Boosting quantification accuracy of chemical exchange saturation transfer MRI with a spatial-spectral redundancy-based denoising method.

Chemical exchange saturation transfer (CEST) is a versatile technique that enables noninvasive detections of endogenous metabolites present in low concentrations in living tissue. However, CEST imaging suffers from an inherently low signal-to-noise ratio (SNR) due to the decreased water signal caused by the transfer of saturated spins. This limitation challenges the accuracy and reliability of quantification in CEST imaging. In this study, a novel spatial-spectral denoising method, called BOOST (suBspace denoising with nOnlocal lOw-rank constraint and Spectral local-smooThness regularization), was proposed to enhance the SNR of CEST images and boost quantification accuracy. More precisely, our method initially decomposes the noisy CEST images into a low-dimensional subspace by leveraging the global spectral low-rank prior. Subsequently, a spatial nonlocal self-similarity prior is applied to the subspace-based images. Simultaneously, the spectral local-smoothness property of Z-spectra is incorporated by imposing a weighted spectral total variation constraint. The efficiency and robustness of BOOST were validated in various scenarios, including numerical simulations and preclinical and clinical conditions, spanning magnetic field strengths from 3.0 to 11.7 T. The results demonstrated that BOOST outperforms state-of-the-art algorithms in terms of noise elimination. As a cost-effective and widely available post-processing method, BOOST can be easily integrated into existing CEST protocols, consequently promoting accuracy and reliability in detecting subtle CEST effects.

Non-contrast assessment of blood-brain barrier permeability to water in mice: An arterial spin labeling study at cerebral veins.

Blood-brain barrier (BBB) plays a critical role in protecting the brain from toxins and pathogens. However, in vivo tools to assess BBB permeability are scarce and often require the use of exogenous contrast agents. In this study, we aimed to develop a non-contrast arterial-spin-labeling (ASL) based MRI technique to estimate BBB permeability to water in mice. By determining the relative fraction of labeled water spins that were exchanged into the brain tissue as opposed to those that remained in the cerebral veins, we estimated indices of global BBB permeability to water including water extraction fraction (E) and permeability surface-area product (PS). First, using multiple post-labeling delay ASL experiments, we estimated the bolus arrival time (BAT) of the labeled spins to reach the great vein of Galen (VG) to be 691.2 ± 14.5 ms (N = 5). Next, we investigated the dependence of the VG ASL signal on labeling duration and identified an optimal imaging protocol with a labeling duration of 1200 ms and a PLD of 100 ms. Quantitative E and PS values in wild-type mice were found to be 59.9 ± 3.2% and 260.9 ± 18.9 ml/100 g/min, respectively. In contrast, mice with Huntington's disease (HD) revealed a significantly higher E (69.7 ± 2.4%, P = 0.026) and PS (318.1 ± 17.1 ml/100 g/min, P = 0.040), suggesting BBB breakdown in this mouse model. Reproducibility studies revealed a coefficient-of-variation (CoV) of 4.9 ± 1.7% and 6.1 ± 1.2% for E and PS, respectively. The proposed method may open new avenues for preclinical research on pathophysiological mechanisms of brain diseases and therapeutic trials in animal models.

Quantification of T1 and T2 of subarachnoid CSF: Implications for water exchange between CSF and brain tissues.

PURPOSE: To quantify the T1 and T2 values of CSF in the subarachnoid space (SAS) at 3 T and interpret them in the context of water exchange between CSF and brain tissues. METHODS: CSF T1 was measured using inversion recovery, and CSF T2 was assessed using T2 -preparation. T1 and T2 values in the SAS were compared with those in the frontal horns of lateral ventricles, which have less brain-CSF exchange. Phantom experiments were performed to examine whether there were spatial variations in T1 and T2 that were unrelated to brain-CSF exchange. Simulations were conducted to investigate the relationship between the brain-CSF exchange rate and the apparent T1 and T2 values of SAS CSF. RESULTS: The CSF T1 and T2 values were 4308.7 ± 146.9 ms and 1885.5 ± 67.9 ms, respectively, in the SAS and were 4454.0 ± 187.9 ms and 2372.9 ± 72.0 ms in the frontal horns. The SAS CSF had shorter T1 (p = 0.006) and T2 (p < 0.0001) than CSF in the frontal horns. Phantom experiments showed negligible (< 6 ms for T1 ; < 1 ms for T2 ) spatial variations in T1 and T2 , suggesting that the T1 and T2 differences between SAS and frontal horns were largely attributed to physiological reasons. Simulations revealed that faster brain-CSF exchange rates lead to shorter apparent T1 and T2 of SAS CSF. However, the experimentally observed T2 difference between SAS and frontal horns was greater than that attributable to typical exchange effect, suggesting that the T2 shortening in SAS may reflect a combined effect of exchange and deoxyhemoglobin susceptibility. CONCLUSION: Quantification of SAS CSF relaxation times may be useful to assess the brain-CSF exchange.

Preoperative Subtyping of WHO Grade 1 Meningiomas Using a Single-Shot Ultrafast MR T2 Mapping.

BACKGROUND: Meningioma subtype is crucial in treatment planning and prognosis delineation, for grade 1 meningiomas. T2 relaxometry could provide detailed microscopic information but is often limited by long scanning times. PURPOSE: To investigate the potential of T2 maps derived from multiple overlapping-echo detachment imaging (MOLED) for predicting meningioma subtypes and Ki-67 index, and to compare the diagnostic efficiency of two different region-of-interest (ROI) placements (whole-tumor and contrast-enhanced, respectively). STUDY TYPE: Prospective. PHANTOM/SUBJECTS: A phantom containing 11 tubes of MnCl2 at different concentrations, eight healthy volunteers, and 75 patients with grade 1 meningioma. FIELD STRENGTH/SEQUENCE: 3 T scanner. MOLED, T2-weighted spin-echo sequence, T2-dark-fluid sequence, and postcontrast T1-weighted gradient echo sequence. ASSESSMENT: Two ROIs were delineated: the whole-tumor area (ROI1) and contrast-enhanced area (ROI2). Histogram parameters were extracted from T2 maps. Meningioma subtypes and Ki-67 index were reviewed by a neuropathologist according to the 2021 classification criteria. STATISTICAL TESTS: Linear regression, Bland-Altman analysis, Pearson's correlation analysis, independent t test, Mann-Whitney U test, Kruskal-Wallis test with Bonferroni correction, and multivariate logistic regression analysis with the P-value significance level of 0.05. RESULTS: The MOLED T2 sequence demonstrated excellent accuracy for phantoms and volunteers (Meandiff = -1.29%, SDdiff = 1.25% and Meandiff = 0.36%, SDdiff = 2.70%, respectively), and good repeatability for volunteers (average coefficient of variance = 1.13%; intraclass correlation coefficient = 0.877). For both ROI1 and ROI2, T2 variance had the highest area under the curves (area under the ROC curve = 0.768 and 0.761, respectively) for meningioma subtyping. There was no significant difference between the two ROIs (P = 0.875). Significant correlations were observed between T2 parameters and Ki-67 index (r = 0.237-0.374). DATA CONCLUSION: MOLED T2 maps can effectively differentiate between meningothelial, fibrous, and transitional meningiomas. Moreover, T2 histogram parameters were significantly correlated with the Ki-67 index. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Novel series of tunable µOR modulators with enhanced brain penetration for the treatment of opioid use disorder, pain and neuropsychiatric indications.

Structural optimization of a previously reported agonist of µOR, PZM21 is described resulting in the discovery of a novel series of amides with at least 4-folds enhanced CNS penetration in rat. Furthermore, these efforts yielded compounds with varying levels of efficacy on the receptor ranging from high efficacy agonists such as compound 20 to antagonists, such as 24. The correlation between in vitro activation of µOR and relative activity in models of analgesia for these compounds is discussed. The compelling results obtained in these studies demonstrate the potential utility of these newly discovered compounds in the treatment of pain and opioid use disorder.

Quantitative cerebrovascular reactivity MRI in mice using acetazolamide challenge.

PURPOSE: To develop a quantitative MRI method to estimate cerebrovascular reactivity (CVR) in mice. METHODS: We described an MRI procedure to measure cerebral vasodilatory response to acetazolamide (ACZ), a vasoactive agent previously used in human clinical imaging. Vascular response was determined by cerebral blood flow (CBF) measured with phase-contrast or pseudo-continuous arterial spin labeling MRI. Vasodilatory input intensity was determined by plasma ACZ level using high-performance liquid chromatography. We verified the source of the CVR MRI signal by comparing ACZ injection to phosphate-buffered saline injection and noninjection experiments. Dose dependence and feasibility of regional CVR measurement were also investigated. RESULTS: Cerebral blood flow revealed an exponential increase following intravenous ACZ injection, with a time constant of 1.62 min. In contrast, phosphate-buffered saline or noninjection exhibited a slow linear CBF increase, consistent with a gradual accumulation of anesthetic agent, isoflurane, used in this study. When comparing different ACZ doses, injections of 30, 60, 120, and 180 mg/kg yielded a linear increase in plasma ACZ concentration (p < 0.0001). On the other hand, CBF changes under these doses were not different from each other (p = 0.50). The pseudo-continuous arterial spin labeling MRI with multiple postlabeling delays revealed similar vascular responses at different postlabeling delay values. There was a regional difference in CVR (p = 0.005), with isocortex (0.81 ± 0.17%/[µg/ml]) showing higher CVR than deep-brain regions. Mice receiving multiple ACZ injections lived for a minimum of 6 months after the study without noticeable aberrant behavior or appearance. CONCLUSIONS: We demonstrated the proof-of-principle of a new quantitative CVR mapping technique in mice.

Huntingtin silencing delays onset and slows progression of Huntington's disease: a biomarker study.

Huntington's disease is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, coding for pathological mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic aetiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest stage, where clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of clinical manifest, it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we aim to develop non-invasive sensitive biomarkers that provide insight into therapeutic efficacy in the premanifest stage of Huntington's disease. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI in the heterozygous zQ175 mice, a full-length mHTT expressing and slowly progressing model with a premanifest period as in human Huntington's disease. Significantly elevated CBVa was evident in premanifest zQ175 mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest Huntington's disease. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study-for the first time-shows that a non-invasive functional MRI measure detects therapeutic efficacy in the premanifest stage and demonstrates long-term benefits of a non-allele-selective HTT silencing treatment introduced in the premanifest Huntington's disease.

Early Thalamocortical Reperfusion Leads to Neurologic Recovery in a Rodent Cardiac Arrest Model.

BACKGROUND: Cerebral blood flow (CBF) plays an important role in neurological recovery after cardiac arrest (CA) resuscitation. However, the variations of CBF recovery in distinct brain regions and its correlation with neurologic recovery after return of spontaneous circulation (ROSC) have not been characterized. This study aimed to investigate the characteristics of regional cerebral reperfusion following resuscitation in predicting neurological recovery. METHODS: Twelve adult male Wistar rats were studied, ten resuscitated from 7-min asphyxial CA and two uninjured rats, which were designated as healthy controls (HCs). Dynamic changes in CBF in the cerebral cortex, hippocampus, thalamus, brainstem, and cerebellum were assessed by pseudocontinuous arterial spin labeling magnetic resonance imaging, starting at 60 min after ROSC to 156 min (or time to spontaneous arousal). Neurologic outcomes were evaluated by the neurologic deficit scale at 24 h post-ROSC in a blinded manner. Correlations between regional CBF (rCBF) and neurological recovery were undertaken. RESULTS: All post-CA animals were found to be nonresponsive during the 60-156 min post ROSC, with reductions in rCBF by 24-42% compared with HC. Analyses of rCBF during the post-ROSC time window from 60 to 156 min showed the rCBF recovery of hippocampus and thalamus were positively associated with better neurological outcomes (rs = 0.82, p = 0.004 and rs = 0.73, p < 0.001, respectively). During 96 min before arousal, thalamic and cortical rCBF exhibited positive correlations with neurological recovery (rs = 0.80, p < 0.001 and rs = 0.65, p < 0.001, respectively); for predicting a favorable neurological outcome, the thalamic rCBF threshold was above 50.84 ml/100 g/min (34% of HC) (area under the curve of 0.96), whereas the cortical rCBF threshold was above 60.43 ml/100 g/min (38% of HC) (area under the curve of 0.88). CONCLUSIONS: Early magnetic resonance imaging analyses showed early rCBF recovery in thalamus, hippocampus, and cortex post ROSC was positively correlated with neurological outcomes at 24 h. Our findings suggest new translational insights into the regional reperfusion and the time window that may be critical in neurological recovery and warrant further validation.

Early detection of Alzheimer's disease using creatine chemical exchange saturation transfer magnetic resonance imaging.

Detecting Alzheimer's disease (AD) at an early stage brings a lot of benefits including disease management and actions to slow the progression of the disease. Here, we demonstrate that reduced creatine chemical exchange saturation transfer (CrCEST) contrast has the potential to serve as a new biomarker for early detection of AD. The results on wild type (WT) mice and two age-matched AD models, namely tauopathy (Tau) and Aß amyloidosis (APP), indicated that CrCEST contrasts of the cortex and corpus callosum in the APP and Tau mice were significantly reduced compared to WT counterpart at an early stage (6-7 months) (p < 0.011). Two main causes of the reduced CrCEST contrast, i.e. cerebral pH and creatine concentration, were investigated. From phantom and hypercapnia experiments, CrCEST showed excellent sensitivity to pH variations. From MRS results, the creatine concentration in WT and AD mouse brain was equivalent, which suggests that the reduced CrCEST contrast was dominated by cerebral pH change involved in the progression of AD. Immunohistochemical analysis revealed that the abnormal cerebral pH in AD mice may relate to neuroinflammation, a known factor that can cause pH reduction.

Traumatic brain injury does not disrupt costimulatory blockade-induced immunological tolerance to glial-restricted progenitor allografts.

BACKGROUND: Cell transplantation-based treatments for neurological disease are promising, yet graft rejection remains a major barrier to successful regenerative therapies. Our group and others have shown that long-lasting tolerance of transplanted stem cells can be achieved in the brain with systemic application of monoclonal antibodies blocking co-stimulation signaling. However, it is unknown if subsequent injury and the blood-brain barrier breach could expose the transplanted cells to systemic immune system spurring fulminant rejection and fatal encephalitis. Therefore, we investigated whether delayed traumatic brain injury (TBI) could trigger graft rejection. METHODS: Glial-restricted precursor cells (GRPs) were intracerebroventricularly transplanted in immunocompetent neonatal mice and co-stimulation blockade (CoB) was applied 0, 2, 4, and 6 days post-grafting. Bioluminescence imaging (BLI) was performed to monitor the grafted cell survival. Mice were subjected to TBI 12 weeks post-transplantation. MRI and open-field test were performed to assess the brain damage and behavioral change, respectively. The animals were decapitated at week 16 post-transplantation, and the brains were harvested. The survival and distribution of grafted cells were verified from brain sections. Hematoxylin and eosin staining (HE) was performed to observe TBI-induced brain legion, and neuroinflammation was evaluated immunohistochemically. RESULTS: BLI showed that grafted GRPs were rejected within 4 weeks after transplantation without CoB, while CoB administration resulted in long-term survival of allografts. BLI signal had a steep rise following TBI and subsequently declined but remained higher than the preinjury level. Open-field test showed TBI-induced anxiety for all animals but neither CoB nor GRP transplantation intensified the symptom. HE and MRI demonstrated a reduction in TBI-induced lesion volume in GRP-transplanted mice compared with non-transplanted mice. Brain sections further validated the survival of grafted GRPs and showed more GRPs surrounding the injured tissue. Furthermore, the brains of post-TBI shiverer mice had increased activation of microglia and astrocytes compared to post-TBI wildtype mice, but infiltration of CD45+ leukocytes remained low. CONCLUSIONS: CoB induces sustained immunological tolerance towards allografted cerebral GRPs which is not disrupted following TBI, and unexpectedly TBI may enhance GRPs engraftment and contribute to post-injury brain tissue repair.

Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study.

Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia in elderly individuals. According to the current biomarker framework for "unbiased descriptive classification", biomarkers of neurodegeneration, "N", constitute a critical component in the tri-category "A/T/N" system. Current biomarkers of neurodegeneration suffer from potential drawbacks such as requiring invasive lumbar puncture, involving ionizing radiation, or representing a late, irreversible marker. Recent human studies have suggested that reduced brain oxygen metabolism may be a new functional marker of neurodegeneration in AD, but the heterogeneity and the presence of mixed pathology in human patients did not allow a full understanding of the role of oxygen extraction and metabolism in AD. In this report, global brain oxygen metabolism and related physiological parameters were studied in two AD mouse models with relatively pure pathology, using advanced MRI techniques including T2 -relaxation-under-spin-tagging (TRUST) and phase contrast (PC) MRI. Additionally, regional cerebral blood flow (CBF) was determined with pseudocontinuous arterial spin labeling. Reduced global oxygen extraction fraction (by -18.7%, p = 0.008), unit-mass cerebral metabolic rate of oxygen (CMRO2 ) (by -17.4%, p = 0.04) and total CMRO2 (by -30.8%, p < 0.001) were observed in Tau4RΔK mice-referred to as the tau AD model-which manifested pronounced neurodegeneration, as measured by diminished brain volume (by -15.2%, p < 0.001). Global and regional CBF in these mice were not different from those of wild-type mice (p > 0.05), suggesting normal vascular function. By contrast, in B6;SJL-Tg [APPSWE]2576Kha (APP) mice-referred to as the amyloid AD model-no brain volume reduction, as well as relatively intact brain oxygen extraction and metabolism, were found (p > 0.05). Consistent with the imaging data, behavioral measures of walking distance were impaired in Tau4RΔK mice (p = 0.004), but not in APP mice (p = 0.88). Collectively, these findings support the hypothesis that noninvasive MRI measurement of brain oxygen metabolism may be a promising biomarker of neurodegeneration in AD.

Common variation of the NSD1 gene is associated with susceptibility to Hirschsprung's disease in Chinese Han population.

BACKGROUND: Hirschsprung's disease (HSCR) is the most common congenital cause of intestinal obstruction in children. Sotos syndrome (SoS) is an overgrowth disorder with constipation and sometimes accompanied by HSCR. NSD1 gene mutation is the main cause of SoS. We aimed to investigate association of NSD1 common single nucleotide polymorphisms (SNPs) with HSCR susceptibility in Chinese Han population. METHOD: We genotyped 15 SNPs encompassing NSD1 gene region in 420 HSCR patients and 1665 controls on Fludigm EP1 platform. Association analysis was performed between cases and controls. RESULT: Rs244709 was the most associated SNP with HSCR susceptibility of the sample set (PAllelic = 9.69 × 10-5, OR = 1.37, 95% CI: 1.17-1.61). Gender stratification analysis revealed that NSD1 SNPs were associated with HSCR in males, but not in females. The nonsynonymous coding SNP rs28932178 in NSD1 exon 5 represented the most significant signal in males (PAllelic = 6.43 × 10-5, OR = 1.42, 95% CI: 1.20-1.69). The associated SNPs were expression quantitative trait loci (eQTLs) of nearby genes in multiple tissues. NSD1 expression levels were higher in aganglionic colon tissues than ganglionic tissues (P = 3.00 × 10-6). CONCLUSION: NSD1 variation conferred risk to HSCR in males, indicating SoS and HSCR may share common genetic factors. IMPACT: This is the first study to reveal that NSD1 variation conferred risk to Hirschsprung's disease susceptibility in males of Chinese Han population, indicating Sotos syndrome and Hirschsprung's disease may share some common genetic background. This study indicates more attention should be paid to the symptom of constipation in patients with Sotos syndrome. Our results raise questions about the role of NSD1 in the development of enteric nervous system and the pathogenesis of Hirschsprung's disease.

Variants in the Enteric Smooth Muscle Actin γ-2 Cause Pediatric Intestinal Pseudo-obstruction in Chinese Patients.

OBJECTIVES: Pediatric intestinal pseudo-obstruction (PIPO) is a severe gastrointestinal disorder occurring in children, leading to failure to thrive, malnutrition, and long-term parenteral nutrition dependence. Enteric smooth muscle actin γ-2 (ACTG2) variants have been reported to be related to the pathogenesis of PIPO. This study aimed to determine the presence of ACTG2 variants in Chinese PIPO patients. METHODS: Whole-exome sequencing was performed using samples from 39 recruited patients, whereas whole ACTG2 Sanger sequencing was performed using samples from 2 patients. Published data was reviewed to determine the number of pathogenic variants and the genotype related to ACTG2 variants in the Chinese population. RESULTS: A total of 21 Chinese probands were found to carry heterozygous missense variants of ACTG2, among which 20 were de novo. Fifteen probands had p.Arg257 variants (c.770G>A and c.769C>T), and the other 2 probands had c.533G>A (p.Arg178His) and c.443G>T (p.Arg148Leu) variants. Four probands had novel variants c.337C>T (p.Pro113Ser), c.588G>C (p.Glu196Asp), c.734A>G (p.Asp245Gly), and c.553G>T (p.Asp185Tyr). CONCLUSIONS: Variants affecting codon 257 of ACTG2 protein sequence appeared to be frequent in both Chinese and Caucasian PIPO patients, whereas p.Arg178 variants were less common in Chinese patients compared with Caucasian patients. The 4 novel variants in ACTG2 were also found to be related to Chinese PIPO.

1H NMR-Based Metabolic Profiles Delineate the Anticancer Effect of Vitamin C and Oxaliplatin on Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide. Because of its high recurrence rate and heterogeneity, effective treatment for advanced stage of HCC is currently lacking. There are accumulating evidences showing the therapeutic potential of pharmacologic vitamin C (VC) on HCC. However, the metabolic basis underlying the anticancer property of VC remains to be elucidated. In this study, we used a high-resolution proton nuclear magnetic resonance-based metabolomics technique to assess the global metabolic changes in HCC cells following VC treatment. In addition, the HCC cells were also treated with oxaliplatin (OXA) to explore the potential synergistic effect induced by the combined VC and OXA treatment. The current metabolomics data suggested different mechanisms of OXA and VC in modulating cell growth and metabolism. In general, VC treatment led to inhibition of energy metabolism via NAD+ depletion and amino acid deprivation. On the other hand, OXA caused significant perturbation in phospholipid biosynthesis and phosphatidylcholine biosynthesis pathways. The current results highlighted glutathione metabolism, and pathways related to succinate and choline may play central roles in conferring the combined effect between OXA and VC. Taken together, this study provided metabolic evidence of VC and OXA in treating HCC and may contribute toward the potential application of combined VC and OXA as complementary HCC therapies.

Acute-stage MRI cerebral oxygen consumption biomarkers predict 24-hour neurological outcome in a rat cardiac arrest model.

Brain injury following cardiac arrest (CA) is thought to be caused by a sudden loss of blood flow resulting in disruption in oxygen delivery, neural function and metabolism. However, temporal trajectories of the brain's physiology in the first few hours following CA have not been fully characterized. Furthermore, the extent to which these early measures can predict future neurological outcomes has not been determined. The present study sought to perform dynamic measurements of cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) with MRI in the first 3 hours following the return of spontaneous circulation (ROSC) in a rat CA model. It was found that CBF, OEF and CMRO2 all revealed a time-dependent increase during the first 3 hours after the ROSC. Furthermore, the temporal trajectories of CBF and CMRO2 , but not OEF, were different across rats and related to neurologic outcomes at a later time (24 hours after the ROSC) (P < .001). Rats who manifested better outcomes revealed faster increases in CBF and CMRO2 during the acute stage. When investigating physiological parameters measured at a single time point, CBF (ρ = 0.82, P = .004) and CMRO2 (ρ = 0.80, P = .006) measured at ~ 3 hours post-ROSC were positively associated with neurologic outcome scores at 24 hours. These findings shed light on brain physiological changes following CA, and suggest that MRI measures of brain perfusion and metabolism may provide a potential biomarker to guide post-CA management.

Delivery of synergistic polyphenol combinations using biopolymer-based systems: Advances in physicochemical properties, stability and bioavailability.

When consumed at sufficiently high levels, polyphenols may provide health benefits, which is linked to their antidiabetic, antiinflamatory, antimicrobial, antioxidant, antitumor, and hypolipidemic properties. Moreover, certain polyphenol combinations exhibit synergistic effects when delivered together - the combined polyphenols have a higher biological activity than the sum of the individual ones. However, the commercial application of polyphenols as nutraceuticals is currently limited because of their poor solubility characteristics; instability when exposed to light, heat, and alkaline conditions; and, low and inconsistent oral bioavailability. Colloidal delivery systems are being developed to overcome these challenges. In this article, we review the design, fabrication, and utilization of food-grade biopolymer-based delivery systems for the encapsulation of one or more polyphenols. In particular, we focus on the creation of delivery systems constructed from edible proteins and polysaccharides. The optimization of biopolymer-based delivery systems may lead to the development of innovative polyphenol-enriched functional foods that can improve human health and wellbeing.

Mutant G2019S-LRRK2 Induces Abnormalities in Arteriolar Cerebral Blood Volume in Mouse Brains: An MRI Study.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease and the most common movement disorder characterized by motor impairments resulting from midbrain dopamine neuron loss. Abnormalities in small pial arteries and arterioles, which are the primary pathways of local delivery of nutrients and oxygen in brain tissue, have been reported in many neurodegenerative diseases including PD. Mutations in LRRK2 cause genetic PD and contribute to sporadic PD. The most common PD-linked mutation LRRK2 G2019S contributes 20-47% of genetic forms of PD in Caucasian populations. The human LRRK2 G2019S transgenic mouse model displays PD-like movement impairment and was used to identify novel LRRK2 inhibitors, which provides a useful model for studying microvascular abnormalities in PD. OBJECTIVES: To investigate abnormalities in arteriolar cerebral blood volume (CBVa) in various brain regions using the inflow-based vascular-space occupancy (iVASO) MRI technique in LRRK2 mouse models of PD. METHODS: Anatomical and iVASO MRI scans were performed in 5 female and 7 male nontransgenic (nTg), 3 female and 4 male wild-type (WT) LRRK2, and 5 female and 7 male G2019S-LRRK2 mice of 9 months of age. CBVa was calculated and compared in the substantia nigra (SN), olfactory cortex, and prefrontal cortex. RESULTS: Compared to nTg mice, G2019S-LRRK2 mice showed decreased CBVa in the SN, but increased CBVa in the olfactory and prefrontal cortex in both male and female groups, whereas WT-LRRK2 mice showed no change in CBVa in the SN (male and female), the olfactory (female), and prefrontal (female) cortex, but a slight increase in CBVa in the olfactory and prefrontal cortex in the male group only. CONCLUSIONS: Alterations in the blood volume of small arteries and arterioles (CBVa) were detected in the G2019S-LRRK2 mouse model of PD. The opposite changes in CBVa in the SN and the cortex indicate that PD pathology may have differential effects in different brain regions. Our results suggest the potential value of CBVa as a marker for clinical PD studies.

Protein aggregation linked to Alzheimer's disease revealed by saturation transfer MRI.

The goal of this study was to develop a molecular biomarker for the detection of protein aggregation involved in Alzheimer's disease (AD) by exploiting the features of the water saturation transfer spectrum (Z-spectrum), the CEST signal of which is sensitive to the molecular configuration of proteins. A radial-sampling steady-state sequence based ultrashort echo time (UTE) readout was implemented to image the Z-spectrum in the mouse brain, especially the contributions from mobile proteins at the frequency offsets for the composite protein amide proton (+3.6 ppm) and aliphatic proton (-3.6 ppm) signals. Using a relatively weak radiofrequency (RF) saturation amplitude, contributions due to strong magnetization transfer contrast (MTC) from solid-like macromolecules and direct water saturation (DS) were minimized. For practical measure of the changes in the mobile protein configuration, we defined a saturation transfer difference (ΔST) by subtracting the Z-spectral signals at ±3.6 ppm from a control signal at 8 ppm. Phantom studies of glutamate solution, protein (egg white) and hair conditioner show the capability of the proposed scheme to minimize the contributions from amine protons, DS, and MTC, respectively. The ST signal at ±3.6 ppm of the cross-linked bovine serum albumin (BSA) solutions demonstrated that the ΔST signal can be used to monitor the aggregation process of the mobile proteins. High-resolution ΔST images of AD mouse brains at ±3.6 ppm of mouse brains showed significantly reduced ΔST (-3.6) signal compared to the age-matched wild-type (WT) mice. Thus, this signal has potential to serve as a molecular biomarker for monitoring protein aggregation in AD.

Optimization of phase-contrast MRI for the estimation of global cerebral blood flow of mice at 11.7T.

PURPOSE: To optimize phase-contrast (PC) MRI for the measurement of global cerebral blood flow (CBF) in the mouse at 11.7T. METHODS: We determined proper velocity encoding (VENC) for internal carotid arteries (ICAs) and vertebral arteries (VAs). Next, we optimized spatial resolution of the sequence. To shorten scan time without compromising data quality, we further optimized repetition time and developed a reduced field-of-view (FOV) scheme for ICA and VA PC MRI. Whole-brain volume was determined with T2 -weighted image to obtain unit-volume CBF. RESULTS: Peak flow velocities were 13.8 ± 1.7, 14.4 ± 0.6, 6.5 ± 1.7, and 6.7 ± 1.3 cm/s for left ICA, right ICA, left VA, and right VA, respectively. Thus, VENC values of 20 and 10 cm/s were chosen for ICA and VA PC MRI, respectively. An in-plane spatial resolution of 50 × 50 µm2 was found to provide a reasonable trade-off between reducing partial-volume effects and maintaining signal-to-noise ratio. Because of the fact that saturated spins in the imaging slice are rapidly replaced by fresh spins, TR of the sequence can be decreased to as short as 15 ms without reducing signal intensity, thereby substantially lowering scan time. Moreover, reduced FOV along the phase-encoding direction was able to shorten scan time by 33.3% while maintaining measurement accuracy. With these optimizations, it took 96 seconds to evaluate CBF with a test-retest variability of approximately 5% and an inter-rater correlation of >0.95. Global unit-volume CBF was found to be 279.5 ± 11.1 mL of blood/100 ml of tissue/min. CONCLUSION: We have optimized PC MRI for noninvasive quantification of blood flow in mice at 11.7T.

Vessel-specific quantification of neonatal cerebral venous oxygenation.

PURPOSE: Noninvasive measurement of cerebral venous oxygenation (Yv ) 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 Yv in neonates. METHODS: We developed a pulse sequence, named accelerated T2 -relaxation-under-phase-contrast (aTRUPC), which consists of velocity-encoding phase-contrast module to isolate pure blood signal, flow-insensitive T2 -preparation to quantify blood T2 , 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 T2 quantification, simulation and experiments were conducted to establish the relationship between TFE-T2 and standard T2 . Finally, the complete aTRUPC sequence was applied on a group of healthy neonates and normative Yv 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-T2 was on average 3.9% lower than standard T2 . These two measures were strongly correlated (R2 = 0.86); thus their difference can be accounted for by a correction equation, T2,standard = 1.2002 × T2,TFE - 10.6276. Neonatal Yv 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 Yv in neonates.