Central vein sign: A diagnostic biomarker in multiple sclerosis (CAVS-MS) study protocol for a prospective multicenter trial.

The specificity and implementation of current MRI-based diagnostic criteria for multiple sclerosis (MS) are imperfect. Approximately 1 in 5 of individuals diagnosed with MS are eventually determined not to have the disease, with overreliance on MRI findings a major cause of MS misdiagnosis. The central vein sign (CVS), a proposed MRI biomarker for MS lesions, has been extensively studied in numerous cross sectional studies and may increase diagnostic specificity for MS. CVS has desirable analytical, measurement, and scalability properties. "Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)" is an NIH-supported, 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as a diagnostic biomarker for immediate translation into clinical care. Study objectives include determining the concordance of CVS and McDonald Criteria to diagnose MS, the sensitivity of CVS to detect MS in those with typical presentations, and the specificity of CVS among those with atypical presentations. The study will recruit a total of 400 participants (200 with typical and 200 with atypical presentations) across 11 sites. T2*-weighted, high-isotropic-resolution, segmented echo-planar MRI will be acquired at baseline and 24 months on 3-tesla scanners, and FLAIR* images (combination of FLAIR and T2*) will be generated for evaluating CVS. Data will be processed on a cloud-based platform that contains clinical and CVS rating modules. Imaging quality control will be conducted by automated methods and neuroradiologist review. CVS will be determined by Select6* and Select3* lesion methods following published criteria at each site and by central readers, including neurologists and neuroradiologists. Automated CVS detection and algorithms for incorporation of CVS into McDonald Criteria will be tested. Diagnosis will be adjudicated by three neurologists who served on the 2017 International Panel on the Diagnosis of MS. The CAVS-MS study aims to definitively establish CVS as a diagnostic biomarker that can be applied broadly to individuals presenting for evaluation of the diagnosis of MS.

Intensity warping for multisite MRI harmonization.

In multisite neuroimaging studies there is often unwanted technical variation across scanners and sites. These "scanner effects" can hinder detection of biological features of interest, produce inconsistent results, and lead to spurious associations. We propose mica (multisite image harmonization by cumulative distribution function alignment), a tool to harmonize images taken on different scanners by identifying and removing within-subject scanner effects. Our goals in the present study were to (1) establish a method that removes scanner effects by leveraging multiple scans collected on the same subject, and, building on this, (2) develop a technique to quantify scanner effects in large multisite studies so these can be reduced as a preprocessing step. We illustrate scanner effects in a brain MRI study in which the same subject was measured twice on seven scanners, and assess our method's performance in a second study in which ten subjects were scanned on two machines. We found that unharmonized images were highly variable across site and scanner type, and our method effectively removed this variability by aligning intensity distributions. We further studied the ability to predict image harmonization results for a scan taken on an existing subject at a new site using cross-validation.

Manganese-Enhanced MRI in Patients with Multiple Sclerosis.

BACKGROUND AND PURPOSE: Cellular uptake of the manganese ion, when administered as a contrast agent for MR imaging, can noninvasively highlight cellular activity and disease processes in both animals and humans. The purpose of this study was to explore the enhancement profile of manganese in patients with multiple sclerosis. MATERIALS AND METHODS: Mangafodipir is a manganese chelate that was clinically approved for MR imaging of liver lesions. We present a case series of 6 adults with multiple sclerosis who were scanned at baseline with gadolinium, then injected with mangafodipir, and followed at variable time points thereafter. RESULTS: Fourteen new lesions formed during or shortly before the study, of which 10 demonstrated manganese enhancement of varying intensity, timing, and spatial pattern. One gadolinium-enhancing extra-axial mass, presumably a meningioma, also demonstrated enhancement with manganese. Most interesting, manganese enhancement was detected in lesions that formed in the days after mangafodipir injection, and this enhancement persisted for several weeks, consistent with contrast coming from intracellular uptake of manganese. Some lesions demonstrated a diffuse pattern of manganese enhancement in an area larger than that of both gadolinium enhancement and T2-FLAIR signal abnormality. CONCLUSIONS: This work demonstrates the first use of a manganese-based contrast agent to enhance MS lesions on MR imaging. Multiple sclerosis lesions were enhanced with a temporal and spatial profile distinct from that of gadolinium. Further experiments are necessary to uncover the mechanism of manganese contrast enhancement as well as cell-specific uptake.

Levels of Acceptance and Forgiveness Reported by Patients With BPD and Personality-Disordered Comparison Subjects Over 20 Years of Prospective Follow-Up.

This study had two objectives: to determine the levels of acceptance and forgiveness reported by patients with borderline personality disorder (BPD) and personality-disordered comparison subjects and by recovered versus non-recovered patients with BPD over 20 years of prospective follow-up. Levels of acceptance and forgiveness were reassessed every 2 years. Patients with BPD reported levels of these states that were approximately 70% lower than comparison subjects at baseline. These states increased significantly over time for patients with BPD but not for comparison subjects. Recovered patients with BPD reported approximately three times the levels of these states than non-recovered patients with BPD. These levels increased for both groups over time; one state (accepting of myself) increased at a significantly steeper rate for recovered patients with BPD. These results suggest that patients with BPD report becoming more accepting and forgiving over time. Additionally, recovery status is significantly associated with increasing time in these states.

Amygdala Resting State Connectivity Differences between Bipolar II and Borderline Personality Disorders.

BACKGROUND: Borderline personality disorder (BPD) and bipolar II disorder (BD II) have significant clinical overlap, leaving the potential for diagnostic inaccuracies and inadequate treatment recommendations. However, few studies have probed for clinical and neurobiological differences between the two disorders. Clinically, some prior studies have linked BPD with greater impulsivity and more frequent negative affective shifts than BD II, whereas previous neuroimaging studies have highlighted both similar and distinct neural abnormalities in BPD and BD II. Notably, no prior study has specifically targeted cortico-limbic neural differences, which have been hypothesized to underlie these core clinical differences. METHODS: Individuals with BPD (n = 14) and BD II (n = 15) completed various clinical measures and a resting state functional imaging scan at 3T. Whole-brain amygdala resting state functional connectivity (RSFC) was compared between the two groups. RESULTS: Relative to the BD II group, BPD participants reported significantly higher levels of impulsivity, trait anxiety, more frequent negative affective shifts, greater interpersonally reactive affective instability, lower overall functioning, and were characterized by lower amygdala-middle frontal gyrus RSFC. Lower amygdala-middle frontal gyrus RSFC was associated with greater impulsivity, trait anxiety, affective shifts, interpersonal affective reactivity, and functional impairment. LIMITATIONS: The current study consisted of small sample sizes and lacked a control group. CONCLUSIONS: This preliminary study suggests that amygdala-frontal RSFC may distinguish BPD from BD II. These results may guide future work aimed at identifying neural markers that can help disentangle these two disorders, leading to greater diagnostic accuracy and appropriate treatment implementation.

The 24-year course of major depression in patients with borderline personality disorder and personality-disordered comparison subjects.

BACKGROUND: This study had two main objectives. The first was to detail the prevalence of major depressive disorder over 24 years of follow-up for both patients with borderline personality disorder (BPD) and comparison subjects with other personality disorders (OPD). The second was to determine time-to-remission, recurrence, and new onset of major depression among these two groups of patients. METHODS: The SCID-I was administered to 290 borderline inpatients and 72 personality-disordered comparison subjects during their index admission. It was also re-administered at 12 contiguous two-year follow-up periods. RESULTS: The prevalence of major depression was significantly higher for borderline patients over time but declined significantly over time for those in both study groups. In terms of time to events, 93% of borderline patients meeting criteria for major depression at baseline experienced a two-year remission by the time of the 24-year follow-up. Recurrences were about as common (90% for those with remitted major depression). New onsets of major depression were also very common (86% for those without major depression during their index admission). LIMITATIONS: Results may not pertain to less severely ill patients with BPD and those in less treatment. CONCLUSIONS: Taken together, the results of this study suggest that the remitting-recurring course of major depression in borderline patients is very similar to the course of major depression in those with other types of personality disorder and those for whom major depression is their primary disorder.

Manganese-Enhanced MRI of the Brain in Healthy Volunteers.

BACKGROUND AND PURPOSE: The manganese ion is used as an intracellular MR imaging contrast agent to study neuronal function in animal models, but it remains unclear whether manganese-enhanced MR imaging can be similarly useful in humans. Using mangafodipir (Teslascan, a chelated manganese-based contrast agent that is FDA-approved), we evaluated the dynamics of manganese enhancement of the brain and glandular structures in the rostral head and neck in healthy volunteers. MATERIALS AND METHODS: We administered mangafodipir intravenously at a rate of 1 mL/minute for a total dose of 5 µmol/kg body weight. Nine healthy adult volunteers (6 men/3 women; median age, 43 years) completed baseline history and physical examination, 3T MR imaging, and blood work. MR imaging also followed mangafodipir administration at various time points from immediate to 7 days, with delayed scans at 1-3 months. RESULTS: The choroid plexus and anterior pituitary gland enhanced within 10 minutes of infusion, with enhancement persisting up to 7 and 30 days, respectively. Exocrine (parotid, submandibular, sublingual, and lacrimal) glands also enhanced avidly as early as 1 hour postadministration, generally resolving by 1 month; 3 volunteers had residual exocrine gland enhancement, which resolved by 2 months in 1 and by 3 months in the other 2. Mangafodipir did not affect clinical parameters, laboratory values, or T1-weighted signal in the basal ganglia. CONCLUSIONS: Manganese ions released from mangafodipir successfully enable noninvasive visualization of intra- and extracranial structures that lie outside the blood-brain barrier without adverse clinical effects, setting the stage for future neuroradiologic investigation in disease.

The Central Vein Sign in Radiologically Isolated Syndrome.

BACKGROUND AND PURPOSE: Radiologically isolated syndrome describes asymptomatic individuals with incidental radiologic abnormalities suggestive of multiple sclerosis. Recent studies have demonstrated that >40% of white matter lesions in MS (and often substantially more) have visible central veins on MR imaging. This "central vein sign" reflects perivenous inflammatory demyelination and can assist in differentiating MS from other white matter disorders. We therefore hypothesized that >40% of white matter lesions in cases of radiologically isolated syndrome would show the central vein sign. MATERIALS AND METHODS: We recruited 20 participants diagnosed with radiologically isolated syndrome after evaluation by a neurologist. We performed 3T MR imaging of the brain and cervical spinal cord. White matter lesions were analyzed for the central vein sign. RESULTS: Of 391 total white matter lesions, 292 (75%) demonstrated the central vein sign (central vein sign+). The median proportion of central vein sign+ lesions per case was 87% (range, 29%-100%). When the "40% rule" that has been proposed to distinguish MS from other disorders was applied, of 20 participants, 18 cases of radiologically isolated syndrome (90%) had ≥40% central vein sign+ lesions (range, 55%-100%). Two participants (10%) had <40% central vein sign+ lesions (29% and 31%). When the simpler "rule of 6" was applied, 19 participants (95%) met these criteria. In multivariable models, the number of spinal cord and infratentorial lesions was associated with a higher proportion of central vein sign+ lesions (P = .002; P = .06, respectively). CONCLUSIONS: Most cases of radiologically isolated syndrome had a high proportion of central vein sign+ lesions, suggesting that lesions in these individuals reflect perivenous inflammatory demyelination. Moreover, we found correlations between the proportion of central vein sign+ lesions and spinal cord lesions, a known risk factor for radiologically isolated syndrome progressing to MS. These findings raise the possibility, testable prospectively, that the central vein sign may have prognostic value in distinguishing patients with radiologically isolated syndrome at risk of developing clinical MS from those with white matter lesions of other etiologies.

Automated Integration of Multimodal MRI for the Probabilistic Detection of the Central Vein Sign in White Matter Lesions.

BACKGROUND AND PURPOSE: The central vein sign is a promising MR imaging diagnostic biomarker for multiple sclerosis. Recent studies have demonstrated that patients with MS have higher proportions of white matter lesions with the central vein sign compared with those with diseases that mimic MS on MR imaging. However, the clinical application of the central vein sign as a biomarker is limited by interrater differences in the adjudication of the central vein sign as well as the time burden required for the determination of the central vein sign for each lesion in a patient's full MR imaging scan. In this study, we present an automated technique for the detection of the central vein sign in white matter lesions. MATERIALS AND METHODS: Using multimodal MR imaging, the proposed method derives a central vein sign probability, πij, for each lesion, as well as a patient-level central vein sign biomarker, ψi. The method is probabilistic in nature, allows site-specific lesion segmentation methods, and is potentially robust to intersite variability. The proposed algorithm was tested on imaging acquired at the University of Vermont in 16 participants who have MS and 15 participants who do not. RESULTS: By means of the proposed automated technique, participants with MS were found to have significantly higher values of ψ than those without MS (ψMS = 0.55 ± 0.18; ψnon-MS = 0.31 ± 0.12; P < .001). The algorithm was also found to show strong discriminative ability between patients with and without MS, with an area under the curve of 0.88. CONCLUSIONS: The current study presents the first fully automated method for detecting the central vein sign in white matter lesions and demonstrates promising performance in a sample of patients with and without MS.

Identification of Chronic Active Multiple Sclerosis Lesions on 3T MRI.

BACKGROUND AND PURPOSE: MR imaging-pathologic studies have reported that paramagnetic rims on 7T susceptibility-based MR imaging identify, in vivo, the subset of MS lesions with compartmentalized inflammation at the lesion edge and associated remyelination failure. Here, we assessed the reliability of detecting these rims on high-resolution 3T phase images. MATERIALS AND METHODS: High-resolution T2* and phase MR imaging was collected in 20 patients with MS at 3T (3D segmented EPI, 0.65 mm3) and 7T (2D gradient-echo, 0.2 × 0.2 × 1 mm) MR imaging. In each case, 5 discrete chronic (nonenhancing) MS lesions were selected on T2 FLAIR images for rim evaluation. Five raters experienced in MS imaging contributed to the rim assessment, of whom 3 worked independently on 3T data, and 2, on 7T data. Consensus agreement was reached for both 3T and 7T rim evaluations. Discrepancies between 3T and 7T were discussed, and consensus was reached. RESULTS: Phase rims were seen in 34 lesions at 7T and in 36 lesions at 3T by consensus. Inter- and intrarater reliability were "substantial/good" both at 3T and 7T analysis (Cohen κ, >0.71). Based on consensus agreement, the reliability of rim visualization at 3T versus 7T was 0.78 (κ) with a pair-wise agreement of 90%. More lesions were judged to be false-positive or false-negative at 3T than at 7T. CONCLUSIONS: Nearly all 7T paramagnetic rims can also be seen at 3T. Imaging at 3T opens the possibility of implementing paramagnetic rims as an outcome measure in multicenter, MR imaging-based clinical trials aimed at treating perilesional persistent inflammation and its potential effects on remyelination.

Use of Rapid Reduced Electric Field Switching to Enhance Compound Specificity for Proton Transfer Reaction-Mass Spectrometry.

The high sensitivity of proton transfer reaction-mass spectrometry (PTR-MS) makes it a suitable analytical tool for detecting trace compounds. Its specificity is primarily determined by the accuracy of identifying the m/ z of the product ions specific to a particular compound. However, specificity can be enhanced by changing the product ions (concentrations and types) through modifying the reduced electric field. For current PTR-MS systems, this is not possible for trace compounds that would only be present in the reaction chamber of a PTR-MS for a short time (seconds). For such circumstances, it is necessary to change the reduce electric field swiftly if specificity enhancements are to be achieved. In this paper we demonstrate such a novel approach, which permits any compound that may only be present in the drift tube for seconds to be thoroughly investigated. Specifically, we have developed hardware and software which permits the reaction region's voltages to be rapidly switched at a frequency of 0.1-5 Hz. We show how this technique can be used to provide a higher confidence in the identification of compounds than is possible by keeping to one reduced electric field value through illustrating the detection of explosives. Although demonstrated for homeland security applications, this new technique has applications in other analytical areas and disciplines where rapid changes in a compound's concentration can occur, for example, in the Earth's atmosphere, plant emissions and in breath. Importantly, this adaptation provides a method for improved selectivity without expensive instrumental changes or the need for high mass resolution instruments.

Improved Visualization of Cortical Lesions in Multiple Sclerosis Using 7T MP2RAGE.

BACKGROUND AND PURPOSE: Cortical lesions are common and often extensive in multiple sclerosis but are difficult to visualize by MRI, leaving important questions about their clinical implications and response to therapy unanswered. Our aim was to determine whether cortical lesions are better visualized using magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) than T2*-weighted imaging on 7T MR imaging. MATERIALS AND METHODS: Brain MR imaging using T1-weighted MP2RAGE at 500-µm isotropic resolution, T2*-weighted gradient-echo, and T2*-weighted segmented echo-planar imaging sequences were collected for 13 patients with MS and 5 age-matched neurologically healthy controls on a 7T research system. One MS case underwent postmortem MR imaging including gradient-echo and MP2RAGE sequences, after which cortical lesions seen on MR imaging were assessed with immunohistochemistry. RESULTS: MP2RAGE detected 203 cortical lesions (median, 16 lesions/case; interquartile range, 15), compared to 92 with T2*gradient-echo (median, 7; interquartile range, 8; P < .001) and 81 with T2*EPI (median, 7; interquartile range, 5; P < .001). This increase in lesion number detected on MP2RAGE versus T2* was observed for juxtacortical, leukocortical, and intracortical lesions. Forty-three percent of all cortical lesions were identified only on MP2RAGE. White matter lesion volume correlated with total juxtacortical (r = 0.86, P < .001) and leukocortical lesion volume (r = 0.70, P < .01) but not intracortical lesion volume, suggesting that pathophysiology may differ by lesion type. Of 4 suspected lesions seen on postmortem imaging, 3 were found to be true cortical lesions while 1 represented postmortem tissue damage. CONCLUSIONS: A combination of MP2RAGE and T2*-weighted imaging at 7T improved detection of cortical lesions and should enable longitudinal studies to elucidate their spatiotemporal dynamics and clinical implications.

Description and prediction of time-to-attainment of excellent recovery for borderline patients followed prospectively for 20 years.

One purpose of this study was to determine the cumulative rates of excellent recovery for borderline patients and axis II comparison subjects followed prospectively for 20 years. Another purpose was to find the best set of baseline predictors of excellent recovery for borderline patients. A total of 290 inpatients meeting rigorous criteria for borderline personality disorder and 72 axis II comparison subjects completed semistructured interviews and self-report measures during their index admission. Subjects were reassessed prospectively over 10 contiguous two-year waves of follow-up. Thirty-nine percent of borderline patients and 73% of personality-disordered comparison subjects met our operationalized definition of excellent recovery (concurrent remission of borderline or another primary personality disorder, good social and full-time vocational functioning, and absence of an axis I disorder associated decreased social and/or vocational functioning). Five variables formed our multivariate predictive model of excellent recovery for borderline patients: higher IQ, good childhood work history, good adult vocational record, lower trait neuroticism, and higher trait agreeableness. The results of this study suggest that complete recovery is difficult for borderline patients to achieve even over long periods of time. They also suggest that competence displayed in both childhood and adulthood is the best predictor of this important outcome.

An Automated Statistical Technique for Counting Distinct Multiple Sclerosis Lesions.

BACKGROUND AND PURPOSE: Lesion load is a common biomarker in multiple sclerosis, yet it has historically shown modest association with clinical outcome. Lesion count, which encapsulates the natural history of lesion formation and is thought to provide complementary information, is difficult to assess in patients with confluent (ie, spatially overlapping) lesions. We introduce a statistical technique for cross-sectionally counting pathologically distinct lesions. MATERIALS AND METHODS: MR imaging was used to assess the probability of a lesion at each location. The texture of this map was quantified using a novel technique, and clusters resembling the center of a lesion were counted. Validity compared with a criterion standard count was demonstrated in 60 subjects observed longitudinally, and reliability was determined using 14 scans of a clinically stable subject acquired at 7 sites. RESULTS: The proposed count and the criterion standard count were highly correlated (r = 0.97, P < .001) and not significantly different (t59 = -.83, P = .41), and the variability of the proposed count across repeat scans was equivalent to that of lesion load. After accounting for lesion load and age, lesion count was negatively associated (t58 = -2.73, P < .01) with the Expanded Disability Status Scale. Average lesion size had a higher association with the Expanded Disability Status Scale (r = 0.35, P < .01) than lesion load (r = 0.10, P = .44) or lesion count (r = -.12, P = .36) alone. CONCLUSIONS: This study introduces a novel technique for counting pathologically distinct lesions using cross-sectional data and demonstrates its ability to recover obscured longitudinal information. The proposed count allows more accurate estimation of lesion size, which correlated more closely with disability scores than either lesion load or lesion count alone.

Therapeutic Advantages of Dual Targeting of PPAR-δ and PPAR-γ in an Experimental Model of Sporadic Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is associated with progressive impairments in brain responsiveness to insulin and insulin-like growth factor (IGF). Although deficiencies in brain insulin and IGF could be ameliorated with trophic factors such as insulin, impairments in receptor expression, binding, and tyrosine kinase activation require alternative strategies. Peroxisome proliferator-activated receptor (PPAR) agonists target genes downstream of insulin/IGF stimulation. Furthermore, their anti-oxidant and anti-inflammatory effects address other pathologies contributing to neurodegeneration. OBJECTIVES: The goal of this research was to examine effects of dual delivery of L165, 041 (PPAR-δ) and F-L-Leu (PPAR-γ) agonists for remediating in the early stages of neurodegeneration. MODEL: Experiments were conducted using frontal lobe slice cultures from an intracerebral Streptozotocin (i.c. STZ) rat model of AD. RESULTS: PPAR-δ+ PPAR-γ agonist treatments increased indices of neuronal and myelin maturation, and mitochondrial proliferation and function, and decreased neuroinflammation, AßPP-Aß, neurotoxicity, ubiquitin, and nitrosative stress, but failed to restore choline acetyl transferase expression and adversely increased HNE(lipid peroxidation) and acetylcholinesterase, which would have further increased stress and reduced cholinergic function in the STZ brain cultures. CONCLUSION: PPAR-δ + PPAR-γ agonist treatments have substantial positive early therapeutic targeting effects on AD-associated molecular and biochemical brain pathologies. However, additional or alternative strategies may be needed to optimize disease remediation during the initial phases of treatment.

Photon-Counting CT of the Brain: In Vivo Human Results and Image-Quality Assessment.

BACKGROUND AND PURPOSE: Photon-counting detectors offer the potential for improved image quality for brain CT but have not yet been evaluated in vivo. The purpose of this study was to compare photon-counting detector CT with conventional energy-integrating detector CT for human brains. MATERIALS AND METHODS: Radiation dose-matched energy-integrating detector and photon-counting detector head CT scans were acquired with standardized protocols (tube voltage/current, 120 kV(peak)/370 mAs) in both an anthropomorphic head phantom and 21 human asymptomatic volunteers (mean age, 58.9 ± 8.5 years). Photon-counting detector thresholds were 22 and 52 keV (low-energy bin, 22-52 keV; high-energy bin, 52-120 keV). Image noise, gray matter, and white matter signal-to-noise ratios and GM-WM contrast and contrast-to-noise ratios were measured. Image quality was scored by 2 neuroradiologists blinded to the CT detector type. Reproducibility was assessed with the intraclass correlation coefficient. Energy-integrating detector and photon-counting detector CT images were compared using a paired t test and the Wilcoxon signed rank test. RESULTS: Photon-counting detector CT images received higher reader scores for GM-WM differentiation with lower image noise (all P < .001). Intrareader and interreader reproducibility was excellent (intraclass correlation coefficient, ≥0.86 and 0.79, respectively). Quantitative analysis showed 12.8%-20.6% less image noise for photon-counting detector CT. The SNR of photon-counting detector CT was 19.0%-20.0% higher than of energy-integrating detector CT for GM and WM. The contrast-to-noise ratio of photon-counting detector CT was 15.7% higher for GM-WM contrast and 33.3% higher for GM-WM contrast-to-noise ratio. CONCLUSIONS: Photon-counting detector brain CT scans demonstrated greater gray-white matter contrast compared with conventional CT. This was due to both higher soft-tissue contrast and lower image noise for photon-counting CT.

Prolonged concurrent hypotension and low bispectral index ('double low') are associated with mortality, serious complications, and prolonged hospitalization after cardiac surgery.

BACKGROUND: Low bispectral index (BIS) and low mean arterial pressure (MAP) are associated with worse outcomes after surgery. We tested the hypothesis that a combination of these risk factors, a 'double low', is associated with death and major complications after cardiac surgery. METHODS: We used data from 8239 cardiac surgical patients from two US hospitals. The primary outcomes were 30-day mortality and a composite of in-hospital mortality and morbidity. We examined whether patients who had a case-averaged double low, defined as time-weighted average BIS and MAP (calculated over an entire case) below the sample mean but not in the reference group, had increased risk of the primary outcomes compared with patients whose BIS and/or MAP were at or higher than the sample mean. We also examined whether a prolonged cumulative duration of a concurrent double low (simultaneous low MAP and BIS) increased the risk of the primary outcomes. RESULTS: Case-averaged double low was not associated with increased risk of 30-day mortality {odds ratio [OR] 1.73 [95% confidence interval (CI) 0.94-3.18] vs reference; P =0.01} or the composite of in-hospital mortality and morbidity [OR 1.47 (95% CI 0.98-2.20); P =0.01] after correction for multiple outcomes. A prolonged concurrent double low was associated with 30-day mortality [OR 1.06 (95% CI 1.01-1.11) per 10-min increase; P =0.001] and the composite of in-hospital mortality and morbidity [OR 1.04 (95% CI 1.01-1.07), P =0.004]. CONCLUSIONS: A prolonged concurrent double low, but not a case-averaged double low, was associated with higher morbidity and mortality after cardiac surgery.

Transverse relaxation of cerebrospinal fluid depends on glucose concentration.

PURPOSE: To evaluate the biophysical processes that generate specific T2 values and their relationship to specific cerebrospinal fluid (CSF) content. MATERIALS AND METHODS: CSF T2s were measured ex vivo (14.1T) from isolated CSF collected from human, rat and non-human primate. CSF T2s were also measured in vivo at different field strength in human (3 and 7T) and rodent (1, 4.7, 9,4 and 11.7T) using different pulse sequences. Then, relaxivities of CSF constituents were measured, in vitro, to determine the major molecule responsible for shortening CSF T2 (2s) compared to saline T2 (3s). The impact of this major molecule on CSF T2 was then validated in rodent, in vivo, by the simultaneous measurement of the major molecule concentration and CSF T2. RESULTS: Ex vivo CSF T2 was about 2.0s at 14.1T for all species. In vivo human CSF T2 approached ex vivo values at 3T (2.0s) but was significantly shorter at 7T (0.9s). In vivo rodent CSF T2 decreased with increasing magnetic field and T2 values similar to the in vitro ones were reached at 1T (1.6s). Glucose had the largest contribution of shortening CSF T2in vitro. This result was validated in rodent in vivo, showing that an acute change in CSF glucose by infusion of glucose into the blood, can be monitored via changes in CSF T2 values. CONCLUSION: This study opens the possibility of monitoring glucose regulation of CSF at the resolution of MRI by quantitating T2.

Volumetric Analysis from a Harmonized Multisite Brain MRI Study of a Single Subject with Multiple Sclerosis.

BACKGROUND AND PURPOSE: MR imaging can be used to measure structural changes in the brains of individuals with multiple sclerosis and is essential for diagnosis, longitudinal monitoring, and therapy evaluation. The North American Imaging in Multiple Sclerosis Cooperative steering committee developed a uniform high-resolution 3T MR imaging protocol relevant to the quantification of cerebral lesions and atrophy and implemented it at 7 sites across the United States. To assess intersite variability in scan data, we imaged a volunteer with relapsing-remitting MS with a scan-rescan at each site. MATERIALS AND METHODS: All imaging was acquired on Siemens scanners (4 Skyra, 2 Tim Trio, and 1 Verio). Expert segmentations were manually obtained for T1-hypointense and T2 (FLAIR) hyperintense lesions. Several automated lesion-detection and whole-brain, cortical, and deep gray matter volumetric pipelines were applied. Statistical analyses were conducted to assess variability across sites, as well as systematic biases in the volumetric measurements that were site-related. RESULTS: Systematic biases due to site differences in expert-traced lesion measurements were significant (P < .01 for both T1 and T2 lesion volumes), with site explaining >90% of the variation (range, 13.0-16.4 mL in T1 and 15.9-20.1 mL in T2) in lesion volumes. Site also explained >80% of the variation in most automated volumetric measurements. Output measures clustered according to scanner models, with similar results from the Skyra versus the other 2 units. CONCLUSIONS: Even in multicenter studies with consistent scanner field strength and manufacturer after protocol harmonization, systematic differences can lead to severe biases in volumetric analyses.