Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles.

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.

Comparison of dynamic susceptibility contrast (DSC) using gadolinium and iron-based contrast agents in high-grade glioma at high-field MRI.

PURPOSE: To compare DSC-MRI using Gadolinium (GBCA) and Ferumoxytol (FBCA) in high-grade glioma at 3T and 7T MRI field strengths. We hypothesized that using FBCA at 7T would enhance the performance of DSC, as measured by contrast-to-noise ratio (CNR). METHODS: Ten patients (13 lesions) were assigned to 3T (6 patients, 6 lesions) or 7T (4 patients, 7 lesions). All lesions received 0.1 mmol/kg of GBCA on day 1. Ten lesions (4 at 3T and 6 at 7T) received a lower dose (0.6 mg/kg) of FBCA, followed by a higher dose (1.0-1.2 mg/kg), while 3 lesions (2 at 3T and 1 at 7T) received only a higher dose on Day 2. CBV maps with leakage correction for GBCA but not for FBCA were generated. The CNR and normalized CBV (nCBV) were analyzed on enhancing and non-enhancing high T2W lesions. RESULTS: Regardless of FBCA dose, GBCA showed higher CNR than FBCA at 7T, which was significant for high-dose FBCA (p < .05). Comparable CNR between GBCA and high-dose FBCA was observed at 3T. There was a trend toward higher CNR for FBCA at 3T than 7T. GBCA also showed nCBV twice that of FBCA at both MRI field strengths with significance at 7T. CONCLUSION: GBCA demonstrated higher image conspicuity, as measured by CNR, than FBCA on 7T. The stronger T2* weighting realized with higher magnetic field strength, combined with FBCA, likely results in more signal loss rather than enhanced performance on DSC. However, at clinical 3T, both GBCA and FBCA, particularly a dosage of 1.0-1.2 mg/kg (optimal for perfusion imaging), yielded comparable CNR.

Prototype Description and Ex Vivo Evaluation of a System for Combined Endorectal Magnetic Resonance Imaging and In-Bore Biopsy of the Prostate.

ABSTRACT: We describe early ex vivo proof-of-concept testing of a novel system composed of a disposable endorectal coil and converging multichannel needle guide with a reusable clamp stand, embedded electronics, and baseplate to allow for endorectal magnetic resonance (MR) imaging and in-bore MRI-targeted biopsy of the prostate as a single integrated procedure. Using prostate phantoms imaged with standard T 2 -weighted sequences in a Siemens 3T Prisma MR scanner, we measured the signal-to-noise ratio in successive 1-cm distances from the novel coil and from a commercially available inflatable balloon coil and measured the lateral and longitudinal deviation of the tip of a deployed MR compatible needle from the intended target point. Signal-to-noise ratio obtained with the novel system was significantly better than the inflatable balloon coil at each of five 1-cm intervals, with a mean improvement of 78% ( P < 0.05). In a representative sampling of 15 guidance channels, the mean lateral deviation for MR imaging-guided needle positioning was 1.7 mm and the mean longitudinal deviation was 2.0 mm. Our ex vivo results suggest that our novel system provides significantly improved signal-to-noise ratio when compared with an inflatable balloon coil and is capable of accurate MRI-guided needle deployment.

Imaging chronic active lesions in multiple sclerosis: a consensus statement.

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis (MS) and have implications for non-relapsing biological progression. In recent years, the discovery of innovative magnetic resonance imaging (MRI) and PET derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with MS, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted (T1-w) and T2-w scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification, and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a Consensus Statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this Consensus Statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge.

Clinical importance of changes in magnetic resonance biomarkers for Duchenne muscular dystrophy.

OBJECTIVE: Magnetic resonance (MR) measures of muscle quality are highly sensitive to disease progression and predictive of meaningful functional milestones in Duchenne muscular dystrophy (DMD). This investigation aimed to establish the reproducibility, responsiveness to disease progression, and minimum clinically important difference (MCID) for multiple MR biomarkers at different disease stages in DMD using a large natural history dataset. METHODS: Longitudinal MR imaging and spectroscopy outcomes and ambulatory function were measured in 180 individuals with DMD at three sites, including repeated measurements on two separate days (within 1 week) in 111 participants. These data were used to calculate day-to-day reproducibility, responsiveness (standardized response mean, SRM), minimum detectable change, and MCID. A survey of experts was also performed. RESULTS: MR spectroscopy fat fraction (FF), as well as MR imaging transverse relaxation time (MRI-T2 ), measures performed in multiple leg muscles, and had high reproducibility (Pearson's R > 0.95). Responsiveness to disease progression varied by disease stage across muscles. The average FF from upper and lower leg muscles was highly responsive (SRM > 0.9) in both ambulatory and nonambulatory individuals. MCID estimated from the distribution of scores, by anchoring to function, and via expert opinion was between 0.01 and 0.05 for FF and between 0.8 and 3.7 ms for MRI-T2 . INTERPRETATION: MR measures of FF and MRI T2 are reliable and highly responsive to disease progression. The MCID for MR measures is less than or equal to the typical annualized change. These results confirm the suitability of these measures for use in DMD and potentially other muscular dystrophies.

Vascular synthesis based on hemodynamic efficiency principle recapitulates measured cerebral circulation properties in the human brain.

Quantifying anatomical and hemodynamical properties of the brain vasculature in vivo is difficult due to limited spatiotemporal resolution neuroimaging, variability between subjects, and bias between acquisition techniques. This work introduces a metabolically inspired vascular synthesis algorithm for creating a digital representation of the cortical blood supply in humans. Spatial organization and segment resistances of a cortical vascular network were generated. Cortical folding and macroscale arterial and venous vessels were reconstructed from anatomical MRI and MR angiography. The remaining network, including ensembles representing the parenchymal capillary bed, were synthesized following a mechanistic principle based on hydrodynamic efficiency of the cortical blood supply. We evaluated the digital model by comparing its simulated values with in vivo healthy human brain measurements of macrovessel blood velocity from phase contrast MRI and capillary bed transit times and bolus arrival times from dynamic susceptibility contrast. We find that measured and simulated values reasonably agree and that relevant neuroimaging observables can be recapitulated in silico. This work provides a basis for describing and testing quantitative aspects of the cerebrovascular circulation that are not directly observable. Future applications of such digital brains include the investigation of the organ-wide effects of simulated vascular and metabolic pathologies.

Multivariate modeling of magnetic resonance biomarkers and clinical outcome measures for Duchenne muscular dystrophy clinical trials.

Although regulatory agencies encourage inclusion of imaging biomarkers in clinical trials for Duchenne muscular dystrophy (DMD), industry receives minimal guidance on how to use these biomarkers most beneficially in trials. This study aims to identify the optimal use of muscle fat fraction biomarkers in DMD clinical trials through a quantitative disease-drug-trial modeling and simulation approach. We simultaneously developed two multivariate models quantifying the longitudinal associations between 6-minute walk distance (6MWD) and fat fraction measures from vastus lateralis and soleus muscles. We leveraged the longitudinal individual-level data collected for 10 years through the ImagingDMD study. Age of the individuals at assessment was chosen as the time metric. After the longitudinal dynamic of each measure was modeled separately, the selected univariate models were combined using correlation parameters. Covariates, including baseline scores of the measures and steroid use, were assessed using the full model approach. The nonlinear mixed-effects modeling was performed in Monolix. The final models showed reasonable precision of the parameter estimates. Simulation-based diagnostics and fivefold cross-validation further showed the model's adequacy. The multivariate models will guide drug developers on using fat fraction assessment most efficiently using available data, including the widely used 6MWD. The models will provide valuable information about how individual characteristics alter disease trajectories. We will extend the multivariate models to incorporate trial design parameters and hypothetical drug effects to inform better clinical trial designs through simulation, which will facilitate the design of clinical trials that are both more inclusive and more conclusive using fat fraction biomarkers.

Processing speed and memory test performance are associated with different brain region volumes in Veterans and others with progressive multiple sclerosis.

Background: Cognitive dysfunction and brain atrophy are both common in progressive multiple sclerosis (MS) but are seldom examined comprehensively in clinical trials. Antioxidant treatment may affect the neurodegeneration characteristic of progressive MS and slow its symptomatic and radiographic correlates. Objectives: This study aims to evaluate cross-sectional associations between cognitive battery components of the Brief International Cognitive Assessment for Multiple Sclerosis with whole and segmented brain volumes and to determine if associations differ between secondary progressive (SPMS) and primary progressive (PPMS) MS subtypes. Design: The study was based on a baseline analysis from a multi-site randomized controlled trial of the antioxidant lipoic acid in veterans and other people with progressive MS (NCT03161028). Methods: Cognitive batteries were conducted by trained research personnel. MRIs were processed at a central processing site for maximum harmonization. Semi-partial Pearson's adjustments evaluated associations between cognitive tests and MRI volumes. Regression analyses evaluated differences in association patterns between SPMS and PPMS cohorts. Results: Of the 114 participants, 70% had SPMS. Veterans with MS made up 26% (n = 30) of the total sample and 73% had SPMS. Participants had a mean age of 59.2 and sd 8.5 years, and 54% of them were women, had a disease duration of 22.4 (sd 11.3) years, and had a median Expanded Disability Status Scale of 6.0 (with an interquartile range of 4.0-6.0, moderate disability). The Symbol Digit Modalities Test (processing speed) correlated with whole brain volume (R = 0.29, p = 0.01) and total white matter volume (R = 0.33, p < 0.01). Both the California Verbal Learning Test (verbal memory) and Brief Visuospatial Memory Test-Revised (visual memory) correlated with mean cortical thickness (R = 0.27, p = 0.02 and R = 0.35, p < 0.01, respectively). Correlation patterns were similar in subgroup analyses. Conclusion: Brain volumes showed differing patterns of correlation across cognitive tasks in progressive MS. Similar results between SPMS and PPMS cohorts suggest combining progressive MS subtypes in studies involving cognition and brain atrophy in these populations. Longitudinal assessment will determine the therapeutic effects of lipoic acid on cognitive tasks, brain atrophy, and their associations.

Vascular disease risk factors in multiple sclerosis: Effect on metabolism and brain volumes.

BACKGROUND: Vascular disease risk factors (VDRF) such as hypertension, hyperlipidemia, obesity, diabetes and heart disease likely play a role in disease progression in people with multiple sclerosis (PwMS) (Marrie, Rudick et al. 2010). Studies exploring the mechanistic connection between vascular disease and MS disease progression are scant. We hypothesized that phosphate energy metabolism impairment in PwMS with VDRFs (VDRF+) will be greater compared to PwMS without VDRFs (VDRF-) and is related to increased brain atrophy in VDRF+. To test this hypothesis, we planned to study the differences in the high energy phosphate (HEP) metabolites in cerebral gray matter as assessed by 31P magnetic resonance spectroscopic imaging (MRSI) and MRI brain volumetric in the VDRF+ and VDRF- PwMS at four different timepoints over a 3 yearlong period using a 7T MR system. We present here the results from the cross-sectional evaluation of HEP metabolites and brain volumes. We also evaluated the differences in clinical impairment, blood metabolic biomarkers and quality of life in VDRF+ and VDRF- PwMS in this cohort. METHODS: Group differences in high energy phosphate metabolites were assessed from a volume of interest in the occipital region using linear mixed models. Brain parenchymal and white matter lesion volumes were determined from MR anatomic images. We present here the cross-sectional analysis of the baseline data collected as part of a longitudinal 3 yearlong study where we obtained baseline and subsequent 6-monthly clinical and laboratory data and annual 7T MRI volumetric and 31P MR spectroscopic imaging (MRSI) data on 52 PwMS with and without VDRF. Key clinical and laboratory outcomes included: body mass index (BMI), waist and thigh circumferences and disability [Expanded Disability Status Scale (EDSS)], safety (complete blood count with differential, complete metabolic), lipid panel including total cholesterol and HbA1C. We analyzed clinical and laboratory data for the group differences using student's t or χ2 test. We investigated relationship between phosphate metabolites and VDRF using mixed effect linear regression. RESULTS: Complete MRI data were available for 29 VDRF+, age 56.3 (6.8) years [mean (SD)] (83% female), and 23 VDRF-, age 52.5 (7.5) years (57% female) individuals with MS. The mean value of normalized adenosine triphosphate (ATP) (calculated as the ratio of ATP to total phosphate signal in a voxel) was decreased by 4.5% (p < .05) in VDRF+ compared to VDRF- MS group. White matter lesion (WML) volume fraction in VDRF+ individuals {0.007 (0.007)} was more than doubled compared to VDRF- participants {0.003 (0.006), p= .02}. CONCLUSIONS: We found significantly lower brain ATP and higher inorganic phosphate (Pi) in those PwMS with VDRFs compared to those without. ATP depletion may reflect mitochondrial dysfunction. Ongoing longitudinal data analysis from this study, not presented here, will evaluate the relationship of phosphate metabolites, brain atrophy and disease progression in PwMS with and without vascular disease.

Brain volumetrics across the lifespan of the rhesus macaque.

The rhesus macaque is a long-lived nonhuman primate (NHP) with a brain structure similar to humans, which may represent a valuable translational animal model in which to study human brain aging. Previous magnetic resonance imaging (MRI) studies of age in rhesus macaque brains have been prone to low statistical power, unbalanced sex ratio and lack of a complete age range. To overcome these problems, the current study surveyed structural T1-weighted magnetic resonance imaging scans of 66 animals, 34 females (aged 6-31 years) and 32 males (aged 5-27 years). Differences observed in older animals, included enlargement of the lateral ventricles and a smaller volume in the frontal cortex, caudate, putamen, hypothalamus, and thalamus. Unexpected, greater volume, were measured in older animals in the hippocampus, amygdala, and globus pallidus. There were also numerous differences between males and females with respect to age in both white and gray matter regions. As an apparent model of normative human aging, the macaque is ideal for studying induction and mitigation of neurodegenerative disease.

Metabolic activity diffusion imaging (MADI): I. Metabolic, cytometric modeling and simulations.

Evidence mounts that the steady-state cellular water efflux (unidirectional) first-order rate constant (kio [s-1 ]) magnitude reflects the ongoing, cellular metabolic rate of the cytolemmal Na+ , K+ -ATPase (NKA), c MRNKA (pmol [ATP consumed by NKA]/s/cell), perhaps biology's most vital enzyme. Optimal 1 H2 O MR kio determinations require paramagnetic contrast agents (CAs) in model systems. However, results suggest that the homeostatic metabolic kio biomarker magnitude in vivo is often too large to be reached with allowable or possible CA living tissue distributions. Thus, we seek a noninvasive (CA-free) method to determine kio in vivo. Because membrane water permeability has long been considered important in tissue water diffusion, we turn to the well-known diffusion-weighted MRI (DWI) modality. To analyze the diffusion tensor magnitude, we use a parsimoniously primitive model featuring Monte Carlo simulations of water diffusion in virtual ensembles comprising water-filled and -immersed randomly sized/shaped contracted Voronoi cells. We find this requires two additional, cytometric properties: the mean cell volume (V [pL]) and the cell number density (ρ [cells/µL]), important biomarkers in their own right. We call this approach metabolic activity diffusion imaging (MADI). We simulate water molecule displacements and transverse MR signal decays covering the entirety of b-space from pure water (ρ = V = 0; kio undefined; diffusion coefficient, D0 ) to zero diffusion. The MADI model confirms that, in compartmented spaces with semipermeable boundaries, diffusion cannot be described as Gaussian: the nanoscopic D (Dn ) is diffusion time-dependent, a manifestation of the "diffusion dispersion". When the "well-mixed" (steady-state) condition is reached, diffusion becomes limited, mainly by the probabilities of (1) encountering (ρ, V), and (2) permeating (kio ) cytoplasmic membranes, and less so by Dn magnitudes. Importantly, for spaces with large area/volume (A/V; claustrophobia) ratios, this can happen in less than a millisecond. The model matches literature experimental data well, with implications for DWI interpretations.

Metabolic activity diffusion imaging (MADI): II. Noninvasive, high-resolution human brain mapping of sodium pump flux and cell metrics.

We introduce a new 1 H2 O magnetic resonance approach: metabolic activity diffusion imaging (MADI). Numerical diffusion-weighted imaging decay simulations characterized by the mean cellular water efflux (unidirectional) rate constant (kio ), mean cell volume (V), and cell number density (ρ) are produced from Monte Carlo random walks in virtual stochastically sized/shaped cell ensembles. Because of active steady-state trans-membrane water cycling (AWC), kio reflects the cytolemmal Na+ , K+ ATPase (NKA) homeostatic cellular metabolic rate (c MRNKA ). A digital 3D "library" contains thousands of simulated single diffusion-encoded (SDE) decays. Library entries match well with disparate, animal, and human experimental SDE decays. The V and ρ values are consistent with estimates from pertinent in vitro cytometric and ex vivo histopathological literature: in vivo V and ρ values were previously unavailable. The library allows noniterative pixel-by-pixel experimental SDE decay library matchings that can be used to advantage. They yield proof-of-concept MADI parametric mappings of the awake, resting human brain. These reflect the tissue morphology seen in conventional MRI. While V is larger in gray matter (GM) than in white matter (WM), the reverse is true for ρ. Many brain structures have kio values too large for current, invasive methods. For example, the median WM kio is 22s-1 ; likely reflecting mostly exchange within myelin. The kio •V product map displays brain tissue c MRNKA variation. The GM activity correlates, quantitatively and qualitatively, with the analogous resting-state brain 18 FDG-PET tissue glucose consumption rate (t MRglucose ) map; but noninvasively, with higher spatial resolution, and no pharmacokinetic requirement. The cortex, thalamus, putamen, and caudate exhibit elevated metabolic activity. MADI accuracy and precision are assessed. The results are contextualized with literature overall homeostatic brain glucose consumption and ATP production/consumption measures. The MADI/PET results suggest different GM and WM metabolic pathways. Preliminary human prostate results are also presented.

Postmortem 7T MRI for guided histopathology and evaluation of cerebrovascular disease.

Postmortem (PM) magnetic resonance imaging (MRI) can serve as a bridge between in vivo imaging and histology by connecting MRI observed macrostructural findings to histological staining and microstructural changes. Data were acquired from 20 formalin-fixed brains including T2, T1, PD, and T2*-weighted images of left hemispheres and 6-mm-thick coronal slices. Tissue slices were bisected, aligned to MR images and used to guide histological sampling. Markers of myelin and oligodendroglia alterations were semiquantitatively rated and compared within white matter hyperintensities (WMHs) and normal-appearing white matter. Tissue priors were created from 3T in vivo data and used to guide segmentation of WMH. PM WMH and hemisphere volumes were compared to volumes derived from in vivo data. PM T2 WMH and T1 hemisphere volumes were correlated with in vivo 3T FLAIR WMH and T1 hemisphere volumes. WMH showed significant myelin loss, decreased GFAP expression and increased vimentin expression. MR-visible perivascular spaces and cortical microvascular lesions were successfully captured on histopathological sections. PM MRI can quantify cerebrovascular disease burden and guide tissue sampling, allowing for more comprehensive characterization of cerebrovascular disease that may be used to study etiologies of age-related cognitive change.

Evaluating Genetic Modifiers of Duchenne Muscular Dystrophy Disease Progression Using Modeling and MRI.

BACKGROUND AND OBJECTIVES: Duchenne muscular dystrophy (DMD) is a progressive muscle degenerative disorder with a well-characterized disease phenotype but considerable interindividual heterogeneity that is not well understood. The aim of this study was to evaluate the effects of dystrophin variations and genetic modifiers of DMD on rate and age of muscle replacement by fat. METHODS: One hundred seventy-five corticosteroid treated participants from the ImagingDMD natural history study underwent repeated magnetic resonance spectroscopy (MRS) of the vastus lateralis (VL) and soleus (SOL) to determine muscle fat fraction (FF). MRS was performed annually in most instances; however, some individuals had additional visits at 3 or 6 monthss intervals. FF changes over time were modeled using nonlinear mixed effects to estimate disease trajectories based on the age that the VL or SOL reached half-maximum change in FF (mu) and the time required for FF change (sigma). Computed mu and sigma values were evaluated for dystrophin variations that have demonstrated the ability to lead to a mild phenotype as well as compared between different genetic polymorphism groups. RESULTS: Participants with dystrophin gene deletions amenable to exon 8 skipping (n = 4) had minimal increases in SOL FF and had an increase in VL mu value by 4.4 years compared with a reference cohort (p = 0.039). Participants with nonsense variations within exons that may produce milder phenotypes (n = 11) also had minimal increases in SOL and VL FFs. No differences in estimated FF trajectories were seen for individuals amenable to exon 44 skipping (n = 10). Modeling of the SPP1, LTBP4, and thrombospondin-1 (THBS1) genetic modifiers did not result in significant differences in muscle FF trajectories between genotype groups (p > 0.05); however, trends were noted for the polymorphisms associated with long-range regulation of LTBP4 and THBS1 that deserve further follow-up. DISCUSSION: The results of this study link the historically mild phenotypes seen in individuals amenable to exon 8 skipping and with certain nonsense variations with alterations in trajectories of lower extremity muscle replacement by fat.

Immediate impact of yogic breathing on pulsatile cerebrospinal fluid dynamics.

Cerebrospinal fluid (CSF), a clear fluid bathing the central nervous system (CNS), undergoes pulsatile movements. Together with interstitial fluid, CSF plays a critical role for the removal of waste products from the brain, and maintenance of the CNS health. As such, understanding the mechanisms driving CSF movement is of high scientific and clinical impact. Since pulsatile CSF dynamics is sensitive and synchronous to respiratory movements, we are interested in identifying potential integrative therapies such as yogic breathing to regulate CSF dynamics, which has not been reported before. Here, we investigated the pre-intervention baseline data from our ongoing randomized controlled trial, and examined the impact of four yogic breathing patterns: (i) slow, (ii) deep abdominal, (iii) deep diaphragmatic, and (iv) deep chest breathing with the last three together forming a yogic breathing called three-part breath. We utilized our previously established non-invasive real-time phase contrast magnetic resonance imaging approach using a 3T MRI instrument, computed and tested differences in single voxel CSF velocities (instantaneous, respiratory, cardiac 1st and 2nd harmonics) at the level of foramen magnum during spontaneous versus yogic breathing. In examinations of 18 healthy participants (eight females, ten males; mean age 34.9 ± 14 (SD) years; age range: 18-61 years), we observed immediate increase in cranially-directed velocities of instantaneous-CSF 16-28% and respiratory-CSF 60-118% during four breathing patterns compared to spontaneous breathing, with the greatest changes during deep abdominal breathing (28%, p = 0.0008, and 118%, p = 0.0001, respectively). Cardiac pulsation was the primary source of pulsatile CSF motion except during deep abdominal breathing, when there was a comparable contribution of respiratory and cardiac 1st harmonic power [0.59 ± 0.78], suggesting respiration can be the primary regulator of CSF depending on the individual differences in breathing techniques. Further work is needed to investigate the impact of sustained training yogic breathing on pulsatile CSF dynamics for CNS health.

Step Activity Monitoring in Boys with Duchenne Muscular Dystrophy and its Correlation with Magnetic Resonance Measures and Functional Performance.

BACKGROUND: Muscles of boys with Duchenne muscular dystrophy (DMD) are progressively replaced by fatty fibrous tissues, and weakness leads to loss of ambulation (LoA). Step activity (SA) monitoring is a quantitative measure of real-world ambulatory function. The relationship between quality of muscle health and SA is unknown in DMD. OBJECTIVE: To determine SA in steroid treated boys with DMD across various age groups, and to evaluate the association of SA with quality of muscle health and ambulatory function. METHODS: Quality of muscle health was measured by magnetic resonance (MR) imaging transverse magnetization relaxation time constant (MRI-T2) and MR spectroscopy fat fraction (MRS-FF). SA was assessed via accelerometry, and functional abilities were assessed through clinical walking tests. Correlations between SA, MR, and functional measures were determined. A threshold value of SA was determined to predict the future LoA. RESULTS: The greatest reduction in SA was observed in the 9- < 11years age group. SA correlated with all functional and MR measures.10m walk/run test had the highest correlation with SA. An increase in muscle MRI-T2 and MRS-FF was associated with a decline in SA. Two years prior to LoA, SA in boys with DMD was 32% lower than age matched boys with DMD who maintained ambulation for more than two-year period. SA monitoring can predict subsequent LoA in Duchenne, as a daily step count of 3200 at baseline was associated with LoA over the next two-years. CONCLUSION: SA monitoring is a feasible and accessible tool to measure functional capacity in the real-world environment.

Development of Contractures in DMD in Relation to MRI-Determined Muscle Quality and Ambulatory Function.

BACKGROUND: Joint contractures are common in boys and men with Duchenne muscular dystrophy (DMD), and management of contractures is an important part of care. The optimal methods to prevent and treat contractures are controversial, and the natural history of contracture development is understudied in glucocorticoid treated individuals at joints beyond the ankle. OBJECTIVE: To describe the development of contractures over time in a large cohort of individuals with DMD in relation to ambulatory ability, functional performance, and muscle quality measured using magnetic resonance imaging (MRI) and spectroscopy (MRS). METHODS: In this longitudinal study, range of motion (ROM) was measured annually at the hip, knee, and ankle, and at the elbow, forearm, and wrist at a subset of visits. Ambulatory function (10 meter walk/run and 6 minute walk test) and MR-determined muscle quality (transverse relaxation time (T2) and fat fraction) were measured at each visit. RESULTS: In 178 boys with DMD, contracture prevalence and severity increased with age. Among ambulatory participants, more severe contractures (defined as greater loss of ROM) were significantly associated with worse ambulatory function, and across all participants, more severe contractures significantly associated with higher MRI T2 or MRS FF (ρ: 0.40-0.61 in the lower extremity; 0.20-0.47 in the upper extremity). Agonist/antagonist differences in MRI T2 were not strong predictors of ROM. CONCLUSIONS: Contracture severity increases with disease progression (increasing age and muscle involvement and decreasing functional ability), but is only moderately predicted by muscle fatty infiltration and MRI T2, suggesting that other changes in the muscle, tendon, or joint contribute meaningfully to contracture formation in DMD.

Characterizing Expiratory Respiratory Muscle Degeneration in Duchenne Muscular Dystrophy Using MRI.

BACKGROUND: Expiratory muscle weakness and impaired airway clearance are early signs of respiratory dysfunction in Duchenne muscular dystrophy (DMD), a degenerative muscle disorder in which muscle cells are damaged and replaced by fibrofatty tissue. Little is known about expiratory muscle pathology and its relationship to cough and airway clearance capacity; however, the level of muscle replacement by fat can be estimated using MRI and expressed as a fat fraction (FF). RESEARCH QUESTION: How does abdominal expiratory muscle fatty infiltration change over time in DMD and relate to clinical expiratory function? STUDY DESIGN AND METHODS: Individuals with DMD underwent longitudinal MRI of the abdomen to determine FF in the internal oblique, external oblique, and rectus abdominis expiratory muscles. FF data were used to estimate a model of expiratory muscle degeneration by using nonlinear mixed effects and a cumulative distribution function. FVC, maximal inspiratory and expiratory pressures, and peak cough flow were collected as clinical correlates to MRI. RESULTS: Forty individuals with DMD (aged 6-18 years at baseline) participated in up to five visits over 36 months. Modeling estimated the internal oblique progresses most quickly and reached 50% replacement by fat at a mean patient age of 13.0 years (external oblique, 14.0 years; rectus abdominis, 16.2 years). Corticosteroid-untreated individuals (n = 4) reached 50% muscle replacement by fat 3 to 4 years prior to treated individuals. Individuals with mild clinical dystrophic phenotypes (n = 3) reached 50% muscle replacement by fat 4 to 5 years later than corticosteroid-treated individuals. Internal and external oblique FFs near 50% were associated with maximal expiratory pressures < 60 cm H2O and peak cough flows < 270 L/min. INTERPRETATION: These data improve understanding of the early phase of respiratory compromise in DMD, which typically presents as airway clearance dysfunction prior to the onset of hypoventilation, and links expiratory muscle fatty infiltration to pulmonary function measures.

DCE-MRI of Brain Fluid Barriers: In Vivo Water Cycling at the Human Choroid Plexus.

Metabolic deficits at brain-fluid barriers are an increasingly recognized feature of cognitive decline in older adults. At the blood-cerebrospinal fluid barrier, water is transported across the choroid plexus (CP) epithelium against large osmotic gradients via processes tightly coupled to activity of the sodium/potassium pump. Here, we quantify CP homeostatic water exchange using dynamic contrast-enhanced MRI and investigate the association of the water efflux rate constant (kco) with cognitive dysfunction in older individuals. Temporal changes in the longitudinal relaxation rate constant (R1) after contrast agent bolus injection were measured in a CP region of interest in 11 participants with mild cognitive dysfunction [CI; 73 ± 6 years] and 28 healthy controls [CN; 72 ± 7 years]. kco was determined from a modified two-site pharmacokinetic exchange analysis of the R1 time-course. Ktrans, a measure of contrast agent extravasation to the interstitial space was also determined. Cognitive function was assessed by neuropsychological test performance. kco averages 5.8 ± 2.7 s-1 in CN individuals and is reduced by 2.4 s-1 [ca. 40%] in CI subjects. Significant associations of kco with global cognition and multiple cognitive domains are observed. Ktrans averages 0.13 ± 0.07 min-1 and declines with age [-0.006 ± 0.002 min-1 yr-1], but shows no difference between CI and CN individuals or association with cognitive performance. Our findings suggest that the CP water efflux rate constant is associated with cognitive dysfunction and shows an age-related decline in later life, consistent with the metabolic disturbances that characterize brain aging.

Gray matter blood-brain barrier water exchange dynamics are reduced in progressive multiple sclerosis.

BACKGROUND AND PURPOSE: To compare transcapillary wall water exchange, a putative marker of cerebral metabolic health, in brain T2 white matter (WM) lesions and normal appearing white and gray matter (NAWM and NAGM, respectively) in individuals with progressive multiple sclerosis (PMS) and healthy controls (HC). METHODS: Dynamic-contrast-enhanced 7T MRI data were obtained from 19 HC and 23 PMS participants. High-resolution pharmacokinetic parametric maps representing tissue microvascular and microstructural properties were created by shutter-speed (SS) paradigm modeling to obtain estimates of blood volume fraction (vb ), water molecule capillary efflux rate constant (kpo ), and the water capillary wall permeability surface area product (Pw S ≡ vb *kpo ). Linear regression models were used to investigate differences in (i) kpo and Pw S between groups in NAWM and NAGM, and (ii) between WM lesions and NAWM in PMS. RESULTS: High-resolution parametric maps were produced to visualize tissue classes and resolve individual WM lesions. Normal-appearing gray matter kpo and Pw S were significantly decreased in PMS compared to HC (p ≤ .01). Twenty-one T2 WM lesions were analyzed in 10 participants with PMS. kpo was significantly decreased in WM lesions compared to PMS NAWM (p < .0001). CONCLUSIONS: Transcapillary water exchange is reduced in PMS NAGM compared to HC and is further reduced in PMS WM lesions, suggesting pathologically impaired brain metabolism. kpo provides a sensitive measure of cerebral metabolic activity and/or coupling, and can be mapped at higher spatial resolution than conventional imaging techniques assessing metabolic activity.