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Purpose: Lack of methods for repeated assessment of tumor pO(2) limits the ability to test and optimize hypoxia-modifying procedures being developed for clinical applications. We report repeated measurements of orthotopic F98 tumor pO(2) and relate this to the effect of carbogen inhalation on tumor growth when combined with hypofractionated radiotherapy.Methods and Materials: Electron paramagnetic resonance (EPR) oximetry was used for repeated measurements of tumor and contralateral brain pO(2) in rats during 30% O(2) and carbogen inhalation for 5 consecutive days. The T(1)-enhanced volumes and diffusion coefficients of the tumors were assessed by magnetic resonance imaging (MRI). The tumors were irradiated with 9.3 Gy x 4 fractions in rats breathing 30% O(2) or carbogen to determine the effect on tumor growth.Results: The pretreatment F98 tumor pO(2) varied between 8 and 16 mmHg, while the contralateral brain had 41 to 45 mmHg pO(2) during repeated measurements. Carbogen breathing led to a significant increase in tumor and contralateral brain pO(2); however, this effect declined over days. Irradiation of the tumors in rats breathing carbogen resulted in a significant decrease in tumor growth and an increase in the diffusion coefficient measured by MRI.Conclusions: The results provide quantitative measurements of the effect of carbogen inhalation on intracerebral tumor pO(2) and its effect on therapeutic outcome. Such direct repeated pO(2) measurements by EPR oximetry can provide temporal information that could be used to improve therapeutic outcome by scheduling doses at times of improved tumor oxygenation. EPR oximetry is currently being tested for clinical applications. [ABSTRACT FROM AUTHOR]

Understanding the effects of white matter (WM) axon fibre microstructure on T1 relaxation is important for neuroimaging. Here, we have studied the interrelationship between T1 and axon fibre configurations at 3T and 7T. T1 and S0 (=signal intensity at zero TI) were computed from MP2RAGE images acquired with six inversion recovery times. Multishell diffusion MRI images were analysed for fractional anisotropy (FA); MD; V1; the volume fractions for the first (f 1 ), second (f 2 ) and third (f 3 ) fibre configuration; and fibre density cross-section images for the first (fdc 1 ), second (fdc 2 ) and third (fdc 3 ) fibres. T1 values were plotted as a function of FA, f 1 , f 2 , f 3 , fdc 1 , fdc 2 and fdc 3 to examine interrelationships between the longitudinal relaxation and the diffusion MRI microstructural measures. T1 values decreased with increasing FA, f 1 and f 2 in a nonlinear fashion. At low FA values (from 0.2 to 0.4), a steep shortening of T1 was followed by a shallow shortening by 6%-10% at both fields. The steep shortening was associated with decreasing S0 and MD. T1 also decreased with increasing fdc 1 values in a nonlinear fashion. Instead, only a small T1 change as a function of either f 3 or fdc 3 was observed. In WM areas selected by fdc 1 only masks, T1 was shorter than in those with fdc 2 /fdc 3 . In WM areas with high single fibre populations, as delineated by f 1 /fdc 1 masks, T1 was shorter than in tissue with high complex fibre configurations, as segmented by f 2 /fdc 2 or f 3 /fdc 3 masks. T1 differences between these WM areas are attributable to combined effects by T1 anisotropy and lowered FA. The current data show strong interrelationships between T1, axon fibre configuration and orientation in healthy WM. It is concluded that diffusion MRI microstructural measures are essential in the effort to interpret quantitative T1 images in terms of tissue state in health and disease., (© 2024 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Purpose: Recent studies indicate that T 1 in white matter (WM) is influenced by fiber orientation in B 0 . The purpose of the study was to investigate the interrelationships between axon fiber orientation in corpus callosum (CC) and T 1 relaxation time in humans in vivo as well as in rat brain ex vivo., Methods: Volunteers were scanned for relaxometric and diffusion MRI at 3 T and 7 T. Angular T 1 plots from WM were computed using fractional anisotropy and fiber-to-field-angle maps. T 1 and fiber-to-field angle were measured in five sections of CC to estimate the effects of inherently varying fiber orientations on T 1 within the same tracts in vivo. Ex vivo rat-brain preparation encompassing posterior CC was rotated in B 0 and T 1 , and diffusion MRI images acquired at 9.4 T. T 1 angular plots were determined at several rotation angles in B 0 ., Results: Angular T 1 plots from global WM provided reference for estimated fiber orientation-linked T 1 changes within CC. In anterior midbody of CC in vivo, where small axons are dominantly present, a shift in axon orientation is accompanied by a change in T 1 , matching that estimated from WM T 1 data. In CC, where large and giant axons are numerous, the measured T 1 change is about 2-fold greater than the estimated one. Ex vivo rotation of the same midsagittal CC region of interest produced angular T 1 plots at 9.4 T, matching those observed at 7 T in vivo., Conclusion: These data causally link axon fiber orientation in B 0 to the T 1 relaxation anisotropy in WM., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

A high degree of structural order by white matter (WM) fibre tracts creates a physicochemical environment where water relaxations are rendered anisotropic. Recently, angularly dependent longitudinal relaxation has been reported in human WM. We have characterised interrelationships between T1 relaxation and diffusion MRI microstructural indices at 3 and 7 T. Eleven volunteers consented to participate in the study. Multishell diffusion MR images were acquired with b-values of 0/1500/3000 and 0/1000/2000 s/mm 2 at 1.5 and 1.05 mm 3 isotropic resolutions at 3 and 7 T, respectively. DTIFIT was used to compute DTI indices; the fibre-to-field angle (θ FB ) maps were obtained using the principal eigenvector images. The orientations and volume fractions of multiple fibre populations were estimated using BedpostX in FSL, and the orientation dispersion index (ODI) was estimated using the NODDI protocol. MP2RAGE was used to acquire images for T1 maps at 1.0 and 0.9 mm 3 isotropic resolutions at 3 and 7 T, respectively. At 3 T, T1 as a function of θ FB in WM with high fractional anisotropy and one-fibre orientation volume fraction or low ODI shows a broad peak centred at 50 o , but a flat baseline at 0 o and 90 o . The broad peak amounted up to 7% of the mean T1. At 7 T, the broad peak appeared at 40 o and T1 in fibres running parallel to B0 was longer by up to 75 ms (8.3% of the mean T1) than in those perpendicular to the field. The peak at 40 o was approximately 5% of mean T1 (i.e., proportionally smaller than that at 54 o at 3 T). The data demonstrate T1 anisotropy in WM with high microstructural order at both fields. The angular patterns are indicative of the B0-dependency of T1 anisotropy. Thus myelinated WM fibres influence T1 contrast both by acting as a T1 contrast agent and rendering T1 dependent on fibre orientation with B0., (© 2022 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

A better understanding of early brain changes that precede loss of independence in diseases like Alzheimer's disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative MRI measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n = 49) compared to healthy older controls (n = 99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in CA1-3 and entorhinal cortex and volume of entorhinal cortex showed some ability to predict cognitive decline, where absolute T2 could not, however further studies are required to verify this result. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative diseases and the study of brain-behaviour relationships., Competing Interests: Declaration of Competing Interest We declare that none of the authors have competing financial or non-financial interests., (Copyright © 2021. Published by Elsevier Inc.)

Background: Here, we address a pivotal factor in Alzheimer's prevention-identifying those at risk early, when dementia can still be avoided. Recent research highlights an accelerated forgetting phenotype as a risk factor for Alzheimer's disease. We hypothesized that delayed recall over 4 weeks would predict cognitive decline over 1 year better than 30-min delayed recall, the current gold standard for detecting episodic memory problems which could be an early clinical manifestation of incipient Alzheimer's disease. We also expected hippocampal subfield volumes to improve predictive accuracy., Methods: Forty-six cognitively healthy older people (mean age 70.7 ± 7.97, 21/46 female), recruited from databases such as Join Dementia Research, or a local database of volunteers, performed 3 memory tasks on which delayed recall was tested after 30 min and 4 weeks, as well as Addenbrooke's Cognitive Examination III (ACE-III) and CANTAB Paired Associates Learning. Medial temporal lobe subregion volumes were automatically measured using high-resolution 3T MRI. The ACE-III was repeated after 12 months to assess the change in cognitive ability. We used univariate linear regressions and ROC curves to assess the ability of tests of delayed recall to predict cognitive decline on ACE-III over the 12 months., Results: Fifteen of the 46 participants declined over the year (≥ 3 points lost on ACE-III). Four-week verbal memory predicted cognitive decline in healthy older people better than clinical gold standard memory tests and hippocampal MRI. The best single-test predictor of cognitive decline was the 4-week delayed recall on the world list (R 2  = .123, p = .018, β = .418). Combined with hippocampal subfield volumetry, 4-week verbal recall identifies those at risk of cognitive decline with 93% sensitivity and 86% specificity (AUC = .918, p < .0001)., Conclusions: We show that a test of accelerated long-term forgetting over 4 weeks can predict cognitive decline in healthy older people where traditional tests of delayed recall cannot. Accelerated long-term forgetting is a sensitive, easy-to-test predictor of cognitive decline in healthy older people. Used alone or with hippocampal MRI, accelerated forgetting probes functionally relevant Alzheimer's-related change. Accelerated forgetting will identify early-stage impairment, helping to target more invasive and expensive molecular biomarker testing.

Background: T 2 relaxation-based magnetic resonance imaging (MRI) signals may provide onset time for acute ischemic strokes with an unknown onset. The ability of visual and quantitative MRI-based methods in a cohort of hyperacute ischemic stroke patients was studied., Methods: A total of 35 patients underwent 3T (3 Tesla) MRI (<9-hour symptom onset). Diffusion-weighted (DWI), apparent diffusion coefficient (ADC), T 1 -weighted (T 1 w), T 2 -weighted (T 2 w), and T 2 relaxation time (T 2 ) images were acquired. T 2 -weighted fluid attenuation inversion recovery (FLAIR) images were acquired for 17 of these patients. Image intensity ratios of the average intensities in ischemic and non-ischemic reference regions were calculated for ADC, DWI, T 2 w, T 2 relaxation, and FLAIR images, and optimal image intensity ratio cut-offs were determined. DWI and FLAIR images were assessed visually for DWI/FLAIR mismatch., Results: The T 2 relaxation time image intensity ratio was the only parameter with significant correlation with stroke duration ( r  = 0.49, P  = .003), an area under the receiver operating characteristic curve (AUC = 0.77, P  < .0001), and an optimal cut-off (T 2 ratio = 1.072) that accurately identified patients within the 4.5-hour thrombolysis treatment window with sensitivity of 0.74 and specificity of 0.74. In the patients with the additional FLAIR, areas under the precision-recall-gain curve (AUPRG) and F 1 scores showed that the T 2 relaxation time ratio (AUPRG = 0.60, F 1  = 0.73) performed considerably better than the FLAIR ratio (AUPRG = 0.39, F 1  = 0.57) and the visual DWI/FLAIR mismatch (F 1  = 0.25)., Conclusions: Quantitative T 2 relaxation time is the preferred MRI parameter in the assessment of patients with unknown onset for treatment stratification., Competing Interests: Declaration of Conflicting Interests:The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Early Alzheimer's disease (AD) diagnosis is vital for development of disease-modifying therapies. Prior to significant brain tissue atrophy, several microstructural changes take place as a result of Alzheimer's pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death. T2 relaxation time, a quantitative MRI measure, is sensitive to these changes and may be a useful non-invasive, early marker of tissue integrity which could predict conversion to dementia. We propose that different microstructural changes affect T2 in opposing ways, such that average 'midpoint' measures of T2 are less sensitive than measuring distribution width (heterogeneity). T2 heterogeneity in the brain may present a sensitive early marker of AD pathology., Methods: In this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a clinical diagnosis of AD. All participants underwent structural MRI including a multi-echo sequence for quantitative T2 assessment. Cognitive change over 1 year was assessed in 20 participants with MCI. T2 distributions were modelled in the hippocampus and thalamus using log-logistic distribution giving measures of log-median value (midpoint; T2μ) and distribution width (heterogeneity; T2σ)., Results: We show an increase in T2 heterogeneity (T2σ; p < .0001) in MCI compared to healthy controls, which was not seen with midpoint (T2μ; p = .149) in the hippocampus and thalamus. Hippocampal T2 heterogeneity predicted cognitive decline over 1 year in MCI participants (p = .018), but midpoint (p = .132) and volume (p = .315) did not. Age affects T2, but the effects described here are significant even after correcting for age., Conclusions: We show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in MCI and predict cognitive decline over a year. We describe a new model that considers the competing effects of factors that both increase and decrease T2. These two opposing forces suggest that previous conclusions based on T2 midpoint may have obscured the true potential of T2 as a marker of subtle neuropathology. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of conditions such as AD.

Proton MRS ( 1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B 0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use., (© 2019 International Society for Magnetic Resonance in Medicine.)

Background and Objective: In hyperacute ischaemic stroke, T2 of cerebral water increases with time. Quantifying this change may be informative of the extent of tissue damage and onset time. Our objective was to develop a user-unbiased method to measure the effect of cerebral ischaemia on T2 to study stroke onset time-dependency in human acute stroke lesions., Methods: Six rats were subjected to permanent middle cerebral occlusion to induce focal ischaemia, and a consecutive cohort of acute stroke patients (n = 38) were recruited within 9 hours from symptom onset. T1-weighted structural, T2 relaxometry, and diffusion MRI for apparent diffusion coefficient (ADC) were acquired. Ischaemic lesions were defined as regions of lowered ADC. The median T2 difference (ΔT2) between lesion and contralateral non-ischaemic control region was determined by the newly-developed spherical reference method, and data compared to that obtained by the mirror reference method. Linear regressions and receiver operating characteristics (ROC) were compared between the two methods., Results: ΔT2 increases linearly in rat brain ischaemia by 1.9 ± 0.8 ms/h during the first 6 hours, as determined by the spherical reference method. In patients, ΔT2 linearly increases by 1.6 ± 1.4 and 1.9 ± 0.9 ms/h in the lesion, as determined by the mirror reference and spherical reference method, respectively. ROC analyses produced areas under the curve of 0.83 and 0.71 for the spherical and mirror reference methods, respectively., Conclusions: Data from the spherical reference method showed that the median T2 increase in the ischaemic lesion is correlated with stroke onset time in a rat as well as in a human patient cohort, opening the possibility of using the approach as a timing tool in clinics.

The apparent diffusion coefficient (ADC) of cerebral water, as measured by diffusion MRI, rapidly decreases in ischaemia, highlighting a lesion in acute stroke patients. The MRI T 2 relaxation time changes in ischaemic brain such that T 2 in ADC lesions may be informative of the extent of tissue damage, potentially aiding in stratification for treatment. We have developed a novel user-unbiased method of determining the changes in T 2 in ADC lesions as a function of clinical symptom duration based on voxel-wise referencing to a contralateral brain volume. The spherical reference method calculates the most probable pre-ischaemic T 2 on a voxel-wise basis, making use of features of the contralateral hemisphere presumed to be largely unaffected. We studied whether T 2 changes in the two main cerebral tissue types, i.e. in grey matter (GM) and white matter (WM), would differ in stroke. Thirty-eight acute stroke patients were accrued within 9 h of symptom onset and scanned at 3 T for 3D T 1 -weighted, multi b-value diffusion and multi-echo spin echo MRI for tissue type segmentation, quantitative ADC and absolute T 2 images, respectively. T 2 changes measured by the spherical reference method were 1.94  ±  0.61, 1.50  ±  0.52 and 1.40  ±  0.54 ms h -1 in the whole, GM, and WM lesions, respectively. Thus, T 2 time courses were comparable between GM and WM independent of brain tissue type involved. We demonstrate that T 2 changes in ADC-delineated lesions can be quantified in the clinical setting in a user unbiased manner and that T 2 change correlated with symptom onset time, opening the possibility of using the approach as a tool to assess severity of tissue damage in the clinical setting.

The overall survival for patients with primary glioblastoma is very poor. Glioblastoma contains a subpopulation of glioma stem cells (GSC) that are responsible for tumour initiation, treatment resistance and recurrence. PPARα is a transcription factor involved in the control of lipid, carbohydrate and amino acid metabolism. We have recently shown that PPARα gene and protein expression is increased in glioblastoma and has independent clinical prognostic significance in multivariate analyses. In this work, we report that PPARα is overexpressed in GSC compared to foetal neural stem cells. To investigate the role of PPARα in GSC, we knocked down its expression using lentiviral transduction with short hairpin RNA (shRNA). Transduced GSC were tagged with luciferase and stereotactically xenografted into the striatum of NOD-SCID mice. Bioluminescent and magnetic resonance imaging showed that knockdown (KD) of PPARα reduced the tumourigenicity of GSC in vivo. PPARα-expressing control GSC xenografts formed invasive histological phenocopies of human glioblastoma, whereas PPARα KD GSC xenografts failed to establish viable intracranial tumours. PPARα KD GSC showed significantly reduced proliferative capacity and clonogenic potential in vitro with an increase in cellular senescence. In addition, PPARα KD resulted in significant downregulation of the stem cell factors c-Myc, nestin and SOX2. This was accompanied by downregulation of the PPARα-target genes and key regulators of fatty acid oxygenation ACOX1 and CPT1A, with no compensatory increase in glycolytic flux. These data establish the aberrant overexpression of PPARα in GSC and demonstrate that this expression functions as an important regulator of tumourigenesis, linking self-renewal and the malignant phenotype in this aggressive cancer stem cell subpopulation. We conclude that targeting GSC PPARα expression may be a therapeutically beneficial strategy with translational potential as an adjuvant treatment. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Background: Quantitative T2 and diffusion MRI indices inform about tissue state and microstructure, both of which may be affected by pathology before tissue atrophy., Purpose: To evaluate the capability of both volumetric and quantitative MRI (qMRI) of the hippocampus and entorhinal cortex (EC) for classification of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease dementia (ADD)., Study Type: Retrospective cross-sectional study., Population: Consecutive cohorts of healthy age-matched controls (n = 62), aMCI patients (n = 25), and ADD patients (n = 14)., Field Strength/sequence: 3T using T1-weighted imaging, T2-weighted imaging, T2 relaxometry and diffusion tensor imaging (DTI)., Assessment: Montreal Cognitive Assessment and paired associate learning tests for cognitive state. Hippocampal subfield volumes by the automated segmentation of hippocampal subfields system from structural brain images. T2 relaxation time and DTI indices quantified for hippocampal subfields. The fraction of voxels with high T2 values (>20 ms above subfield median) was calculated and regionalized for hippocampus and EC., Statistical Tests: Support vector machine and receiver operating characteristic analyses from cognitive and MRI data., Results: qMRI classified aMCI and ADD with excellent sensitivity (79.0% and 94.5%, respectively) and specificity (85.6% and 86.1%, respectively), superior to volumes alone (70.0% and 84.5% for respective sensitivities; 82.2 and 91.1 for respective specificities) and similar to cognitive tests (61.7% and 87.5% for respective sensitivities; 88.2% and 90.7% for respective specificities). Regions of high T2 are dispersed throughout each hippocampal subfield in aMCI and ADD with higher concentration than controls, and was most pronounced in the EC. No other individual qMRI marker than EC volume can separate aMCI from ADD, however. DATA CONCLUSION: qMRI markers of hippocampal and entorhinal tissue states are sensitive and specific classifiers of aMCI and ADD. They may serve as markers of a neurodegenerative state preceding volume loss., Level of Evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:445-455., (© 2018 International Society for Magnetic Resonance in Medicine.)

Background and Purpose: Incomplete hippocampal inversion (IHI) is an atypical anatomical pattern presented by the hippocampus. It is associated with several neuropathological conditions and is thought to be a factor of susceptibility to hippocampal sclerosis and loss of volume. The volume loss of hippocampus is an inevitable consequence of aging, and when accelerated it is commonly considered an imaging biomarker of Alzheimer's disease dementia., Methods: We have studied the relationship between IHI and hippocampal subfield volumes in a cohort of 60 healthy participants of 49-87 years of age. The presence and severity of IHI and hippocampal subfield volumes were quantified from T2 magnetic resonance (MR) images acquired at 3T., Results: It was found that IHI presented in 23.3% of participants. Right unilateral IHI was rare (two cases, 3.3%) in comparison to left unilateral IHI (nine cases, 15%), with three (5%) of participants showing bilateral IHI. No significant relationships between the whole hippocampal volumes and IHI were observed. Instead, significant relationships between the volumes of the left and right cornu ammonis subfield-1 (CA1) and IHI scores were evident., Conclusions: The rates of IHI prevalence in the current cohort are similar to those previously reported in healthy cohorts. The IHI severity is related to hippocampal subfield volumes, most notably the CA1, which is a novel finding with potential implications in research on aging and dementia., (Copyright © 2018 by the American Society of Neuroimaging.)

Background and Purpose: Preterm birth is associated with worse neurodevelopmental outcome, but brain maturation in preterm infants is poorly characterized with standard methods. We evaluated white matter (WM) of infant brains at term-equivalent age, as a function of gestational age at birth, using multimodal magnetic resonance imaging (MRI)., Methods: Infants born very preterm (<32 weeks gestation) and late preterm (33-36 weeks gestation) were scanned at 3 T at term-equivalent age using diffusion tensor imaging (DTI) and T2 relaxometry. MRI data were analyzed using tract-based spatial statistics, and anisotropy of T2 relaxation was also determined. Principal component analysis and linear discriminant analysis were applied to seek the variables best distinguishing very preterm and late preterm groups., Results: Across widespread regions of WM, T2 is longer in very preterm infants than in late preterm ones. These effects are more prevalent in regions of WM that myelinate earlier and faster. Similar effects are obtained from DTI, showing that fractional anisotropy (FA) is lower and radial diffusivity higher in the very preterm group, with a bias toward earlier myelinating regions. Discriminant analysis shows high sensitivity and specificity of combined T2 relaxometry and DTI for the detection of a distinct WM development pathway in very preterm infants. T2 relaxation is anisotropic, depending on the angle between WM fiber and magnetic field, and this effect is modulated by FA., Conclusions: Combined T2 relaxometry and DTI characterizes specific patterns of retarded WM maturation, at term equivalent age, in infants born very preterm relative to late preterm., (Copyright © 2017 by the American Society of Neuroimaging.)

Background and Objective: Multiple factors including chemical composition and microstructure influence relaxivity of tissue water in vivo. We have quantified T1 in the human white mater (WM) together with diffusion tensor imaging to study a possible relationship between water T1, diffusional fractional anisotropy (FA) and fibre-to-field angle., Methods: An inversion recovery (IR) pulse sequence with 6 inversion times for T1 and a multi-band diffusion tensor sequence with 60 diffusion sensitizing gradient directions for FA and the fibre-to-field angle θ (between the principal direction of diffusion and B 0 ) were used at 3 Tesla in 40 healthy subjects. T1 was assessed using the method previously applied to anisotropy of coherence lifetime to provide a heuristic demonstration as a surface plot of T1 as a function of FA and the angle θ., Results: Our data show that in the WM voxels with FA > 0.3 T1 becomes longer (i.e. 1/T1 = R1 slower) when fibre-to-field angle is 50-60°, approximating the magic angle of 54.7°. The longer T1 around the magic angle was found in a number of WM tracts independent of anatomy. S0 signal intensity, computed from IR fits, mirrored that of T1 being greater in the WM voxels when the fibre-to-field angle was 50-60°., Conclusions: The current data point to fibre-to-field-angle dependent T1 relaxation in WM as an indication of effects of microstructure on the longitudinal relaxation of water.

Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to underpin object/event recognition. Despite huge motivation to treat age-related human memory disorders, interaction between human CA3 and dentate subfields is difficult to investigate due to small size and proximity. We tested the hypothesis that human dentate gyrus is critical for pattern separation, whereas, CA3 underpins identical object recognition. Using 3 T MR hippocampal subfield volumetry combined with a behavioural pattern separation task, we demonstrate that dentate gyrus volume predicts accuracy and response time during behavioural pattern separation whereas CA3 predicts performance in object recognition memory. Critically, human dentate gyrus volume decreases with age whereas CA3 volume is age-independent. Further, decreased dentate gyrus volume, and no other subfield volume, mediates adverse effects of aging on memory. Thus, we demonstrate distinct roles for CA3 and dentate gyrus in human memory and uncover the variegated effects of human ageing across hippocampal regions. Accurate pinpointing of focal memory-related deficits will allow future targeted treatment for memory loss.

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T1 and T2 MRI relaxation times (qT1 and qT2) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemisphere increase with time from stroke onset. The time dependency of MRI relaxation time differences is heuristically described by a linear function and thus provides a simple estimate of stroke onset time. Additionally, the volumes of abnormal qT1 and qT2 within the ischemic lesion increase linearly with time providing a complementary method for stroke timing. A (semi)automated computer routine based on the quantified diffusion coefficient is presented to delineate acute ischemic stroke tissue in rat ischemia. This routine also determines hemispheric differences in qT1 and qT2 relaxation times and the location and volume of abnormal qT1 and qT2 voxels within the lesion. Uncertainties associated with onset time estimates of qT1 and qT2 MRI data vary from ± 25 min to ± 47 min for the first 5 hours of stroke. The most accurate onset time estimates can be obtained by quantifying the volume of overlapping abnormal qT1 and qT2 lesion volumes, termed 'V overlap ' (± 25 min) or by quantifying hemispheric differences in qT2 relaxation times only (± 28 min). Overall, qT2 derived parameters outperform those from qT1. The current MRI protocol is tested in the hyperacute phase of a permanent focal ischemia model, which may not be applicable to transient focal brain ischemia.

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T 1 and T 2 MRI relaxation times (qT 1 and qT 2 ) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemisphere increase with time from stroke onset. The time dependency of MRI relaxation time differences is heuristically described by a linear function and thus provides a simple estimate of stroke onset time. Additionally, the volumes of abnormal qT 1 and qT 2 within the ischemic lesion increase linearly with time providing a complementary method for stroke timing. A (semi)automated computer routine based on the quantified diffusion coefficient is presented to delineate acute ischemic stroke tissue in rat ischemia. This routine also determines hemispheric differences in qT 1 and qT 2 relaxation times and the location and volume of abnormal qT 1 and qT 2 voxels within the lesion. Uncertainties associated with onset time estimates of qT 1 and qT 2 MRI data vary from ± 25 min to ± 47 min for the first 5 hours of stroke. The most accurate onset time estimates can be obtained by quantifying the volume of overlapping abnormal qT 1 and qT 2 lesion volumes, termed 'V overlap ' (± 25 min) or by quantifying hemispheric differences in qT 2 relaxation times only (± 28 min). Overall, qT 2 derived parameters outperform those from qT 1 . The current MRI protocol is tested in the hyperacute phase of a permanent focal ischemia model, which may not be applicable to transient focal brain ischemia.

Background: Objective timing of stroke in emergency departments is expected to improve patient stratification. Magnetic resonance imaging (MRI) relaxations times, T 2 and T 1 ρ , in abnormal diffusion delineated ischaemic tissue were used as proxies of stroke time in a rat model., Methods: Both 'non-ischaemic reference'-dependent and -independent estimators were generated. Apparent diffusion coefficient (ADC), T 2 and T 1 ρ , were sequentially quantified for up to 6 hours of stroke in rats (n = 8) at 4.7T. The ischaemic lesion was identified as a contiguous collection of voxels with low ADC. T 2 and T 1 ρ in the ischaemic lesion and in the contralateral non-ischaemic brain tissue were determined. Differences in mean MRI relaxation times between ischaemic and non-ischaemic volumes were used to create reference-dependent estimator. For the reference-independent procedure, only the parameters associated with log-logistic fits to the T 2 and T 1 ρ distributions within the ADC-delineated lesions were used for the onset time estimation., Result: The reference-independent estimators from T 2 and T 1 ρ data provided stroke onset time with precisions of ±32 and ±27 minutes, respectively. The reference-dependent estimators yielded respective precisions of ±47 and ±54 minutes., Conclusions: A 'non-ischaemic anatomical reference'-independent estimator for stroke onset time from relaxometric MRI data is shown to yield greater timing precision than previously obtained through reference-dependent procedures.

Magnetic resonance imaging (MRI) provides an excellent means of studying tissue microstructure noninvasively since the microscopic tissue environment is imprinted on the MRI signal even at macroscopic voxel level. Mesoscopic variations in magnetic field, created by microstructure, influence the transverse relaxation time (T 2 ) in an orientation-dependent fashion (T 2  is anisotropic). However, predicting the effects of microstructure upon MRI observables is challenging and requires theoretical insight. We provide a formalism for calculating the effects upon T 2 of tissue microstructure, using a model of cylindrical magnetic field perturbers. In a cohort of clinically healthy adults, we show that the angular information in spin-echo T 2 is consistent with this model. We show that T 2 in brain white matter of nondemented volunteers follows a U-shaped trajectory with age, passing its minimum at an age of ∼30 but that this depends on the particular white matter tract. The anisotropy of T 2 also interacts with age and declines with increasing age. Late-myelinating white matter is more susceptible to age-related change than early-myelinating white matter, consistent with the retrogenesis hypothesis. T 2 mapping may therefore be incorporated into microstructural imaging., (Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to examine age-dependent changes in both T 1 -weighted and T 2 -weighted image contrasts and spin-echo T 2 relaxation time in the human brain during healthy ageing., Methods: A total of 37 participants between the ages of 49 and 87 years old were scanned with a 3 Tesla system, using T 1 -weighted, T 2 weighted and quantitative spin-echo T 2 imaging. Contrast between image intensities and T 2 values was calculated for various regions, including between individual hippocampal subfields., Results: The T 1 contrast-to-noise (CNR) and gray:white signal intensity ratio (GWR) did not change in the hippocampus, but it declined in the cingulate cortex with age. In contrast, T 2 CNR and GWR declined in both brain regions. T 2 relaxation time was almost constant in gray matter and most (but not all) hippocampal subfields, but increased substantially in white matter, pointing to an age effect on water relaxation in white matter., Conclusions: Changes in T 1 and T 2 MR characteristics influence the appearance of brain images in later life and should be considered in image analyses of aged subjects. It is speculated that alterations at the cell biology level, with concomitant alterations to the local magnetic environment, reduce dephasing and subsequently prolong spin-echo T 2 through reduced diffusion effects in later life., Competing Interests: The authors declare no conflicts of interest. Research involving human participants All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.

In MRI, the coherence lifetime T2 is sensitive to the magnetic environment imposed by tissue microstructure and biochemistry in vivo. Here we explore the possibility that the use of T2 relaxometry may provide information complementary to that provided by diffusion tensor imaging (DTI) in ageing of healthy controls (HC), Alzheimer's disease (AD) and mild cognitive impairment (MCI). T2 and diffusion MRI metrics were quantified in HC and patients with MCI and mild AD using multi-echo MRI and DTI. We used tract-based spatial statistics (TBSS) to evaluate quantitative MRI parameters in white matter (WM). A prolonged T2 in WM was associated with AD, and able to distinguish AD from MCI, and AD from HC. Shorter WM T2 was associated with better cognition and younger age in general. In no case was a reduction in T2 associated with poorer cognition. We also applied principal component analysis, showing that WM volume changes independently of  T2, MRI diffusion indices and cognitive performance indices. Our data add to the evidence that age-related and AD-related decline in cognition is in part attributable to WM tissue state, and much less to WM quantity. These observations suggest that WM is involved in AD pathology, and that T2 relaxometry is a potential imaging modality for detecting and characterising WM in cognitive decline and dementia.

In NMR or MRI of complex materials, including biological tissues and porous materials, magnetic susceptibility differences within the material result in local magnetic field inhomogeneities, even if the applied magnetic field is homogeneous. Mobile nuclear spins move though the inhomogeneous field, by translational diffusion and other mechanisms, resulting in decoherence of nuclear spin phase more rapidly than transverse relaxation alone. The objective of this paper is to simulate this diffusion-mediated decoherence and demonstrate that it may substantially reduce coherence lifetimes of nuclear spin phase, in an anisotropic fashion. We do so using a model of cylindrical pores within an otherwise homogeneous material, and calculate the resulting magnetic field inhomogeneities. Our simulations show that diffusion-mediated decoherence in a system of parallel cylindrical pores is anisotropic, with coherence lifetime minimised when the array of cylindrical pores is perpendicular to B0. We also show that this anisotropy of coherence lifetime is reduced if the orientations of cylindrical pores are disordered within the system. In addition we characterise the dependence on B0, the magnetic susceptibility of the cylindrical pores relative to the surroundings, the diffusion coefficient and cylinder wall thickness. Our findings may aid in the interpretation of NMR and MRI relaxation data., (Copyright © 2016. Published by Elsevier Inc.)

Background: Quantitative T2 relaxation magnetic resonance imaging allows estimation of stroke onset time., Aims: We aimed to examine the accuracy of quantitative T1 and quantitative T2 relaxation times alone and in combination to provide estimates of stroke onset time in a rat model of permanent focal cerebral ischemia and map the spatial distribution of elevated quantitative T1 and quantitative T2 to assess tissue status., Methods: Permanent middle cerebral artery occlusion was induced in Wistar rats. Animals were scanned at 9.4T for quantitative T1, quantitative T2, and Trace of Diffusion Tensor (Dav) up to 4 h post-middle cerebral artery occlusion. Time courses of differentials of quantitative T1 and quantitative T2 in ischemic and non-ischemic contralateral brain tissue (ΔT1, ΔT2) and volumes of tissue with elevated T1 and T2 relaxation times (f1, f2) were determined. TTC staining was used to highlight permanent ischemic damage., Results: ΔT1, ΔT2, f1, f2, and the volume of tissue with both elevated quantitative T1 and quantitative T2 (V(Overlap)) increased with time post-middle cerebral artery occlusion allowing stroke onset time to be estimated. V(Overlap) provided the most accurate estimate with an uncertainty of ±25 min. At all times-points regions with elevated relaxation times were smaller than areas with Dav defined ischemia., Conclusions: Stroke onset time can be determined by quantitative T1 and quantitative T2 relaxation times and tissue volumes. Combining quantitative T1 and quantitative T2 provides the most accurate estimate and potentially identifies irreversibly damaged brain tissue., (© 2016 World Stroke Organization.)

The objective of this study is to present a mathematical model which can describe the spatiotemporal progression of cerebral ischaemia and predict magnetic resonance observables including the apparent diffusion coefficient (ADC) of water and transverse relaxation time T2 This is motivated by the sensitivity of the ADC to the location of cerebral ischaemia and T2 to its time-course, and that it has thus far proven challenging to relate observations of changes in these MR parameters to stroke timing, which is of considerable importance in making treatment choices in clinics. Our mathematical model, called the cytotoxic oedema/dissociation (CED) model, is based on the transit of water from the extra- to the intra-cellular environment (cytotoxic oedema) and concomitant degradation of supramacromolecular and macromolecular structures (such as microtubules and the cytoskeleton). It explains experimental observations of ADC and T2, as well as identifying the rate of spread of effects of ischaemia through a tissue as a dominant system parameter. The model brings the direct extraction of the timing of ischaemic stroke from quantitative MRI closer to reality, as well as providing insight on ischaemia pathology by imaging in general. We anticipate that this may improve patient access to thrombolytic treatment as a future application., (© The Author(s) 2015.)

Recent pharmaceutical trials have demonstrated that slowing or reversing pathology in Alzheimer's disease is likely to be possible only in the earliest stages of disease, perhaps even before significant symptoms develop. Pathology in Alzheimer's disease accumulates for well over a decade before symptoms are detected giving a large potential window of opportunity for intervention. It is therefore important that imaging techniques detect subtle changes in brain tissue before significant macroscopic brain atrophy. Current diagnostic techniques often do not permit early diagnosis or are too expensive for routine clinical use. Magnetic Resonance Imaging (MRI) is the most versatile, affordable, and powerful imaging modality currently available, being able to deliver detailed analyses of anatomy, tissue volumes, and tissue state. In this mini-review, we consider how MRI might detect patients at risk of future dementia in the early stages of pathological change when symptoms are mild. We consider the contributions made by the various modalities of MRI (structural, diffusion, perfusion, relaxometry) in identifying not just atrophy (a late-stage AD symptom) but more subtle changes reflective of early dementia pathology. The sensitivity of MRI not just to gross anatomy but to the underlying "health" at the cellular (and even molecular) scales, makes it very well suited to this task.

Understanding how spatially remote brain regions interact to form functional brain networks, and how these develop during the neonatal period, provides fundamental insights into normal brain development, and how mechanisms of brain disorder and recovery may function in the immature brain. A key imaging tool in characterising functional brain networks is examination of T2*-weighted fMRI signal during rest (resting state fMRI, rs-fMRI). The majority of rs-fMRI studies have concentrated on slow signal fluctuations occurring at <0.1 Hz, even though neuronal rhythms, and haemodynamic responses to these fluctuate more rapidly, and there is emerging evidence for crucial information about functional brain connectivity occurring more rapidly than these limits. The characterisation of higher frequency components has been limited by the sampling frequency achievable with standard T2* echoplanar imaging (EPI) sequences. We describe patterns of neonatal functional brain network connectivity derived using accelerated T2*-weighted EPI MRI. We acquired whole brain rs-fMRI data, at subsecond sampling frequency, from preterm infants at term equivalent age and compared this to rs-fMRI data acquired with standard EPI acquisition protocol. We provide the first evidence that rapid rs-fMRI acquisition in neonates, and adoption of an extended frequency range for analysis, allows identification of a substantial proportion of signal power residing above 0.2 Hz. We thereby describe changes in brain connectivity associated with increasing maturity which are not evident using standard rs-fMRI protocols. Development of optimised neonatal fMRI protocols, including use of high speed acquisition sequences, is crucial for understanding the physiology and pathophysiology of the developing brain., (© 2015 Wiley Periodicals, Inc.)

One in four ischaemic stroke patients are ineligible for thrombolytic treatment due to unknown onset time. Quantification of absolute MR relaxation times and signal intensities are potential methods for estimating stroke duration. We compared the accuracy of these approaches and determined whether changes in relaxation times and signal intensities identify the same ischaemic tissue as diffusion MRI. Seven Wistar rats underwent permanent middle cerebral artery occlusion to induce focal ischaemia and were scanned at six time points. The trace of the diffusion tensor (DAV), T1ρ and T2 were acquired at 4.7 T. Results show relaxation times, and signal intensities of the MR relaxation parameters increase linearly with ischaemia duration (P<0.001). Using T1ρ and T2 relaxation times, an estimate of 4.5 h after occlusion has an uncertainty of ± 12 and ± 35 min, respectively, compared with over 50 min for signal intensities. In addition, we present a pixel-by-pixel method that simultaneously estimates stroke onset time and identifies potentially irreversible ischaemic tissue using absolute relaxation times. This method demonstrates signal intensity changes during ischaemia display an ambiguous pattern and highlights the possibility that diffusion MRI overestimates the true extent of irreversible ischaemia. In conclusion, quantification of absolute relaxation times at a single time point enables a more accurate estimation of stroke duration than signal intensities and provides more information about tissue status in ischaemia.

Ischaemia is a condition in which blood flow either drops to zero or proceeds at severely decreased levels that cannot supply sufficient oxidizable substrates to maintain energy metabolism in vivo. Brain, a highly oxidative organ, is particularly susceptible to ischaemia. Ischaemia leads to loss of consciousness in seconds and, if prolonged, permanent tissue damage is inevitable. Ischaemia primarily results in a collapse of cerebral energy state, followed by a series of subtle changes in anaerobic metabolism, ion and water homeostasis that eventually initiate destructive internal and external processes in brain tissue. (31)P and (1)H NMR spectroscopy were initially used to evaluate anaerobic metabolism in brain. However, since the early 1990s (1)H Magnetic Resonance Imaging (MRI), exploiting the nuclear magnetism of tissue water, has become the key method for assessment of ischaemic brain tissue. This article summarises multi-parametric (1)H MRI work that has exploited diffusion, relaxation and magnetisation transfer as 'contrasts' to image ischaemic brain in preclinical models for the first few hours, with a view to assessing evolution of ischaemia and tissue viability in a non-invasive manner., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units., (RSNA, 2014)

Purpose: To study vascular responsiveness to hypoxia and hypercarbia together with vessel size index (VSI) in a 9L rat glioma (n = 11) using multimodal MRI., Materials and Methods: VSI was determined using T2 and T2* MRI following AMI-227 contrast agent. Blood oxygenation level dependent (BOLD) signal response was determined using T2 EPI MRI, blood volume changes using AMI-227 and blood flow by means of continuous arterial spin labeling., Results: VSI in the cortex, tumor rim, and core of 2.2 ± 1.0, 18.2 ± 5.4, and 23.9 ± 14.7 μm, respectively, showing a larger average vessel size in glioma than in the brain parenchyma. BOLD and blood volume signal changes to hypoxia and hypercapnia were much more profound in the tumor rim than the core. Hypoxia led to rim BOLD signal change that was larger in amplitude and it attained the low value much faster than either core or brain cortex. The vasculature in the rim appears more responsive to respiratory challenges in terms of volume adaptation than the core. Blood flow values within the gliomas were much lower than in the contralateral brain. Neither hypercarbia nor hypoxia had an effect on the tumor blood flow., Conclusion: Vascular responses of 9L gliomas to respiratory challenge, in particular hypoxia, are heterogeneous between the core and rim zones, potentially offering a means to classify and separate intratumor tissues with differing hemodynamic characteristics., (Copyright © 2013 Wiley Periodicals, Inc.)

Cerebral ischemia alters the molecular dynamics and content of water in brain tissue, which is reflected in NMR relaxation, diffusion and magnetization transfer (MT) parameters. In this study, the behavior of two new MRI contrasts, Relaxation Along a Fictitious Field (RAFF) and Z-spectroscopy using Alternating-Phase Irradiation (ZAPI), were quantified together with conventional relaxation parameters (T1, T2 and T1ρ) and MT ratios in acute cerebral ischemia in rat. The right middle cerebral artery was permanently occluded and quantitative MRI data was acquired sequentially for the above parameters for up to 6 hours. The following conclusions were drawn: 1) Time-dependent changes in RAFF and T1ρ relaxation are not coupled to those in MT. 2) RAFF relaxation evolves more like transverse, rather than longitudinal relaxation. 3) MT measured with ZAPI is less sensitive to ischemia than conventional MT. 4) ZAPI data suggest alterations in the T2 distribution of macromolecules in acute cerebral ischemia. It was shown that both RAFF and ZAPI provide complementary MRI information from acute ischemic brain tissue. The presented multiparametric MRI data may aid in the assessment of brain tissue status early in ischemic stroke.

Increases in 1 H nuclear magnetic resonance spectroscopy (NMR) visible lipids are a well-documented sign of treatment response in cancers. Lipids in cytoplasmic lipid droplets (LDs) are the main contributors to the NMR lipid signals. Two human primitive neuroectodermal tumour cell lines with different sensitivities to cisplatin treatment were studied. Increases in NMR visible saturated and unsaturated lipids in cisplatin treated DAOY cells were associated with the accumulation of LDs prior to DNA fragmentation due to apoptosis. An increase in unsaturated fatty acids (UFAs) was detected in isolated LDs from DAOY cells, in contrast to a slight decrease in UFAs in lipid extracts from whole cells. Oleic acid and linoleic acid were identified as the accumulating UFAs in LDs by heteronuclear single quantum coherence spectroscopy (HSQC). 1 H NMR lipids in non-responding PFSK-1 cells were unchanged by exposure to 10 μM cisplatin. These findings support the potential of NMR detectable UFAs to serve as a non-invasive marker of tumour cell response to treatment.

Background: Brain tumours cause the highest mortality and morbidity rate of all childhood tumour groups and new methods are required to improve clinical management. (1)H magnetic resonance spectroscopy (MRS) allows non-invasive concentration measurements of small molecules present in tumour tissue, providing clinically useful imaging biomarkers. The primary aim of this study was to investigate whether MRS detectable molecules can predict the survival of paediatric brain tumour patients., Patients and Methods: Short echo time (30ms) single voxel (1)H MRS was performed on children attending Birmingham Children's Hospital with a suspected brain tumour and 115 patients were included in the survival analysis. Patients were followed-up for a median period of 35 months and Cox-Regression was used to establish the prognostic value of individual MRS detectable molecules. A multivariate model of survival was also investigated to improve prognostic power., Results: Lipids and scyllo-inositol predicted poor survival whilst glutamine and N-acetyl aspartate predicted improved survival (p<0.05). A multivariate model of survival based on three MRS biomarkers predicted survival with a similar accuracy to histologic grading (p<5e-5). A negative correlation between lipids and glutamine was found, suggesting a functional link between these molecules., Conclusions: MRS detectable biomolecules have been identified that predict survival of paediatric brain tumour patients across a range of tumour types. The evaluation of these biomarkers in large prospective studies of specific tumour types should be undertaken. The correlation between lipids and glutamine provides new insight into paediatric brain tumour metabolism that may present novel targets for therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Object: Cytoplasmic lipid droplets (LDs) are dynamic cellular organelles; their accumulation is associated with several cellular processes, such as cell proliferation, apoptosis and necrosis. (1)H Nuclear Magnetic Resonance (NMR) spectroscopy detects resonances from lipids present in cytoplasmic (LDs); an understanding of the relationship between LD characteristics and NMR lipid signals is important., Materials and Methods: In this study, five nervous system cancer cell lines were investigated. Nile red staining was used to measure the diameter of LDs. High-resolution magic angle spinning NMR (HR-MAS) was performed on harvested cell pellets to quantify the patterns of lipid signals., Results: LDs were present in all five cell lines with different morphology. An average LD diameter of approximately 0.2 μm was found in all cell types. Diameter of the largest LDs varied across the cell lines. The intensity of NMR lipid signals varied greatly between cell types, and a good correlation was found between total volume of LDs and the proton NMR lipid signal intensity at 0.9 and 1.3 ppm., Conclusion: The correlation implied that little NMR signal is detected from LDs of diameters less than approximately 0.34 μm, most likely due to restriction of rotational motion of the lipids.

Biomarkers of early response to treatment have the potential to improve cancer therapy by allowing treatment to be tailored to the individual. Alterations in lipids detected by in vivo MRS have been suggested as noninvasive biomarkers of cell stress and early indicators of cell death. An improved understanding of the relationship between MRS lipids and cell stress in vitro would aid in the translation of this technique into clinical use. Rat BT4C glioma cells were treated with 50 µ m cis-dichlorodiammineplatinum II (cisplatin), a commonly used chemotherapeutic agent, and harvested at several time points up to 72 h. High-resolution magic angle spinning (1) H MRS of cells was then performed on a 600-MHz NMR spectrometer. The metabolites were quantified using a time domain fitting method, TARQUIN. Increases were detected in saturated and polyunsaturated fatty acid resonances early during the exposure to cisplatin. The fatty acid CH(2) /CH(3) ratio was unaltered by treatment after allowing for contributions of macromolecules. Polyunsaturated fatty acids increased on treatment, with the group -CH=CH-CH(2) -CH=CH- accounting for all the unsaturated fatty acid signals. Transmission electron microscopy, in addition to Nile red and 4',6-diamino-2-phenylindole co-staining, revealed that the lipid increase was associated with cytoplasmic neutral lipid droplets. Small numbers of apoptotic and necrotic cells were detected by trypan blue, annexin V-fluorescein isothiocyanate-labelled flow cytometry and DNA laddering after up to 48 h of cisplatin exposure. Propidium iodide flow cytometry revealed that cells accumulated in the G1 stage of the cell growth cycle. In conclusion, an increase in the size of the lipid droplets is detected in morphologically viable cells during cisplatin exposure. (1) H MRS can detect lipid alterations during cell cycle arrest and progression of cell death, and has the potential to provide a noninvasive biomarker of treatment efficacy in vivo., (Copyright © 2012 John Wiley & Sons, Ltd.)

Pleural and peritoneal mesotheliomas (MMs) are chemoresistant tumors with no effective therapeutic strategies. The authors first injected multifunctional, acid-prepared mesoporous spheres (APMS), microparticles functionalized with tetraethylene glycol oligomers, intraperitoneally into rodents. Biodistribution of APMS was observed in major organs, peritoneal lavage fluid (PLF), and urine of normal mice and rats. After verification of increased mesothelin in human mesotheliomas injected into severe combined immunodeficient (SCID) mice, APMS were then functionalized with an antibody to mesothelin (APMS-MB) or bovine serum albumin (BSA), a nonspecific protein control, and tumor targeting was evaluated by inductively coupled plasma mass spectrometry and multifluorescence confocal microscopy. Some APMS were initially cleared via the urine over a 24 hr period, and small amounts were observed in liver, spleen, and kidneys at 24 hr and 6 days. Targeting with APMS-MB increased APMS uptake in mesenteric tumors at 6 days. Approximately 10% to 12% of the initially injected amount was observed in both spheroid and mesenteric MM at this time point. The data suggest that localized delivery of APMS-MB into the peritoneal cavity after encapsulation of drugs, DNA, or macromolecules is a novel therapeutic approach for MM and other tumors (ovarian and pancreatic) that overexpress mesothelin.

Purpose: To investigate how kainic acid-induced epileptiform activity is related to hemodynamic changes probed by blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI)., Methods: Epileptiform activity was induced with kainic acid (KA) (10 mg/kg, i.p.), and simultaneous fMRI at 7 Tesla, and deep electrode local field potential (LFP) recordings were performed from the right hippocampus in awake and medetomidine-sedated adult Wistar rats., Key Findings: Recurrent seizure activity induced by KA was detected in LFP both in medetomidine-sedated and awake rats, even though medetomidine sedation reduced the mean duration of individual seizures as compared to awake rats (33 ± 24 and 46 ± 34 s, respectively, mean ± SD p < 0.01). KA administration also triggered robust positive BOLD responses bilaterally in the hippocampus both in awake and medetomidine-sedated rats; however, in both animal groups some of the seizures detected in LFP recording did not cause detectable BOLD signal change., Significance: Our data suggest that medetomidine sedation can be used for simultaneous fMRI and electrophysiologic studies of normal and epileptic brain function, even though seizure duration after medetomidine administration was shorter than that in awake animals. The results also indicate that neuronal activity and BOLD response can become decoupled during recurrent kainic acid-induced seizures, which may have implications to interpretation of fMRI data obtained during prolonged epileptiform activity., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

(1)H nuclear magnetic resonance spectroscopy (NMR) resonances from lipids in tumours are associated with tumour grade and treatment response. The origin of these NMR signals is mainly considered to be cytoplasmic lipid droplets (LDs). Techniques exist for isolating LDs but little is known about their composition and its relationship to NMR signals. In this work, density-gradient ultracentrifugation was performed on homogenised human cancer cells to isolate LDs. (1)H NMR was performed on whole cells, isolated LDs and their extracts. Heteronuclear single quantum coherence spectroscopy (HSQC) and liquid chromatography mass spectroscopy (LC-MS) were performed on lipid extracts of LDs. Staining and microscopy were used to characterize isolated LDs. An excellent agreement in chemical shift and relative signal intensity was observed between lipid resonances in cells and isolated LD spectra supporting that NMR-visible lipids originate primarily from LDs. Isolated LDs showed high concentrations of unsaturated lipids, a oleic-to-linoleic acid ratio greater than two and a cholesteryl ester (ChE)-to-cholesterol (Ch) ratio close to unity. These ratios were several-fold greater than respective ratios in whole cells, demonstrating isolation is important to characterize LD composition. LDs contain a specific group of lipid species that are likely to contribute to the (1)H NMR spectrum of cells.