Organization of neurochemical interactions in young and older brains as revealed with a network approach: Evidence from proton magnetic resonance spectroscopy (1H-MRS).

Aging is associated with alterations in the brain including structural and metabolic changes. Previous research has focused on neurometabolite level differences associated to age in a variety of brain regions, but the relationship among metabolites across the brain has been much less studied. Investigating these relationships can reveal underlying neurometabolic processes, their interdependency, and their progress throughout the lifespan. Using 1H-MRS, we investigated the relationship among metabolite concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myo-Inositol (mIns) and glutamate-glutamine complex (Glx) in seven voxel locations, i.e., bilateral sensorimotor cortex, bilateral striatum, pre-supplementary motor area, right inferior frontal gyrus and occipital cortex. These measurements were performed on 59 human participants divided in two age groups: young adults (YA: 23.2 ± 4.3; 18-34 years) and older adults (OA: 67.5 ± 3.9; 61-74 years). Our results showed age-related differences in NAA, Cho, and mIns across brain regions, suggesting the presence of neurodegeneration and altered gliosis. Moreover, associative patterns among NAA, Cho and Cr were observed across the selected brain regions, which differed between young and older adults. Whereas most of metabolite concentrations were inhomogeneous across different brain regions, Cho levels were shown to be strongly related across brain regions in both age groups. Finally, we found metabolic associations between homologous brain regions (SM1 and striatum) in the OA group, with NAA showing a significant correlation between bilateral sensorimotor cortices (SM1) and mIns levels being correlated between the bilateral striata. We posit that a network perspective provides important insights regarding the potential interactions among neurochemicals underlying metabolic processes at a local and global level and their relationship with aging.

Folic Acid Fortification Prevents Morphological and Behavioral Consequences of X-Ray Exposure During Neurulation.

Previous studies suggested a causal link between pre-natal exposure to ionizing radiation and birth defects such as microphthalmos and exencephaly. In mice, these defects arise primarily after high-dose X-irradiation during early neurulation. However, the impact of sublethal (low) X-ray doses during this early developmental time window on adult behavior and morphology of central nervous system structures is not known. In addition, the efficacy of folic acid (FA) in preventing radiation-induced birth defects and persistent radiation-induced anomalies has remained unexplored. To assess the efficacy of FA in preventing radiation-induced defects, pregnant C57BL6/J mice were X-irradiated at embryonic day (E)7.5 and were fed FA-fortified food. FA partially prevented radiation-induced (1.0 Gy) anophthalmos, exencephaly and gastroschisis at E18, and reduced the number of pre-natal deaths, fetal weight loss and defects in the cervical vertebrae resulting from irradiation. Furthermore, FA food fortification counteracted radiation-induced impairments in vision and olfaction, which were evidenced after exposure to doses ≥0.1 Gy. These findings coincided with the observation of a reduction in thickness of the retinal ganglion cell and nerve fiber layer, and a decreased axial length of the eye following exposure to 0.5 Gy. Finally, MRI studies revealed a volumetric decrease of the hippocampus, striatum, thalamus, midbrain and pons following 0.5 Gy irradiation, which could be partially ameliorated after FA food fortification. Altogether, our study is the first to offer detailed insights into the long-term consequences of X-ray exposure during neurulation, and supports the use of FA as a radioprotectant and antiteratogen to counter the detrimental effects of X-ray exposure during this crucial period of gestation.

Neurometabolic Correlates of Reactive and Proactive Motor Inhibition in Young and Older Adults: Evidence from Multiple Regional 1H-MR Spectroscopy.

Suboptimal inhibitory control is a major factor contributing to motor/cognitive deficits in older age and pathology. Here, we provide novel insights into the neurochemical biomarkers of inhibitory control in healthy young and older adults and highlight putative neurometabolic correlates of deficient inhibitory functions in normal aging. Age-related alterations in levels of glutamate-glutamine complex (Glx), N-acetylaspartate (NAA), choline (Cho), and myo-inositol (mIns) were assessed in the right inferior frontal gyrus (RIFG), pre-supplementary motor area (preSMA), bilateral sensorimotor cortex (SM1), bilateral striatum (STR), and occipital cortex (OCC) with proton magnetic resonance spectroscopy (1H-MRS). Data were collected from 30 young (age range 18-34 years) and 29 older (age range 60-74 years) adults. Associations between age-related changes in the levels of these metabolites and performance measures or reactive/proactive inhibition were examined for each age group. Glx levels in the right striatum and preSMA were associated with more efficient proactive inhibition in young adults but were not predictive for reactive inhibition performance. Higher NAA/mIns ratios in the preSMA and RIFG and lower mIns levels in the OCC were associated with better deployment of proactive and reactive inhibition in older adults. Overall, these findings suggest that altered regional concentrations of NAA and mIns constitute potential biomarkers of suboptimal inhibitory control in aging.

Bioluminescence imaging increases in vivo screening efficiency for antifungal activity against device-associated Candida albicans biofilms.

Fungal infections are a major problem for a growing number of mostly immunocompromised patients. Candida albicans is an important human fungal pathogen causing mucosal and deep tissue infections, of which the majority are associated with biofilm formation on medical implants. Animal models that are currently in use to test antifungal drugs are limited to ex vivo analyses, requiring host sacrifice that excludes longitudinal monitoring of dynamic processes during biofilm formation in the live host. As a solution, we introduce non-invasive, dynamic imaging and quantification of C. albicans biofilm formation in vivo and subsequent evaluation of treatment efficacy against these biofilms using bioluminescent C. albicans in a catheter-associated mouse model. Bioluminescence imaging (BLI) allowed us to evaluate baseline biofilm load before the start of therapy, which is necessary for correct evaluation and interpretation of antibiofilm efficacy in vivo. Moreover, we demonstrate that this BLI approach monitors the antibiofilm activity of different antifungal agents efficiently in vitro and in vivo. In this study, BLI revealed superior antibiofilm activity for echinocandins compared with amphotericin B and fluconazole. In vitro, anidulafungin showed the highest antibiofilm activity, followed by micafungin and caspofungin. In vivo, caspofungin significantly decreased the biofilm fungal load, as documented by the lower BLI signal and confirmed by CFU counts. In conclusion, this BLI approach increases the power and efficiency of screening and validation of antimycotics both under in vitro and in vivo conditions, thereby refining pre-clinical therapy studies.

Cerebral dopaminergic and glutamatergic transmission relate to different subjective responses of acute alcohol intake: an in vivo multimodal imaging study.

Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [18 F]fallypride and [18 F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton-magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [18 F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P < 0.05, corrected for multiple comparisons). Dopamine release in the ACC and orbitofrontal and ventromedial PFCs were correlated with subjective 'liking' and 'wanting' effects (P < 0.05). In contrast, baseline mGluR5 availability was positively correlated with the 'high' effect of alcohol in dorsolateral, ventrolateral and ventromedial PFCs and in the medial temporal lobe, thalamus and caudate nucleus (P < 0.05). Although neither proton-magnetic resonance spectroscopy glutamate nor glutamine levels were affected by alcohol, baseline ACC glutamate levels were negatively associated with the alcohol 'liking' effect (P < 0.003). These data reveal new mechanistic understanding and differential neurobiological underpinnings of the effects of acute alcohol consumption on human behavior. Specifically, prefrontal dopamine release may encode alcohol 'liking' and 'wanting' effects in specific areas underlying value processing and motivation, whereas mGluR5 availability in distinct prefrontal-temporal-subcortical regions is more related to the alcohol 'high' effect.

Murine Pancreatic Acinar Cell Carcinoma Growth Kinetics Are Independent of Dietary Vitamin D Deficiency or Supplementation.

Vitamin D has been proposed as a therapeutic strategy in pancreatic cancer, yet evidence for an effect of dietary vitamin D on pancreatic cancer is ambiguous, with conflicting data from human epidemiological and intervention studies. Here, we tested the role of dietary vitamin D in the in vivo context of the well-characterized Ela1-TAg transgenic mouse model of pancreatic acinar cell carcinoma. Through longitudinal magnetic resonance imaging of mice under conditions of either dietary vitamin D deficiency (<5 IU/kg vitamin D) or excess (76,500 IU/kg vitamin D), compared to control diet (1,500 IU/kg vitamin D), we measured the effect of variation of dietary vitamin D on tumor kinetics. No measurable impact of dietary vitamin D was found on pancreatic acinar cell carcinoma development, growth or mortality, casting further doubt on the already equivocal data supporting potential therapeutic use in humans. The lack of any detectable effect of vitamin D, within the physiological range of dietary deficiency or supplementation, in this model further erodes confidence in vitamin D as an effective antitumor therapeutic in pancreatic acinar cell carcinoma.

Towards non-invasive monitoring of pathogen-host interactions during Candida albicans biofilm formation using in vivo bioluminescence.

Candida albicans is a major human fungal pathogen causing mucosal and deep tissue infections of which the majority is associated with biofilm formation on medical implants. Biofilms have a huge impact on public health, as fungal biofilms are highly resistant against most antimycotics. Animal models of biofilm formation are indispensable for improving our understanding of biofilm development inside the host, their antifungal resistance and their interaction with the host immune defence system. In currently used models, evaluation of biofilm development or the efficacy of antifungal treatment is limited to ex vivo analyses, requiring host sacrifice, which excludes longitudinal monitoring of dynamic processes during biofilm formation in the live host. In this study, we have demonstrated for the first time that non-invasive, dynamic imaging and quantification of in vitro and in vivo C. albicans biofilm formation including morphogenesis from the yeast to hyphae state is feasible by using growth-phase dependent bioluminescent C. albicans strains in a subcutaneous catheter model in rodents. We have shown the defect in biofilm formation of a bioluminescent bcr1 mutant strain. This approach has immediate applications for the screening and validation ofantimycotics under in vivo conditions, for studying host-biofilm interactions in different transgenic mouse models and for testing the virulence of luminescent C. albicans mutants, hereby contributing to a better understanding of the pathogenesis of biofilm-associated yeast infections.

Magnetic resonance spectroscopy detects biochemical changes in the brain associated with chronic low back pain: a preliminary report.

Magnetic resonance (MR) spectroscopy is a noninvasive technique that can be used to detect and measure the concentration of metabolites and neurotransmitters in the brain and other organs. We used in vivo (1)H MR spectroscopy in subjects with low back pain compared with control subjects to detect alterations in biochemistry in three brain regions associated with pain processing. A pattern recognition approach was used to determine whether it was possible to discriminate accurately subjects with low back pain from control subjects based on MR spectroscopy. MR spectra were obtained from the prefrontal cortex, anterior cingulate cortex, and thalamus of 32 subjects with low back pain and 33 control subjects without pain. Spectra were analyzed and compared between groups using a pattern recognition method (Statistical Classification Strategy). Using this approach, it was possible to discriminate between subjects with low back pain and control subjects with accuracies of 100%, 99%, and 97% using spectra obtained from the anterior cingulate cortex, thalamus, and prefrontal cortex, respectively. These results demonstrate that MR spectroscopy, in combination with an appropriate pattern recognition approach, is able to detect brain biochemical changes associated with chronic pain with a high degree of accuracy.