Spectral editing allows direct measurement of low-concentration metabolites, such as GABA, glutathione (GSH) and lactate (Lac), relevant for understanding brain (patho)physiology. The most widely used spectral editing technique is MEGA-PRESS, which has been diversely implemented across research sites and vendors, resulting in variations in the final resolved edited signal. In this paper, we describe an effort to develop a new universal MEGA-PRESS sequence with HERMES functionality for the major MR vendor platforms with standardized RF pulse shapes, durations, amplitudes and timings. New RF pulses were generated for the universal sequence. Phantom experiments were conducted on Philips, Siemens, GE and Canon 3 T MRI scanners using 32-channel head coils. In vivo experiments were performed on the same six subjects on Philips and Siemens scanners, and on two additional subjects, one on GE and one on Canon scanners. On each platform, edited MRS experiments were conducted with the vendor-native and universal MEGA-PRESS sequences for GABA (TE ¼ 68 ms) and Lac editing (TE ¼ 140 ms). Additionally, HERMES for GABA and GSH was performed using the universal sequence at TE ¼ 80 ms. The universal sequence improves inter-vendor similarity of GABA-edited and Lac-edited MEGA-PRESS spectra. The universal HERMES sequence yields both GABA-and GSH-edited spectra with negligible levels of crosstalk on all four platforms, and with strong agreement among vendors for both edited spectra. In vivo GABAþ/Cr, Lac/Cr and GSH/Cr ratios showed relatively low variation between scanners using the universal sequence. In conclusion, phantom and in vivo experiments demonstrate successful implementation of the universal sequence across all four major vendors, allowing editing of several metabolites across a range of TEs.

Objective: Blood-brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer disease (AD) and vascular disease, is still poorly understood. The present study measured human BBB function in mild cognitive impairment (MCI) patients on 2 molecular scales, specifically BBB's permeability to water and albumin molecules. Methods: Fifty-five elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new magnetic resonance imaging technique, water extraction with phase contrast arterial spin tagging. BBB permeability to albumin was determined using cerebrospinal fluid (CSF)/serum albumin ratio. Cognitive performance was assessed by domain-specific composite scores. AD pathology (including CSF Aβ and ptau) and vascular risk factors were examined. Results: Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF Aβ and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors, especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function. Interpretation: These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance.

Background: Alzheimer's disease and vascular cognitive impairment (VCI), as well as their concurrence, represent the most common types of cognitive dysfunction. Treatment strategies for these two conditions are quite different; however, there exists a considerable overlap in their clinical manifestations, and most biomarkers reveal similar abnormalities between these two conditions. Purpose: To evaluate the potential of cerebral oxygen extraction fraction (OEF) as a biomarker for differential diagnosis of Alzheimer's disease and VCI. We hypothesized that in Alzheimer's disease OEF will be reduced (decreased oxygen consumption due to decreased neural activity), while in vascular diseases OEF will be elevated (increased oxygen extraction due to abnormally decreased blood flow). Study Type: Prospective cross-sectional. Population: Sixty-five subjects aged 52-89 years, including 33 mild cognitive impairment (MCI), 7 dementia, and 25 cognitively normal subjects. Field Strength/Sequence: 3T T 2-relaxation-under-spin-tagging (TRUST) and fluid-attenuated inversion recovery imaging (FLAIR). Assessment: OEF, consensus diagnoses of cognitive impairment, vascular risk factors (such as hypertension, hypercholesterolemia, diabetes, smoking, and obesity), cognitive assessments, and cerebrospinal fluid concentration of amyloid and tau were assessed. Statistical Tests: Multiple linear regression analyses of OEF with diagnostic category (normal, MCI, or dementia), vascular risks, cognitive performance, amyloid and tau pathology. Results: When evaluating the entire group, OEF was found to be lower with more severe cognitive impairment (β = −2.70 AE 1.15, T = −2.34, P = 0.02), but was higher with greater vascular risk factors (β = 1.36 AE 0.55, T = 2.48, P = 0.02). Further investigation of the subgroup of participants with low vascular risks (N = 44) revealed that lower OEF was associated with worse cognitive performance (β = 0.04 AE 0.01, T = 3.27, P = 0.002) and greater amyloid burden (β = 92.12 AE 41.23, T = 2.23, P = 0.03). Among cognitively impaired individuals (N = 40), higher OEF was associated with greater vascular risk factors (β = 2.19 AE 0.71, T = 3.08, P = 0.004). Data Conclusion: These findings suggest that OEF is differentially affected by Alzheimer's disease and VCI pathology and may be useful in etiology-based diagnosis of cognitive impairment. Level of Evidence: 1 Technical Efficacy: Stage 3

Background Diffusion MRI is routinely used to evaluate brain injury in neonatal encephalopathy. Although abnormal mean diffusivity (MD) is often attributed to cytotoxic edema, the specific contribution from neuronal pathology is unclear. Purpose To determine whether MD from high‐resolution diffusion tensor imaging (DTI) can detect variable degrees of neuronal degeneration and pathology in piglets with brain injury induced by excitotoxicity or global hypoxia‐ischemia (HI) with or without overt infarction. Study Type Prospective. Animal Model Excitotoxic brain injury was induced in six neonatal piglets by intrastriatal stereotaxic injection of the glutamate receptor agonist quinolinic acid (QA). Three piglets underwent global HI or a sham procedure. Piglets recovered for 20–96 hours before undergoing MRI (n = 9). Field Strength/Sequence 3.0T MRI with DTI, T1‐ and T2‐weighted imaging. Assessment MD, fractional anisotropy (FA), and qualitative T2 injury were assessed in the putamen and caudate. The cell bodies of normal neurons, degenerating neurons (excitotoxic necrosis, ischemic necrosis, or necrosis–apoptosis cell death continuum), and injured neurons with equivocal degeneration were counted by histopathology. Statistical Tests Spearman correlations were used to compare MD and FA to normal, degenerating, and injured neurons. T2 injury and neuron counts were evaluated by descriptive analysis. Results The QA insult generated titratable levels of neuronal pathology. In QA, HI, and sham piglets, lower MD correlated with higher ratios of degenerating‐to‐total neurons (P < 0.05), lower ratios of normal‐to‐total neurons (P < 0.05), and greater numbers of degenerating neurons (P < 0.05). MD did not correlate with abnormal neurons exhibiting nascent injury (P > 0.99). Neuron counts were not related to FA (P > 0.30) or to qualitative injury from T2‐weighted MRI. Data Conclusion MD is more accurate than FA for detecting neuronal degeneration and loss during acute recovery from neonatal excitotoxic and HI brain injury. MD does not reliably detect nonfulminant, nascent, and potentially reversible neuronal injury. Evidence Level 1 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2020;52:1216–1226.

Purpose: To evaluate the accuracy of T 2-based whole-brain oxygen extraction fraction (OEF) estimation by comparing it with gold standard 15 O-PET measurements. Methods: Sixteen healthy adult subjects underwent MRI and 15 O-PET OEF measurements on the same day. On MRI, whole-brain OEF was quantified by T 2-relaxation-under-spin-tagging (TRUST) MRI, based on subject-specific hematocrit. The TRUST OEF was compared to the whole-brain averaged OEF produced by 15 O-PET. Agreement between TRUST and 15 O-PET whole-brain OEF measurements was examined in terms of intraclass correlation coefficient (ICC) and in absolute OEF values. In a subset of 10 subjects, test-retest reproducibility of whole-brain OEF was also evaluated and compared between the two modalities. Results: Across the 16 subjects, the mean whole-brain OEF of TRUST and 15 O-PET were 36.44 ± 4.07% and 36.45 ± 3.65%, respectively, showing no difference between the two modalities (P = .99). TRUST whole-brain OEF strongly correlated with that of 15 O-PET (N = 16, ICC = 0.90, P = 4 × 10 −7). The coefficient-of-variation of TRUST and 15 O-PET whole-brain OEF measurements were 1.79 ± 0.67% and 2.06 ± 1.55%, respectively, showing no difference between the two modalities (N = 10, P = .64). Further analyses on the effect of hematocrit revealed that correlation between PET OEF and TRUST OEF with assumed hematocrit remained significant (ICC = 0.8, P < 2 × 10 −5). Conclusion: Whole-brain OEF measured by TRUST was in excellent agreement with gold standard 15 O-PET, with highly comparable accuracy and reproducibility.

This work suggests that harmonized TRUST MRI can yield highly compatible Y measurements across different vendors. Magn Reson Med 80:1125-1131, 2018. © 2018 International Society for Magnetic Resonance in Medicine.

Purpose: Noninvasive measurement of cerebral venous oxygenation (Y v ) in neonates is important in the assessment of brain oxygen extraction and consumption, and may be useful in characterizing brain development and neonatal brain diseases.This study aims to develop a rapid method for vessel-specific measurement of Y v in neonates. Methods: We developed a pulse sequence, named accelerated T 2 -relaxation-underphase-contrast (aTRUPC), which consists of velocity-encoding phase-contrast module to isolate pure blood signal, flow-insensitive T 2 -preparation to quantify blood T 2 , and turbo-field-echo (TFE) scheme for rapid image acquisition, which is critical for neonatal MRI. A series of studies were conducted. First, the pulse sequence was optimized in terms of TFE factor, velocity encoding (VENC), and slice thickness for best sensitivity. Second, to account for the influence of TFE acquisition on T 2 quantification, simulation and experiments were conducted to establish the relationship between TFE-T 2 and standard T 2 . Finally, the complete aTRUPC sequence was applied on a group of healthy neonates and normative Y v values were determined. Results: Optimal parameters of aTRUPC in neonates were found to be a TFE factor of 15, VENC of 5 cm/s, and slice thickness of 10 mm. The TFE-T 2 was on average 3.9% lower than standard T 2 . These two measures were strongly correlated (R 2 = 0.86); thus their difference can be accounted for by a correction equation, T 2,standard = 1.2002 × T 2,TFE − 10.6276. Neonatal Y v values in veins draining cortical brain and those draining central brain were 64.8 ± 2.9% and 70.2 ± 3.3%, respectively, with a significant difference (P =.02). Conclusion:The aTRUPC MRI has the potential to provide vessel-specific quantification of cerebral Y v in neonates. |JIANG et Al.

The specific cytopathology that causes abnormal fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor imaging (DTI) after neonatal hypoxia‐ischemia (HI) is not completely understood. The panoply of cell types in the brain might contribute differentially to changes in DTI metrics. Because glia are the predominant cell type in brain, we hypothesized that changes in FA and MD would signify perturbations in glial microstructure. Using a 3‐Tesla clinical scanner, we conducted in vivo DTI MRI in nine neonatal piglets at 20–96 h after excitotoxic brain injury from striatal quinolinic acid injection or global HI. FA and MD from putamen, caudate, and internal capsule in toto were correlated with astrocyte swelling, neuronal excitotoxicity, and white matter injury. Low FA correlated with more swollen astrocytes immunophenotyped by aquaporin‐4 (AQP4), glial fibrillary acidic protein (GFAP), and glutamate transporter‐1 (GLT‐1). Low FA was also related to the loss of neurons with perineuronal GLT‐1+ astrocyte decorations, large myelin swellings, lower myelin density, and oligodendrocyte cell death identified by 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase, bridging integrator‐1, and nuclear morphology. MD correlated with degenerating oligodendrocytes and depletion of normal GFAP+ astrocytes but not with astrocyte or myelin swelling. We conclude that FA is associated with cytotoxic edema in astrocytes and oligodendrocyte processes as well as myelin injury at the cellular level. MD can detect glial cell death and loss, but it may not discern subtle pathology in swollen astrocytes, oligodendrocytes, or myelin. This study provides a cytopathologic basis for interpreting DTI in the neonatal brain after HI.