The role of gray and white matter segmentation in quantitative proton MR spectroscopic imaging

Since the brain's gray matter (GM) and white matter (WM) metabolite concentrations differ, their partial volumes can vary the voxel's ¹H MR spectroscopy (¹H‐MRS) signal, reducing sensitivity to changes. While single‐voxel ¹H‐MRS cannot differentiate between WM and GM signals, partial volume correction is feasible by MR spectroscopic imaging (MRSI) using segmentation of the MRI acquired for VOI placement. To determine the magnitude of this effect on metabolic quantification, we segmented a 1‐mm³ resolution MRI into GM, WM and CSF masks that were co‐registered with the MRSI grid to yield their partial volumes in approximately every 1 cm³ spectroscopic voxel. Each voxel then provided one equation with two unknowns: its i‐ metabolite's GM and WM concentrations C_i^GM, C_i^WM. With the voxels' GM and WM volumes as independent coefficients, the over‐determined system of equations was solved for the global averaged C_i^GM and C_i^WM. Trading off local concentration differences offers three advantages: (i) higher sensitivity due to combined data from many voxels; (ii) improved specificity to WM versus GM changes; and (iii) reduced susceptibility to partial volume effects. These improvements made no additional demands on the protocol, measurement time or hardware. Applying this approach to 18 volunteered 3D MRSI sets of 480 voxels each yielded N‐acetylaspartate, creatine, choline and myo‐inositol C_i^GM concentrations of 8.5 ± 0.7, 6.9 ± 0.6, 1.2 ± 0.2, 5.3 ± 0.6mM, respectively, and C_i^WM concentrations of 7.7 ± 0.6, 4.9 ± 0.5, 1.4 ± 0.1 and 4.4 ± 0.6mM, respectively. We showed that unaccounted voxel WM or GM partial volume can vary absolute quantification by 5–10% (more for ratios), which can often double the sample size required to establish statistical significance. Copyright © 2012 John Wiley & Sons, Ltd.     

Global brain metabolic quantification with whole‐head proton MRS at 3 T

Total N‐acetyl‐aspartate + N‐acetyl‐aspartate–glutamate (NAA), total creatine (Cr) and total choline (Cho) proton MRS (¹H–MRS) signals are often used as surrogate markers in diffuse neurological pathologies, but spatial coverage of this methodology is limited to 1%–65% of the brain. Here we wish to demonstrate that non‐localized, whole‐head (WH) ¹H–MRS captures just the brain's contribution to the Cho and Cr signals, ignoring all other compartments. Towards this end, 27 young healthy adults (18 men, 9 women), 29.9 ± 8.5 years old, were recruited and underwent T₁‐weighted MRI for tissue segmentation, non‐localizing, approximately 3 min WH ¹H–MRS (T_E/T_R/T_I = 5/10 1 /940 ms) and 30 min ¹H–MR spectroscopic imaging (MRSI) (T_E/T_R = 35/2100 ms) in a 360 cm³ volume of interest (VOI) at the brain's center. The VOI absolute NAA, Cr and Cho concentrations, 7.7 ± 0.5, 5.5 ± 0.4 and 1.3 ± 0.2 mM, were all within 10% of the WH: 8.6 ± 1.1, 6.0 ± 1.0 and 1.3 ± 0.2 mM. The mean NAA/Cr and NAA/Cho ratios in the WH were only slightly higher than the “brain‐only” VOI: 1.5 versus 1.4 (7%) and 6.6 versus 5.9 (11%); Cho/Cr were not different. The brain/WH volume ratio was 0.31 ± 0.03 (brain ≈ 30% of WH volume). Air‐tissue susceptibility‐driven local magnetic field changes going from the brain outwards showed sharp gradients of more than 100 Hz/cm (1 ppm/cm), explaining the skull's Cr and Cho signal losses through resonance shifts, line broadening and destructive interference. The similarity of non‐localized WH and localized VOI NAA, Cr and Cho concentrations and their ratios suggests that their signals originate predominantly from the brain. Therefore, the fast, comprehensive WH‐¹H‐MRS method may facilitate quantification of these metabolites, which are common surrogate markers in neurological disorders.     

Three‐dimensional echo planar spectroscopic imaging for differentiation of true progression from pseudoprogression in patients with glioblastoma

Accurate differentiation of true progression (TP) from pseudoprogression (PsP) in patients with glioblastomas (GBMs) is essential for planning adequate treatment and for estimating clinical outcome measures and future prognosis. The purpose of this study was to investigate the utility of three‐dimensional echo planar spectroscopic imaging (3D‐EPSI) in distinguishing TP from PsP in GBM patients. For this institutional review board approved and HIPAA compliant retrospective study, 27 patients with GBM demonstrating enhancing lesions within six months of completion of concurrent chemo‐radiation therapy were included. Of these, 18 were subsequently classified as TP and 9 as PsP based on histological features or follow‐up MRI studies. Parametric maps of choline/creatine (Cho/Cr) and choline/N‐acetylaspartate (Cho/NAA) were computed and co‐registered with post‐contrast T₁‐weighted and FLAIR images. All lesions were segmented into contrast enhancing (CER), immediate peritumoral (IPR), and distal peritumoral (DPR) regions. For each region, Cho/Cr and Cho/NAA ratios were normalized to corresponding metabolite ratios from contralateral normal parenchyma and compared between TP and PsP groups. Logistic regression analyses were performed to obtain the best model to distinguish TP from PsP. Significantly higher Cho/NAA was observed from CER (2.69 ± 1.00 versus 1.56 ± 0.51, p = 0.003), IPR (2.31 ± 0.92 versus 1.53 ± 0.56, p = 0.030), and DPR (1.80 ± 0.68 versus 1.19 ± 0.28, p = 0.035) regions in TP patients compared with those with PsP. Additionally, significantly elevated Cho/Cr (1.74 ± 0.44 versus 1.34 ± 0.26, p = 0.023) from CER was observed in TP compared with PsP. When these parameters were incorporated in multivariate regression analyses, a discriminatory model with a sensitivity of 94% and a specificity of 87% was observed in distinguishing TP from PsP. These results indicate the utility of 3D‐EPSI in differentiating TP from PsP with high sensitivity and specificity.     

Time‐efficient measurement of multi‐phase arterial spin labeling MR signal in white matter

White matter (WM) perfusion has great potential as a physiological biomarker in many neurological diseases. Although it has been demonstrated previously that arterial spin labeling magnetic resonance imaging (ASL‐MRI) enables the detection of the perfusion‐weighted signal in most voxels in WM, studies of cerebral blood flow (CBF) in WM by ASL‐MRI are relatively scarce because of its particular challenges, such as significantly lower perfusion and longer arterial transit times relative to gray matter (GM). Recently, ASL with a spectroscopic readout has been proposed to enhance the sensitivity for the measurement of WM perfusion. However, this approach suffers from long acquisition times, especially when acquiring multi‐phase ASL datasets to improve CBF quantification. Furthermore, the potential increase in the signal‐to‐noise ratio (SNR) by spectroscopic readout compared with echo planar imaging (EPI) readout has not been proven experimentally. In this study, we propose the use of time‐encoded pseudo‐continuous ASL (te‐pCASL) with single‐voxel point‐resolved spectroscopy (PRESS) readout to quantify WM cerebral perfusion in a more time‐efficient manner. Results are compared with te‐pCASL with a conventional EPI readout for both WM and GM perfusion measurements. Perfusion measurements by te‐pCASL PRESS and conventional EPI showed no significant difference for quantitative WM CBF values (Student's t‐test, p = 0.19) or temporal SNR (p = 0.33 and p = 0.81 for GM and WM, respectively), whereas GM CBF values (p = 0.016) were higher using PRESS than EPI readout. WM CBF values were found to be 18.2 ± 7.6 mL/100 g/min (PRESS) and 12.5 ± 5.5 mL/100 g/min (EPI), whereas GM CBF values were found to be 77.1 ± 11.2 mL/100 g/min (PRESS) and 53.6 ± 9.6 mL/100 g/min (EPI). This study demonstrates the feasibility of te‐pCASL PRESS for the quantification of WM perfusion changes in a highly time‐efficient manner, but it does not result in improved temporal SNR, as does traditional te‐pCASL EPI, which remains the preferred option because of its flexibility in use.     

Measurement of glycine in healthy and tumorous brain by triple‐refocusing MRS at 3 T in vivo

Glycine (Gly) has been implicated in several neurological disorders, including malignant brain tumors. The precise measurement of Gly is challenging largely as a result of the spectral overlap with myo‐inositol (mI). We report a new triple‐refocusing sequence for the reliable co‐detection of Gly and mI at 3 T and for the evaluation of Gly in healthy and tumorous brain. The sequence parameters were optimized with density‐matrix simulations and phantom validation. With a total TE of 134 ms, the sequence gave complete suppression of the mI signal between 3.5 and 3.6 ppm and, consequently, well‐defined Gly (3.55 ppm) and mI (3.64 ppm) peaks. In vivo ¹H magnetic resonance spectroscopy (MRS) data were acquired from the gray matter (GM)‐dominant medial occipital and white matter (WM)‐dominant left parietal regions in six healthy subjects, and analyzed with LCModel using in‐house‐calculated basis spectra. Tissue segmentation was performed to obtain the GM and WM contents within the MRS voxels. Metabolites were quantified with reference to GM‐rich medial occipital total creatine at 8 mM. The Gly and mI concentrations were estimated to be 0.63 ± 0.05 and 8.6 ± 0.6 mM for the medial occipital and 0.34 ± 0.05 and 5.3 ± 0.8 mM for the left parietal regions, respectively. From linear regression of the metabolite estimates versus fractional GM content, the concentration ratios between pure GM and pure WM were estimated to be 2.6 and 2.1 for Gly and mI, respectively. Clinical application of the optimized sequence was performed in four subjects with brain tumor. The Gly levels in tumors were higher than those of healthy brain. Gly elevation was more extensive in a post‐contrast enhancing region than in a non‐enhancing region. The data indicate that the optimized triple‐refocusing sequence may provide reliable co‐detection of Gly and mI, and alterations of Gly in brain tumors can be precisely evaluated.     

Regional neonatal brain absolute thermometry by 1H MRS

Therapeutic hypothermia is standard care for infants with moderate to severe encephalopathy. ¹H MRS thermometry (MRSt) measures regional brain absolute temperature using the temperature‐dependent water chemical shift. This study evaluates the clinical feasibility of MRSt in human neonates, and correlates white matter (WM) and thalamus (Thal) MRSt with conventional rectal temperature (T_rectal) measurement. Fifty‐six infants born at term underwent perinatal MRSt for suspected hypoxic–ischaemic brain injury and 33 infants born preterm had MRSt at a term‐equivalent age; 56 of the 89 had T_rectal measured after MRSt of either a Thal or posterior WM voxel, or both. MRSt used point‐resolved spectroscopy (no water suppression; TR = 1370 ms; TE = 288 ms; 1.5 × 1.5 × 1.5 cm³ Thal and 1.1 × 1.3 × 1.4 cm³ WM voxels). Time domain data were phase and frequency corrected before summation and motion‐corrupted data were excluded from further analysis using simple criteria [preprocessing + quality assurance (QA)]. Two published water temperature‐dependence calibrations [both using cerebral creatine (Cr), choline (Cho) and N‐acetylaspartate (Naa) as independent reference peaks] were compared. The temperature measurements derived from Cr, Cho and Naa were combined to give a single amplitude‐weighted combination temperature (T_AWC). WM and Thal T_AWC correlated linearly with T_rectal (Thal slope, 0.82 ± 0.04, R² = 0.85, p < 0.05; WM slope, 0.95 ± 0.04, R² = 0.78, p < 0.05). Preprocessing + QA improved the correlation between WM T_AWC and T_rectal (R² increased from 0.27 to 0.78, p < 0.001). Both calibration datasets showed specific inconsistencies between the temperatures calculated using Cr, Cho and Naa reference peaks when applied to this neonatal dataset. Neonatal MRSt is clinically feasible. Preprocessing + QA improved MRSt reliability in WM. The consideration of MRSt calibration internal biases is necessary before combining MRSt temperatures from multiple reference peaks to obtain T_AWC. Copyright © 2012 John Wiley & Sons, Ltd.     

Non‐invasive diagnosis and metabolic consequences of congenital portosystemic shunts in C57BL/6 J mice

This study demonstrates the suitability of magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) for the imaging of congenital portosystemic shunts (PSS) in mice, a vascular abnormality in which mesenteric blood bypasses the liver and is instead drained directly to the systemic circulation. The non‐invasive diagnosis performed in tandem with other experimental assessments permits further characterization of liver, whole‐body and brain metabolic defects associated with PSS. Magnetic resonance measurements were performed in a 26‐cm, horizontal‐bore, 14.1‐T magnet. MRA was obtained with a three‐dimensional gradient echo sequence (GRE; in‐plane resolution, 234 × 250 × 234 μm³) using a birdcage coil. Two‐dimensional GRE MRI with high spatial resolution (in‐plane resolution, 100 × 130 μm²; slices, 30 × 0.3 mm) was performed using a surface coil. Brain‐ (dorsal hippocampus) and liver‐localized ¹H magnetic resonance spectroscopy (MRS) was also performed with the surface coil. Whole‐body metabolic status was evaluated with an oral glucose tolerance test (OGTT). Both MRA and anatomical MRI allowed the identification of hepatic vessels and the diagnosis of PSS in mice. The incidence of PSS was about 10%. Hepatic lipid content was higher in PSS than in control mice (5.1 ± 2.8% versus 1.8 ± 0.6%, p = 0.02). PSS mice had higher brain glutamine concentration than controls (7.3 ± 1.0 μmol/g versus 2.7 ± 0.6 μmol/g, p < 0.0001) and, conversely, lower myo‐inositol (4.2 ± 0.6 μmol/g versus 6.0 ± 0.4 μmol/g, p < 0.0001), taurine (9.7 ± 1.2 μmol/g versus 11.0 ± 0.4 μmol/g, p < 0.01) and total choline (0.9 ± 0.1 μmol/g versus 1.2 ± 0.1 μmol/g, p < 0.001) concentrations. Fasting blood glucose and plasma insulin were lower in PSS than in control mice (4.7 ± 0.5mM versus 8.8 ± 0.6mM, p < 0.0001; and 0.04 ± 0.03 μg/L versus 0.3 ± 0.2 μg/L, p = 0.02, respectively). Glucose clearance during OGTT was delayed and less efficient in PSS mice than in controls. Thus, given the non‐negligible incidence of PSS in inbred mice, the undiagnosed presence of PSS will, importantly, have an impact on experimental outcomes, notably in studies addressing brain, liver or whole‐body metabolism.     

二维磁共振波谱分析在评价颅内胶质瘤中的临床应用

目的探讨脑胶质瘤二维磁共振波谱分析(2D 1H-MRS)表现及其主要代谢物含量变化。方法选择120例幕上脑胶质瘤行常规MRI及2D-1H-MRS检查并定量检测其主要代谢物N-乙酰天门冬胺酸(NAA)、含胆碱化合物(Cho)、肌酸(Cr)、乳酸(Lac)和脂质(Lip)含量。采用t检验进一步探讨各级别胶质瘤代谢物含量的差异。结果120例接受常规MRI和2D-1H-MRS检查的病例按术后病理结果分为三组:星形细胞瘤(AS)40例,间变性星形细胞瘤(AA)40例,胶质母细胞瘤(GM)40例。随胶质瘤恶性程度的增加,NAA呈下降趋势,Cho呈上升趋势,Cr变化不明显或轻度下降,Lip-Lac呈升高趋势。在AS与AA、AS与GM、AA与GM间NAA含量差异显著(p<0.01)。在AS与GM间Cr含量差异显著(P<0.05),在AS与AA、GM间Cho含量差异显著(p<0.01)。在AS与AA、AS与GM、AA与GM间Cho/cr比值差异显著(p<0.01);在AS与AA、GM间及AA与GM间NAA/Cho比值差异显著(p<0.01,P<0.05);在AS与AA、GM间Lip/lac比值差异显著(p<0.01)。结论胶质瘤2D1H-MRS表现及其代谢物定量研究有助于胶质瘤临床诊断与肿瘤恶性度分级。     

Bi‐exponential 23Na T2* component analysis in the human brain

The purpose of this study was to measure the sodium transverse relaxation time T₂* in the healthy human brain. Five healthy subjects were scanned with 18 echo times (TEs) as short as 0.17 ms. T₂* values were fitted on a voxel‐by‐voxel basis using a bi‐exponential model. Data were also analysed using a continuous distribution fit with a region of interest‐based inverse Laplace transform. Average T₂* values were 3.4 ± 0.2 ms and 23.5 ± 1.8 ms in white matter (WM) for the short and long components, respectively, and 3.9 ± 0.5 ms and 26.3 ± 2.6 ms in grey matter (GM) for the short and long components, respectively, using the bi‐exponential model. Continuous distribution fits yielded results of 3.1 ± 0.3 ms and 18.8 ± 3.2 ms in WM for the short and long components, respectively, and 2.9 ± 0.4 ms and 17.2 ± 2 ms in GM for the short and long components, respectively. ²³Na T₂* values of the brain for the short and long components for various anatomical locations using ultra‐short TEs are presented for the first time.     

Effects of exercise‐induced intracellular acidosis on the phosphocreatine recovery kinetics: a 31P MRS study in three muscle groups in humans

Little is known about the metabolic differences that exist among different muscle groups within the same subjects. Therefore, we used ³¹P‐magnetic resonance spectroscopy (³¹P‐MRS) to investigate muscle oxidative capacity and the potential effects of pH on PCr recovery kinetics between muscles of different phenotypes (quadriceps (Q), finger (FF) and plantar flexors (PF)) in the same cohort of 16 untrained adults. The estimated muscle oxidative capacity was lower in Q (29 ± 12 mM min^‐1, CV_{inter‐subject} = 42%) as compared with PF (46 ± 20 mM min^‐1, CV_{inter‐subject} = 44%) and tended to be higher in FF (43 ± 35 mM min^‐1, CV_{inter‐subject} = 80%). The coefficient of variation (CV) of oxidative capacity between muscles within the group was 59 ± 24%. PCr recovery time constant was correlated with end‐exercise pH in Q (p < 0.01), FF (p < 0.05) and PF (p <0.05) as well as proton efflux rate in FF (p < 0.01), PF (p < 0.01) and Q (p = 0.12). We also observed a steeper slope of the relationship between end‐exercise acidosis and PCr recovery kinetics in FF compared with either PF or Q muscles. Overall, this study supports the concept of skeletal muscle heterogeneity by revealing a comparable inter‐ and intra‐individual variability in oxidative capacity across three skeletal muscles in untrained individuals. These findings also indicate that the sensitivity of mitochondrial respiration to the inhibition associated with cytosolic acidosis is greater in the finger flexor muscles compared with locomotor muscles, which might be related to differences in permeability in the mitochondrial membrane and, to some extent, to proton efflux rates. Copyright © 2013 John Wiley & Sons, Ltd.     

Automated whole‐brain N‐acetylaspartate proton MRS quantification

Concentration of the neuronal marker, N‐acetylaspartate (NAA), a quantitative metric for the health and density of neurons, is currently obtained by integration of the manually defined peak in whole‐head proton (¹H)‐MRS. Our goal was to develop a full spectral modeling approach for the automatic estimation of the whole‐brain NAA concentration (WBNAA) and to compare the performance of this approach with a manual frequency‐range peak integration approach previously employed. MRI and whole‐head ¹H‐MRS from 18 healthy young adults were examined. Non‐localized, whole‐head ¹H‐MRS obtained at 3 T yielded the NAA peak area through both manually defined frequency‐range integration and the new, full spectral simulation. The NAA peak area was converted into an absolute amount with phantom replacement and normalized for brain volume (segmented from T₁‐weighted MRI) to yield WBNAA. A paired‐sample t test was used to compare the means of the WBNAA paradigms and a likelihood ratio test used to compare their coefficients of variation. While the between‐subject WBNAA means were nearly identical (12.8 ± 2.5 mm for integration, 12.8 ± 1.4 mm for spectral modeling), the latter's standard deviation was significantly smaller (by ~50%, p = 0.026). The within‐subject variability was 11.7% (±1.3 mm ) for integration versus 7.0% (±0.8 mm ) for spectral modeling, i.e., a 40% improvement. The (quantifiable) quality of the modeling approach was high, as reflected by Cramer–Rao lower bounds below 0.1% and vanishingly small (experimental ‐ fitted) residuals. Modeling of the whole‐head ¹H‐MRS increases WBNAA quantification reliability by reducing its variability, its susceptibility to operator bias and baseline roll, and by providing quality‐control feedback. Together, these enhance the usefulness of the technique for monitoring the diffuse progression and treatment response of neurological disorders. Copyright © 2014 John Wiley & Sons, Ltd.     

Simultaneous voxel‐based magnetic susceptibility and morphometry analysis using magnetization‐prepared spoiled turbo multiple gradient echo

This study aimed to develop and test a simultaneous acquisition and analysis pipeline for voxel‐based magnetic susceptibility and morphometry (VBMSM) on a single dataset using young volunteers, elderly healthy volunteers, and an Alzheimer's disease (AD) group. 3D T₁‐weighted and multi‐echo phase images for VBM and quantitative susceptibility mapping (QSM) were simultaneously acquired using a magnetization‐prepared spoiled turbo multiple gradient echo sequence with inversion pulse for QSM (MP‐QSM). The magnitude image was split into gray matter (GM) and white matter (WM) and was spatially normalized. The susceptibility map was reconstructed from the phase images. The segmented image and susceptibility map were compared with those obtained from conventional multiple spoiled gradient echo (mGRE) and MP‐spoiled gradient echo (MP‐GRE) in healthy volunteers to validate the availability of MP‐QSM by numerical measurements. To assess the feasibility of the VBMSM analysis pipeline, voxel‐based comparisons of susceptibility and morphometry in MP‐QSM were conducted in volunteers with a bimodal age distribution, and in elderly volunteers and the AD group, using spatially normalized GM and WM volume images and a susceptibility map. GM/WM contrasts in MP‐QSM, MP‐GRE, and mGRE were 0.14 ± 0.011, 0.17 ± 0.015, and 0.045 ± 0.010, respectively. Segmented GM and WM volumes in the MP‐QSM closely coincided with those in the MP‐GRE. Region of interest analyses indicated that the mean susceptibility values in MP‐QSM were completely in agreement with those in mGRE. In an evaluation of the aging effect, a significant increase and decrease in susceptibility and volume were found by VBMSM in deep GM and WM, respectively. Between the elderly volunteers and the AD group, the characteristic susceptibility and volume changes in GM and WM were observed. The proposed MP‐QSM sequence makes it possible to acquire acceptable‐quality images for simultaneous analysis and determine brain atrophy and susceptibility distribution without image registration by using voxel‐based analyses.     

Metabolic changes detected in vivo by 1H MRS in the MPTP‐intoxicated mouse

We used in vivo proton (¹H) Magnetic Resonance Spectroscopy (MRS) to measure the levels of the main excitatory amino acid, glutamate (Glu) and also glutamine (Gln) and GABA in the striatum and cerebral cortex in the MPTP‐intoxicated mouse, a model of dopaminergic denervation, before and after dopamine (DA) replacement. The study was performed at 9.4T on control mice (n = 8) and MPTP‐intoxicated mice (n = 8). In vivo spectra were acquired in a voxel (8 µL) centered in the striatum, and in the cortex (4.6 µL). Three days after basal MRS acquisitions new spectra were acquired in the striatum and cortex, after levodopa (200 mg.kg^?1). Glu, Gln and GABA concentrations obtained in the basal state were significantly increased in the striatum of MPTP‐lesioned mice (Glu: 20.2 ± 0.8 vs 11.4 ± 0.9 mM, p < 0.001; Gln: 5.4 ± 1.6 vs 2.0 ± 0.6 mM, p < 0.05; GABA: 3.6 ± 0.8 vs 1.6 ± 0.2 mM, p < 0.05). Levodopa lowered metabolites concentrations in the striatum of MPTP‐lesioned mice (Glu: 20.2 ± 0.8 vs 11.2 ± 0.4 mM (+ Ldopa), p < 0.001; Gln: 5.4 ± 1.6 vs 1.6 ± 0.4 mM (+ Ldopa), p < 0.05; GABA: 3.6 ± 0.8 vs 1.7 ± 0.4 mM (+ Ldopa), p < 0.01). Metabolite levels in the striatum of MPTP‐intoxicated mice + levodopa were not significantly different from those in the striatum of controls. No change was found in the cortex after DA denervation and after DA replacement between the two animals groups. These results strongly support a predominant change in striatal Glu synaptic activity in the cortico‐striatal pathway. Acute levodopa administration reverses the increase of metabolites in the striatum. Copyright © 2010 John Wiley & Sons, Ltd.     

Errors in 1H‐MRS estimates of brain metabolite concentrations caused by failing to take into account tissue‐specific signal relaxation

Accurate measurement of brain metabolite concentrations with proton magnetic resonance spectroscopy (¹H‐MRS) can be problematic because of large voxels with mixed tissue composition, requiring adjustment for differing relaxation rates in each tissue if absolute concentration estimates are desired. Adjusting for tissue‐specific metabolite signal relaxation, however, also requires a knowledge of the relative concentrations of the metabolite in gray (GM) and white (WM) matter, which are not known a priori. Expressions for the estimation of the molality and molarity of brain metabolites with ¹H‐MRS are extended to account for tissue‐specific relaxation of the metabolite signals and examined under different assumptions with simulated and real data. Although the modified equations have two unknowns, and hence are unsolvable explicitly, they are nonetheless useful for the estimation of the effect of tissue‐specific metabolite relaxation rates on concentration estimates under a range of assumptions and experimental parameters using simulated and real data. In simulated data using reported GM and WM T₁ and T₂ times for N‐acetylaspartate (NAA) at 3 T and a hypothetical GM/WM NAA ratio, errors of 6.5–7.8% in concentrations resulted when TR = 1.5 s and TE = 0.144 s, but were reduced to less than 0.5% when TR = 6 s and TE = 0.006 s. In real data obtained at TR/TE = 1.5 s/0.04 s, the difference in the results (4%) was similar to that obtained with simulated data when assuming tissue‐specific relaxation times rather than GM–WM‐averaged times. Using the expressions introduced in this article, these results can be extrapolated to any metabolite or set of assumptions regarding tissue‐specific relaxation. Furthermore, although serving to bound the problem, this work underscores the challenge of correcting for relaxation effects, given that relaxation times are generally not known and impractical to measure in most studies. To minimize such effects, the data should be acquired with pulse sequence parameters that minimize the effect of signal relaxation.     

Aerobic Fitness and the Brain: Increased N-Acetyl-Aspartate and Choline Concentrations in Endurance-Trained Middle-Aged Adults

Engagement in regular aerobic exercise is associated with cognitive benefits, but information on the mechanisms governing these changes in humans is limited. The goal of the current study was to compare neurometabolite concentrations relating to cellular metabolism, structure, and viability in endurance-trained and sedentary middle-aged adults. Twenty-eight endurance-trained and 27 sedentary adults, aged 40–65 years, underwent general health assessment, cardiorespiratory fitness measurement, neuropsychological testing, and proton magnetic resonance spectroscopy (¹H MRS). ¹H MRS was used to examine N-acetyl-aspartate (NAA), creatine (Cr), myo-inositol (mI), choline (Cho), and glutamate (Glu) concentrations in frontal and occipitoparietal grey matter. Group differences in concentrations of NAA, Cho, mI, and Glu, calculated as ratios over Cr, were explored using ANOVA. There were no significant differences in global cognitive function, memory, and executive function performance between the groups. In comparison to sedentary adults, the endurance-trained group displayed significantly higher NAA/Cr in the frontal grey matter (F(1, 53) = 5.367, p = 0.024) and higher Cho/Cr in the occipitoparietal grey matter (F(1, 53) = 5.138, p = 0.028). Within our middle-aged sample, endurance-trained adults demonstrated higher levels of NAA/Cr in the frontal grey matter and higher Cho/Cr in the occipitoparietal grey matter. Higher levels of NAA may indicate greater neuronal integrity and higher cerebral metabolic efficiency in association with cardiorespiratory fitness, whereas increased Cho may represent increased phospholipid levels secondary to neural plasticity.     

Response of HT29 colorectal xenograft model to cediranib assessed with 18F‐fluoromisonidazole positron emission tomography,dynamic contrast‐enhanced and diffusion‐weighted MRI

Cediranib is a small‐molecule pan‐vascular endothelial growth factor receptor inhibitor. The tumor response to short‐term cediranib treatment was studied using dynamic contrast‐enhanced and diffusion‐weighted MRI at 7 T, as well as ¹⁸F‐fluoromisonidazole positron emission tomography and histological markers. Rats bearing subcutaneous HT29 human colorectal tumors were imaged at baseline; they then received three doses of cediranib (3 mg/kg per dose daily) or vehicle (dosed daily), with follow‐up imaging performed 2 h after the final cediranib or vehicle dose. Tumors were excised and evaluated for the perfusion marker Hoechst 33342, the endothelial cell marker CD31, smooth muscle actin, intercapillary distance and tumor necrosis. Dynamic contrast‐enhanced MRI‐derived parameters decreased significantly in cediranib‐treated tumors relative to pretreatment values [the muscle‐normalized initial area under the gadolinium concentration curve decreased by 48% (p = 0.002), the enhancing fraction by 43% (p = 0.003) and K^trans by 57% (p = 0.003)], but remained unchanged in controls. No change between the pre‐ and post‐treatment tumor apparent diffusion coefficients in either the cediranib‐ or vehicle‐treated group was observed over the course of this study. The ¹⁸F‐fluoromisonidazole mean standardized uptake value decreased by 33% (p = 0.008) in the cediranib group, but showed no significant change in the control group. Histological analysis showed that the number of CD31‐positive vessels (59 per mm²), the fraction of smooth muscle actin‐positive vessels (80–87%) and the intercapillary distance (0.17 mm) were similar in cediranib‐ and vehicle‐treated groups. The fraction of perfused blood vessels in cediranib‐treated tumors (81 ± 7%) was lower than that in vehicle controls (91 ± 3%, p = 0.02). The necrotic fraction was slightly higher in cediranib‐treated rats (34 ± 12%) than in controls (26 ± 10%, p = 0.23). These findings suggest that short‐term treatment with cediranib causes a decrease in tumor perfusion/permeability across the tumor cross‐section, but changes in vascular morphology, vessel density or tumor cellularity are not manifested at this early time point. Copyright © 2012 John Wiley & Sons, Ltd.     

Precision and accuracy of diffusion kurtosis estimation and the influence of b‐value selection

Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging that accounts for leading non‐Gaussian diffusion effects. In DKI studies, a wide range of different gradient strengths (b‐values) is used, which is known to affect the estimated diffusivity and kurtosis parameters. Hence there is a need to assess the accuracy and precision of the estimated parameters as a function of b‐value. This work examines the error in the estimation of mean of the kurtosis tensor (MKT) with respect to the ground truth, using simulations based on a biophysical model for both gray (GM) and white (WM) matter. Model parameters are derived from densely sampled experimental data acquired in ex vivo rat brain and in vivo human brain. Additionally, the variability of MKT is studied using the experimental data. Prevalent fitting protocols are implemented and investigated. The results show strong dependence on the maximum b‐value of both net relative error and standard deviation of error for all of the employed fitting protocols. The choice of b‐values with minimum MKT estimation error and standard deviation of error was found to depend on the protocol type and the tissue. Protocols that utilize two terms of the cumulant expansion (DKI) were found to achieve minimum error in GM at b‐values less than 1 ms/μm², whereas maximal b‐values of about 2.5 ms/μm² were found to be optimal in WM. Protocols including additional higher order terms of the cumulant expansion were found to provide higher accuracy for the more commonly used b‐value regime in GM, but were associated with higher error in WM. Averaged over multiple voxels, a net average error of around 15% for both WM and GM was observed for the optimal b‐value choice. These results suggest caution when using DKI generated metrics for microstructural modeling and when comparing results obtained using different fitting techniques and b‐values.     

Effect of respiratory hyperoxic challenge on magnetic susceptibility in human brain assessed by quantitative susceptibility mapping (QSM)

The purpose of this study was to measure the regional change of magnetic susceptibility in human brain upon inhalation of 100% oxygen by MRI quantitative susceptibility mapping (QSM). Fourteen healthy volunteers were scanned in a 3 T MR scanner with a 3D multi‐gradient‐echo sequence while breathing medical air (normoxia) and pure oxygen (hyperoxia). QSM images and R₂* maps were calculated. Mean susceptibility differences versus white matter were measured in regions of interest covering veins, gray matter (GM), and cerebrospinal fluid (CSF) under both conditions. Hyperoxia resulted in a strong susceptibility decrease in large veins (?154.4 ± 65.9 ppb, p < 10^?6), in a smaller reduction in GM (?1.3 ± 1 ppb, p < 0.001), and in a susceptibility increase in ventricular CSF (3.8 ± 1.8 ppb, p < 10^?5). The susceptibility decrease in veins implied an increase of venous oxygen saturation (SvO₂) by 10.1 ± 4.0%. Compared with QSM, R₂* was more seriously affected by long‐distance effects not related to local tissue oxygenation and increased in cerebral frontal regions (3 ± 2 s^?1, p < 0.0004) due to paramagnetic molecular oxygen in cavities. The results highlight the potential of QSM to yield region‐specific quantitative oxygenation information, and, thus, for applications such as oxygen‐therapy monitoring or identification of hypoxic tumor tissue during radiotherapy planning. Copyright © 2015 John Wiley & Sons, Ltd.     

BOLD‐based cerebrovascular reactivity vascular transfer function isolates amplitude and timing responses to better characterize cerebral small vessel disease

Cerebrovascular reactivity (CVR) is a dynamic measure of the cerebral blood vessel response to vasoactive stimulus. Conventional CVR measures amplitude changes in the blood‐oxygenation‐level‐dependent (BOLD) signal per unit change in end‐tidal CO₂ (P_ETCO₂), effectively discarding potential timing information. This study proposes a deconvolution procedure to characterize CVR responses based on a vascular transfer function (VTF) that separates amplitude and timing CVR effects. We implemented the CVR‐VTF to primarily evaluate normal‐appearing white matter (WM) responses in those with a range of small vessel disease. Comparisons between simulations of P_ETCO₂ input models revealed that boxcar and ramp hypercapnia paradigms had the lowest relative deconvolution error. We used a T₂* BOLD‐MRI sequence on a 3 T MRI scanner, with a boxcar delivery model of CO₂, to test the CVR‐VTF approach in 18 healthy adults and three white matter hyperintensity (WMH) groups: 20 adults with moderate WMH, 12 adults with severe WMH, and 10 adults with genetic WMH (CADASIL). A subset of participants performed a second CVR session at a one‐year follow‐up. Conventional CVR, area under the curve of VTF (VTF‐AUC), and VTF time‐to‐peak (VTF‐TTP) were assessed in WM and grey matter (GM) at baseline and one‐year follow‐up. WMH groups had lower WM VTF‐AUC compared with the healthy group (p < 0.0001), whereas GM CVR did not differ between groups (p > 0.1). WM VTF‐TTP of the healthy group was less than that in the moderate WMH group (p = 0.016). Baseline VTF‐AUC was lower than follow‐up VTF‐AUC in WM (p = 0.013) and GM (p = 0.026). The intraclass correlation for VTF‐AUC in WM was 0.39 and coefficient of repeatability was 0.08 [%BOLD/mm Hg]. This study assessed CVR timing and amplitude information without applying model assumptions to the CVR response; this approach may be useful in the development of robust clinical biomarkers of CSVD.     

Age‐ and sex‐related differences in muscle phosphocreatine and oxygenation kinetics during high‐intensity exercise in adolescents and adults

The aim of this investigation was to examine the adaptation of the muscle phosphates (e.g. phosphocreatine (PCr) and ADP) implicated in regulating oxidative phosphorylation, and oxygenation at the onset of high intensity exercise in children and adults. The hypotheses were threefold: primary PCr kinetics would be faster in children than adults; the amplitude of the PCr slow component would be attenuated in children; and the amplitude of the deoxyhaemoglobin/myoglobin (HHb) slow component would be reduced in children. Eleven children (5 girls, 6 boys, 13 ± 1 years) and 11 adults (5 women, 6 men, 24 ± 4 years) completed two to four constant work rate exercise tests within a 1.5 T MR scanner. Quadriceps muscle energetics during high intensity exercise were monitored using ³¹P‐MRS. Muscle oxygenation was monitored using near‐infrared spectroscopy. The time constant for the PCr response was not significantly different in boys (31 ± 10 s), girls (31 ± 10 s), men (44 ± 20 s) or women (29 ± 14 s, main effects: age, p = 0.37, sex, p = 0.25). The amplitude of the PCr slow component relative to end‐exercise PCr was not significantly different between children (23 ± 23%) and adults (17 ± 13%, p = 0.47). End‐exercise [PCr] was significantly lower, and [ADP] higher, in females (18 ± 4 mM and 53 ± 16 µM) than males (23 ± 4 mM, p = 0.02 and 37 ± 11 µM, p = 0.02), but did not differ with age ([PCr]: p = 0.96, [ADP]: p = 0.72). The mean response time for muscle tissue deoxygenation was significantly faster in children (22 ± 4 s) than adults (27 ± 7 s, p = 0.01). The results of this study show that the control of oxidative metabolism at the onset of high intensity exercise is adult‐like in 13‐year‐old children, but that matching of oxygen delivery to extraction is more precise in adults. Copyright © 2010 John Wiley & Sons, Ltd.