The long-term effect of erythropoiesis stimulating agents given to preterm infants: a proton magnetic resonance spectroscopy study on neurometabolites in early childhood.

BACKGROUND: Erythropoiesis stimulating agents (ESAs) are neuroprotective in cell and animal models of preterm birth. Prematurity has been shown to alter neurometabolite levels in children in studies using proton magnetic resonance spectroscopy (1H-MRS). OBJECTIVE: We hypothesized that ESA treatment in premature infants would tend to normalize neurometabolites by 4-6 years of age. MATERIALS AND METHODS: Children in a longitudinal study of neurodevelopment underwent MRI and 1H-MRS at approximately 4 years and 6 years of age. Prematurely born children (500-1,250 g birth weight) received ESAs (erythropoietin or darbepoetin) or placebo during their neonatal hospitalization, and these groups were compared to healthy term controls. 1H-MRS spectra were obtained from the anterior cingulate (gray matter) and frontal lobe white matter, assessing combined N-acetylaspartate and N-acetylaspartylglutamate (tNAA), myo-inositol, choline compounds (Cho), combined creatine and phosphocreatine, and combined glutamate and glutamine. RESULTS: No significant (P≤0.5) group differences were observed for any metabolite level. Significant age-related increases in white-matter tNAA and Cho were observed, as well as a trend for increased gray-matter tNAA. CONCLUSION: Neither prematurity nor neonatal ESA treatment was associated with differences in brain metabolite levels in the children of this study at a significance level of 0.05. These findings suggest that earlier differences that might have existed had normalized by 4-6 years of age or were too small to be statistically significant in the current sample.

MRI measurements of Blood-Brain Barrier function in dementia: A review of recent studies.

Blood-brain barrier (BBB) separates the systemic circulation and the brain, regulating transport of most molecules to protect the brain microenvironment. Multiple structural and functional components preserve the integrity of the BBB. Several imaging modalities are available to study disruption of the BBB. However, the subtle changes in BBB leakage that occurs in vascular cognitive impairment and Alzheimer's disease have been less well studied. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is the most widely adopted non-invasive imaging technique for evaluating BBB breakdown. It is used as a significant marker for a wide variety of diseases with large permeability leaks, such as brain tumors and multiple sclerosis, to more subtle disruption in chronic vascular disease and dementia. DCE-MRI analysis of BBB includes both model-free parameters and quantitative parameters using pharmacokinetic modelling. We review MRI studies of BBB breakdown in dementia. The challenges in measuring subtle BBB changes and the state of the art techniques are initially examined. Subsequently, a systematic review comparing methodologies from recent in-vivo MRI studies is presented. Various factors related to subtle BBB permeability measurement such as DCE-MRI acquisition parameters, arterial input assessment, T1 mapping and data analysis methods are reviewed with the focus on finding the optimal technique. Finally, the reported BBB permeability values in dementia are compared across different studies and across various brain regions. We conclude that reliable measurement of low-level BBB permeability across sites remains a difficult problem and a standardization of the methodology for both data acquisition and quantitative analysis is required. This article is part of the Special Issue entitled 'Cerebral Ischemia'.

Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin.

BACKGROUND: We previously reported improved neurodevelopmental outcomes at 2 years among infants treated with the erythropoiesis-stimulating agents (ESAs) darbepoetin alfa (darbepoetin) or erythropoietin. Here we characterize 4-year outcomes. METHODS: Former preterm infants randomly assigned to receive darbepoetin (10 µg/kg, once per week), erythropoietin (400 U/kg, 3 times/week), or placebo through 35 weeks' postconceptual age were evaluated at 3.5 to 4 years of age. For comparison, healthy children formerly delivered full term (term controls [TCs]) were also recruited. All participants were assessed by using measures of full-scale IQ (FSIQ) and general language from the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, and an overall measure of executive function, on the basis of tests evaluating inhibitory control and spatial working memory. Rates of neurodevelopmental impairment were compared across groups. RESULTS: Multivariate analysis of variance compared children randomly assigned to ESAs (n = 39), placebo (n =14), and TCs (n = 24). FSIQ and performance IQ were significantly higher in the ESA group than in the placebo group (FSIQ: 91.1 ± 17.5 vs 79.2 ± 18.5, P = .036; performance IQ: 93.0 ± 17.0 vs 79.5 ± 19.5, P = .018). Follow-up analyses revealed that the children receiving ESAs performed better than those who received placebo on executive function tasks. The ESA group's performance was below that of TCs, but the results did not reach significance on executive function. The incidence of neurodevelopmental impairment was greater in the placebo group than in the ESA group. CONCLUSIONS: ESA-treated infants had better cognitive outcomes and less developmental impairment at 3.5 to 4 years of age compared with placebo-treated infants. ESAs show promise in improving long-term cognitive outcomes of infants born prematurely.

Long-term effects of marijuana use on the brain.

Questions surrounding the effects of chronic marijuana use on brain structure continue to increase. To date, however, findings remain inconclusive. In this comprehensive study that aimed to characterize brain alterations associated with chronic marijuana use, we measured gray matter (GM) volume via structural MRI across the whole brain by using voxel-based morphology, synchrony among abnormal GM regions during resting state via functional connectivity MRI, and white matter integrity (i.e., structural connectivity) between the abnormal GM regions via diffusion tensor imaging in 48 marijuana users and 62 age- and sex-matched nonusing controls. The results showed that compared with controls, marijuana users had significantly less bilateral orbitofrontal gyri volume, higher functional connectivity in the orbitofrontal cortex (OFC) network, and higher structural connectivity in tracts that innervate the OFC (forceps minor) as measured by fractional anisotropy (FA). Increased OFC functional connectivity in marijuana users was associated with earlier age of onset. Lastly, a quadratic trend was observed suggesting that the FA of the forceps minor tract initially increased following regular marijuana use but decreased with protracted regular use. This pattern may indicate differential effects of initial and chronic marijuana use that may reflect complex neuroadaptive processes in response to marijuana use. Despite the observed age of onset effects, longitudinal studies are needed to determine causality of these effects.

Diffusion tensor imaging of white matter networks in individuals with current and remitted alcohol use disorders and comorbid conditions.

Individuals with alcohol use disorders show white matter abnormality relative to normal samples, but differences in white matter profiles have not yet been investigated as a function of abstinence. Individuals with current alcohol use disorders (AUD-C; n = 10), individuals with alcohol use disorders in remission for at least 1 year (AUD-R; n = 9), and healthy control participants (HC; n = 15) matched to alcohol groups on age and smoking status underwent MRI. Diffusion tensor imaging (DTI) data were analyzed using tract-based spatial statistics (TBSS). Compared with HC, AUD-C showed reduced axial diffusivity in bilateral frontal and temporal white matter. In AUD-R, lower fractional anisotropy relative to HC was widespread in bilateral parietal regions. A combined AUD-C and AUD-R group had decreased fractional anisotropy primarily in the fornix and thalamus. In conclusion, AUD-R manifested damage in parietal regions integral to processing of visuospatial information and self-awareness whereas AUD-C showed abnormal diffusivity in fronto-temporal regions that regulate impulsivity, attention, and memory. As a combined group, AUD individuals exhibited abnormality in subcortical areas associated with sensory processing and memory. White matter differences in individuals with AUD may be attributable to premorbid vulnerability or persisting effects of alcohol abuse, but the pattern of abnormality across groups suggests that these abnormalities may be secondary to alcohol use.

Perturbation of the glutamate-glutamine system in alcohol dependence and remission.

As acute ethanol exposure inhibits N-methyl-D-aspartate glutamate (Glu) receptors, sudden withdrawal from chronic alcohol use may lead to an increased activation of these receptors with excitotoxic effects. In the longer term, brain levels of Glu and its metabolites, such as glutamine (Gln), are likely to be chronically altered by alcohol, possibly providing a measure of overall abnormal Glu-Gln cycling. However, few studies have assessed concentrations of these metabolites in clinical populations of individuals with alcohol use disorders. Glu and Gln levels were compared in groups of 17 healthy controls and in 13 participants with alcohol dependence. Within the alcohol-dependent group, seven participants had current alcohol use disorder (AUD), and six had AUD in remission for at least 1 year (AUD-R). Neurometabolite concentrations were measured with proton magnetic resonance spectroscopy ((1)H-MRS) in a predominantly gray matter voxel that included the bilateral anterior cingulate gyri. Tissue segmentation provided an assessment of the proportion of gray matter in the (1)H-MRS voxel. The Drinker Inventory of Consequences (DrInC) and Form-90 were administered to all participants to quantify alcohol consequences and use. Glu level was lower and Gln level was higher in the AUD and AUD-R groups relative to the control group; creatine, choline, myo-inositol, and total N-acetyl groups, primarily N-acetylaspartate did not differ across groups. These results were not confounded by age, sex, or proportion of gray matter in the (1)H-MRS voxel. Neurometabolite concentrations did not differ between AUD and AUD-R groups. Subsequent regressions in the combined clinical group, treating voxel gray matter proportion as a covariate, revealed that total score on the DrInC was positively correlated with Gln but negatively correlated with both Glu and gray matter proportion. Regression analyses, including DrInC scores and smoking variables, identified a marginal independent effect of smoking on Gln. The current findings of higher Gln and lower Glu in the combined AUD and AUD-R groups might indicate a perturbation of the Glu-Gln cycle in alcohol use disorders. The absence of differences in mean Glu and Gln between the AUD and AUD-R groups suggests that altered Glu-Gln metabolism may either predate the onset of abuse or persist during prolonged abstinence.

Failure of Rhodiola rosea to alter skeletal muscle phosphate kinetics in trained men.

Rhodiola rosea is an herbal supplement purported to improve resistance to stressors and to enhance physical performance, potentially by improving adenosine triphosphate (ATP) turnover. Phosphocreatine (PCr) kinetics serves as a reflection of ATP turnover. The purpose of this investigation was to examine the effect of R rosea ingestion on human skeletal muscle PCr recovery after exhaustive exercise. Twelve resistance-trained men, aged 19 to 39 years, completed incremental forearm wrist flexion exercise to volitional fatigue, once after ingesting 1500 mg R rosea per day for 4 days, and once after ingesting an equivalent placebo dose. During exercise and recovery from exercise, muscle phosphates were examined using phosphorus 31 nuclear magnetic resonance spectroscopy. [PCr] during recovery was fit with a monoexponential function, and the resulting rate constants (k) were compared between groups. Rating of perceived exertion per stage and time to exhaustion were also compared between groups. For R rosea, k=0.3744+/-0.1532, whereas for placebo, k=0.3956+/-0.2238. Although rating of perceived exertion significantly increased within groups as workload increased, it did not differ between conditions, nor did time to exhaustion (R rosea, 10.71+/-0.54 minutes; placebo, 10.48+/-0.68 minutes). Estimates of [PCr] at time 0, 5, 10, 15, and 20 minutes of recovery were nearly identical between groups. In summary, there were no significant differences between groups for any of theparameters measured. Based on these results, we conclude that R rosea ingestion does not improve ATP turnover during or immediately after exercise.

CO2 rebreathing model in COPD: blood-to-gas equilibration.

Rebreathing in a closed system can be used to estimate mixed venous PCO2 (PvCO2) and cardiac output, but these estimates are affected by VA/Q heterogeneity. The purpose of this study was to validate a mathematical model of CO2 exchange during CO2 rebreathing in 29 patients with chronic obstructive pulmonary disease (COPD), with baseline arterial PCO2 (PaCO2) ranging from 28 to 60 mmHg. Rebreathing increased end-tidal PCO2 (PETCO2) by 20 mmHg over 2.2 min. This model employed baseline values for inspired (bag) PCO2, estimated PvCO2, distribution of ventilation and blood flow in one high VA/Q and one low VA/Q compartment, the ventilation increase and conservation of mass equations to simulate time courses of PICO2, PETCO2, PvCO2, and PaCO2. Measured PICO2 and PETCO2 during rebreathing differed by an average (SEM) of 1.4 (0.4) mmHg from simulated values. By end of rebreathing, predicted PvCO2 was lower than measured and predicted PaCO2, indicating gas to blood CO2 flux. Estimates of the ventilatory response to CO2, quantified as the slope (S) of the ventilation increase versus PETCO2, were inversely related to gas-to-blood PCO2 disequilibria due to VA/Q heterogeneity and buffer capacity (BC), but not airflow limitation. S may be corrected for these artifacts to restore S as a more valid noninvasive index of central CO2 responsiveness. We conclude that a rebreathing model incorporating baseline VA/Q heterogeneity and BC can simulate gas and blood PCO2 in patients with COPD, where VA/Q variations are large and variable.

Análise de sinais Doppler de velocidade de fluxo arterial por microcomputador / Analysis of the arterial blood flow velocity waveform with microcamputer

A técnica Doppler é uma das mais usadas em clínicas de Angiologia para avaliaçäo da circulaçäo periférica. Sendo método näo-invasivo, é preferível à angiografia de contraste para acompanhamento de casos. Foi desenvolvido um microcomputador e um método para a obtençäo automática de alguns parâmetros de interesse clínico a partir do sinal de velocidade de fluxo arterial obtido por fluxômetro Doppler de onda contínua. O hardware é baseado no micronP 8085A e consta de 16 k de RAM, 18k de EPROM, interfaces para teclado, vídeo, impressora e conversores A/D e D/A, que permitem a monitoraçäo dos sinais durante a coleta e seu registro gráfico após o exame. O software foi desenvolvido parte em Assembly e parte em Basic. O sistema foi testado em sinais previamente gravados em 72 membros inferiores, sendo analisado, para cada caso, um trecho de 17s e fornecidas na listagem de saída a média, o desvio padräo e o coeficiente de variaçäo para cada parâmetro. O teste demonstrou que o sistema funciona para diversos tipos de formas de onda e facilita a obtençäo dos parâmetros desejados, tornando a rotina menos laboriosa e mais rápida