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Background and aims Neuropsychiatric symptoms in hepatitis C (HCV) patients resemble those of patients with autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), whilst the mechanisms behind them are unknown. Here we looked for cerebral metabolic and/or microstructural alterations in patients with HCV, AIH or PBC as possible causes behind these symptoms. Methods Patients with HCV infection (n = 17), AIH (n = 14) or PBC (n = 11) and age-adjusted healthy controls (n = 18) underwent brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and psychometric assessment of memory and attention. Brain relative proton density (PD) and T2 relaxation time (T2) were determined in 17 regions of interest (ROIs), as were the concentrations of N-acetyl-aspartate, choline, creatine, myo-inositol and glutamine + glutamate in frontal- (fWM) and parietal white matter (pWM). One-way analysis of variance and Kruskal-Wallis tests were used for group comparison. Correlations between altered neuropsychological findings and MRI/MRS observations were estimated with the Spearman ρ test. Results HCV, AIH and PBC patients revealed similar alterations in brain PD and metabolites compared to controls: significantly decreased PD in 7/17 ROIs in the HCV group, 16/17 ROIs in the PBC group and 14/17 ROIs in the AIH group, significantly increased N-acetyl-aspartate in fWM in all patients, significantly increased choline in the PBC group in both fWM and pWM, in the AIH group only in pWM and with a trend in the HCV group in pWM. Correlation analysis did not reveal significant associations between MRI/MRS alterations and neuropsychological dysfunction. Conclusion The findings suggest similar pathophysiological mechanisms behind neuropsychiatric symptoms associated with HCV infection, AIH and PBC.

Aging effects on striato-thalamic metabolism in healthy human brains were studied in vivo using short-TE whole brain 1H-MR spectroscopic imaging (wbMRSI) on eighty healthy subjects aged evenly between 20 to 70 years at 3T. Relative concentrations of N-acetyl-aspartate (NAA), choline, total creatine (tCr), myo-inositol (mI), glutamate, and glutamine in bilateral caudate nucleus, putamen, pallidum, and thalamus were determined using signal normalization relative to brain tissue water. Linear regression analysis was used to analyze the age-dependence of the metabolite concentrations. The metabolite concentrations revealed spatial inhomogeneity across brain regions and metabolites. With age, NAA decreased significantly in bilateral caudate nucleus and putamen, left pallidum, and left thalamus, tCr decreased in left putamen and bilateral pallidum, mI increased in bilateral caudate nucleus and right thalamus, and spectral linewidth increased in left putamen and right thalamus. In conclusion, normal aging of striato-thalamic metabolism in healthy human is associated with regional specific decreases of NAA and tCr and increases of mI, which may reflect the individual role of each brain structure within brain functionality.

(1) Purpose: Quantitative magnetic resonance imaging (qMRI) measurements can be used to sensitively estimate brain morphological alterations and may support clinical diagnosis of neurodegenerative diseases (ND). We aimed to establish a normative reference database for a clinical applicable quantitative MR morphologic measurement on neurodegenerative changes in patients, (2) Methods: Healthy subjects (HCs, n = 120) with an evenly distribution between 21 to 70 years and amyotrophic lateral sclerosis (ALS) patients (n = 11, mean age = 52.45 ± 6.80 years), as an example of ND patients, underwent magnetic resonance imaging (MRI) examinations under routine diagnostic conditions. Regional cortical thickness (rCTh) in 68 regions of interest (ROIs) and subcortical grey matter volume (SGMV) in 14 ROIs were determined from all subjects by using Computational Anatomy Toolbox. Those derived from HCs were analyzed to determine age-related differences and subsequently used as reference to estimate ALS-related alterations, (3) Results: In HCs, the rCTh (in 49/68 regions) and the SGMV (in 9/14 regions) in elderly subjects were less than those in younger subjects and exhibited negative linear correlations to age (p &lt, 0.0007 for rCTh and p &lt, 0.004 for SGMV). In comparison to age- and sex-matched HCs, the ALS patients revealed significant decreases of rCTh in eight ROIs, majorly located in frontal and temporal lobes, (4) Conclusion: The present study proves an overall grey matter decline with normal ageing as reported previously. The provided reference may be used for detection of grey matter alterations in neurodegenerative diseases that are not apparent in standard MR scans, indicating the potential of using qMRI as an add-on diagnostic tool in a clinical setting.

BACKGROUND AND PURPOSE To detect brain morphological alterations in patients with early Parkinson's disease (PD) by using magnetic resonance imaging (MRI) morphometry under radiological diagnostic conditions. METHODS T1-weighted brain images of 18 early PD patients and 18 age-sex-matched healthy controls (HCs) were analyzed with free software Computational Anatomy Toolbox (CAT12). Regional cortical thickness (rCTh) in 68 atlas-defined regions-of-interest (ROIs) and subcortical gray matter volume (SGMV) in 14 atlas-defined ROIs were determined and compared between patients and HCs by paired comparison using both ROI-wise and voxel-wise analyses. False-discovery rate (FDR) was used multiple comparison correction. Possible correlations between brain morphological changes in patients and clinical observations were also analyzed. RESULTS Comparing to the HCs, the ROI-wise analysis revealed rCTh thinning significantly in left medial orbitofrontal (P = .001), by trend (P < .05 but not significant after FDR correction) in four other ROIs located in frontal and temporal lobes, and a volume decreasing trend in left pallidum of the PD patients, while the voxel-wise analysis revealed one cluster with rCTh thinning trend located between left insula and superior temporal region of the patients. In addition, the patients showed more distinct rCTh thinning in ipsilateral hemisphere and SGMV deceasing trends in contralateral hemisphere in respect of the symptom-onset body side. CONCLUSION Brain morphological alterations in early PD patients are evident despite of their inconspicuous findings in standard MRI. Quantitative morphological measurements with CAT12 may be an applicable add-on tool for clinical diagnosis of early PD. These results have to be verified in future studies with larger patient samples.

PURPOSE: The aim of this study was to compare a recently established whole brain MR spectroscopic imaging (wbMRSI) technique using spin-echo planar spectroscopic imaging (EPSI) acquisition and the Metabolic Imaging and Data Analysis System (MIDAS) software package with single voxel spectroscopy (SVS) technique and LCModel analysis for determination of relative metabolite concentrations in aging human brain. METHODS: A total of 59 healthy subjects aged 20–70 years (n ≥ 5 per age decade for each gender) underwent a wbEPSI scan and 3 SVS scans of a 4ml voxel volume located in the right basal ganglia, occipital grey matter and parietal white matter. Concentration ratios to total creatine (tCr) for N-acetylaspartate (NAA/tCr), total choline (tCho/tCr), glutamine (Gln/tCr), glutamate (Glu/tCr) and myoinositol (mI/tCr) were obtained both from EPSI and SVS acquisitions with either LCModel or MIDAS. In addition, an aqueous phantom containing known metabolite concentrations was also measured. RESULTS: Metabolite concentrations obtained with wbMRSI and SVS were comparable and consistent with those reported previously. Decreases of NAA/tCr and increases of line width with age were found with both techniques, while the results obtained from EPSI acquisition revealed generally narrower line widths and smaller Cramer-Rao lower bounds than those from SVS data. CONCLUSION: The wbMRSI could be used to estimate metabolites in vivo and in vitro with the same reliability as using SVS, with the main advantage being the ability to determine metabolite concentrations in multiple brain structure simultaneously in vivo. It is expected to be widely used in clinical diagnostics and neuroscience.

Calcineurin inhibitors (CNIs) frequently induce neurological complications early after orthotopic liver transplantation (OLT). We hypothesize that longterm CNI therapy after OLT causes dose-dependent cognitive dysfunction and alteration of brain structure. In this study, 85 OLT patients (20 with CNI-free, 35 with CNI low-dose, and 30 with standard-dose CNI immunosuppression) underwent psychometric testing and cerebral magnetic resonance imaging approximately 10 years after OLT to assess brain function and structural brain alterations. A total of 33 healthy patients adjusted for age, sex, and education served as controls. Patients receiving CNI showed a significantly worse visuospatial/constructional ability compared with controls (P ≤ 0.04). Furthermore, patients on low-dose CNI therapy had an overall impaired cognitive function compared with controls (P = 0.01). The tacrolimus total dose and mean trough level were negatively correlated to cognitive function. CNI doses had been adjusted in 91% of the patients in the low-dose and CNI-free groups in the past due to CNI-induced kidney damage. Patients treated with CNI showed significantly more white matter hyperintensities (WMH) than patients on CNI-free immunosuppression and controls (P < 0.05). Both the mean cyclosporine A and tacrolimus trough levels correlated significantly with WMH. In conclusion, longterm CNI therapy carries a risk of cognitive dysfunction especially in patients who already showed nephrotoxic side effects indicating an increased susceptibility of these patients against toxic CNI effects. This subgroup of patients might benefit from a change to CNI-free immunosuppression. Liver Transplantation 24 56-66 2018 AASLD.

Adaptive response of human brain to stress plays a key role in maintaining health. Knowledge about how stress affects neurometabolism may help to understand adaptive stress responses, and distinguish maladaptation in neuropsychiatric disorders. In this study, neurometabolic responses to fasting stress in healthy women were investigated. Fifteen healthy females were examined for mood and cognition and using whole-brain MR spectroscopic imaging before and immediately after a 72-h fasting. Results were compared to 15 age-matched healthy females who did not taken part in fasting (non-fasting). Maps of the distributions in the brain of N-acetylaspartate (NAA), total choline (tCho), total creatine (tCr), glutamine/glutamate (Glx), and myo-Inositol (mI) were derived. Metabolite concentrations of each brain lobe and cerebellum measured before fasting were compared to those of post-fasting and non-fasting by repeated-measures ANOVA. After fasting, mood scores significantly increased. Glx decreased in all nine brain regions, tCho in eight, NAA in four and tCr in one, with Glx having the greatest change and the frontal lobes being the most affected brain region. In conclusion, fasting directly influences neurometabolism, and the adaptive brain response to maintain energy homeostasis under food deprivation in healthy women is associated with metabolite-selective and region-dependent changes of metabolite contents.

Accurate estimation of the state of charge (SOC) of lithium batteries is the research hotspot. As a dynamic recurrent neural network, Elman neural network has a simple structure and can adapt to time-varying characteristics, which have led to its widespread application in the field of SOC prediction. However, the simple network structure can also cause problems such as low learning efficiency, easy to fall into local extremes, and difficulty converge to the optimal weight solution. This paper proposes to combine the whale optimization algorithm (WOA) with genetic algorithm (GA) to optimize the weights and thresholds of the Elman neural network, thus improving the learning speed and prediction accuracy. We select three parameters of current, voltage and temperature as system variables, and simulate the experimental data. The experimental results show that, compared with the traditional Elman neural network and the Elman neural network optimized only by genetic algorithm, the hybrid algorithm performs best. The number of network iterations is small, and the average error drops below 1%.

PURPOSE: To study brain metabolic changes under normal aging and to collect reference data for the study of neurodegenerative diseases. METHODS: A total of 55 healthy subjects aged 20–70 years (n ≥ 5 per age decade for each gender) underwent whole-brain magnetic resonance spectroscopic imaging at 3T after completing a DemTect test and the Beck depressions inventory II to exclude cognitive impairment and mental disorder. Regional concentrations of N–acetylaspartate (NAA), choline-containing compounds (Cho), total creatine (tCr), glutamine and glutamate (Glx), and myo-inositol (mI) were determined in 12 brain regions of interest (ROIs). The two-sided t-test was used to estimate gender differences and linear regression analysis was carried out to estimate age dependence of brain regional metabolite contents. RESULTS: Brain regional metabolite concentrations changed with age in the majority of selected brain regions. The NAA decreased in 8 ROIs with a rate varying from −4.9% to −1.9% per decade, reflecting a general reduction of brain neuronal function or volume and density in older age; Cho increased in 4 ROIs with a rate varying from 4.3% to 6.1%; tCr and mI increased in one ROI (4.2% and 8.2% per decade, respectively), whereas Glx decreased in one ROI (–5.1% per decade), indicating an inhomogeneous increase of cell membrane turnover (Cho) with altered energy metabolism (tCr) and glutamatergic neuronal activity (Glx) as well as function of glia cell (mI) in normal aging brain. CONCLUSION: Healthy aging up to the seventh decade of life is associated with regional dependent alterations of brain metabolism. These results provide a reference database for future studies of patients.

Objective: To estimate alterations in neurometabolic profile of patients with early stage Parkinson's disease (PD) by using a short echo-time whole brain magnetic resonance spectroscopic imaging (wbMRSI) as possible biomarker for early diagnosis and monitoring of PD.Methods: 20 PD patients in early stage (H&Y ≤ 2) without evidence of severe other diseases and 20 age and sex matched healthy controls underwent wbMRSI. In each subject brain regional concentrations of metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), glutamine (Gln), glutamate (Glu), and myo-inositol (mIns) were obtained in atlas-defined lobar structures including subcortical basal ganglia structures (the left and right frontal lobes, temporal lobes, parietal lobes, occipital lobes, and the cerebellum) and compared between patients and matched healthy controls. Clinical characteristics of the PD patients were correlated with spectroscopic findings.Results: In comparison to controls the PD patients revealed altered lobar metabolite levels in all brain lobes contralateral to dominantly affected body side, i.e., decreases of temporal NAA, Cho, and tCr, parietal NAA and tCr, and frontal as well as occipital NAA. The frontal NAA correlated negatively with the MDS-UPDRS II (R = 22120.585, p = 0.008), MDS-UPDRS IV (R = −0.458, p = 0.048) and total MDS-UPDRS scores (R = −0.679, p = 0.001).Conclusion: In early PD stages metabolic alterations are evident in all contralateral brain lobes demonstrating that the neurodegenerative process affects not only local areas by dopaminergic denervation, but also the functional network within different brain regions. The wbMRSI-detectable brain metabolic alterations reveal the potential to serve as biomarkers for early PD.

Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. To investigate neuronal decline in normal aging brain eighty-one healthy subjects aged between 20 and 70years were studied with MRI and whole-brain (1)H MR spectroscopic imaging. Concentrations of brain metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), and glutamine+glutamate (Glx) in ratios to internal water, and the fractional volumes of brain tissue were estimated simultaneously in eight cerebral lobes and in cerebellum. Results demonstrated that an age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Both lobar NAA and the fractional volume of gray matter (FVGM) decreased with age in all cerebral lobes, indicating that the decreased NAA was predominantly associated with decreased gray matter volume and neuronal density or metabolic activity. In cerebral white matter Cho, tCr, and mI increased with age in association with increased fractional volume, showing altered cellular membrane turn-over, energy metabolism, and glial activity in human aging white matter. In cerebellum tCr increased while brain tissue volume decreased with age, showing difference to cerebral aging. The observed age-related metabolic and microstructural variations suggest that physiological neuronal decline in aging human brain is associated with a reduction of gray matter volume and neuronal density, in combination with cellular aging in white matter indicated by microstructural alterations and altered energy metabolism in the cerebellum.

PurposeTo investigate cerebral microstructural alterations in patients treated with calcineurin inhibitors (CNI) after orthotopic liver transplantation (OLT) using quantitative magnetic resonance imaging (qMRI) and a cross-sectional study design.MethodsCerebral qMRI was performed in 85 patients in a median 10 years after OLT compared to 31 healthy controls. Patients were treated with different dosages of CNI or with a CNI-free immunosuppression (CNI-free: n = 19; CNI-low: n = 36; CNI-standard: n = 30). T2-, T2*- and T2'- relaxation times, as well as apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in brain gray and white matter by using the regions of interest method.ResultsIn comparison to controls, patients revealed significantly increased T2, T2*, T2', ADC and reduced FA, predominantly in the frontal white matter, indicating microstructural brain alterations represented by increased free water (increased T2), reduced neuronal metabolism (increased T2') and a lower degree of spatial organization of the nervous fibers (reduced FA). CNI-low and CNI-free patients showed more alterations than CNI-standard patients. Analysis of their history revealed impairment of kidney function while under standard CNI dose suggesting that these patients may be more vulnerable to toxic CNI side-effects.ConclusionOur findings suggest that the individual sensitivity to toxic side effects should be considered when choosing an appropriate immunosuppressive regimen in patients after liver transplantation.

BACKGROUND Calcineurin inhibitor (CNI) neurotoxicity after liver transplantation might be due to impairment of the cerebral metabolism. AIMS To investigate CNI-related alterations of brain metabolite distributions and associations between cognitive function and brain metabolism in patients with long-term CNI treatment after liver transplantation. METHODS Eighty-two patients (19 CNI free, 34 CNI low-dose and 29 standard-dose CNI immunosuppression) 10 years after liver transplantation and 32 adjusted healthy controls underwent nonlocalised brain phosphorus magnetic resonance spectroscopy (MRS) and single voxel proton MRS in the parietal white matter to estimate brain metabolite contents. The MRS results were correlated with psychometric data assessing cognitive function. RESULTS Phosphorus metabolite concentrations with the exception of phosphocreatine (PCr) were reduced in patients compared to controls. Particularly, patients with low-dose CNI therapy showed a significant decrease in adenosine triphosphate (0.209 ± 0.012 vs 0.222 ± 0.010; P

Chronic fatigue, mood alterations and cognitive impairment are frequent accessory symptoms of HCV infection. Fatigue and mood alterations have also been observed in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), but not in hepatitis B virus (HBV)-infection, thus indicating an autoimmune response as possible cause of HCV infection-associated encephalopathy. Data, however, are sparse. This study aimed to prove that HCV patients feature similar to those with autoimmune liver disease but contrary to HBV patients regarding neuropsychiatric symptoms. A total of 132 noncirrhotic patients (HCV: 46, HBV: 22, AIH: 27, PBC: 29, AIH/PBC: 8) completed questionnaires addressing the domains mentioned above. Eighty-eight underwent a comprehensive neuropsychological assessment. Patient groups were compared among each other and to 33 healthy controls. Fatigue, anxiety and depression scores were significantly increased, and the SF-36 mental score significantly decreased in all patient groups compared to controls. Fatigue was significantly more pronounced in HCV than in HBV patients. HCV patients scored significantly worse than HBV patients but not AIH and PBC patients in the SF-36. HCV, AIH and PBC but not HBV patients did significantly worse than controls in word learning. Recognition of words was impaired in HCV, AIH and PBC patients and recognition of figures in HCV patients, exclusively (P ≤ 0.002). HCV patients did also worse than controls and HBV patients concerning alertness and working memory (P ≤ 0.001). The neuropsychiatric profiles of HCV patients are similar to those of AIH and PBC patients but differ from those of HBV patients, suggesting an autoimmune response as a possible cause for these differences.

BACKGROUND AND PURPOSE: Knowledge of age-related physiological changes in the human brain is a prerequisite to identify neurodegenerative diseases. Therefore, in this study whole-brain 1 H-MRS was used in combination with quantitative MR imaging to study the effects of normal aging on healthy human brain metabolites and microstructure. MATERIALS AND METHODS: Sixty healthy volunteers, 21–70 years of age, were studied. Brain maps of the metabolites NAA, creatine and phosphocreatine, and Cho and the tissue irreversible and reversible transverse relaxation times T2 and T2′ were derived from the datasets. The relative metabolite concentrations and the values of relaxation times were measured with ROIs placed within the frontal and parietal WM, centrum semiovale, splenium of the corpus callosum, hand motor area, occipital GM, putamen, thalamus, pons ventral/dorsal, and cerebellar white matter and posterior lobe. Linear regression analysis and Pearson correlation tests were used to analyze the data. RESULTS: Aging resulted in decreased NAA concentrations in the occipital GM, putamen, splenium of the corpus callosum, and pons ventral and decreased creatine and phosphocreatine concentrations in the pons dorsal and putamen. Cho concentrations did not change significantly in selected brain regions. T2 increased in the cerebellar white matter and decreased in the splenium of the corpus callosum with aging, while the T2′ decreased in the occipital GM, hand motor area, and putamen, and increased in the splenium of the corpus callosum. Correlations were found between NAA concentrations and T2′ in the occipital GM and putamen and between creatine and phosphocreatine concentrations and T2′ in the putamen. CONCLUSIONS: The effects of normal aging on brain metabolites and microstructure are region-dependent. Correlations between both processes are evident in the gray matter. The obtained data could be used as references for future studies on patients.

Purpose A feasibility study of an echo-planar spectroscopic imaging (EPSI) using a short echo time (TE) that trades off sensitivity, compared with other short-TE methods, to achieve whole brain coverage using inversion recovery and spatial oversampling to control lipid bleeding. Methods Twenty subjects were scanned to examine intersubject variance. One subject was scanned five times to examine intrasubject reproducibility. Data were analyzed to determine coefficients of variance (COV) and intraclass correlation coefficient (ICC) for N–acetylaspartate (NAA), total creatine (tCr), total choline (tCho), glutamine/glutamate (Glx), and myo-inositol (mI). Regional metabolite concentrations were derived by using multi-voxel analysis based on lobar-level anatomic regions. Results For whole-brain mean values, the intrasubject COVs were 14%, 15%, and 20% for NAA, tCr, and tCho, respectively, and 31% for Glx and mI. The intersubject COVs were up to 6% higher. For regional distributions, the intrasubject COVs were ≤ 5% for NAA, tCr, and tCho; ≤ 9% for Glx; and ≤15% for mI, with about 6% higher intersubject COVs. The ICCs of 5 metabolites were ≥ 0.7, indicating the reliability of the measurements. Conclusion The present EPSI method enables estimation of the whole-brain metabolite distributions, including Glx and mI with small voxel size, and a reasonable scan time and reproducibility. Magn Reson Med 73:921–928, 2015. © 2014 Wiley Periodicals, Inc.

Approximately one-third of epilepsy patients are pharmacoresistant. Overexpression of P-glycoprotein and other multidrug transporters at the blood–brain barrier is thought to play an important role in drug-refractory epilepsy. Thus, quantification of regionally different P-glycoprotein activity in the brain in vivo is essential to identify P-glycoprotein overactivity as the relevant mechanism for drug resistance in an individual patient. Using the radiolabeled P-glycoprotein substrate ( R )-[ 11 C]verapamil and different doses of coadministered tariquidar, which is an inhibitor of P-glycoprotein, we evaluated whether small-animal positron emission tomography can quantify regional changes in transporter function in the rat brain at baseline and 48 h after a pilocarpine-induced status epilepticus. P-glycoprotein expression was additionally quantified by immunohistochemistry. To reveal putative seizure-induced changes in blood–brain barrier integrity, we performed gadolinium-enhanced magnetic resonance scans on a 7.0 tesla small-animal scanner. Before P-glycoprotein modulation, brain uptake of ( R )-[ 11 C]verapamil was low in all regions investigated in control and post-status epilepticus rats. After administration of 3 mg/kg tariquidar, which inhibits P-glycoprotein only partially, we observed increased regional differentiation in brain activity uptake in post-status epilepticus versus control rats, which diminished after maximal P-glycoprotein inhibition. Regional increases in the efflux rate constant k 2 , but not in distribution volume V T or influx rate constant K 1 , correlated significantly with increases in P-glycoprotein expression measured by immunohistochemistry. This imaging protocol proves to be suitable to detect seizure-induced regional changes in P-glycoprotein activity and is readily applicable to humans, with the aim to detect relevant mechanisms of pharmacoresistance in epilepsy in vivo .

Biallelic mutations in the gene encoding HCLS-associated protein X-1 (HAX1) cause autosomal recessive severe congenital neutropenia (SCN). Some of these patients have neurological abnormalities including developmental delay, cognitive impairment, and/or epilepsy. Recent genotype-phenotype studies have shown that mutations in HAX1 affecting transcripts A (NM_006118.3) and B (NM_001018837.1) cause the phenotype of SCN with neurological impairment, while mutations affecting isoform A but not B lead to SCN without neurological aberrations. In this study, we identified a consanguineous family with two patients suffering from SCN and neurological disease caused by a novel, homozygous genomic deletion including exons 4-7 of the HAX1 gene. Quantitative MRI analyses showed generalized alterations in cerebral proton density in both of the patients, as well as in an additional unrelated patient with another HAX1 mutation (Arg86X) known to be associated with neurological manifestations. This study provides first in vivo evidence of aberrant neuroimaging findings associated with HAX1 deficiency in SCN patients.

Overactivity of the multidrug efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) is believed to play an important role in resistance to central nervous system drug treatment. (R)-[(11)C]verapamil (VPM) PET can be used to measure the function of P-gp at the BBB, but low brain uptake of VPM hampers the mapping of regional differences in cerebral P-gp function and expression. The aim of this study was to evaluate the dose-response relationship of two potent P-gp inhibitors and to investigate if increased brain uptake of VPM mediated by P-gp inhibition can be used to assess regional differences in P-gp activity.Two groups of Sprague-Dawley rats (n = 12) underwent single VPM PET scans at 120 min after administration of different doses of the P-gp inhibitors tariquidar and elacridar. In an additional six rats, paired VPM PET scans were performed before and after administration of 3 mg/kg tariquidar.Inhibitor administration resulted in an up to 11-fold increase in VPM brain distribution volumes (DV) with half-maximum effective dose (ED(50)) values of 3.0 +/- 0.2 and 1.2 +/- 0.1 mg/kg for tariquidar and elacridar, respectively. In paired PET scans, 3 mg/kg tariquidar resulted in regionally different enhancement of brain activity distribution, with lowest DV in cerebellum and highest DV in thalamus.Our data show that tariquidar and elacridar are able to increase VPM brain distribution in rat brain up to 11-fold over baseline at maximum effective doses, with elacridar being about three times more potent than tariquidar. Regional differences in tariquidar-induced modulation of VPM brain uptake point to regional differences in cerebral P-gp function and expression in rat brain.

Optic neuritis (ON) and any other early manifestation of multiple sclerosis (MS) are referred to as clinically isolated syndrome (CIS) as long as MS is suspected. In this prospective study we aimed to determine whether diffusion tensor imaging (DTI) could quantify structural changes in patients with early MS. A total of 24 patients and 15 control subjects were prospectively followed by clinical examinations and MRI. the main inclusion criterion was presentation with ON. Patients underwent serial MRI scans: MRI1 (baseline, n=24), MRI2 (mean 6.6 months, n=24), MRI3 (mean 13.0 months, n=14), MRI4 (mean 39.4 months, n=5). Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were derived from DTI. Four regions of interest (ROIs) were defined in normal-appearing white matter (NAWM). In the temporal course FA decreased in the genu of the callosal body (GCC) from MRI1 to MRI4 (P=0.005) and in the splenium of the callosal body (SCC) (P=0.006). Patients already had lower FA values in the SCC (P

BACKGROUND AND PURPOSE: Development of callosal fibers is important for psychomotor and cognitive functions. We hypothesized that brain maturation changes are detectable beyond 2 years of age by using diffusion tensor imaging (DTI) of the corpus callosum (CC). MATERIALS AND METHODS: T2 and fractional anisotropy (FA) maps of the brain of 55 healthy subjects between 0.2 and 39 years of age were obtained. Quantitative T2 and FA values were measured at the genu and splenium of the CC (gCC and sCC). Fiber tracking, volumetric determination, and the fiber density calculations of the CC were related to age. A paired t test was used for significant differences between the values at the gCC and sCC. RESULTS: T2 relaxation times at gCC and sCC decrease fast in the first months of life and very little after 2 years of age. The FAgCC increases until 5 years of age and remains nearly constant thereafter; it showed a significant increase from 0 to 2 years versus 2–5 years, whereas there was no difference in the other age groups. FAsCC values showed no significant changes after 2 years of age. The fiber density of the CC shows a tendency of inverse age dependence from childhood to adulthood. CONCLUSION: Rapid ongoing changes in brain maturation (increase in FAgCC) are detectable until 5 years of age. DTI reveals more information about brain maturation than T2 relaxometry.

A feasibility study of an echo-planar spectroscopic imaging (EPSI) using a short echo time (TE) that trades off sensitivity, compared with other short-TE methods, to achieve whole brain coverage using inversion recovery and spatial oversampling to control lipid bleeding.Twenty subjects were scanned to examine intersubject variance. One subject was scanned five times to examine intrasubject reproducibility. Data were analyzed to determine coefficients of variance (COV) and intraclass correlation coefficient (ICC) for N-acetylaspartate (NAA), total creatine (tCr), total choline (tCho), glutamine/glutamate (Glx), and myo-inositol (mI). Regional metabolite concentrations were derived by using multi-voxel analysis based on lobar-level anatomic regions.For whole-brain mean values, the intrasubject COVs were 14%, 15%, and 20% for NAA, tCr, and tCho, respectively, and 31% for Glx and mI. The intersubject COVs were up to 6% higher. For regional distributions, the intrasubject COVs were ≤ 5% for NAA, tCr, and tCho; ≤ 9% for Glx; and ≤15% for mI, with about 6% higher intersubject COVs. The ICCs of 5 metabolites were ≥ 0.7, indicating the reliability of the measurements.The present EPSI method enables estimation of the whole-brain metabolite distributions, including Glx and mI with small voxel size, and a reasonable scan time and reproducibility.

Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma (PCNSL). Clinically, the disease typically presents with a rapidly progressive dementia and unsteadiness of gait. Its presentation on cerebral MRI, which is characterised by diffuse leukoencephalopathy without contrast enhancement, often causes diagnostic confusion1 with suspected diagnoses ranging from Binswanger’s disease to leukoencephalopathy or encephalomyelitis. Here we report a patient with subacute dementia and diffuse bilateral white matter changes in the cerebral hemispheres and additional involvement of the brainstem, basal ganglia and thalamus on MRI. Initially, she was considered to suffer from an autoimmune encephalitis, transiently responded to immunosuppression but then developed multiple solid appearing cerebral lymphomas. This 65-year-old woman had a history of insidious personality changes and forgetfulness of several months. Shortly before admission she developed double vision. Neurological examination revealed bilateral sixth nerve palsy. Neuropsychological examination showed mild dementia. CSF examination showed an increased protein level (931 mg/l; normal 150–400) and cell count (18/μl; normal