Diffusion-Weighted Imaging Fluid-Attenuated Inversion Recovery Mismatch on Portable, Low-Field Magnetic Resonance Imaging Among Acute Stroke Patients.

OBJECTIVE: For stroke patients with unknown time of onset, mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) can guide thrombolytic intervention. However, access to MRI for hyperacute stroke is limited. Here, we sought to evaluate whether a portable, low-field (LF)-MRI scanner can identify DWI-FLAIR mismatch in acute ischemic stroke. METHODS: Eligible patients with a diagnosis of acute ischemic stroke underwent LF-MRI acquisition on a 0.064-T scanner within 24 h of last known well. Qualitative and quantitative metrics were evaluated. Two trained assessors determined the visibility of stroke lesions on LF-FLAIR. An image coregistration pipeline was developed, and the LF-FLAIR signal intensity ratio (SIR) was derived. RESULTS: The study included 71 patients aged 71 ± 14 years and a National Institutes of Health Stroke Scale of 6 (interquartile range 3-14). The interobserver agreement for identifying visible FLAIR hyperintensities was high (κ = 0.85, 95% CI 0.70-0.99). Visual DWI-FLAIR mismatch had a 60% sensitivity and 82% specificity for stroke patients <4.5 h, with a negative predictive value of 93%. LF-FLAIR SIR had a mean value of 1.18 ± 0.18 <4.5 h, 1.24 ± 0.39 4.5-6 h, and 1.40 ± 0.23 >6 h of stroke onset. The optimal cut-point for LF-FLAIR SIR was 1.15, with 85% sensitivity and 70% specificity. A cut-point of 6.6 h was established for a FLAIR SIR <1.15, with an 89% sensitivity and 62% specificity. INTERPRETATION: A 0.064-T portable LF-MRI can identify DWI-FLAIR mismatch among patients with acute ischemic stroke. Future research is needed to prospectively validate thresholds and evaluate a role of LF-MRI in guiding thrombolysis among stroke patients with uncertain time of onset. ANN NEUROL 2024.

Workplace food purchases, dietary intake, and gut microbial metabolites in a secondary analysis of the ChooseWell 365 study.

BACKGROUND: Dietary choices can affect human health through alterations in gut microbial metabolism, and gut microbial metabolites could serve as biomarkers for disease risk conferred by dietary intake. However, self-reported dietary intake may not reflect true intake. OBJECTIVES: We identified circulating metabolites, including gut microbiome-related metabolites, associated with adherence to a healthy diet in the ChooseWell 365 study. In this randomized clinical trial, the dietary choices of hospital employees were assessed over 24 mo using not only 24-h dietary recalls but also electronic records of hospital cafeteria purchases. METHODS: Plasma metabolites were profiled from 470 participants. Two targeted metabolomics methods were developed and implemented to expand detection coverage for metabolites related to gut microbial activity. Linear regression models were used to associate metabolites with Healthy Purchasing Scores (HPSs) derived from cafeteria purchases and Healthy Eating Index-2015 (HEI-15) scores derived from dietary recalls. RESULTS: Fourteen metabolites were concordantly associated with the HPS and HEI-15 scores in multivariable models adjusted for age, gender, and race, including the gut microbiome-related metabolites indole-3-propionic acid (HPS, ß: 0.16, 95% CI: 0.07, 0.26, P = 7.32 × 10-4; HEI-15, ß: 0.16, 95% CI: 0.07, 0.25, P = 6.79 × 10-4), hippuric acid (HPS, ß: 0.11, 95% CI: 0.02, 0.21, P = 1.97 × 10-2; HEI-15, ß: 0.10, 95% CI: 0.01, 0.19, P = 3.14 × 10-2), and indoxyl sulfate (HPS, ß = -0.13, 95% CI: -0.23, -0.03, P = 8.21 × 10-3; HEI-15, ß: -0.12, 95% CI: -0.22, -0.03, P = 8.50 × 10-3). These gut microbial metabolites were associated with the intake of specific food groups, such as whole fruits. These metabolites were also associated with clinical variables, including blood pressure, diabetes or prediabetes, and body mass index. CONCLUSIONS: In a secondary analysis of the ChooseWell 365 study, associations between circulating gut microbiome-related metabolites and a healthy diet were confirmed using both objective and subjective measures of consumption. Accurate identification of diet-associated metabolites may help guide dietary or microbiome-based interventions aimed at disease prevention.

Impact of repeated blast exposure on active-duty United States Special Operations Forces.

United States (US) Special Operations Forces (SOF) are frequently exposed to explosive blasts in training and combat, but the effects of repeated blast exposure (RBE) on SOF brain health are incompletely understood. Furthermore, there is no diagnostic test to detect brain injury from RBE. As a result, SOF personnel may experience cognitive, physical, and psychological symptoms for which the cause is never identified, and they may return to training or combat during a period of brain vulnerability. In 30 active-duty US SOF, we assessed the relationship between cumulative blast exposure and cognitive performance, psychological health, physical symptoms, blood proteomics, and neuroimaging measures (Connectome structural and diffusion MRI, 7 Tesla functional MRI, [11C]PBR28 translocator protein [TSPO] positron emission tomography [PET]-MRI, and [18F]MK6240 tau PET-MRI), adjusting for age, combat exposure, and blunt head trauma. Higher blast exposure was associated with increased cortical thickness in the left rostral anterior cingulate cortex (rACC), a finding that remained significant after multiple comparison correction. In uncorrected analyses, higher blast exposure was associated with worse health-related quality of life, decreased functional connectivity in the executive control network, decreased TSPO signal in the right rACC, and increased cortical thickness in the right rACC, right insula, and right medial orbitofrontal cortex-nodes of the executive control, salience, and default mode networks. These observations suggest that the rACC may be susceptible to blast overpressure and that a multimodal, network-based diagnostic approach has the potential to detect brain injury associated with RBE in active-duty SOF.

Omega-3 Fatty Acids and Risk of Ischemic Stroke in REGARDS.

We examined associations between lipidomic profiles and incident ischemic stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Plasma lipids (n = 195) were measured from baseline blood samples, and lipids were consolidated into underlying factors using exploratory factor analysis. Cox proportional hazards models were used to test associations between lipid factors and incident stroke, linear regressions to determine associations between dietary intake and lipid factors, and the inverse odds ratio weighting (IORW) approach to test mediation. The study followed participants over a median (IQR) of 7 (3.4-11) years, and the case-cohort substudy included 1075 incident ischemic stroke and 968 non-stroke participants. One lipid factor, enriched for docosahexaenoic acid (DHA, an omega-3 fatty acid), was inversely associated with stroke risk in a base model (HR = 0.84; 95%CI 0.79-0.90; P = 8.33 × 10-8) and fully adjusted model (HR = 0.88; 95%CI 0.83-0.94; P = 2.79 × 10-4). This factor was associated with a healthy diet pattern (ß = 0.21; 95%CI 0.12-0.30; P = 2.06 × 10-6), specifically with fish intake (ß = 1.96; 95%CI 0.95-2.96; P = 1.36 × 10-4). DHA was a mediator between fish intake and incident ischemic stroke (30% P = 5.78 × 10-3). Taken together, DHA-containing plasma lipids were inversely associated with incident ischemic stroke and mediated the relationship between fish intake and stroke risk.

Sex-Associated Metabolites and Incident Stroke, Incident Coronary Heart Disease, Hypertension, and Chronic Kidney Disease in the REGARDS Cohort.

BACKGROUND: Sex disparities exist in cardiometabolic diseases. Metabolomic profiling offers insight into disease mechanisms, as the metabolome is influenced by environmental and genetic factors. We identified metabolites associated with sex and determined if sex-associated metabolites are associated with incident stoke, incident coronary heart disease, prevalent hypertension, and prevalent chronic kidney disease. METHODS AND RESULTS: Targeted metabolomics was conducted for 357 metabolites in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) case-cohort substudy for incident stroke. Weighted logistic regression models were used to identify metabolites associated with sex in REGARDS. Sex-associated metabolites were replicated in the HyperGEN (Hypertension Genetic Epidemiology Network) and using the literature. Weighted Cox proportional hazard models were used to evaluate associations between metabolites and incident stroke. Cox proportional hazard models were used to evaluate associations between metabolites and incident coronary heart disease. Weighted logistic regression models were used to evaluate associations between metabolites and hypertension and chronic kidney disease. Fifty-one replicated metabolites were associated with sex. Higher levels of 6 phosphatidylethanolamines were associated with incident stroke. No metabolites were associated with incident coronary heart disease. Higher levels of uric acid and leucine and lower levels of a lysophosphatidylcholine were associated with hypertension. Higher levels of indole-3-lactic acid, 7 phosphatidylethanolamines, and uric acid, and lower levels of betaine and bilirubin were associated with chronic kidney disease. CONCLUSIONS: These findings suggest that the sexual dimorphism of the metabolome may contribute to sex differences in stroke, hypertension, and chronic kidney disease.

Feasibility and tolerability of portable, low-field brain MRI for patients with multiple sclerosis.

Low-field, portable MRI (LF-MRI) promises to expand neuroimaging access for patients with multiple sclerosis (MS). We aimed to measure the feasibility and tolerability of LF-MRI for clinical use in 50 people with MS (mean age 46.5 ± 15.3 years; 72 % female; median disease duration 5.9 years), 38 % of whom reported barriers to undergoing MRI, and 34 % of whom were low-income or unemployed. Experience ratings of LF-MRI were strongly positive (mean rating of 9.2 on a ten-point scale). Seventy percent of participants were willing to receive future LF-MRI scans, and 46 % preferred LF-MRI to standard MRI (35 % undecided). The overall feasibility and tolerability of LF-MRI support its integration into a one-stop, patient-centered model of outpatient MS care.

Plasma Metabolites and Life's Simple 7 in REGARDS.

BACKGROUND: The American Heart Association's Life's Simple 7 (LS7) is a health metric that captures important factors associated with cardiovascular and cerebrovascular health. Previous studies highlight the potential of plasma metabolites to serve as a marker for lifestyle and health behavior that could be a target for stroke prevention. The objectives of this study were to identify metabolites that were associated with LS7 and incident ischemic stroke and mediate the relationship between the two. METHODS: Targeted metabolomic profiling of 162 metabolites by liquid chromatography-tandem mass spectrometry was used to identify candidate metabolites in a stroke case-cohort nested within the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Weighted linear regression and weighted Cox proportional hazard models were used to identify metabolites that were associated with LS7 and incident ischemic stroke, respectively. Effect measures were based on a 1-SD change in metabolite level. Metabolite mediators were examined using inverse odds ratio weighting mediation analysis. RESULTS: The study comprised 1075 ischemic stroke cases and 968 participants in the random cohort sample. Three out of 162 metabolites were associated with the overall LS7 score including guanosine (ß, -0.46 [95% CI, -0.65 to -0.27]; P=2.87×10-6), cotinine (ß, -0.49 [95% CI, -0.70 to -0.28]; P=7.74×10-6), and acetylneuraminic acid (ß, -0.59 [95% CI, -0.77 to -0.42]; P=4.29×10-11). Guanosine (hazard ratio, 1.47 [95% CI, 1.31-1.65]; P=6.97×10-11), cotinine (hazard ratio, 1.30 [95% CI, 1.16-1.44]; P=2.09×10-6), and acetylneuraminic acid (hazard ratio, 1.29 [95% CI, 1.15-1.45]; P=9.24×10-6) were associated with incident ischemic stroke. The mediation analysis identified guanosine (27% mediation, indirect effect; P=0.002), cotinine (30% mediation, indirect effect; P=0.004), and acetylneurminic acid (22% mediation, indirect effect; P=0.041) partially mediated the relationship between LS7 and ischemic stroke. CONCLUSIONS: We identified guanosine, cotinine, and acetylneuraminic acid that were associated with LS7, incident ischemic stroke, and mediated the relationship between LS7 and ischemic stroke.

NK1 tachykinin receptor antagonist treatment reduces cerebral edema and intracranial pressure in an ovine model of ischemic stroke.

Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep (n = 24) were subject to 2-hours tMCAo and randomized (n = 6/group) to receive early NK1-R treatment (days 1-3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation.

Analysis of brain edema in RHAPSODY.

BACKGROUND: Cerebral edema is a secondary complication of acute ischemic stroke, but its time course and imaging markers are not fully understood. Recently, net water uptake (NWU) has been proposed as a novel marker of edema. AIMS: Studying the RHAPSODY trial cohort, we sought to characterize the time course of edema and test the hypothesis that NWU provides distinct information when added to traditional markers of cerebral edema after stroke by examining its association with other markers. METHODS: A total of 65 patients had measurable supratentorial ischemic lesions. Patients underwent head computed tomography (CT), brain magnetic resonance imaging (MRI) scans, or both at the baseline visit and after 2, 7, 30, and 90 days following enrollment. CT and MRI scans were used to measure four imaging markers of edema: midline shift (MLS), hemisphere volume ratio (HVR), cerebrospinal fluid (CSF) volume, and NWU using semi-quantitative threshold analysis. Trajectories of the markers were summarized, as available. Correlations of the markers of edema were computed and the markers compared by clinical outcome. Regression models were used to examine the effect of 3K3A-activated protein C (APC) treatment. RESULTS: Two measures of mass effect, MLS and HVR, could be measured on all imaging modalities, and had values available across all time points. Accordingly, mass effect reached a maximum level by day 7, normalized by day 30, and then reversed by day 90 for both measures. In the first 2 days after stroke, the change in CSF volume was associated with MLS (ρ = -0.57, p = 0.0001) and HVR (ρ = -0.66, p < 0.0001). In contrast, the change in NWU was not associated with the other imaging markers (all p ⩾ 0.49). While being directionally consistent, we did not observe a difference in the edema markers by clinical outcome. In addition, baseline stroke volume was associated with all markers (MLS (p < 0.001), HVR (p < 0.001), change in CSF volume (p = 0.003)) with the exception of NWU (p = 0.5). Exploratory analysis did not reveal a difference in cerebral edema markers by treatment arm. CONCLUSIONS: Existing cerebral edema imaging markers potentially describe two distinct processes, including lesional water concentration (i.e. NWU) and mass effect (MLS, HVR, and CSF volume). These two types of imaging markers may represent distinct aspects of cerebral edema, which could be useful for future trials targeting this process.

Managing Patients With Unlabeled Passive Implants on MR Systems Operating Below 1.5 T.

The standard of care for managing a patient with an implant is to identify the item and to assess the relative safety of scanning the patient. Because the 1.5 T MR system is the most prevalent scanner in the world and 3 T is the highest field strength in widespread use, implants typically have "MR Conditional" (i.e., an item with demonstrated safety in the MR environment within defined conditions) labeling at 1.5 and/or 3 T only. This presents challenges for a facility that has a scanner operating at a field strength below 1.5 T when encountering a patient with an implant, because scanning the patient is considered "off-label." In this case, the supervising physician is responsible for deciding whether to scan the patient based on the risks associated with the implant and the benefit of magnetic resonance imaging (MRI). For a passive implant, the MRI safety-related concerns are static magnetic field interactions (i.e., force and torque) and radiofrequency (RF) field-induced heating. The worldwide utilization of scanners operating below 1.5 T combined with the increasing incidence of patients with implants that need MRI creates circumstances that include patients potentially being subjected to unsafe imaging conditions or being denied access to MRI because physicians often lack the knowledge to perform an assessment of risk vs. benefit. Thus, physicians must have a complete understanding of the MRI-related safety issues that impact passive implants when managing patients with these products on scanners operating below 1.5 T. This monograph provides an overview of the various clinical MR systems operating below 1.5 T and discusses the MRI-related factors that influence safety for passive implants. Suggestions are provided for the management of patients with passive implants labeled MR Conditional at 1.5 and/or 3 T, referred to scanners operating below 1.5 T. The purpose of this information is to empower supervising physicians with the essential knowledge to perform MRI exams confidently and safely in patients with passive implants. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Optimizing Brain Health of United States Special Operations Forces.

United States Special Operations Forces (SOF) personnel are frequently exposed to explosive blasts in training and combat. However, the effects of repeated blast exposure on the human brain are incompletely understood. Moreover, there is currently no diagnostic test to detect repeated blast brain injury (rBBI). In this "Human Performance Optimization" article, we discuss how the development and implementation of a reliable diagnostic test for rBBI has the potential to promote SOF brain health, combat readiness, and quality of life.

Metabolite profiles and DNA methylation in metabolic syndrome: a two-sample, bidirectional Mendelian randomization.

Introduction: Metabolic syndrome (MetS) increases the risk of cardiovascular disease and death. Previous '-omics' studies have identified dysregulated serum metabolites and aberrant DNA methylation in the setting of MetS. However, the relationship between the metabolome and epigenome have not been elucidated. In this study, we identified serum metabolites associated with MetS and DNA methylation, and we conducted bidirectional Mendelian randomization (MR) to assess causal relationships between metabolites and methylation. Methods: We leveraged metabolomic and genomic data from a national United States cohort of older adults (REGARDS), as well as metabolomic, epigenomic, and genomic data from a family-based study of hypertension (HyperGEN). We conducted metabolite profiling for MetS in REGARDS using weighted logistic regression models and validated them in HyperGEN. Validated metabolites were selected for methylation studies which fit linear mixed models between metabolites and six CpG sites previously linked to MetS. Statistically significant metabolite-CpG pairs were selected for two-sample, bidirectional MR. Results: Forward MR indicated that glucose and serine metabolites were causal on CpG methylation near CPT1A [B(SE): -0.003 (0.002), p = 0.028 and B(SE): 0.029 (0.011), p = 0.030, respectively] and that serine metabolites were causal on ABCG1 [B(SE): -0.008(0.003), p = 0.006] and SREBF1 [B(SE): -0.009(0.004), p = 0.018] methylation, which suggested a protective effect of serine. Reverse MR showed a bidirectional relationship between cg06500161 (ABCG1) and serine [B(SE): -1.534 (0.668), p = 0.023]. Discussion: The metabolome may contribute to the relationship between MetS and epigenetic modifications.

Detection of Intracerebral Hemorrhage Using Low-Field, Portable Magnetic Resonance Imaging in Patients With Stroke.

BACKGROUND: Neuroimaging is essential for detecting spontaneous, nontraumatic intracerebral hemorrhage (ICH). Recent data suggest ICH can be characterized using low-field magnetic resonance imaging (MRI). Our primary objective was to investigate the sensitivity and specificity of ICH on a 0.064T portable MRI (pMRI) scanner using a methodology that provided clinical information to inform rater interpretations. As a secondary aim, we investigated whether the incorporation of a deep learning (DL) reconstruction algorithm affected ICH detection. METHODS: The pMRI device was deployed at Yale New Haven Hospital to examine patients presenting with stroke symptoms from October 26, 2020 to February 21, 2022. Three raters independently evaluated pMRI examinations. Raters were provided the images alongside the patient's clinical information to simulate real-world context of use. Ground truth was the closest conventional computed tomography or 1.5/3T MRI. Sensitivity and specificity results were grouped by DL and non-DL software to investigate the effects of software advances. RESULTS: A total of 189 exams (38 ICH, 89 acute ischemic stroke, 8 subarachnoid hemorrhage, 3 primary intraventricular hemorrhage, 51 no intracranial abnormality) were evaluated. Exams were correctly classified as positive or negative for ICH in 185 of 189 cases (97.9% overall accuracy). ICH was correctly detected in 35 of 38 cases (92.1% sensitivity). Ischemic stroke and no intracranial abnormality cases were correctly identified as blood-negative in 139 of 140 cases (99.3% specificity). Non-DL scans had a sensitivity and specificity for ICH of 77.8% and 97.1%, respectively. DL scans had a sensitivity and specificity for ICH of 96.6% and 99.3%, respectively. CONCLUSIONS: These results demonstrate improvements in ICH detection accuracy on pMRI that may be attributed to the integration of clinical information in rater review and the incorporation of a DL-based algorithm. The use of pMRI holds promise in providing diagnostic neuroimaging for patients with ICH.

Brain imaging with portable low-field MRI.

The advent of portable, low-field MRI (LF-MRI) heralds new opportunities in neuroimaging. Low power requirements and transportability have enabled scanning outside the controlled environment of a conventional MRI suite, enhancing access to neuroimaging for indications that are not well suited to existing technologies. Maximizing the information extracted from the reduced signal-to-noise ratio of LF-MRI is crucial to developing clinically useful diagnostic images. Progress in electromagnetic noise cancellation and machine learning reconstruction algorithms from sparse k-space data as well as new approaches to image enhancement have now enabled these advancements. Coupling technological innovation with bedside imaging creates new prospects in visualizing the healthy brain and detecting acute and chronic pathological changes. Ongoing development of hardware, improvements in pulse sequences and image reconstruction, and validation of clinical utility will continue to accelerate this field. As further innovation occurs, portable LF-MRI will facilitate the democratization of MRI and create new applications not previously feasible with conventional systems.

Trimethylamine N-Oxide and White Matter Hyperintensity Volume Among Patients With Acute Ischemic Stroke.

Importance: Although increasing evidence suggests that trimethylamine N-oxide (TMAO) is associated with atherosclerosis, little is known about whether TMAO and its related metabolites (ie, choline, betaine, and carnitine) are associated with small vessel disease. Objective: To evaluate the association between TMAO and its related metabolites with features of cerebral small vessel disease, including white matter hyperintensity volume (WMHV) and acute lacunar infarction. Design, Setting, and Participants: This cross-sectional study included patients enrolled in the Specialized Programs of Translational Research in Acute Stroke biorepository. The registry included 522 patients with acute ischemic stroke who were 18 years or older who presented at the Massachusetts General Hospital or Brigham and Women's Hospital within 9 hours after onset between January 2007 and April 2010. The analyses in this study were conducted between November 2022 and April 2023. Exposures: Plasma TMAO, choline, betaine, and carnitine were measured by liquid chromatography-tandem mass spectrometry. Main Outcomes and Measures: WMHV was quantified by a semiautomated approach using signal intensity threshold with subsequent manual editing. Ischemic stroke subtype was classified using the Causative Classification System. Results: Among 351 patients included in this study, the mean (SD) age was 69 (15) years; 209 patients (59.5%) were male and had a median (IQR) admission National Institute of Health Stroke Scale of 6 (3-13). The magnetic resonance imaging subgroup consisted of 291 patients with a mean (SD) age of 67 (15) years. Among these, the median (IQR) WMHV was 3.2 (1.31-8.4) cm3. TMAO was associated with WMHV after adjustment for age and sex (ß, 0.15; 95% CI, 0.01-0.29; P < .001). TMAO remained significant in a multivariate analysis adjusted for age, sex, hypertension, diabetes, and smoking (ß, 0.14; 95% CI, 0-0.29; P = .05). TMAO was associated with lacunar stroke but not other ischemic stroke subtypes in a model adjusted for age, sex, hypertension, diabetes, and smoking (OR, 1.67; 95% CI, 1.05-2.66; P = .03). Conclusions and Relevance: In this observational study, TMAO was associated with cerebral small vessel disease determined by WMHV and acute lacunar infarction. The association was independent of traditional vascular risk factors.

Acetylglutamine Differentially Associated with First-Time Versus Recurrent Stroke.

Approximately one-quarter of strokes occur in individuals with prior stroke. Despite the advancement in secondary stroke prevention, the long-term risk of recurrent stroke has remained unchanged. The objective of this study was to identify metabolite risk markers that are associated with recurrent stroke. We performed targeted metabolomic profiling of 162 metabolites by liquid chromatography-tandem mass spectrometry in baseline plasma in a stroke case-cohort study nested within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, an observational cohort study of 30,239 individuals aged 45 and older enrolled in 2003-2007. Weighted Cox proportional hazard models were used to identify metabolites that had a differential effect on first-time versus recurrent stroke using an interaction term between metabolite and prior stroke at baseline (yes or no). The study included 1391 incident stroke cases identified during 7.1 ± 4.5 years of follow-up and 1050 participants in the random cohort sample. Among 162 metabolites, 13 candidates had a metabolite-by-prior stroke interaction at a p-value <0.05, with one metabolite, acetylglutamine, surpassing the Bonferroni adjusted p-value threshold (p for interaction = 5.78 × 10-5). In an adjusted model that included traditional stroke risk factors, acetylglutamine was associated with recurrent stroke (HR = 2.27 per SD increment, 95% CI = 1.60-3.20, p = 3.52 × 10-6) but not with first-time stroke (HR = 0.96 per SD increment, 95% CI = 0.87-1.06, p = 0.44). Acetylglutamine was associated with recurrent stroke but not first-time stroke, independent of traditional stroke risk factors. Future studies are warranted to elucidate the pathogenesis of acetylglutamine and recurrent stroke risk.

Portable MRI to assess optic chiasm decompression after endoscopic endonasal resection of sellar and suprasellar lesions.

OBJECTIVE: Low-field portable MRI (pMRI) is a recent technological advancement with potential for broad applications. Compared with conventional MRI, pMRI is less resource-intensive with regard to operational costs and scan time. The application of pMRI in neurosurgical oncology has not been previously described. The goal of this study was to demonstrate the efficacy of pMRI in assessing optic nerve decompression after endoscopic endonasal surgery for sellar and suprasellar pathologies. METHODS: Patients who underwent endoscopic endonasal surgery for sellar and suprasellar lesions at a single institution and for whom pMRI and routine MRI were performed postoperatively were retrospectively reviewed to compare the two imaging systems. To assess the relative resolution of pMRI compared with MRI, the distance from the optic chiasm to the top of the third ventricle was measured, and the measurements were compared between paired equivalent slices on T2-weighted coronal images. The inter- and intrarater correlations were analyzed. RESULTS: Twelve patients were included in this study (10 with pituitary adenomas and 2 with craniopharyngiomas) with varying degrees of optic chiasm compression on preoperative imaging. Measurements were averaged across raters before calculating agreement between pMRI and MRI, which demonstrated significant interrater reliability (intraclass correlation coefficient [ICC] = 0.78, p < 0.01). Agreement between raters within the pMRI measurements was also significantly reliable (ICC = 0.93, p < 0.01). Finally, a linear mixed-effects model was specified to demonstrate that MRI measurement could be predicted using the pMRI measurement with the patient and rater set as random effects (pMRI ß coefficient = 0.80, p < 0.01). CONCLUSIONS: The results of this study suggest that resolution of pMRI is comparable to that of conventional MRI in assessing the optic chiasm position in relation to the third ventricle. Portable MRI sufficiently demonstrates decompression of the optic chiasm after endoscopic endonasal surgery. It can be an alternative strategy in cases in which cost, scan-time considerations, or lack of intraoperative MRI availability may preclude the ability to assess adequate optic nerve decompression after endoscopic endonasal surgery for sellar and suprasellar lesions.

Association of Circulating Metabolites With Racial Disparities in Hypertension and Stroke in the REGARDS Study.

BACKGROUND AND OBJECTIVES: In the United States, the risk of stroke is greater among Black compared with that among White individuals. However, the reasons for the difference in stroke incidence are not fully elucidated. We aimed to identify metabolites that account for higher prevalent hypertension and incident ischemic stroke among Black adults. METHODS: We used a stroke case cohort nested within the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Targeted metabolomic profiling of 162 plasma metabolites was performed by liquid chromatography-tandem mass spectrometry. We identified metabolites that were associated with prevalent hypertension and incident ischemic stroke and mediated the relationship between hypertension and ischemic stroke by weighted logistic regression, Cox proportional hazard model, and inverse odds ratio weighting mediation analysis. RESULTS: Incident ischemic stroke cases adjudicated through April 1, 2019 (n = 1,075) were included in the study. The random cohort sample was derived from the full cohort using stratified sampling (n = 968). Among 162 metabolites, gluconic acid was associated with prevalent hypertension in Black adults (odds ratio [OR] 1.86, 95% CI 1.39-2.47, p = 2.58 × 10-5) but not in White adults (OR 1.00, 95% CI 0.80-1.24, p = 0.97; p for interaction = 4.57 × 10-4). Gluconic acid also demonstrated an association with incident ischemic stroke among Black participants (hazard ratio [HR] 1.53, 95% CI 1.28-1.81, p = 1.76 × 10-6) but not White participants (HR 1.16, 95% CI 1.00-1.34, p = 0.057; p for interaction = 0.019). In mediation analysis, gluconic acid mediated 25.4% (95% CI 4.1%-46.8%, p = 0.02) of the association between prevalent hypertension and incident ischemic stroke among Black individuals. Specific socioeconomic factors were linked to elevated gluconic acid level among Black adults in multivariable analysis, including a Southern dietary pattern (ß = 0.18, 95% CI 0.08-0.28, p < 0.001), lower educational attainment (ß = 0.45, 95% CI 0.19-0.72, p = 0.001), and a lack of exercise (ß = 0.26, 95% CI 0.01-0.51, p = 0.045). DISCUSSION: Gluconic acid is associated with prevalent hypertension and incident ischemic stroke and mediates the relationship between hypertension and ischemic stroke in Black but not White adults. Gluconic acid is a biomarker that is associated with social determinants of health including a Southern diet, low educational attainment, and low physical activity.

Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus.

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.

Gut microbiota-associated metabolites and risk of ischemic stroke in REGARDS.

Several metabolite markers are independently associated with incident ischemic stroke. However, prior studies have not accounted for intercorrelated metabolite networks. We used exploratory factor analysis (EFA) to determine if metabolite factors were associated with incident ischemic stroke. Metabolites (n = 162) were measured in a case-control cohort nested in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, which included 1,075 ischemic stroke cases and 968 random cohort participants. Cox models were adjusted for age, gender, race, and age-race interaction (base model) and further adjusted for the Framingham stroke risk factors (fully adjusted model). EFA identified fifteen metabolite factors, each representing a well-defined metabolic pathway. Of these, factor 3, a gut microbiome metabolism factor, was associated with an increased risk of stroke in the base (hazard ratio per one-unit standard deviation, HR = 1.23; 95%CI = 1.15-1.31; P = 1.98 × 10-10) and fully adjusted models (HR = 1.13; 95%CI = 1.06-1.21; P = 4.49 × 10-4). The highest tertile had a 45% increased risk relative to the lowest (HR = 1.45; 95%CI = 1.25-1.70; P = 2.24 × 10-6). Factor 3 was also associated with the Southern diet pattern, a dietary pattern previously linked to increased stroke risk in REGARDS (ß = 0.11; 95%CI = 0.03-0.18; P = 8.75 × 10-3). These findings highlight the role of diet and gut microbial metabolism in relation to incident ischemic stroke.