Associations between vascular health, brain stiffness and global cognitive function.

Vascular brain injury results in loss of structural and functional connectivity and leads to cognitive impairment. Its various manifestations, including microinfarcts, microhaemorrhages and white matter hyperintensities, result in microstructural tissue integrity loss and secondary neurodegeneration. Among these, tissue microstructural alteration is a relatively early event compared with atrophy along the aging and neurodegeneration continuum. Understanding its association with cognition may provide the opportunity to further elucidate the relationship between vascular health and clinical outcomes. Magnetic resonance elastography offers a non-invasive approach to evaluate tissue mechanical properties, providing a window into the microstructural integrity of the brain. This retrospective study evaluated brain stiffness as a potential biomarker for vascular brain injury and its role in mediating the impact of vascular dysfunction on cognitive impairment. Seventy-five participants from the Mayo Clinic Study of Aging underwent brain imaging using a 3T MR imager with a spin-echo echo-planar imaging sequence for magnetic resonance elastography and T1- and T2-weighted pulse sequences. This study evaluated the effects of vascular biomarkers (white matter hyperintensities and cardiometabolic condition score) on brain stiffness using voxelwise analysis. Partial correlation analysis explored associations between brain stiffness, white matter hyperintensities, cardiometabolic condition and global cognition. Mediation analysis determined the role of stiffness in mediating the relationship between vascular biomarkers and cognitive performance. Statistical significance was set at P-values < 0.05. Diagnostic accuracy of magnetic resonance elastography stiffness for white matter hyperintensities and cardiometabolic condition was evaluated using receiver operator characteristic curves. Voxelwise linear regression analysis indicated white matter hyperintensities negatively correlate with brain stiffness, specifically in periventricular regions with high white matter hyperintensity levels. A negative association between cardiovascular risk factors and stiffness was also observed across the brain. No significant patterns of stiffness changes were associated with amyloid load. Global stiffness (µ) negatively correlated with both white matter hyperintensities and cardiometabolic condition when all other covariables including amyloid load were controlled. The positive correlation between white matter hyperintensities and cardiometabolic condition weakened and became statistically insignificant when controlling for other covariables. Brain stiffness and global cognition were positively correlated, maintaining statistical significance after adjusting for all covariables. These findings suggest mechanical alterations are associated with cognitive dysfunction and vascular brain injury. Brain stiffness significantly mediated the indirect effects of white matter hyperintensities and cardiometabolic condition on global cognition. Local cerebrovascular diseases (assessed by white matter hyperintensities) and systemic vascular risk factors (assessed by cardiometabolic condition) impact brain stiffness with spatially and statistically distinct effects. Global brain stiffness is a significant mediator between vascular disease measures and cognitive function, highlighting the value of magnetic resonance elastography-based mechanical assessments in understanding this relationship.

Differential effect of dementia etiology on cortical stiffness as assessed by MR elastography.

BACKGROUND: Aging and dementia involve the disruption of brain molecular pathways leading to the alterations in tissue composition and gross morphology of the brain. Phenotypic and biomarker overlap between various etiologies of dementia supports a need for new modes of information to more accurately distinguish these disorders. Brain mechanical properties, which can be measured noninvasively by MR elastography, represent one understudied feature that are sensitive to neurodegenerative processes. In this study, we used two stiffness estimation schemes to test the hypothesis that different etiologies of dementia are associated with unique patterns of mechanical alterations across the cerebral cortex. METHODS: MR elastography data were acquired for six clinical groups including amyloid-negative cognitively unimpaired (CU), amyloid-positive cognitively unimpaired (A + CU), amyloid-positive participants with mild cognitive impairment (A + MCI), amyloid-positive participants with Alzheimer's clinical syndrome (A + ACS), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Stiffness maps were computed using two neural network inversions with the objective to at least partially separate the parenchyma-specific and morphological effects of neurodegeneration on mechanical property estimates. A tissue-confined inversion algorithm was designed to obtain the best estimate of stiffness in the brain parenchyma itself, while a regionally-aware inversion algorithm was used to measure the tissue stiffness along with the surroundings. Mean stiffness of 15 bilateral gray matter cortical regions were considered for statistical analysis. First, we tested the hypothesis that cortical stiffness changes in the aging brain. Next, we tested the overall study hypothesis by first comparing stiffness in each clinical group to the CU group, and then comparing the clinical groups against one another. Finally, we assessed the spatial and statistical overlap between atrophy and stiffness changes for both inversions. RESULTS: Cortical brain regions become softer with age for both inversions with larger effects observed using regionally-aware stiffness. Stiffness decreases in the range 0.010-0.027 kPa per year were observed. Pairwise comparisons of each clinical group with cognitively unimpaired participants demonstrated 5 statistically significant differences in stiffness for tissue-confined measurements and 19 statistically different stiffness changes for the regionally-aware stiffness measurements. Pairwise comparisons between clinical groups further demonstrated unique patterns of stiffness differences. Analysis of the atrophy-versus-stiffness relationship showed that regionally-aware stiffness measurements exhibit higher sensitivity to neurodegeneration with findings that are not fully explained by partial volume effects or atrophy. CONCLUSIONS: Both tissue-confined and regionally-aware stiffness estimates exhibited unique and complementary stiffness differences in various etiologies of dementia. Our results suggest that mechanical alterations measured by MRE reflect both tissue-specific differences as well as environmental effects. Multi-inversion schemes in MRE may provide new insights into the relationships between neuropathology and brain biomechanics.

High-fidelity control of spin ensemble dynamics via artificial intelligence: from quantum computing to NMR spectroscopy and imaging.

High-fidelity control of spin ensemble dynamics is essential for many research areas, spanning from quantum computing and radio-frequency (RF) engineering to NMR spectroscopy and imaging. However, attaining robust and high-fidelity spin operations remains an unmet challenge. Using an evolutionary algorithm and artificial intelligence (AI), we designed new RF pulses with customizable spatial or temporal field inhomogeneity compensation. Compared with the standard RF shapes, the new AI-generated pulses show superior performance for bandwidth, robustness, and tolerance to field imperfections. As a benchmark, we constructed a spin entanglement operator for the weakly coupled two-spin-1/2 system of 13CHCl3, achieving high-fidelity transformations under multiple inhomogeneity sources. We then generated band-selective and ultra-broadband RF pulses typical of biomolecular NMR spectroscopy. When implemented in multipulse NMR experiments, the AI-generated pulses significantly increased the sensitivity of medium-size and large protein spectra relative to standard pulse sequences. Finally, we applied the new pulses to typical imaging experiments, showing a remarkable tolerance to changes in the RF field. These AI-generated RF pulses can be directly implemented in quantum information, NMR spectroscopy of biomolecules, magnetic resonance imaging techniques for in vivo and materials sciences.

Design and applications of water irradiation devoid RF pulses for ultra-high field biomolecular NMR spectroscopy.

Water suppression is of paramount importance for many biological and analytical NMR spectroscopy applications. Here, we report the design of a new set of binomial-like radio frequency (RF) pulses that elude water irradiation while exciting or refocusing the remainder of the 1H spectrum. These pulses were generated using a combination of an evolutionary algorithm and artificial intelligence. They display higher sensitivity relative to classical water suppression schemes and tunable water selectivity to avoid suppressing 1H resonances near the water signal. The broad bandwidth excitation obtained with these RF pulses makes them suitable for several NMR applications at high and ultra-high-field magnetic fields.

Impact of material homogeneity assumption on cortical stiffness estimates by MR elastography.

PURPOSE: Inversion algorithms used to convert acquired MR elastography wave data into material property estimates often assume that the underlying materials are locally homogeneous. Here we evaluate the impact of that assumption on stiffness estimates in gray-matter regions of interest in brain MR elastography. METHODS: We describe an updated neural network inversion framework using finite-difference model-derived data to train convolutional neural network inversion algorithms. Neural network inversions trained on homogeneous simulations (homogeneous learned inversions [HLIs]) or inhomogeneous simulations (inhomogeneous learned inversions [ILIs]) are generated with a variety of kernel sizes. These inversions are evaluated in a brain MR elastography simulation experiment and in vivo in a test-retest repeatability experiment including 10 healthy volunteers. RESULTS: In simulation and in vivo, HLI and ILI with small kernels produce similar results. As kernel size increases, the assumption of homogeneity has a larger effect, and HLI and ILI stiffness estimates show larger differences. At each inversion's optimal kernel size in simulation (7 × 7 × 7 for HLI, 11 × 11 × 11 for ILI), ILI is more sensitive to true changes in stiffness in gray-matter regions of interest in simulation. In vivo, there is no difference in the region-level repeatability of stiffness estimates between the inversions, although ILI appears to better maintain the stiffness map structure as kernel size increases, while decreasing the spatial variance in stiffness estimates. CONCLUSIONS: This study suggests that inhomogeneous inversions provide small but significant benefits even when large stiffness gradients are absent.

Unlabeled aspirin as an activatable theranostic MRI agent for breast cancer.

Rationale: Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is emerging as an alternative to gadolinium-based contrast MRI. We have evaluated the possibility of CEST MRI of orthotopic breast tumor xenografts with unlabeled aspirin's conversion to salicylic acid (SA) through various enzymatic activities, most notably inhibition of cyclooxygenase (COX)-1/-2 enzymes. Methods: We measured the COX-1/-2 expression in four breast cancer cell lines by Western Blot analysis and selected the highest and lowest expressing cell lines. We then performed CEST MRI following aspirin treatment to detect SA levels and ELISA to measure levels of downstream prostaglandin E2 (PGE2). We also injected aspirin into the tail vein of mice growing orthotopic tumor xenografts which expressed high and low COX-1/-2 and acquired SA CEST MR images of these tumor xenografts for up to 70 minutes. Tumors were then harvested to perform Western Blot and ELISA experiments to measure COX-1/-2 expression and PGE2 levels, respectively. Results: Western Blots determined that SUM159 cells contained significantly higher COX-1/-2 expression levels than MDA-MB-231 cells, in line with higher levels of downstream PGE2. SA CEST MRI yielded similar contrast at approximately 3% for both cell lines, independent of COX-1/-2 expression level. PGE2 levels decreased by about 50% following aspirin treatment. Results from our mouse study aligned with cultured cells, the overall SA CEST MRI contrast in both MDA-MB-231 and SUM159 tumor xenograft models was 5~8% at one hour post injection. PGE2 levels were ten times higher in SUM159 than MDA-MB-231 and decreased by 50%. The CEST contrast directly depended on the injected dose, with ~6%, ~3% and ~1.5% contrast observed following injection of 100 µL of 300 mM, 200 mM and 150 mM aspirin, respectively. Conclusions: Our data demonstrate the feasibility of using aspirin as a noninvasive activatable CEST MRI contrast agent for breast tumor detection.

Dynamic Contrast Enhanced-MR CEST Urography: An Emerging Tool in the Diagnosis and Management of Upper Urinary Tract Obstruction.

Upper urinary tract obstructions (UTOs) are blockages that inhibit the flow of urine through its normal course, leading to impaired kidney function. Imaging plays a significant role in the initial diagnosis of UTO, with anatomic imaging (primarily ultrasound (US) and non-contrast computed tomography (CT)) serving as screening tools for the detection of the dilation of the urinary collecting systems (i.e., hydronephrosis). Whether hydronephrosis represents UTO or a non-obstructive process is determined by functional imaging (typically nuclear medicine renal scintigraphy). If these exams reveal evidence of UTO but no discernable source, multiphase contrast enhanced CT urography and/or dynamic contrast enhanced MR urography (DCE-MRU) may be performed to delineate a cause. These are often performed in conjunction with direct ureteroscopic evaluation. While contrast-enhanced CT currently predominates, it can induce renal injury due to contrast induced nephropathy (CIN), subject patients to ionizing radiation and is limited in quantifying renal function (traditionally assessed by renal scintigraphy) and establishing the extent to which hydronephrosis is due to functional obstruction. Traditional MRI is similarly limited in its ability to quantify function. DCE-MRU presents concerns regarding nephrogenic systemic fibrosis (NSF), although decreased with newer gadolinium-based contrast agents, and regarding cumulative gadolinium deposition in the basal ganglia. DCE-MR CEST urography is a promising alternative, employing new MRI contrast agents and imaging schemes and allowing for concurrent assessment of renal anatomy and functional parameters. In this review we highlight clinical challenges in the diagnosis and management of UTO, identify key advances in imaging agents and techniques for DCE-MR CEST urography and provide perspective on how this technique may evolve in clinical importance.

Amplified detection of phosphocreatine and creatine after supplementation using CEST MRI at high and ultrahigh magnetic fields.

Creatine is an important metabolite involved in muscle contraction. Administration of exogenous creatine (Cr) or phosphocreatine (PCr) has been used for improving exercise performance and protecting the heart during surgery including during valve replacements, coronary artery bypass grafting and repair of congenital heart defects. In this work we investigate whether it is possible to use chemical exchange saturation transfer (CEST) MRI to monitor uptake and clearance of exogenous creatine and phosphocreatine following supplementation. We were furthermore interested in determining the limiting conditions for distinguishing between creatine (1.9 ppm) and phosphocreatine (2.6 ppm) signals at ultra-high fields (21 T) and determine their concentrations could be reliably obtained using Bloch equation fits of the experimental CEST spectra. We have tested these items by performing CEST MRI of hind limb muscle and kidneys at 11.7 T and 21.1 T both before and after intravenous administration of PCr. We observed up to 4% increase in contrast in the kidneys at 2.6 ppm which peaked ~30 min after administration and a relative ratio of 1.3 in PCr:Cr signal. Overall, these results demonstrate the feasibility of independent monitoring of PCr and Cr concentration changes using CEST MRI.

Noninvasive monitoring of chronic kidney disease using pH and perfusion imaging.

Chronic Kidney Disease (CKD) is a cardinal feature of methylmalonic acidemia (MMA), a prototypic organic acidemia. Impaired growth, low activity, and protein restriction affect muscle mass and lower serum creatinine, which can delay diagnosis and management of renal disease. We have designed an alternative strategy for monitoring renal function based on administration of a pH sensitive MRI agent and assessed this in a mouse model. This protocol produced three metrics: kidney contrast, ~4% for severe renal disease mice compared to ~13% and ~25% for moderate renal disease and healthy controls, filtration fraction (FF), ~15% for severe renal disease mice compared to ~79% and 100% for moderate renal disease and healthy controls, and variation in pH, ~0.45 units for severe disease mice compared to 0.06 and 0.01 for moderate disease and healthy controls. Our results demonstrate that MRI can be used for early detection and monitoring of CKD.

Gradient echo single scan inversion recovery: application to proton and fluorine relaxation studies.

Single scan longitudinal relaxation measurement experiments enable rapid estimation of the spin-lattice relaxation time (T1 ) as the time series of spin relaxation is encoded spatially in the sample at different slices resulting in an order of magnitude saving in time. We consider here a single scan inversion recovery pulse sequence that incorporates a gradient echo sequence. The proposed pulse sequence provides spectra with significantly enhanced signal to noise ratio leading to an accurate estimation of T1 values. The method is applicable for measuring a range of T1 values, thus indicating the possibility of routine use of the method for several systems. A comparative study of different single scan methods currently available is presented, and the advantage of the proposed sequence is highlighted. The possibility of the use of the method for the study of cross-correlation effects for the case of fluorine in a single shot is also demonstrated.