Prevalence, recovery and phenotype of dysphagia in patients with ischaemic cerebellar stroke.

BACKGROUND AND PURPOSE: Swallowing is a complex task, moderated by a sophisticated bilateral network including multiple supratentorial regions, the brainstem and the cerebellum. To date, conflicting data exist about whether focal lesions to the cerebellum are associated with dysphagia. Therefore, the aim of the study was to evaluate dysphagia prevalence, recovery and dysphagia pattern in patients with ischaemic cerebellar stroke. METHODS: A retrospective analysis of patients consecutively admitted to an academic stroke centre with ischaemic stroke found only in the cerebellum was performed. The presence of dysphagia was the primary end-point and was assessed by a speech-language pathologist, according to defined criteria. Dysphagia pattern was evaluated by analysing the videos of the flexible endoscopic evaluation of swallowing. Brain imaging was used to identify lesion size and location associated with dysphagia. RESULTS: Between January 2016 and December 2021, 102 patients (35.3% female) with a mean age of 52.8 ± 17.3 years were included. Thirteen (12.7%) patients presented with dysphagia. The most frequently observed flexible endoscopic evaluation of swallowing phenotype was premature spillage (n = 7; 58.3%), whilst significant residues or aspiration did not occur. One patient died (7.7%); the other patients showed improvement of dysphagia and one patient (7.7%) was discharged with dietary restrictions. CONCLUSIONS: Although the involvement of the cerebellum in deglutition has become increasingly evident, isolated lesions to the cerebellum are less likely to cause clinically relevant and persisting dysphagia compared to other brain regions. The observed dysphagia pattern shows a lack of coordination and control, resulting in premature spillage or fragmented bolus transfer in some patients.

Multiparametric quantitative MRI reveals progressive cortical damage over time in clinically stable relapsing-remitting MS.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), cortical grey matter pathology relevantly contributes to long-term disability. Still, diffuse cortical inflammation cannot be detected with conventional MRI. OBJECTIVE: We aimed to assess microstructural damage of cortical grey matter over time and the relation to clinical disability as well as relapse activity in patients with RRMS using multiparametric quantitative (q)MRI techniques. METHODS: On 40 patients with RRMS and 33 age-matched and sex-matched healthy controls, quantitative T1, T2, T2* and proton density (PD) mapping was performed at baseline and follow-up after 2 years. Cortical qMRI parameter values were extracted with the FreeSurfer software using a surface-based approach. QMRI parameters, cortical thickness and white matter lesion (WML) load, as well as Expanded Disability Status Scale (EDSS) and relapse rate, were compared between time points. RESULTS: Over 2 years, significant increases of T1 (p≤0.001), PD (p≤0.001) and T2 (p=0.005) values were found in the patient, but not in the control group. At decreased relapse rate over time (p=0.001), cortical thickness, WML volume and EDSS remained unchanged. CONCLUSION: Despite clinical stability, cortical T1, T2 and PD values increased over time, indicating progressive demyelination and increasing water content. These parameters represent promising surrogate parameters of diffuse cortical inflammation in RRMS.

Opsoclonus-myoclonus syndrome associated with pancreatic neuroendocrine tumor: a case report.

BACKGROUND: Opsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET). CASE PRESENTATION: A 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids. CONCLUSIONS: This case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy.

Association of Lesion Pattern and Dysphagia in Acute Intracerebral Hemorrhage.

Background and Purpose: Dysphagia is a common and severe symptom of acute stroke. Although intracerebral hemorrhages (ICHs) account for 10% to 15% of all strokes, the occurrence of dysphagia in this subtype of stroke has not been widely investigated. The aim of this study was to evaluate the overall frequency and associated lesion locations and clinical predictors of dysphagia in patients with acute ICH. Methods: Our analysis included 132 patients with acute ICH. Clinical swallowing assessment was performed within 48 hours after admission. All patients underwent computed tomography imaging. Voxel-based lesion-symptom mapping was performed to determine lesion sites associated with dysphagia. Results: Eighty-four patients (63.6%) were classified as dysphagic. Higher scores on the National Institutes of Health Stroke Scale, larger ICH volumes, and higher degree of disability were associated with dysphagia. Voxels showing a statistically significant association with dysphagia were mainly located in the right insular cortex, the right central operculum, as well as the basal ganglia, corona radiata, and the left thalamus and left internal capsule. In contrast to lobar regions, in subcortical deep brain areas also small lesion volumes (<10 mL) were associated with a substantial risk of dysphagia. Intraventricular ICH extension and midline shift as imaging findings indicating a space-occupying effect were not associated with dysphagia in multivariate analysis. Conclusions: Dysphagia is a frequent symptom in acute ICH. Distinct cortical and subcortical lesion sites are related to swallowing dysfunction and predictive for the development of dysphagia. Therefore, patients with ICH should be carefully evaluated for dysphagia independently from lesion size, in particular if deep brain regions are affected.

Cortical Changes in Epilepsy Patients With Focal Cortical Dysplasia: New Insights With T2 Mapping.

BACKGROUND: In epilepsy patients with focal cortical dysplasia (FCD) as the epileptogenic focus, global cortical signal changes are generally not visible on conventional MRI. However, epileptic seizures or antiepileptic medication might affect normal-appearing cerebral cortex and lead to subtle damage. PURPOSE: To investigate cortical properties outside FCD regions with T2 -relaxometry. STUDY TYPE: Prospective study. SUBJECTS: Sixteen patients with epilepsy and FCD and 16 age-/sex-matched healthy controls. FIELD STRENGTH/SEQUENCE: 3T, fast spin-echo T2 -mapping, fluid-attenuated inversion recovery (FLAIR), and synthetic T1 -weighted magnetization-prepared rapid acquisition of gradient-echoes (MP-RAGE) datasets derived from T1 -maps. ASSESSMENT: Reconstruction of the white matter and cortical surfaces based on MP-RAGE structural images was performed to extract cortical T2 values, excluding lesion areas. Three independent raters confirmed that morphological cortical/juxtacortical changes in the conventional FLAIR datasets outside the FCD areas were definitely absent for all patients. Averaged global cortical T2 values were compared between groups. Furthermore, group comparisons of regional cortical T2 values were performed using a surface-based approach. Tests for correlations with clinical parameters were carried out. STATISTICAL TESTS: General linear model analysis, permutation simulations, paired and unpaired t-tests, and Pearson correlations. RESULTS: Cortical T2 values were increased outside FCD regions in patients (83.4 ± 2.1 msec, control group 81.4 ± 2.1 msec, P = 0.01). T2 increases were widespread, affecting mainly frontal, but also parietal and temporal regions of both hemispheres. Significant correlations were not observed (P ≥ 0.55) between cortical T2 values in the patient group and the number of seizures in the last 3 months or the number of anticonvulsive drugs in the medical history. DATA CONCLUSION: Widespread increases in cortical T2 in FCD-associated epilepsy patients were found, suggesting that structural epilepsy in patients with FCD is not only a symptom of a focal cerebral lesion, but also leads to global cortical damage not visible on conventional MRI. EVIDENCE LEVEL: 21 TECHNICAL EFFICACY STAGE: 3 J. MAGN. RESON. IMAGING 2020;52:1783-1789.

Flat Panel Computed Tomography Pooled Blood Volume and Infarct Prediction in Endovascular Stroke Treatment.

Background and Purpose- Patients with large-vessel stroke frequently need to be transferred to comprehensive stroke centers for endovascular treatment. An update of physiological perfusion parameters and stroke progression on arrival is desirable. We examined the reliability of preinterventional pooled blood volume (PBV)-maps acquired by flat-panel detector computed tomography (CT) in the interventional angiography suite. Methods- The volumes of preinterventional perfusion deficit in flat-panel detector CT-PBV source images were compared with final infarct volume on follow-up multislice-CT after endovascular treatment of 29 consecutive patients with occlusion of the middle cerebral artery (MCA) or the distal internal carotid artery (ICA). Results- Endovascular treatment was successful in 26 patients (Thrombolysis in Cerebral Infarction, 2b-3). Overall, the median preinterventional PBV-deficit was 9×larger than median final infarct volume on multislice-CT (86.4 mL [10.3; 111.6] versus 9.6 mL [3.6; 36.8]). This was especially evident in the subgroup of successful recanalization (PBV-deficit: 87.5 mL [10.6; 115.1], final infarct: 8.7 mL [3.6; 29]). In futile recanalization, the final infarct tended to be underestimated (PBV-deficit: 86.4 mL [5.9; -] and final infarct: 116.4 mL [3.5; -]). Conclusions- Flat panel detector CT-PBV is not reliable in predicting the final infarct volume and should not be used in clinical decision making for endovascular treatment of acute cerebral artery occlusions.

Revascularization of High-Grade Carotid Stenosis Restores Global Cerebral Energy Metabolism.

Background and Purpose- Chronic cerebral hemodynamic impairment due to high-grade occlusive carotid disease may lead to compromised energy metabolism. This might result in chronic subtle tissue damage, even in patients without overt brain infarction. The aim of this study was to investigate hypoperfusion-related changes of cerebral energy metabolism and their potential restitution after revascularization. For this purpose, 3-dimensional 31P magnetic resonance spectroscopy and oxygenation-sensitive T2' magnetic resonance imaging were used (with 1/T2'=1/T2*-1/T2), which were expected to cross-validate each other. Methods- Ten patients with unilateral high-grade carotid artery stenosis resulting in a transient ischemic attack or a nondisabling cerebral ischemia were included. Then, high-energy metabolites, intracellular pH, and oxygenation-sensitive quantitative (q)T2' values were determined in noninfarcted hypoperfused areas delineated on time-to-peak maps from perfusion-weighted imaging and in unaffected contralateral areas before and shortly after carotid stenting/endarterectomy. Repeated measures ANOVA was used to test for intervention effects. Results- Within dependent hypoperfused areas ipsilateral to the stenosis, qT2' was significantly decreased ( P<0.05) as compared to corresponding contralateral areas before carotid intervention. There was a significant effect of carotid intervention on qT2' values in both hemispheres ( P<0.001). No differences between hemispheres were found for qT2' after revascularization. Intracellular pH and qT2' values showed a significant negative relationship ( P=0.005) irrespective of time point and hemisphere. Conclusions- After revascularization of unilateral high-grade carotid stenosis, previously decreased qT2' in the dependent hypoperfused territory as marker of hypoxia reincreases not only in the dependent territory but also in corresponding contralateral brain tissue. This might indicate a restriction of the whole-brain oxygen metabolism in case of unilateral high-grade carotid stenosis and an improvement of whole-brain oxygenation after revascularization that goes beyond acute clinically apparent affection of the dependent territory. Furthermore, tissue oxygen supply seems to be closely linked to intracellular pH.

Oxygenation-Sensitive Magnetic Resonance Imaging in Acute Ischemic Stroke Using T2'/R2' Mapping: Influence of Relative Cerebral Blood Volume.

BACKGROUND AND PURPOSE: Quantitative T2'/R2' mapping detect locally increased concentrations of deoxygenated hemoglobin-causing a decrease of T2' and increase of R2'-and might reflect increased cerebral oxygen extraction fraction. Because increases of (relative) cerebral blood volume (rCBV) may influence T2' and R2' through accumulation of deoxygenated hemoglobin, we aimed to investigate the impact of rCBV on T2'/R2' in patients with ischemic stroke. METHODS: Data from patients with acute internal carotid artery and middle cerebral artery occlusion were analyzed. T2', R2', and rCBV were measured within the ischemic core, slightly and severely hypoperfused areas, and their relationship was examined. RESULTS: A strong negative correlation with rCBV was found for R2' (r=-0.544; P=0.002), and T2' correlated positively with rCBV (r=0.546; P=0.001) in time-to-peak-delayed areas. T2'/R2' within hypoperfused tissue remained unchanged at normal or elevated rCBV levels. CONCLUSIONS: T2' decrease/R2' increase within hypoperfused areas in ischemic stroke is not caused by local elevations of rCBV but most probably only by increased cerebral oxygen extraction fraction. However, considering rCBV is crucial to assess extent of oxygen extraction fraction changes by means of T2'/R2'.

Quantitative T2'-mapping in acute ischemic stroke.

BACKGROUND AND PURPOSE: Quantitative T2'-mapping detects regional changes in the relation of oxygenated and deoxygenated haemoglobine and might reflect areas with increased oxygen extraction. T2'-mapping in conjunction with an elaborate algorithm for motion correction was performed in patients with acute large-vessel stroke, and quantitative T2'-values were determined within the diffusion-weighted imaging lesion and perfusion-restricted tissue. METHODS: Eleven patients (median age, 71 years) with acute middle cerebral or internal carotid artery occlusion underwent MRI before scheduled endovascular treatment. MR-examination included diffusion- and perfusion-weighted imaging and quantitative, motion-corrected mapping of T2'. Time-to-peak maps were thresholded for different degrees of perfusion delays (eg, ≥0 s, ≥ 2s) when compared with a reference time-to-peak value from healthy contralateral tissue. Mean T2'-values in areas with reduced apparent diffusion coefficient and in areas with impaired perfusion were compared with T2'-values in corresponding contralateral areas. RESULTS: Median time between symptom onset and MRI was 238 minutes. T2'-values were significantly reduced within the apparent diffusion coefficient -lesion when compared with contralateral healthy tissue (83 ms [67, 97] versus 97 ms [91, 111]; P<0.003). In perfusion-restricted tissue, T2'-values were also significantly lower when compared with contralateral healthy tissue (ie, for time to peak, ≥0 s 93 ms [86, 102] versus 104 [90, 110]; P=0.008) but were significantly higher than within the apparent diffusion coefficient lesion. The severity of the perfusion impairment had no influence on median T2'-values. CONCLUSIONS: Motion-corrected T2'-mapping reveals significant and gradually declining values from healthy to perfusion-disturbed to apparent diffusion coefficient-restricted tissue. Current T2'-mapping can differentiate between the ischemic core and the perfusion-impaired areas but not on its own between penumbral and oligemic tissue.

Pial collaterals limit stroke progression and metabolic stress in hypoperfused tissue: An MRI perfusion and mq-BOLD study.

BACKGROUND AND PURPOSE: In acute ischemic stroke (AIS) due to large-vessel occlusion (LVO), the relationship between cerebral oxygen extraction fraction (OEF) as the hallmark of the ischemic penumbra and leptomeningeal collateral supply is not well established. We aimed to investigate the relationship between pial collateralization and tissue oxygen extraction in patients with LVO using magnetic resonance imaging (MRI). METHODS: Data from 14 patients with anterior circulation LVO who underwent MRI before acute stroke treatment were analyzed. In addition to diffusion-weighted imaging and perfusion-weighted imaging (PWI), the protocol comprised sequences for multiparametric quantitative blood-oxygen-level-dependent imaging for the calculation of relative OEF (rOEF). Pial collateral supply was quantitatively assessed by analyzing the signal variance in T2*-weighted PWI time series. Relationships between collateral supply, infarct volume, rOEF in peri-infarct hypoperfused tissue, and clinical stroke severity were assessed. RESULTS: The PWI-based parameter quantifying collateral supply was negatively correlated with baseline ischemic core volume and rOEF in the hypoperfused peri-infarct area (p < .01). Both reduced collateral supply and increased rOEF correlated significantly with higher scores on the National Institutes of Health Stroke Scale (p < .05). Increased rOEF within hypoperfused tissue was associated with higher baseline (p = .043) and follow-up infarct volume (p = .009). CONCLUSIONS: Signal variance-based mapping of collaterals with PWI depicts pial collateral supply, which is closely tied to tissue pathophysiology and clinical and imaging outcomes. Magnetic-resonance-derived mapping of cerebral rOEF reveals penumbral characteristics of hypoperfused tissue and might provide a promising imaging biomarker in AIS.

Cortical microstructural involvement in cerebral small vessel disease.

Background: In cerebral small vessel disease (CSVD), cortical atrophy occurs at a later stage compared to microstructural abnormalities and therefore cannot be used for monitoring short-term disease progression. We aimed to investigate whether cortical diffusion tensor imaging (DTI) and quantitative (q) magnetic resonance imaging (MRI) are able to detect early microstructural involvement of the cerebral cortex in CSVD. Materials and Methods: 33 CSVD patients without significant cortical or whole-brain atrophy and 16 healthy control subjects were included and underwent structural MRI, DTI and high-resolution qMRI with T2, T2* and T2' mapping at 3 T as well as comprehensive cognitive assessment. After tissue segmentation and reconstruction of the cortical boundaries with the Freesurfer software, DTI and qMRI parameters were saved as surface datasets and averaged across all vertices. Results: Cortical diffusivity and quantitative T2 values were significantly increased in patients compared to controls (p < 0.05). T2 values correlated significantly positively with white matter hyperintensity (WMH) volume (p < 0.01). Both cortical diffusivity and T2 showed significant negative associations with axonal damage to the white matter fiber tracts (p < 0.05). Conclusions: Cortical diffusivity and quantitative T2 mapping are suitable to detect microstructural involvement of the cerebral cortex in CSVD and represent promising imaging biomarkers for monitoring disease progression and effects of therapeutical interventions in clinical studies.

12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases.

Protein tyrosine phosphatases (PTPs) are regulated through reversible oxidation of the active-site cysteine. Previous studies have implied soluble reactive oxygen species (ROS), like H(2)O(2), as the mediators of PTP oxidation. The potential role(s) of peroxidized lipids in PTP oxidation have not been described. This study demonstrates that increases in cellular lipid peroxides, induced by disruption of glutathione peroxidase 4, induce cellular PTP oxidation and reduce the activity of PDGF receptor targeting PTPs. These effects were accompanied by site-selective increased PDGF beta-receptor phosphorylation, sensitive to 12/15-lipoxygenase (12/15-LOX) inhibitors, and increased PDGF-induced cytoskeletal rearrangements. Importantly, the 12/15-LOX-derived 15-OOH-eicosatetraenoic acid lipid peroxide was much more effective than H(2)O(2) in induction of in vitro PTP oxidation. Our study thus establishes that lipid peroxides are previously unrecognized inducers of oxidation of PTPs. This identifies a pathway for control of receptor tyrosine kinase signaling, which might also be involved in the etiology of diseases associated with increased lipid peroxidation.

Impaired oxygen extraction and adaptation of intracellular energy metabolism in cerebral small vessel disease.

Background: We aimed to investigate whether combined phosphorous (31P) magnetic resonance spectroscopic imaging (MRSI) and quantitative T 2 ' mapping are able to detect alterations of the cerebral oxygen extraction fraction (OEF) and intracellular pH (pHi) as markers the of cellular energy metabolism in cerebral small vessel disease (SVD). Materials and methods: 32 patients with SVD and 17 age-matched healthy control subjects were examined with 3-dimensional 31P MRSI and oxygenation-sensitive quantitative T 2 ' mapping (1/ T 2 '  = 1/T2* - 1/T2) at 3 Tesla (T). PHi was measured within the white matter hyperintensities (WMH) in SVD patients. Quantitative T 2 ' values were averaged across the entire white matter (WM). Furthermore, T 2 ' values were extracted from normal-appearing WM (NAWM) and the WMH and compared between patients and controls. Results: Quantitative T 2 ' values were significantly increased across the entire WM and in the NAWM in patients compared to control subjects (149.51 ± 16.94 vs. 138.19 ± 12.66 ms and 147.45 ± 18.14 vs. 137.99 ± 12.19 ms, p < 0.05). WM T 2 ' values correlated significantly with the WMH load (ρ=0.441, p = 0.006). Increased T 2 ' was significantly associated with more alkaline pHi (ρ=0.299, p < 0.05). Both T 2 ' and pHi were significantly positively correlated with vascular pulsatility in the distal carotid arteries (ρ=0.596, p = 0.001 and ρ=0.452, p = 0.016). Conclusions: This exploratory study found evidence of impaired cerebral OEF in SVD, which is associated with intracellular alkalosis as an adaptive mechanism. The employed techniques provide new insights into the pathophysiology of SVD with regard to disease-related consequences on the cellular metabolic state.

Focal epilepsy without overt epileptogenic lesions: no evidence of microstructural brain tissue damage in multi-parametric quantitative MRI.

Background and purpose: In patients with epilepsies of structural origin, brain atrophy and pathological alterations of the tissue microstructure extending beyond the putative epileptogenic lesion have been reported. However, in patients without any evidence of epileptogenic lesions on diagnostic magnetic resonance imaging (MRI), impairment of the brain microstructure has been scarcely elucidated. Using multiparametric quantitative (q) magnetic resonance imaging MRI, we aimed to investigate diffuse impairment of the microstructural tissue integrity in MRI-negative focal epilepsy patients. Methods: 27 MRI-negative patients with focal epilepsy (mean age 33.1 ± 14.2 years) and 27 matched healthy control subjects underwent multiparametric qMRI including T1, T2, and PD mapping at 3 T. After tissue segmentation based on synthetic anatomies, mean qMRI parameter values were extracted from the cerebral cortex, the white matter (WM) and the deep gray matter (GM) and compared between patients and control subjects. Apart from calculating mean values for the qMRI parameters across the respective compartments, voxel-wise analyses were performed for each tissue class. Results: There were no significant differences for mean values of quantitative T1, T2, and PD obtained from the cortex, the WM and the deep GM between the groups. Furthermore, the voxel-wise analyses did not reveal any clusters indicating significant differences between patients and control subjects for the qMRI parameters in the respective compartments. Conclusions: Based on the employed methodology, no indication for an impairment of the cerebral microstructural tissue integrity in MRI-negative patients with focal epilepsy was found in this study. Further research will be necessary to identify relevant factors and mechanisms contributing to microstructural brain tissue damage in various subgroups of patients with epilepsy.

T2' imaging within perfusion-restricted tissue in high-grade occlusive carotid disease.

BACKGROUND AND PURPOSE: Quantitative T2' imaging presumably detects regional changes in the relation of oxygenated and deoxygenated hemoglobin. Regional differences in hemoglobin oxygenation might reflect areas with increased oxygen extraction for compensation of reduced perfusion pressure. We investigated quantitative T2' imaging in patients with high-grade stenoses of brain-supplying arteries and hypothesized that T2' values are lower in perfusion-restricted areas as compared with normally perfused tissue. METHODS: Eighteen patients (15 men; mean age±SD, 54±12.8 years) with unilateral symptomatic or asymptomatic high-grade extracranial or intracranial internal carotid artery or proximal middle cerebral artery stenosis/occlusion were included. MR examination included perfusion-weighted imaging and quantitative, motion-corrected mapping of T2' time. Time-to-peak and mean transit time maps were thresholded for different degrees of perfusion delays (eg, >0 seconds, ≥2 seconds) compared with the contralateral hemisphere. Mean T2' values in areas of impaired perfusion were compared with T2' values in corresponding contralateral or ipsilateral, normoperfused areas. RESULTS: Mean size of perfusion-impaired areas in time-to-peak maps (time-to-peak delay>0 seconds) was 10.8 mL (±6.3) and 11.5 mL (±6.4) in mean transit time maps (mean transit time delay>0 seconds). T2' values were significantly (P<0.01) lower in all perfusion-restricted compared with corresponding contralateral brain areas (ipsilateral versus contralateral). For time-to-peak delay >0 seconds, T2' values were 115 ms (±9) versus 125 ms (±12). For mean transit time delay>0 seconds, T2' values were 115 ms (±9) versus 128 ms (±10). Differences in T2' values increased with the severity of the perfusion delay. Ipsilateral T2' values outside the perfusion-disturbed areas did not differ from contralateral T2' values. CONCLUSIONS: Motion-corrected T2' imaging presumably detects areas with increased oxygen extraction within perfusion-restricted tissue in patients with high-grade occlusive vessel disease.

Cysteine mutant of mammalian GPx4 rescues cell death induced by disruption of the wild-type selenoenzyme.

Selenoproteins are expressed in many organisms, including bacteria, insects, fish, and mammals. Yet, it has remained obscure why some organisms rely on selenoproteins while others, like yeast and plants, express Cys-containing homologues. This study addressed the possible advantage of selenocysteine (Sec) vs. Cys in the essential selenoprotein glutathione peroxidase 4 (GPx4), using 4-hydroxy-tamoxifen-inducible Cre-excision of loxP-flanked GPx4 alleles in murine cells. Previously, it was shown that GPx4 disruption caused rapid cell death, which was prevented by α-tocopherol. Results presented herein demonstrate that the expression of wild-type (WT) GPx4 and its Sec/Cys (U46C) mutant rescued cell death of GPx4(-/-) cells, whereas the Sec/Ser (U46S) mutant failed. Notably, the specific activity of U46C was decreased by ∼90% and was indistinguishable from U46S-expressing and mock-transfected cells. Hence, the U46C mutant prevented apoptosis despite hardly measurable in vitro activity. Doxycycline-inducible expression revealed that minute amounts of either U46C or WT GPx4 prevented cell death, albeit WT GPx4 was more efficient. Interestingly, at the same expression level, proliferation was promoted in U46C-expressing cells but attenuated in WT-expressing cells. In summary, both catalytic efficiency and the expression level of GPx4 control the balance between cell survival and proliferation.

Distribution Pattern Analysis of Cortical Brain Infarcts on Diffusion-Weighted Magnetic Resonance Imaging: A Hypothesis-Generating Approach to the Burden of Silent Embolic Stroke.

Background In patients with covert cerebrovascular disease or proximal source of embolism, embolic silent brain infarction may precede major stroke events. Therefore, characterization of particularly cortical silent brain infarction is essential for identifying affected patients and commencing adequate secondary prevention. This study aimed to investigate differences in the distribution pattern of cortical ischemic stroke lesions to assess potential predilection sites of cortical silent brain infarction. Methods and Results We prospectively included all consecutive patients with stroke presenting from January 1 to December 31, 2018. Diffusion-weighted imaging lesions were used to generate voxel-based lesion maps and assigned to atlas-based cortical regions of interest in middle cerebral artery territories. Each region-of-interest lesion frequency was related to the respective region-of-interest volume to identify frequently affected and underrepresented cerebral cortex areas. Diffusion-weighted imaging data for voxel-based lesion maps were available in 334 out of 633 patients. Primary analysis revealed that small- (<0.24 cc) and medium-sized (0.24-2640 cc) lesions distributed predominantly along regions associated with sensorimotor or language function. Detailed analysis within middle cerebral artery territories showed an approximated frequency of missed cortical stroke lesions of up to 67% in the right and 69% in the left hemisphere. In particular, the frontal, temporal, and occipital cortices were underrepresented. Larger lesion size and areas associated with higher cortical function led to hospital admission. Conclusions Cortical brain infarcts in hospitalized patients are not dispersed equally but are predominantly located in brain structures associated with motor control and sensory and language function. Matching underrepresented cerebral cortex regions to symptoms not yet associated with stroke warrants further exploration.

System x(c)- and thioredoxin reductase 1 cooperatively rescue glutathione deficiency.

GSH is the major antioxidant and detoxifier of xenobiotics in mammalian cells. A strong decrease of intracellular GSH has been frequently linked to pathological conditions like ischemia/reperfusion injury and degenerative diseases including diabetes, atherosclerosis, and neurodegeneration. Although GSH is essential for survival, the deleterious effects of GSH deficiency can often be compensated by thiol-containing antioxidants. Using three genetically defined cellular systems, we show here that forced expression of xCT, the substrate-specific subunit of the cystine/glutamate antiporter, in gamma-glutamylcysteine synthetase knock-out cells rescues GSH deficiency by increasing cellular cystine uptake, leading to augmented intracellular and surprisingly high extracellular cysteine levels. Moreover, we provide evidence that under GSH deprivation, the cytosolic thioredoxin/thioredoxin reductase system plays an essential role for the cells to deal with the excess amount of intracellular cystine. Our studies provide first evidence that GSH deficiency can be rescued by an intrinsic genetic mechanism to be considered when designing therapeutic rationales targeting specific redox enzymes to combat diseases linked to GSH deprivation.

Quantitative T*2-mapping based on multi-slice multiple gradient echo flash imaging: retrospective correction for subject motion effects.

Numerous clinical and research applications for quantitative mapping of the effective transverse relaxation time T*(2) have been described. Subject motion can severely deteriorate the quality and accuracy of results. A correction method for T*(2) maps acquired with multi-slice multiple gradient echo FLASH imaging is presented, based on acquisition repetition with reduced spatial resolution (and consequently reduced acquisition time) and weighted averaging of both data sets, choosing weighting factors individually for each k-space line to reduce the influence of motion. In detail, the procedure is based on the fact that motion artifacts reduce the correlation between acquired and exponentially fitted data. A target data set is constructed in image space, choosing the data yielding best correlation from the two acquired data sets. The k-space representation of the target is subsequently approximated as linear combination of original raw data, yielding the required weighting factors. As this method only requires a single acquisition repetition with reduced spatial resolution, it can be employed on any clinical system offering a suitable sequence with export of modulus and phase images. Experimental results show that the method works well for sparse motion, but fails for strong motion affecting the same k-space lines in both acquisitions.

Remodeling of nuclear architecture by the thiodioxoxpiperazine metabolite chaetocin.

Extensive changes of higher order chromatin arrangements can be observed during prometaphase, terminal cell differentiation and cellular senescence. Experimental systems where major reorganization of nuclear architecture can be induced under defined conditions, may help to better understand the functional implications of such changes. Here, we report on profound chromatin reorganization in fibroblast nuclei by chaetocin, a thiodioxopiperazine metabolite. Chaetocin induces strong condensation of chromosome territories separated by a wide interchromatin space largely void of DNA. Cell viability is maintained irrespective of this peculiar chromatin phenotype. Cell cycle markers, histone signatures, and tests for cellular senescence and for oxidative stress indicate that chaetocin induced chromatin condensation/clustering (CICC) represents a distinct entity among nuclear phenotypes associated with condensed chromatin. The territorial organization of entire chromosomes is maintained in CICC nuclei; however, the conventional nuclear architecture harboring gene-dense chromatin in the nuclear interior and gene-poor chromatin at the nuclear periphery is lost. Instead gene-dense and transcriptionally active chromatin is shifted to the periphery of individual condensed chromosome territories where nascent RNA becomes highly enriched around their outer surface. This chromatin reorganization makes CICC nuclei an attractive model system to study this border zone as a distinct compartment for transcription. Induction of CICC is fully inhibited by thiol-dependent antioxidants, but is not related to the production of reactive oxygen species. Our results suggest that chaetocin functionally impairs the thioredoxin (Trx) system, which is essential for deoxynucleotide synthesis, but in addition involved in a wide range of cellular functions. The mechanisms involved in CICC formation remain to be fully explored.