of persistent type II endoleak 2.11-times in multivariate analysis (OR=2.11; 95% CI: 1.05-4.25; P=0.037). No association between persistent type II endoleak and selected polymorphisms associated with AAA and other observed factors were found. CONCLUSIONS: Risk of persistent type II endoleak was more than doubled in patients taking calcium channel blockers. Patients with persistent type II endoleak had greater anteroposterior sac diameter and sac volume compared to patients without persistent type II endoleak.

In vivo macromolecule signals in rat brain 1 H-MR spectra at 9.4T: Parametrization, spline baseline estimation, and T2 relaxation times.

PURPOSE: Reliable detection and fitting of macromolecules (MM) are crucial for accurate quantification of brain short-echo time (TE) 1 H-MR spectra. An experimentally acquired single MM spectrum is commonly used. Higher spectral resolution at ultra-high field (UHF) led to increased interest in using a parametrized MM spectrum together with flexible spline baselines to address unpredicted spectroscopic components. Herein, we aimed to: (1) implement an advanced methodological approach for post-processing, fitting, and parametrization of 9.4T rat brain MM spectra; (2) assess the concomitant impact of the LCModel baseline and MM model (ie, single vs parametrized); and (3) estimate the apparent T2 relaxation times for seven MM components. METHODS: A single inversion recovery sequence combined with advanced AMARES prior knowledge was used to eliminate the metabolite residuals, fit, and parametrize 10 MM components directly from 9.4T rat brain in vivo 1 H-MR spectra at different TEs. Monte Carlo simulations were also used to assess the concomitant influence of parametrized MM and DKNTMN parameter in LCModel. RESULTS: A very stiff baseline (DKNTMN ≥ 1 ppm) in combination with a single MM spectrum led to deviations in metabolite concentrations. For some metabolites the parametrized MM showed deviations from the ground truth for all DKNTMN values. Adding prior knowledge on parametrized MM improved MM and metabolite quantification. The apparent T2 ranged between 12 and 24 ms for seven MM peaks. CONCLUSION: Moderate flexibility in the spline baseline was required for reliable quantification of real/experimental spectra based on in vivo and Monte Carlo data. Prior knowledge on parametrized MM improved MM and metabolite quantification.

Long-term behavioral effects observed in mice chronically exposed to static ultra-high magnetic fields.

PURPOSE: The primary goal of this study was to investigate whether chronic exposures to ultra-high B0 fields can induce long-term cognitive, behavioral, or biological changes in C57BL/6 mice. METHODS: C57BL/6 mice were chronically exposed to 10.5-T or 16.4-T magnetic fields (3-h exposures, two exposure sessions per week, 4 or 8 weeks of exposure). In vivo single-voxel 1 H magnetic resonance spectroscopy was used to investigate possible neurochemical changes in the hippocampus. In addition, a battery of behavioral tests, including the Morris water-maze, balance-beam, rotarod, and fear-conditioning tests, were used to examine long-term changes induced by B0 exposures. RESULTS: Hippocampal neurochemical profile, cognitive, and basic motor functions were not impaired by chronic magnetic field exposures. However, the balance-beam-walking test and the Morris water-maze testing revealed B0 -induced changes in motor coordination and balance. The tight-circling locomotor behavior during Morris water-maze tests was found as the most sensitive factor indexing B0 -induced changes. Long-term behavioral changes were observed days or even weeks subsequent to the last B0 exposure at 16.4 T but not at 10.5 T. Fast motion of mice in and out of the 16.4-T magnet was not sufficient to induce such changes. CONCLUSION: Observed results suggest that the chronic exposure to a magnetic field as high as 16.4 T may result in long-term impairment of the vestibular system in mice. Although observation of mice may not directly translate to humans, nevertheless, they indicate that studies focused on human safety at very high magnetic fields are necessary.

Minimum Reporting Standards for in vivo Magnetic Resonance Spectroscopy (MRSinMRS): Experts' consensus recommendations.

The translation of MRS to clinical practice has been impeded by the lack of technical standardization. There are multiple methods of acquisition, post-processing, and analysis whose details greatly impact the interpretation of the results. These details are often not fully reported, making it difficult to assess MRS studies on a standardized basis. This hampers the reviewing of manuscripts, limits the reproducibility of study results, and complicates meta-analysis of the literature. In this paper a consensus group of MRS experts provides minimum guidelines for the reporting of MRS methods and results, including the standardized description of MRS hardware, data acquisition, analysis, and quality assessment. This consensus statement describes each of these requirements in detail and includes a checklist to assist authors and journal reviewers and to provide a practical way for journal editors to ensure that MRS studies are reported in full.

Water and lipid suppression techniques for advanced 1 H MRS and MRSI of the human brain: Experts' consensus recommendations.

The neurochemical information provided by proton magnetic resonance spectroscopy (MRS) or MR spectroscopic imaging (MRSI) can be severely compromised if strong signals originating from brain water and extracranial lipids are not properly suppressed. The authors of this paper present an overview of advanced water/lipid-suppression techniques and describe their advantages and disadvantages. Moreover, they provide recommendations for choosing the most appropriate techniques for proper use. Methods of water signal handling are primarily focused on the VAPOR technique and on MRS without water suppression (metabolite cycling). The section on lipid-suppression methods in MRSI is divided into three parts. First, lipid-suppression techniques that can be implemented on most clinical MR scanners (volume preselection, outer-volume suppression, selective lipid suppression) are described. Second, lipid-suppression techniques utilizing the combination of k-space filtering, high spatial resolutions and lipid regularization are presented. Finally, three promising new lipid-suppression techniques, which require special hardware (a multi-channel transmit system for dynamic B1+ shimming, a dedicated second-order gradient system or an outer volume crusher coil) are introduced.

Contribution of macromolecules to brain 1 H MR spectra: Experts' consensus recommendations.

Proton MR spectra of the brain, especially those measured at short and intermediate echo times, contain signals from mobile macromolecules (MM). A description of the main MM is provided in this consensus paper. These broad peaks of MM underlie the narrower peaks of metabolites and often complicate their quantification but they also may have potential importance as biomarkers in specific diseases. Thus, separation of broad MM signals from low molecular weight metabolites enables accurate determination of metabolite concentrations and is of primary interest in many studies. Other studies attempt to understand the origin of the MM spectrum, to decompose it into individual spectral regions or peaks and to use the components of the MM spectrum as markers of various physiological or pathological conditions in biomedical research or clinical practice. The aim of this consensus paper is to provide an overview and some recommendations on how to handle the MM signals in different types of studies together with a list of open issues in the field, which are all summarized at the end of the paper.

AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival.

Lactate is used as an energy source by producer cells or shuttled to neighboring cells and tissues. Both glucose and lactate fulfill the bioenergetic demand of neurons, the latter imported from astrocytes. The contribution of astrocytic lactate to neuronal bioenergetics and the mechanisms of astrocytic lactate production are incompletely understood. Through in vivo1H magnetic resonance spectroscopy, 13C glucose mass spectroscopy, and electroencephalographic and molecular studies, here we show that the energy sensor AMP activated protein kinase (AMPK) regulates neuronal survival in a non-cell-autonomous manner. Ampk-null mice are deficient in brain lactate and are seizure prone. Ampk deletion in astroglia, but not neurons, causes neuronal loss in both mammalian and fly brains. Mechanistically, astrocytic AMPK phosphorylated and destabilized thioredoxin-interacting protein (TXNIP), enabling expression and surface translocation of the glucose transporter GLUT1, glucose uptake, and lactate production. Ampk loss in astrocytes causes TXNIP hyperstability, GLUT1 misregulation, inadequate glucose metabolism, and neuronal loss.