The live biotherapeutic SYNB1353 decreases plasma methionine via directed degradation in animal models and healthy volunteers.

Methionine is an essential proteinogenic amino acid, but its excess can lead to deleterious effects. Inborn errors of methionine metabolism resulting from loss of function in cystathionine ß-synthase (CBS) cause classic homocystinuria (HCU), which is managed by a methionine-restricted diet. Synthetic biotics are gastrointestinal tract-targeted live biotherapeutics that can be engineered to replicate the benefits of dietary restriction. In this study, we assess whether SYNB1353, an E. coli Nissle 1917 derivative, impacts circulating methionine and homocysteine levels in animals and healthy volunteers. In both mice and nonhuman primates (NHPs), SYNB1353 blunts the appearance of plasma methionine and plasma homocysteine in response to an oral methionine load. A phase 1 clinical study conducted in healthy volunteers subjected to an oral methionine challenge demonstrates that SYNB1353 is well tolerated and blunts plasma methionine by 26%. Overall, SYNB1353 represents a promising approach for methionine reduction with potential utility for the treatment of HCU.

Exploring the links of skeletal muscle mitochondrial oxidative capacity, physical functionality, and mental well-being of cancer survivors.

Physical impairments following cancer treatment have been linked with the toxic effects of these treatments on muscle mass and strength, through their deleterious effects on skeletal muscle mitochondrial oxidative capacity. Accordingly, we designed the present study to explore relationships of skeletal muscle mitochondrial oxidative capacity with physical performance and perceived cancer-related psychosocial experiences of cancer survivors. We assessed skeletal muscle mitochondrial oxidative capacity using in vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS), measuring the postexercise phosphocreatine resynthesis time constant, τPCr, in 11 post-chemotherapy participants aged 34-70 years. During the MRS procedure, participants performed rapid ballistic knee extension exercise to deplete phosphocreatine (PCr); hence, measuring the primary study outcome, which was the recovery rate of PCr (τPCr). Patient-reported outcomes of psychosocial symptoms and well-being were assessed using the Patient-Reported Outcomes Measurement Information System and the 36-Item Short Form health survey (SF-36). Rapid bioenergetic recovery, reflected through a smaller value of τPCr was associated with worse depression (rho ρ = - 0.69, p = 0.018, and Cohen's d = - 1.104), anxiety (ρ = - 0.61, p = .046, d = - 0.677), and overall mental health (ρ = 0.74, p = 0.010, d = 2.198) scores, but better resilience (ρ = 0.65, p = 0.029), and coping-self efficacy (ρ = 0.63, p = 0.04) scores. This is the first study to link skeletal muscle mitochondrial oxidative capacity with subjective reports of cancer-related behavioral toxicities. Further investigations are warranted to confirm these findings probing into the role of disease status and personal attributes in these preliminary results.

Association of Plasma Markers of Alzheimer's Disease, Neurodegeneration, and Neuroinflammation with the Choroid Plexus Integrity in Aging.

The choroid plexus (CP) is a vital brain structure essential for cerebrospinal fluid (CSF) production. Moreover, alterations in the CP's structure and function are implicated in molecular conditions and neuropathologies including multiple sclerosis, Alzheimer's disease, and stroke. Our goal is to provide the first characterization of the association between variation in the CP microstructure and macrostructure/volume using advanced magnetic resonance imaging (MRI) methodology, and blood-based biomarkers of Alzheimer's disease (Aß42/40 ratio; pTau181), neuroinflammation and neuronal injury (GFAP; NfL). We hypothesized that plasma biomarkers of brain pathology are associated with disordered CP structure. Moreover, since cerebral microstructural changes can precede macrostructural changes, we also conjecture that these differences would be evident in the CP microstructural integrity. Our cross-sectional study was conducted on a cohort of 108 well-characterized individuals, spanning 22-94 years of age, after excluding participants with cognitive impairments and non-exploitable MR imaging data. Established automated segmentation methods were used to identify the CP volume/macrostructure using structural MR images, while the microstructural integrity of the CP was assessed using our advanced quantitative high-resolution MR imaging of longitudinal and transverse relaxation times (T1 and T2). After adjusting for relevant covariates, positive associations were observed between pTau181, NfL and GFAP and all MRI metrics. These associations reached significance (p<0.05) except for CP volume vs. pTau181 (p=0.14), CP volume vs. NfL (p=0.35), and T2 vs. NFL (p=0.07). Further, negative associations between Aß42/40 and all MRI metrics were observed but reached significance only for Aß42/40 vs. T2 (p=0.04). These novel findings demonstrate that reduced CP macrostructural and microstructural integrity is positively associated with blood-based biomarkers of AD pathology, neurodegeneration/neuroinflammation and neurodegeneration. Degradation of the CP structure may co-occur with AD pathology and neuroinflammation ahead of clinically detectable cognitive impairment, making the CP a potential structure of interest for early disease detection or treatment monitoring.

C-NODDI: a constrained NODDI model for axonal density and orientation determinations in cerebral white matter.

Purpose: Neurite orientation dispersion and density imaging (NODDI) provides measures of neurite density and dispersion through computation of the neurite density index (NDI) and the orientation dispersion index (ODI). However, NODDI overestimates the cerebrospinal fluid water fraction in white matter (WM) and provides physiologically unrealistic high NDI values. Furthermore, derived NDI values are echo-time (TE)-dependent. In this work, we propose a modification of NODDI, named constrained NODDI (C-NODDI), for NDI and ODI mapping in WM. Methods: Using NODDI and C-NODDI, we investigated age-related alterations in WM in a cohort of 58 cognitively unimpaired adults. Further, NDI values derived using NODDI or C-NODDI were correlated with the neurofilament light chain (NfL) concentration levels, a plasma biomarker of axonal degeneration. Finally, we investigated the TE dependence of NODDI or C-NODDI derived NDI and ODI. Results: ODI derived values using both approaches were virtually identical, exhibiting constant trends with age. Further, our results indicated a quadratic relationship between NDI and age suggesting that axonal maturation continues until middle age followed by a decrease. This quadratic association was notably significant in several WM regions using C-NODDI, while limited to a few regions using NODDI. Further, C-NODDI-NDI values exhibited a stronger correlation with NfL concentration levels as compared to NODDI-NDI, with lower NDI values corresponding to higher levels of NfL. Finally, we confirmed the previous finding that NDI estimation using NODDI was dependent on TE, while NDI derived values using C-NODDI exhibited lower sensitivity to TE in WM. Conclusion: C-NODDI provides a complementary method to NODDI for determination of NDI in white matter.

The Effect of the Human Brainstem Myelination on Gait Speed in Normative Aging.

The brainstem functions as a relay and integrative brain center and plays an essential role in motor function. Whether brainstem tissue deterioration, including demyelination, affects motor function has not been studied. Understanding the potential relationship between brainstem demyelination and motor function may be useful for the early diagnosis of neurodegenerative diseases and to understand age-related gait impairments that have no apparent cause. In this work, we investigated the associations between rapid or usual gait speeds, as integrative measures of motor function, and cerebral myelin content. In 118 individuals (age 22-94 years) free of neurodegenerative diseases or cognitive impairment, myelin content was assessed as the myelin water fraction, a direct magnetic resonance imaging measure of myelin content, and longitudinal and transverse relaxation rates (R1 and R2), which are sensitive magnetic resonance imaging measures of myelin content. Our results indicate that participants with lower usual or rapid gait speed exhibited lower values of myelin water fraction and R1 in the main brainstem regions, which were more evident and statistically significant in the midbrain. In contrast, we found no significant associations between gait speeds and R2, an expected result because various physiological factors confound R2. These original findings provide evidence that the level of brainstem myelination may affect gait performance among cognitively unimpaired adults who are free from any clinically detectable neurodegenerative diseases. Further studies are needed to understand the longitudinal changes in brainstem myelination with aging and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

Age-related changes in human skeletal muscle microstructure and architecture assessed by diffusion-tensor magnetic resonance imaging and their association with muscle strength.

Diffusion-tensor magnetic resonance imaging (DT-MRI) offers objective measures of muscle characteristics, providing insights into age-related changes. We used DT-MRI to probe skeletal muscle microstructure and architecture in a large healthy-aging cohort, with the aim of characterizing age-related differences and comparing these to muscle strength. We recruited 94 participants (43 female; median age = 56, range = 22-89 years) and measured microstructure parameters-fractional anisotropy (FA) and mean diffusivity (MD)-in 12 thigh muscles, and architecture parameters-pennation angle, fascicle length, fiber curvature, and physiological cross-sectional area (PCSA)-in the rectus femoris (RF) and biceps femoris longus (BFL). Knee extension and flexion torques were also measured for comparison to architecture measures. FA and MD were associated with age (ß = 0.33, p = 0.001, R2 = 0.10; and ß = -0.36, p < 0.001, R2 = 0.12), and FA was negatively associated with Type I fiber proportions from the literature (ß = -0.70, p = 0.024, and R2 = 0.43). Pennation angle, fiber curvature, fascicle length, and PCSA were associated with age in the RF (ß = -0.22, 0.26, -0.23, and -0.31, respectively; p < 0.05), while in the BFL only curvature and fascicle length were associated with age (ß = 0.36, and -0.40, respectively; p < 0.001). In the RF, pennation angle and PCSA were associated with strength (ß = 0.29, and 0.46, respectively; p < 0.01); in the BFL, only PCSA was associated with strength (ß = 0.43; p < 0.001). Our results show skeletal muscle architectural changes with aging and intermuscular differences in the microstructure. DT-MRI may prove useful for elucidating muscle changes in the early stages of sarcopenia and monitoring interventions aimed at preventing age-associated microstructural changes in muscle that lead to functional impairment.

An engineered bacterial therapeutic lowers urinary oxalate in preclinical models and in silico simulations of enteric hyperoxaluria.

Enteric hyperoxaluria (EH) is a metabolic disease caused by excessive absorption of dietary oxalate leading to the formation of chronic kidney stones and kidney failure. There are no approved pharmaceutical treatments for EH. SYNB8802 is an engineered bacterial therapeutic designed to consume oxalate in the gut and lower urinary oxalate as a potential treatment for EH. Oral administration of SYNB8802 leads to significantly decreased urinary oxalate excretion in healthy mice and non-human primates, demonstrating the strain's ability to consume oxalate in vivo. A mathematical modeling framework was constructed that combines in vitro and in vivo preclinical data to predict the effects of SYNB8802 administration on urinary oxalate excretion in humans. Simulations of SYNB8802 administration predict a clinically meaningful lowering of urinary oxalate excretion in healthy volunteers and EH patients. Together, these findings suggest that SYNB8802 is a promising treatment for EH.

Age-related estimates of aggregate g-ratio of white matter structures assessed using quantitative magnetic resonance neuroimaging.

The g-ratio, defined as the inner-to-outer diameter of a myelinated axon, is associated with the speed of nerve impulse conduction, and represents an index of axonal myelination and integrity. It has been shown to be a sensitive and specific biomarker of neurodevelopment and neurodegeneration. However, there have been very few magnetic resonance imaging studies of the g-ratio in the context of normative aging; characterizing regional and time-dependent cerebral changes in g-ratio in cognitively normal subjects will be a crucial step in differentiating normal from abnormal microstructural alterations. In the current study, we investigated age-related differences in aggregate g-ratio, that is, g-ratio averaged over all fibers within regions of interest, in several white matter regions in a cohort of 52 cognitively unimpaired participants ranging in age from 21 to 84 years. We found a quadratic, U-shaped, relationship between aggregate g-ratio and age in most cerebral regions investigated, suggesting myelin maturation until middle age followed by a decrease at older ages. As expected, we observed that these age-related differences vary across different brain regions, with the frontal lobes and parietal lobes exhibiting slightly earlier ages of minimum aggregate g-ratio as compared to more posterior structures such as the occipital lobes and temporal lobes; this agrees with the retrogenesis paradigm. Our results provide evidence for a nonlinear association between age and aggregate g-ratio in a sample of adults from a highly controlled population. Finally, sex differences in aggregate g-ratio were observed in several cerebral regions, with women exhibiting overall lower values as compared to men; this likely reflects the greater myelin content in women's brain, in agreement with recent investigations.

Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity.

Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine.

Quantitative age-dependent differences in human brainstem myelination assessed using high-resolution magnetic resonance mapping.

Previous in-vivo magnetic resonance imaging (MRI)-based studies of age-related differences in the human brainstem have focused on volumetric morphometry. These investigations have provided pivotal insights into regional brainstem atrophy but have not addressed microstructural age differences. However, growing evidence indicates the sensitivity of quantitative MRI to microstructural tissue changes in the brain. These studies have largely focused on the cerebrum, with very few MR investigations addressing age-dependent differences in the brainstem, in spite of its central role in the regulation of vital functions. Several studies indicate early brainstem alterations in a myriad of neurodegenerative diseases and dementias. The paucity of MR-focused investigations is likely due in part to the challenges imposed by the small structural scale of the brainstem itself as well as of substructures within, requiring accurate high spatial resolution imaging studies. In this work, we applied our recently developed approach to high-resolution myelin water fraction (MWF) mapping, a proxy for myelin content, to investigate myelin differences with normal aging within the brainstem. In this cross-sectional investigation, we studied a large cohort (n = 125) of cognitively unimpaired participants spanning a wide age range (21-94 years) and found a decrease in myelination with age in most brainstem regions studied, with several regions exhibiting a quadratic association between myelin and age. We believe that this study is the first investigation of MWF differences with normative aging in the adult brainstem. Further, our results provide reference MWF values.

Adult brain aging investigated using BMC-mcDESPOT-based myelin water fraction imaging.

The relationship between regional brain myelination and aging has been the subject of intense study, with magnetic resonance imaging perhaps the most effective modality for elucidating this. However, most of these studies have used nonspecific methods to probe myelin content, including diffusion tensor imaging, magnetization transfer ratio, and relaxation times. In the present study, we used the BMC-mcDESPOT analysis, a direct and specific method for imaging of myelin water fraction (MWF), a surrogate of myelin content. We investigated age-related differences in MWF in several brain regions in a large cohort of cognitively unimpaired participants, spanning a wide age range. Our results indicate a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by decreases at older ages. We also observed that these age-related differences vary across different brain regions, as expected. Our results provide evidence for nonlinear associations between age and myelin in a large sample of well-characterized adults, using a direct myelin content imaging method.

Age and Muscle Function Are More Closely Associated With Intracellular Magnesium, as Assessed by 31P Magnetic Resonance Spectroscopy, Than With Serum Magnesium.

Total serum magnesium is a common clinical measurement for assessing magnesium status; however, magnesium in blood represents less than 1% of the body's total magnesium content. We measured intramuscular ionized magnesium by phosphorus magnetic resonance spectroscopy (31P-MRS) and tested the hypothesis that this measure better correlates with skeletal muscle function and captures more closely the effect of aging than the traditional measure of total serum magnesium. Data were collected from 441 participants (age 24-98 years) in the Baltimore Longitudinal Study of Aging (BLSA), a study of normative aging that encompasses a broad age range. Results showed that intramuscular ionized magnesium was negatively associated with age (ß = -0.29, p < 0.001, R 2 = 0.08) and positively associated with knee-extension strength (ß = 0.31, p < 0.001, and R 2 = 0.1 in women; and ß = 0.2, p = 0.003, and R 2 = 0.04 in men), while total serum magnesium showed no association with age or strength (p = 0.27 and 0.1, respectively). Intramuscular ionized magnesium was significantly lower in women that in men (p < 0.001), perhaps due to chronic latent Mg deficiency in women that is not otherwise detected by serum magnesium levels. Based on these findings, we suggest that intramuscular ionized magnesium from 31P-MRS is a better clinical measure of magnesium status than total serum magnesium, and could be measured when muscle weakness of unidentified etiology is detected. It may also be used to monitor the effectiveness of oral magnesium interventions, including supplementation.

The Role of Muscle Perfusion in the Age-Associated Decline of Mitochondrial Function in Healthy Individuals.

Maximum oxidative capacity of skeletal muscle measured by in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) declines with age, and negatively affects whole-body aerobic capacity. However, it remains unclear whether the loss of oxidative capacity is caused by reduced volume and function of mitochondria or limited substrate availability secondary to impaired muscle perfusion. Therefore, we sought to elucidate the role of muscle perfusion on the age-related decline of muscle oxidative capacity and ultimately whole-body aerobic capacity. Muscle oxidative capacity was assessed by 31P-MRS post-exercise phosphocreatine recovery time (τPCr), with higher τPCr reflecting lower oxidative capacity, in 75 healthy participants (48 men, 22-89 years) of the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing study. Muscle perfusion was characterized as an index of blood volume at rest using a customized diffusion-weighted MRI technique and analysis method developed in our laboratory. Aerobic capacity (peak-VO2) was also measured during a graded treadmill exercise test in the same visit. Muscle oxidative capacity, peak-VO2, and resting muscle perfusion were significantly lower at older ages independent of sex, race, and body mass index (BMI). τPCr was significantly associated with resting muscle perfusion independent of age, sex, race, and BMI (p-value = 0.004, ß = -0.34). τPCr was also a significant independent predictor of peak-VO2 and, in a mediation analysis, significantly attenuated the association between muscle perfusion and peak-VO2 (34% reduction for ß in perfusion). These findings suggest that the age-associated decline in muscle oxidative capacity is partly due to impaired muscle perfusion and not mitochondrial dysfunction alone. Furthermore, our findings show that part of the decline in whole-body aerobic capacity observed with aging is also due to reduced microvascular blood volume at rest, representing a basal capacity of the microvascular system, which is mediated by muscle oxidative capacity. This finding suggests potential benefit of interventions that target an overall increase in muscle perfusion for the restoration of energetic capacity and mitochondrial function with aging.

Diffusion-weighted MRI with intravoxel incoherent motion modeling for assessment of muscle perfusion in the thigh during post-exercise hyperemia in younger and older adults.

Aging is associated with impaired endothelium-dependent vasodilation that leads to muscle perfusion impairment and contributes to organ dysfunction. Impaired muscle perfusion may result in inadequate delivery of oxygen and nutrients during and after muscle contraction, leading to muscle damage. The ability to study the relationship between perfusion and muscle damage has been limited using traditional muscle perfusion measures, which are invasive and risky. To overcome this limitation, we optimized a diffusion-weighted MRI sequence and validated an intravoxel incoherent motion (IVIM) analysis based on Monte Carlo simulation to study muscle perfusion impairment with aging during post-exercise hyperemia. Simulation results demonstrated that the bias of IVIM-derived perfusion fraction (fp ) and diffusion of water molecules in extra-vascular tissue (D) ranged from -3.3% to 14% and from -16.5% to 0.002%, respectively, in the optimized experimental condition. The dispersion in fp and D ranged from 3.2% to 9.5% and from 0.9% to 1.1%, respectively. The mid-thigh of the left leg of four younger (21-30 year old) and four older (60-90 year old) healthy females was studied using the optimized protocol at baseline and at seven time increments occurring every 3.25 min following in-magnet dynamic knee extension exercise performed using a MR-compatible ergometer with a workload of 0.4 bar for 2.5 min. After exercise, both fp and D significantly increased in the rectus femoris (active muscle during exercise) but not in adductor magnus (inactive muscle), reflecting the fact that the local increase in perfusion with both groups showed a maximum value in the second post-exercise time-point. A significantly greater increase in perfusion from the baseline (p < 0.05) was observed in the younger group (37 ± 12.05%) compared with the older group (17.57 ± 15.92%) at the first post-exercise measurement. This work establishes a reliable non-invasive method that can be used to study the effects of aging on dynamic changes in muscle perfusion as they relate to important measures of physical function.

An innovative mobile data collection technology for public health in a field setting.

OBJECTIVES: The Canadian Network for Public Health Intelligence (CNPHI) is a secure, web-based scientific informatics and biosurveillance platform that leverages disparate public health information resources and expertise for the direct benefit of local, regional and national decision makers. CNPHI fosters collaboration and consultation through innovation in disease surveillance, intelligence exchange, research and response to protect, promote and support public health. The objective of this article is to present the CNPHI 'on the go' mobile application, and to discuss preliminary evaluation of the technology. The mobile application is intended to enable rapid mobile data collection using both online and offline modes supporting various stages of surveillance and response through the extension of data collection and analysis to the mobile environment. METHODS: Two needs assessment meetings were held with stakeholders representing individuals from government, academia and research institutions, to inform the development of the CNPHI "on the go" mobile application. An initial version of the mobile technology (an "app") was developed and piloted by end-users with expertise in the field. Two focused pilots were conducted to test the technology: Pilot 1: 17-7-2017 to 21-11-2017 (6 participants); Pilot 2: 25-7-2017 to 15-9-2017 (2 participants). An initial consultation was held with the project leads to identify data elements for mobile data collection. A custom data collection form was designed using CNPHI's Web Data technology for each pilot, which was then made available through the mobile app. The technology was assessed using feedback received during each pilot as well as through a survey that was conducted at the conclusion of pilots. RESULTS: Pilot participants reported that the mobile technology allowed seamless data collection, data management and rapid information sharing. Participants also reported that the entire process was seamless, simple, efficient, and that fewer steps were required for data collection and management. Further, significant efficiencies were gained by directly entering information using the mobile app without having to transfer handwritten information into an electronic database. An overall positive experience was reported by participants from both pilots. DISCUSSION: Literature suggests that traditional methods of surveillance and data collection using a paper based methodology pose many challenges such as data loss and duplication, difficulty in managing the database, and lack of timely access to the data. Accurate and rapid access is critical for public health professionals in order to effectively make decisions and respond to public health emergencies. Results show that the CNPHI "on the go" app is well poised to address some of the suggested challenges. A limitation of this study was that sample size for pilot participation was small for capturing overall feedback on the readiness of the technology for integration into regular surveillance activities and response procedures. CONCLUSIONS: CNPHI "on the go" is a customizable technology developed within an already thriving collaborative CNPHI platform used by public health professionals, and performs well as a tool for rapid data collection and secure information sharing.

Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria.

Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine (Phe), which can result in neurotoxicity. To provide a potential alternative to a protein-restricted diet, we engineered Escherichia coli Nissle to express genes encoding Phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. Administration of our synthetic strain, SYNB1618, to the Pahenu2/enu2 PKU mouse model reduced blood Phe concentration by 38% compared with the control, independent of dietary protein intake. In healthy Cynomolgus monkeys, we found that SYNB1618 inhibited increases in serum Phe after an oral Phe dietary challenge. In mice and primates, Phe was converted to trans-cinnamate by SYNB1618, quantitatively metabolized by the host to hippurate and excreted in the urine, acting as a predictive biomarker for strain activity. SYNB1618 was detectable in murine or primate feces after a single oral dose, permitting the evaluation of pharmacodynamic properties. Our results define a strategy for translation of live bacterial therapeutics to treat metabolic disorders.

Spatially adaptive unsupervised multispectral nonlocal filtering for improved cerebral blood flow mapping using arterial spin labeling magnetic resonance imaging.

BACKGROUND: Cerebral blood flow (CBF) is an emerging biomarker for normal aging and neurodegenerative diseases. Arterial spin labeling (ASL) perfusion MRI permits noninvasive quantification of CBF. However, high-quality mapping of CBF from ASL imaging is challenging, largely due to noise. NEW METHOD: We demonstrate the ability of the recently introduced nonlocal estimation of multispectral magnitudes (NESMA) filter to greatly improve determination of CBF estimates from ASL imaging data. We evaluated the results of NESMA-ASL for CBF mapping from data obtained on human brain (n = 10) across a wide age range (21-74 years) using a standard clinical protocol. Results were compared to those obtained from unfiltered images or filtered images using conventional and advanced filters. Quantitative analyses for different spatial image resolutions and signal-to-noise ratios, SNRs, were also conducted. RESULTS: Our results demonstrate the potential of NESMA-ASL to permit high-quality high-resolution CBF mapping. NESMA-ASL substantially reduces random variation in derived CBF estimates while preserving edges and small structures, with minimal bias and dispersion in derived CBF estimates. COMPARISON WITH EXISTING METHODS: NESMA-ASL outperforms all evaluated filters in terms of noise reduction and detail preservation. Further, unlike other filters, NESMA-ASL is straightforward to implement requiring only one user-defined parameter, which is relatively insensitive to SNR or local image structure. CONCLUSIONS: In-vivo estimation of CBF in the human brain from ASL imaging data was markedly improved through use of the NESMA-ASL filter. The use of NESMA-ASL may contribute significantly to the goal of high-quality high-resolution CBF mapping within a clinically feasible acquisition time.

Rapid B1 field mapping at 3 T using the 180° signal null method with extended flip angle.

PURPOSE: To extend the null signal method (NSM) for B1 mapping to 3 T magnetic resonance imaging (MRI). BACKGROUND: The NSM operates in the steady state regime and exploits the linearity of the spoiled gradient recalled echo (SPGR) signal around the 180° flip angle (FA). Using linear regression, B1 maps are derived from three SPGR images acquired at different FAs with a short repetition time. While the conventional NSM allows accurate mapping of B1 for moderate B1 variation, we observed that this method fails for the larger B1 variations typical of high-field MRI. METHODS: We analyzed the effect of the FA range of the acquired SPGR images on B1 determination using the NSM for 3 T MRI through extensive numerical and in vivo analyses. B1 maps derived from the extended angle-range NSM (EA-NSM) were calculated and compared to those derived from the conventional, more restricted angle range, NSM, and to those derived from the reference, but much more time-consuming, double angle method (DAM). Furthermore, we investigated the compatibility of EA-NSM B1 mapping and the half-scan and SENSE reconstruction methods for accelerating acquisition time. RESULTS: Our results show that the use of the conventional FA range leads to substantial inaccuracies in B1 determination. Both numerical and in vivo analyses demonstrate that expanding the FA range of the acquired SPGR images substantially improves the accuracy of B1 maps. Furthermore, B1 maps derived from EA-NSM were demonstrated to be quantitatively comparable to those derived from the lengthy DAM protocol. We also found that B1 maps derived from SPGR images using the EA-NSM and imaging acceleration methods were comparable to those derived from images acquired without acceleration. Finally, the use of half scanning combined with SENSE reconstruction permits whole-brain B1 mapping in ~1 min. CONCLUSIONS: The EA-NSM permits accurate, fast, and practical B1 mapping in a 3 T clinical setting.

Evidence of demyelination in mild cognitive impairment and dementia using a direct and specific magnetic resonance imaging measure of myelin content.

INTRODUCTION: We investigated brain demyelination in aging, mild cognitive impairment (MCI), and dementia using a direct magnetic resonance imaging marker of myelin. METHODS: Brains of young and old controls, and old subjects with MCI, Alzheimer's disease, or vascular dementia were scanned using our recently developed myelin water fraction (MWF) mapping technique, which provides greatly improved accuracy over previous comparable methods. Maps of MWF, a direct and specific myelin measure, and relaxation times and magnetization transfer ratio, indirect and nonspecific measures, were constructed. RESULTS: MCI subjects showed decreased MWF compared with old controls. Demyelination was greater in Alzheimer's disease or vascular dementia. As expected, decreased MWF was accompanied by decreased magnetization transfer ratio and increased relaxation times. The young subjects showed greater myelin content than the old subjects. DISCUSSION: We believe this to be the first demonstration of myelin loss in MCI, Alzheimer's disease, and vascular dementia using a method that provides a quantitative magnetic resonance imaging-based measure of myelin. Our findings add to the emerging evidence that myelination may represent an important biomarker for the pathology of MCI and dementia. This study supports the investigation of the role of myelination in MCI and dementia through use of this quantitative magnetic resonance imaging approach in clinical studies of disease progression, and relationship of functional status to myelination status. Furthermore, mapping MWF may permit myelin to serve as a therapeutic target in clinical trials.