Neuroimaging findings and neurological manifestations in hospitalized COVID-19 patients: Impact of cancer and ventilatory support status.

INTRODUCTION: Coronavirus 2019 (COVID-19) is known to affect the central nervous system. Neurologic morbidity associated with COVID-19 is commonly attributed to sequelae of some combination of thrombotic and inflammatory processes. The aim of this retrospective observational study was to evaluate neuroimaging findings in hospitalized COVID-19 patients with neurological manifestations in cancer versus non-cancer patients, and in patients with versus without ventilatory support (with ventilatory support defined as including patients with intubation and noninvasive ventilation). Cancer patients are frequently in an immunocompromised or prothrombotic state with side effects from chemotherapy and radiation that may cause neurological issues and increase vulnerability to systemic illness. We wanted to determine whether neurological and/or neuroimaging findings differed between patients with and without cancer. METHODS: Eighty adults (44 male, 36 female, 64.5 ±14 years) hospitalized in the Mount Sinai Health System in New York City between March 2020 and April 2021 with reverse-transcriptase polymerase chain reaction-confirmed COVID-19 underwent magnetic resonance imaging (MRI) during their admissions. The cohort consisted of four equal subgroups based on cancer and ventilatory support status. Clinical and imaging data were acquired and analyzed. RESULTS: Neuroimaging findings included non-ischemic parenchymal T2/FLAIR signal hyperintensities (36.3%), acute/subacute infarcts (26.3%), chronic infarcts (25.0%), microhemorrhages (23.8%), chronic macrohemorrhages (10.0%), acute macrohemorrhages (7.5%), and encephalitis-like findings (7.5%). There were no significant differences in neuroimaging findings between cancer and non-cancer subgroups. Clinical neurological manifestations varied. The most common was encephalopathy (77.5%), followed by impaired responsiveness/coma (38.8%) and stroke (26.3%). There were significant differences between patients with versus without ventilatory support. Encephalopathy and impaired responsiveness/coma were more prevalent in patients with ventilatory support (p = 0.02). Focal weakness was more frequently seen in patients without ventilatory support (p = 0.01). DISCUSSION: This study suggests COVID-19 is associated with neurological manifestations that may be visible with brain imaging techniques such as MRI. In our COVID-19 cohort, there was no association between cancer status and neuroimaging findings. Future studies might include more prospectively enrolled systematically characterized patients, allowing for more rigorous statistical analysis.

Phosphorus metabolism in the brain of cognitively normal midlife individuals at risk for Alzheimer's disease.

Background: Neurometabolic abnormalities and amyloid-beta plaque deposition are important early pathophysiologic changes in Alzheimer's disease (AD). This study investigated the relationship between high-energy phosphorus-containing metabolites, glucose uptake, and amyloid plaque using phosphorus magnetic resonance spectroscopy (31P-MRS) and positron emission tomography (PET). Methods: We measured 31P-MRS, fluorodeoxyglucose (FDG)-PET, and Pittsburgh Compound B (PiB)-PET in a cohort of 20 cognitively normal middle-aged adults at risk for AD. We assessed 31P-MRS reliability by scanning a separate cohort of 13 healthy volunteers twice each. We calculated the coefficient-of-variation (CV) of metabolite ratios phosphocreatine-to-adenosine triphosphate (PCr/α-ATP), inorganic phosphate (Pi)-to-α-ATP, and phosphomonoesters-to-phosphodiesters (PME/PDE), and pH in pre-defined brain regions. We performed linear regression analysis to determine the relationship between 31P measurements and tracer uptake, and Dunn's multiple comparison tests to investigate regional differences in phosphorus metabolism. Finally, we performed linear regression analysis on 31P-MRS measurements in both cohorts to investigate the relationship of phosphorus metabolism with age. Results: Most regional 31P metabolite ratio and pH inter- and intra-day CVs were well below 10%. There was an inverse relationship between FDG-SUV levels and metabolite ratios PCr/α-ATP, Pi/α-ATP, and PME/PDE in several brain regions in the AD risk group. There were also several regional differences among 31P metabolites and pH in the AD risk group including elevated PCr/α-ATP, depressed PME/PDE, and elevated pH in the temporal cortices. Increased PCr/α-ATP throughout the brain was associated with aging. Conclusions: Phosphorus spectroscopy in the brain can be performed with high repeatability. Phosphorus metabolism varies with region and age, and is related to glucose uptake in adults at risk for AD. Phosphorus spectroscopy may be a valuable approach to study early changes in brain energetics in high-risk populations.

Semi-automated Segmentation and Quantification of Perivascular Spaces at 7 Tesla in COVID-19.

While COVID-19 is primarily considered a respiratory disease, it has been shown to affect the central nervous system. Mounting evidence shows that COVID-19 is associated with neurological complications as well as effects thought to be related to neuroinflammatory processes. Due to the novelty of COVID-19, there is a need to better understand the possible long-term effects it may have on patients, particularly linkage to neuroinflammatory processes. Perivascular spaces (PVS) are small fluid-filled spaces in the brain that appear on MRI scans near blood vessels and are believed to play a role in modulation of the immune response, leukocyte trafficking, and glymphatic drainage. Some studies have suggested that increased number or presence of PVS could be considered a marker of increased blood-brain barrier permeability or dysfunction and may be involved in or precede cascades leading to neuroinflammatory processes. Due to their size, PVS are better detected on MRI at ultrahigh magnetic field strengths such as 7 Tesla, with improved sensitivity and resolution to quantify both concentration and size. As such, the objective of this prospective study was to leverage a semi-automated detection tool to identify and quantify differences in perivascular spaces between a group of 10 COVID-19 patients and a similar subset of controls to determine whether PVS might be biomarkers of COVID-19-mediated neuroinflammation. Results demonstrate a detectable difference in neuroinflammatory measures in the patient group compared to controls. PVS count and white matter volume were significantly different in the patient group compared to controls, yet there was no significant association between PVS count and symptom measures. Our findings suggest that the PVS count may be a viable marker for neuroinflammation in COVID-19, and other diseases which may be linked to neuroinflammatory processes.

Design, Construction, and Implementation of a Magnetic Resonance Elastography Actuator for Research Purposes.

Magnetic resonance elastography (MRE) is a technique for determining the mechanical response of soft materials using applied harmonic deformation of the material and a motion-sensitive magnetic resonance imaging sequence. This technique can elucidate significant information about the health and development of human tissue such as liver and brain, and has been used on phantom models (e.g., agar, silicone) to determine their suitability for use as a mechanical surrogate for human tissues in experimental models. The applied harmonic deformation used in MRE is generated by an actuator, transmitted in bursts of a specified duration, and synchronized with the magnetic resonance signal excitation. These actuators are most often a pneumatic design (common for human tissues or phantoms) or a piezoelectric design (common for small animal tissues or phantoms). Here, we describe how to design and assemble both a pneumatic and a piezoelectric MRE actuator for research purposes. For each of these actuator types, we discuss displacement requirements, end-effector options and challenges, electronics and electronic-driving requirements and considerations, and full MRE implementation. We also discuss how to choose the actuator type, size, and power based on the intended material and use. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Design, construction, and implementation of a convertible pneumatic MRE actuator for use with tissues and phantom models Basic Protocol 2: Design, construction, and implementation of a piezoelectric MRE actuator for localized excitation in phantom models.

Dynamic phosphocreatine imaging with unlocalized pH assessment of the human lower leg muscle following exercise at 3T.

PURPOSE: To develop a high temporal resolution imaging method that measures muscle-specific phosphocreatine (PCr) resynthesis time constant (τPCr ) and pH changes in muscles of the lower leg following exercise on a clinical 3T MRI scanner. METHODS: We developed a frequency-selective 3D non-Cartesian FLORET sequence to measure PCr with 17-mm nominal isotropic resolution (28 mm actual resolution) and 6-s temporal resolution to capture dynamic metabolic muscle activity. The sequence was designed to additionally collect inorganic phosphate spectra for pH quantification, which were localized using sensitivity profiles of individual coil elements. Nineteen healthy volunteers were scanned while performing a plantar flexion exercise on an in-house developed ergometer. Data were acquired with a dual-tuned multichannel coil array that enabled phosphorus imaging and proton localization for muscle segmentation. RESULTS: After a 90-s plantar flexion exercise at 0.66 Hz with resistance set to 40% of the maximum voluntary contraction, τPCr was estimated at 22.9 ± 8.8 s (mean ± standard deviation) with statistical coefficient of determination r2 = 0.89 ± 0.05. The corresponding pH values after exercise were in the range of 6.9-7.1 in the gastrocnemius muscle. CONCLUSION: The developed technique allows measurement of muscle-specific PCr resynthesis kinetics and pH changes following exercise, with a temporal resolution and accuracy comparable to that of single voxel 31 P-MRS sequences. Magn Reson Med 79:974-980, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

A low-cost Mr compatible ergometer to assess post-exercise phosphocreatine recovery kinetics.

OBJECTIVE: To develop a low-cost pedal ergometer compatible with ultrahigh (7 T) field MR systems to reliably quantify metabolic parameters in human lower leg muscle using phosphorus magnetic resonance spectroscopy. MATERIALS AND METHODS: We constructed an MR compatible ergometer using commercially available materials and elastic bands that provide resistance to movement. We recruited ten healthy subjects (eight men and two women, mean age ± standard deviation: 32.8 ± 6.0 years, BMI: 24.1 ± 3.9 kg/m2). All subjects were scanned on a 7 T whole-body magnet. Each subject was scanned on two visits and performed a 90 s plantar flexion exercise at 40% maximum voluntary contraction during each scan. During the first visit, each subject performed the exercise twice in order for us to estimate the intra-exam repeatability, and once during the second visit in order to estimate the inter-exam repeatability of the time constant of phosphocreatine recovery kinetics. We assessed the intra and inter-exam reliability in terms of the within-subject coefficient of variation (CV). RESULTS: We acquired reliable measurements of PCr recovery kinetics with an intra- and inter-exam CV of 7.9% and 5.7%, respectively. CONCLUSION: We constructed a low-cost pedal ergometer compatible with ultrahigh (7 T) field MR systems, which allowed us to quantify reliably PCr recovery kinetics in lower leg muscle using 31P-MRS.

Magnetic Resonance Imaging of Phosphocreatine and Determination of BOLD Kinetics in Lower Extremity Muscles using a Dual-Frequency Coil Array.

Magnetic resonance imaging (MRI) provides the unique ability to study metabolic and microvasculature functions in skeletal muscle using phosphorus and proton measurements. However, the low sensitivity of these techniques can make it difficult to capture dynamic muscle activity due to the temporal resolution required for kinetic measurements during and after exercise tasks. Here, we report the design of a dual-nuclei coil array that enables proton and phosphorus MRI of the human lower extremities with high spatial and temporal resolution. We developed an array with whole-volume coverage of the calf and a phosphorus signal-to-noise ratio of more than double that of a birdcage coil in the gastrocnemius muscles. This enabled the local assessment of phosphocreatine recovery kinetics following a plantar flexion exercise using an efficient sampling scheme with a 6 s temporal resolution. The integrated proton array demonstrated image quality approximately equal to that of a clinical state-of-the-art knee coil, which enabled fat quantification and dynamic blood oxygen level-dependent measurements that reflect microvasculature function. The developed array and time-efficient pulse sequences were combined to create a localized assessment of calf metabolism using phosphorus measurements and vasculature function using proton measurements, which could provide new insights into muscle function.

Increased Water Diffusion in the Parcellated Cortical Regions from the Patients with Amnestic Mild Cognitive Impairment and Alzheimer's Disease.

Background: The loss of cortical neuron environment integrity is the hallmark of neurodegeneration diseases such as Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). To reveal the microenvironment changes in cerebral cortex, the current study aimed to examine the changes of mean diffusivity (MD) in parcellated brain among AD, aMCI patients and normal controls (NC). Methods: Diffusion tensor imaging data with the whole brain coverage were acquired from 28 AD (aged 69.4 ± 8.2 year old), 41 aMCI patients (aged 68.2 ± 6.4 year old) and 40 NC subjects (aged 65.7 ± 6.4 year old). Subsequently, the MD values were parcellated according to the standard automatic anatomic labeling (AAL) template. Only the 90 regions located in the cerebral cortex were used in the final analysis. The mean values of MD from each brain region were extracted and compared among the participant groups. The integrity of the white matter tracts and gray matter atrophy was analyzed using the track-based spatial statistics and voxel-based morphometry approaches, respectively. Results: Significant differences of MD were noticed both in aMCI and AD patients, in terms of the affected regions and the amount of increase. The hippocampus, parahippocampal gyrus and cingulum were the most significantly affected regions in AD patients. From all the 90 cerebral cortex regions, significant increase of MD in the AD patients was found in 40 regions, compared to only one (fusiform gyrus on the right) in aMCI patients. In the disease affected regions, the MD from aMCI patients is in state between NC and AD patients. Conclusions: Increased MD in the specific regions of the brain shows the feasibility of MD as an indicator of the early stage cortical degeneration in aMCI and AD patients.

Multisite Kinetic Modeling of (13)C Metabolic MR Using [1-(13)C]Pyruvate.

Hyperpolarized (13)C imaging allows real-time in vivo measurements of metabolite levels. Quantification of metabolite conversion between [1-(13)C]pyruvate and downstream metabolites [1-(13)C]alanine, [1-(13)C]lactate, and [(13)C]bicarbonate can be achieved through kinetic modeling. Since pyruvate interacts dynamically and simultaneously with its downstream metabolites, the purpose of this work is the determination of parameter values through a multisite, dynamic model involving possible biochemical pathways present in MR spectroscopy. Kinetic modeling parameters were determined by fitting the multisite model to time-domain dynamic metabolite data. The results for different pyruvate doses were compared with those of different two-site models to evaluate the hypothesis that for identical data the uncertainty of a model and the signal-to-noise ratio determine the sensitivity in detecting small physiological differences in the target metabolism. In comparison to the two-site exchange models, the multisite model yielded metabolic conversion rates with smaller bias and smaller standard deviation, as demonstrated in simulations with different signal-to-noise ratio. Pyruvate dose effects observed previously were confirmed and quantified through metabolic conversion rate values. Parameter interdependency allowed an accurate quantification and can therefore be useful for monitoring metabolic activity in different tissues.

Multimodal assessment of in vivo metabolism with hyperpolarized [1-13C]MR spectroscopy and 18F-FDG PET imaging in hepatocellular carcinoma tumor-bearing rats.

UNLABELLED: Abnormalities of tumor metabolism can be exploited for molecular imaging. PET imaging of (18)F-FDG is a well-established method using the avid glucose uptake of tumor cells. (13)C MR spectroscopic imaging (MRSI) of hyperpolarized [1-(13)C]pyruvate and its metabolites, meanwhile, represents a new method to study energy metabolism by visualizing, for example, the augmented lactate dehydrogenase activity in tumor cells. Because of rapid signal loss, this method underlies strict temporal limitations, and the acquisition of data-encoding spatial, temporal, and spectral information within this time frame-is challenging. The object of our study was to compare spectroscopic images with (18)F-FDG PET images for visualizing tumor metabolism in a rat model. METHODS: (13)C MRSI with IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation) chemical shift imaging in combination with single-shot spiral acquisition was used to obtain dynamic data from 23 rats bearing a subcutaneous hepatocellular carcinoma and from reference regions of the same animals. Static and dynamic analysis of (18)F-FDG PET images of the same animals was performed. The data were analyzed qualitatively (visual assessment) and quantitatively (magnitude and dynamics of (18)F-FDG uptake, (13)C MRSI dynamics, and physiologic parameters). RESULTS: In most animals increased [1-(13)C]lactate signals in the tumor could be detected by simple display of integrated [1-(13)C]lactate images with corresponding enhanced (18)F-FDG uptake. Low [1-(13)C]pyruvate or [1-(13)C]lactate signals did not correlate with histologic or physiologic parameters. Significantly less pyruvate reached the tumors than the gastrointestinal tract, but in tumors a significantly higher amount of pyruvate was converted to lactate and alanine within seconds after intravenous administration. CONCLUSION: This study reveals that PET and (13)C MRSI can be used to visualize increased glycolytic flux in malignant tissue. The combination of signals will allow the quantitative dissection of substrate metabolism, with respect to uptake and downstream metabolic pathways. Although hyperpolarized [1-(13)C]pyruvate increases the sensitivity of MR imaging, signal-to-noise ratio constraints still apply for spatially and temporally resolved (13)C MRSI, emphasizing the need for further MR methodologic development. These first imaging data suggest the feasibility of (13)C MRSI for future clinical use.

Saturation-recovery metabolic-exchange rate imaging with hyperpolarized [1-13C] pyruvate using spectral-spatial excitation.

Within the last decade hyperpolarized [1-13C] pyruvate chemical-shift imaging has demonstrated impressive potential for metabolic MR imaging for a wide range of applications in oncology, cardiology, and neurology. In this work, a highly efficient pulse sequence is described for time-resolved, multislice chemical shift imaging of the injected substrate and obtained downstream metabolites. Using spectral-spatial excitation in combination with single-shot spiral data acquisition, the overall encoding is evenly distributed between excitation and signal reception, allowing the encoding of one full two-dimensional metabolite image per excitation. The signal-to-noise ratio can be flexibly adjusted and optimized using lower flip angles for the pyruvate substrate and larger ones for the downstream metabolites. Selectively adjusting the excitation of the down-stream metabolites to 90° leads to a so-called "saturation-recovery" scheme with the detected signal content being determined by forward conversion of the available pyruvate. In case of repetitive excitations, the polarization is preserved using smaller flip angles for pyruvate. Metabolic exchange rates are determined spatially resolved from the metabolite images using a simplified two-site exchange model. This novel contrast is an important step toward more quantitative metabolic imaging. Goal of this work was to derive, analyze, and implement this "saturation-recovery metabolic exchange rate imaging" and demonstrate its capabilities in four rats bearing subcutaneous tumors.

IDEAL spiral CSI for dynamic metabolic MR imaging of hyperpolarized [1-13C]pyruvate.

Metabolic imaging with hyperpolarized [1-(13)C]pyruvate offers the unique opportunity for a minimally invasive detection of cellular metabolism. Efficient and robust acquisition and reconstruction techniques are required for capturing the wealth of information present for the limited duration of the hyperpolarized state (~1 min). In this study, the Dixon/IDEAL type of water-fat separation is expanded toward spectroscopic imaging of [1-(13) C]pyruvate and its down-stream metabolites. For this purpose, the spectral-spatial encoding is based on single-shot spiral image encoding and echo-time shifting in between excitations for the chemical-shift encoding. In addition, also a free-induction decay spectrum is acquired and the obtained chemical-shift prior knowledge is efficiently used in the reconstruction. The spectral-spatial reconstruction problem is found to efficiently separate into a chemical-shift inversion followed by a spatial reconstruction. The method is successfully demonstrated for dynamic, multislice [1-(13)C]pyruvate metabolic MR imaging in phantom and in vivo rat experiments.