351 research outputs found
Blood-brain barrier permeability measured using dynamic contrast-enhanced magnetic resonance imaging: a validation study
No full textBlood–brain barrier (BBB) leakage can be measured using dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) as the influx constant Ki. To validate this method we compared measured Ki with biological expectations, namely (1) higher Ki in healthy individual grey matter (GM) versus white matter (WM), (2) GM/WM cerebral blood volume (CBV) ratio close to the histologically established GM/WM vascular density ratio, (3) higher Ki in visibly enhancing multiple sclerosis (MS) lesions versus MS normal appearing white matter (NAWM), and (4) higher Ki in MS NAWM versus healthy individual NAWM. We recruited 13 healthy individuals and 12 patients with MS and performed whole‐brain 3D DCE‐MRI at 3 T. Ki and CBV were calculated using Patlak modelling for manual regions of interest (ROI) and segmented tissue masks. Ki was higher in control GM versus WM (P = 0.001). CBV was higher in GM versus WM (P = 0.005, mean ratio 1.9). Ki was higher in visibly enhancing MS lesions versus MS NAWM (P = 0.002), and in MS NAWM versus controls (P = 0.014). Bland–Altman analysis showed no significant difference between ROI and segmentation methods (P = 0.638) and an intra‐class correlation coefficient showed moderate single measure consistency (0.610). Ki behaves as expected for a compound marker of permeability and surface area. The GM/WM CBV ratio measured by this technique is in agreement with the literature. This adds evidence to the validity of Ki measured by DCE‐MRI as a marker of overall BBB leakage
Conodonts in the Ordovician biostratigraphy of the British Isles: an update
No full textAn update of the conodont biostratugraphy is provided for the Ordovician
Permeability of the blood-brain barrier predicts no evidence of disease activity at two years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis
No full textOBJECTIVE: To investigate if blood-brain barrier (BBB) permeability, as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), can provide early detection of sub-optimal treatment response in relapsing-remitting multiple sclerosis (RRMS).METHODS: 35 RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the CNS, were scanned with DCE-MRI at 3T prior to treatment and at three and six-months post-treatment. We calculated the influx constant Ki , a measure of BBB permeability, using the Patlak model. Sub-optimal treatment response was defined as loss of no evidence of disease activity (NEDA-3) status after two years of treatment.RESULTS: Subjects with loss of NEDA status at 2 years had a 51% higher mean Ki in normal-appearing white matter (NAWM) measured after six months of treatment, compared to subjects with maintained NEDA status (mean difference 0.06 (CI 0.02-0.09) ml/100g/min; p=0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at two years (AUC 0.84, CI 0.70-0.99; p=0.003) and a value above 0.136 ml/100/g/min yielded an odds ratio of 12.4 for sub-optimal treatment response at 2 years, with a sensitivity of 73% and a specificity of 82%.INTERPRETATION: Our results suggest that BBB permeability as measured by DCE-MRI reliably predicts sub-optimal treatment response and is a surrogate marker of the state of health of the BBB. We find a predictive threshold for disease activity, which is remarkably identical in clinically isolated syndrome as previously reported and established RRMS as investigated here
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No full textTo quantify gene regulation, a function is required that relates transcription factor binding to DNA (input) to the rate of mRNA synthesis from a target gene (output). Such a 'gene regulation function' (GRF) generally cannot be measured because the experimental titration of inputs and simultaneous readout of outputs is difficult. Here we show that GRFs may instead be inferred from natural changes in cellular gene expression, as exemplified for the cell cycle in the yeast S. cerevisiae. We develop this inference approach based on a time series of mRNA synthesis rates from a synchronized population of cells observed over three cell cycles. We first estimate the functional form of how input transcription factors determine mRNA output and then derive GRFs for target genes in the clb2 gene cluster that are expressed during G2/M phase. Systematic analysis of additional GRFs suggests a network architecture that rationalizes transcriptional cell cycle oscillations. We find that a transcription factor network alone can produce oscillations in mRNA expression, but that additional input from cyclin oscillations is required to arrive at the native behaviour of the cell cycle oscillator
Cerebrospinal fluid neurofilament light chain in acute optic neuritis and its predictive ability of multiple sclerosis
No full textBackground: Studies on the capability of cerebrospinal fluid neurofilament light chain (cNfL) to predict multiple sclerosis (MS) conversion in clinically isolated syndromes have yielded varying results. Objectives: To expand our understanding of cNfL in optic neuritis (ON) and investigate whether incorporating cNfL into the 2017 McDonald criteria could accelerate the diagnosis of MS in patients with ON. Methods: cNfL was measured in diagnostic samples from 74 patients with verified ON. MS was diagnosed using the 2017 McDonald criteria with a minimum observation time of two years from ON onset. Results: 20.5% of 44 MS-converters did not fulfil the 2017 McDonald criteria at ON onset. A doubling of cNfL was associated with 207% (74%–514%) higher odds of MS (p = 0.00042, adjusted for age). Fulfilment of ≥ 1 MRI criterion for dissemination in space (DIS) and presence of brain contrast-enhancing lesions were associated with higher cNfL. Furthermore, cNfL correlated with inter-eye differences in retinal nerve fiber layer (RNFL) thickness (Spearman’s ρ = 0.46, p = 8 × 10
–5). Incorporating cNfL ≥ 906 pg/mL as a substitute for either dissemination in time or one MRI criterion for DIS increased the sensitivity (90.9% vs. 79.6%) and accuracy (91.9% vs. 87.8%), but also reduced the specificity (93.3% vs. 100%) of the 2017 McDonald criteria. Conclusion: cNfL was related to MS diagnostic parameters and the degree of RNFL swelling. Clinical use of cNfL may aid in identification of ON patients with increased risk of MS until larger studies have elaborated on the potential loss of specificity if used diagnostically.</p
Measurement variability of blood-brain barrier permeability using dynamic contrast-enhanced magnetic resonance imaging
No full textDynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is used to quantify the blood-brain barrier (BBB) permeability-surface area product. Serial measurements can indicate changes in BBB health, of interest to the study of normal physiology, neurological disease, and the effect of therapeutics. We performed a scan-rescan study to inform both sample size calculation for future studies and an appropriate reference change value for patient care. The final dataset included 28 healthy individuals (mean age 53.0, 82% female) scanned twice with mean interval 9.9 weeks. DCE-MRI was performed at 3T using a 3D gradient echo sequence with whole brain coverage, T1 mapping using variable flip angles, and a 16-minute dynamic sequence with a 3.2 second time resolution. Segmentation of white and grey matter (WM/GM) was performed using a 3D magnetization-prepared gradient echo image. The influx constant Ki was calculated using the Patlak method. The primary outcome was the within-subject coefficient of variation (CV) of Ki in both WM and GM. Ki values followed biological expectations in relation to known GM/WM differences in cerebral blood volume (CBV) and consequently vascular surface area.Subject-derived arterial input functions showed marked within-subject variability which were significantly reduced by using a venous input function (CV of area-under-the-curve 46 vs 12%, p < 0.001). Use of the venous input function significantly improved the CV of Ki in both WM (30 vs 59%, p < 0.001) and GM (21 vs 53%, p < 0.001). Further improvement was obtained using motion correction, scaling the venous input function by the artery, and using the median rather than the mean of individual voxel data. The final method gave CV of 27% and 17% in WM and GM respectively. No further improvement was obtained by replacing the subject-derived input function by one standard population input function. CV of Ki was shown to be highly sensitive to dynamic sequence duration, with shorter measurement periods giving marked deterioration especially in WM. In conclusion, measurement variability of 3D brain DCE-MRI is sensitive to analysis method and a large precision improvement is obtained using a venous input function
Insights from DCE-MRI:blood–brain barrier permeability in the context of MS relapses and methylprednisolone treatment
No full textBackground: Detecting multiple sclerosis (MS) relapses remains challenging due to symptom variability and confounding factors, such as flare-ups and infections. Methylprednisolone (MP) is used for severe relapses, decreasing the number of contrast-enhancing lesions on MRI. The influx constant (Ki) derived from dynamic contrast-enhanced MRI (DCE-MRI), a marker of blood–brain barrier (BBB) permeability, has shown promise as a predictor of disease activity in relapsing–remitting MS (RRMS).Objectives: To investigate the predictive value of Ki in relation to clinical MS relapses and MP treatment, comparing its performance with traditional MRI markers.Methods: We studied 20 RRMS subjects admitted for possible relapse, using DCE-MRI on admission to assess Ki in normal-appearing white matter (NAWM) via the Patlak model. Mixed-effects modeling compared the predictive accuracy of Ki, the presence of contrast-enhancing lesions (CEL), evidence of brain lesions (EBL; defined as the presence of CEL or new T2 lesions), and MP treatment on clinical relapse events. Five models were evaluated, including combinations of Ki, CEL, EBL, and MP, to determine the most robust predictors of clinical relapse. Model performance was assessed using accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), with bootstrapped confidence intervals.Results: Superior predictive accuracy was demonstrated with the inclusion of EBL and Ki, alongside MP treatment (AIC = 66.12, p = 0.006), outperforming other models with a classification accuracy of 83% (CI: 73–92%), sensitivity of 78% (CI: 60–94%), and specificity of 86% (CI: 74–97%). This model showed the highest combined PPV (78%, CI: 60–94%) and NPV (86%, CI: 74–98%) compared to models with EBL or CEL alone, suggesting an added value of Ki in enhancing predictive reliability.Conclusion: These results support the use of Ki alongside conventional MRI imaging metrics, to improve clinical relapse prediction in RRMS. The findings underscore the utility of Ki as a marker of MS-related neuroinflammation, with potential for integration into relapse monitoring protocols. Further validation in larger cohorts is recommended to confirm the model’s generalizability and clinical application.Background: Detecting multiple sclerosis (MS) relapses remains challenging due to symptom variability and confounding factors, such as flare-ups and infections. Methylprednisolone (MP) is used for severe relapses, decreasing the number of contrast-enhancing lesions on MRI. The influx constant (Ki) derived from dynamic contrast-enhanced MRI (DCE-MRI), a marker of blood–brain barrier (BBB) permeability, has shown promise as a predictor of disease activity in relapsing–remitting MS (RRMS). Objectives: To investigate the predictive value of Ki in relation to clinical MS relapses and MP treatment, comparing its performance with traditional MRI markers. Methods: We studied 20 RRMS subjects admitted for possible relapse, using DCE-MRI on admission to assess Ki in normal-appearing white matter (NAWM) via the Patlak model. Mixed-effects modeling compared the predictive accuracy of Ki, the presence of contrast-enhancing lesions (CEL), evidence of brain lesions (EBL; defined as the presence of CEL or new T2 lesions), and MP treatment on clinical relapse events. Five models were evaluated, including combinations of Ki, CEL, EBL, and MP, to determine the most robust predictors of clinical relapse. Model performance was assessed using accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), with bootstrapped confidence intervals. Results: Superior predictive accuracy was demonstrated with the inclusion of EBL and Ki, alongside MP treatment (AIC = 66.12, p = 0.006), outperforming other models with a classification accuracy of 83% (CI: 73–92%), sensitivity of 78% (CI: 60–94%), and specificity of 86% (CI: 74–97%). This model showed the highest combined PPV (78%, CI: 60–94%) and NPV (86%, CI: 74–98%) compared to models with EBL or CEL alone, suggesting an added value of Ki in enhancing predictive reliability. Conclusion: These results support the use of Ki alongside conventional MRI imaging metrics, to improve clinical relapse prediction in RRMS. The findings underscore the utility of Ki as a marker of MS-related neuroinflammation, with potential for integration into relapse monitoring protocols. Further validation in larger cohorts is recommended to confirm the model’s generalizability and clinical application.</p
Blood-brain barrier permeability changes in the first year after alemtuzumab treatment predict 2-year outcomes in relapsing-remitting multiple sclerosis
No full textBackground: in relapsing-remitting multiple sclerosis (RRMS), early disease control reduces the risk of permanent disability. The blood-brain barrier (BBB) is compromised in MS, and its permeability is a potential biomarker.Objective: to investigate BBB permeability measured by MRI as a marker of alemtuzumab efficacy.Methods: patients with RRMS initiating alemtuzumab treatment were recruited prospectively. BBB permeability was assessed as the Patlak-derived influx constant (Ki) by dynamic contrast-enhanced MRI before and 6, 12, and 18 months after the first course of alemtuzumab. No Evidence of Disease Activity-3 (NEDA-3) status was ascertained two years after treatment initiation.Results: patients who maintained NEDA-3 status at two years (n = 7) had a larger decrease in Ki between baseline and six months (-0.029 ml/100 g/min [CI -0.005 to -0.053]) and between baseline and 12 months in normal appearing white matter (0.043 [CI 0.022 to -0.065]), than those who experienced disease activity (n = 8). ROC curve analysis of the Ki change between baseline and 12 months in NAWM predicted a loss of NEDA status at 2 years with 86% sensitivity and 86% specificity (AUC 0.98, p = 0.002).Conclusion: BBB permeability predicted alemtuzumab efficacy at two years, indicating that BBB permeability is a biomarker of treatment response in RRMS
Association of retroplacental blood with basal plate myofibers
No full textObjectives: Diagnosed clinical abruption showing blood clot should be signed out in the pathology report as retroplacental hemorrhage with or without parenchymal indentation, and submitted clot separate from the placenta should be weighed. In our experience some cases sent as clinical abruptions have been cases of morbid adherence. This study was undertaken to evaluate the association of retroplacental blood with basal plate myofibers (BPMF).
Methods: 156 placentas reviewed by a board certified pediatric pathologist at a community hospital were evaluated for significant retroplacental blood. Basal plates were reviewed for deviations from normal.
Results: 33/156 placentas (21%) had significant retroplacental blood. 21/156 (13%) had a separate clot, of which 11/21 (52%) had basal plate myofibers (BPMF). 11 BPMF‐associated separate clots ranged from 10.5‐60 gms (average 23); while the clots of 10 cases with no demonstrated BPMF ranged from 19‐440 gms (average 82), tending to be larger (p<.03). Basal plate damage prior to delivery was noted in both sets of placentas. BPMF placentas could have myometrial damage prior to delivery.
Conclusions: Since BPMF may confer a risk for accreta in a subsequent pregnancy, submission of a separate clot with the placenta should lead the pathologist to evaluate for basal plate myofibers on H&E, and consider if there is an evidencebased indication to do an actin stain; before presuming a diagnosis of abruption.Peer reviewedAbstract published as Wyand, R. Cramer, S., Oshri, A., Heller, D. (2017). Association of retroplacental blood with basal plate myofibers. Placenta, 57, 280. http://dx.doi.org/10.1016/j.placenta.2017.07.18
Zonulin and blood-brain barrier permeability are dissociated in humans
No full textZonulin regulates intestinal epithelial tight junctions but its role in blood-brain barrier permeability in humans is unclear. Three techniques were utilized to assess blood-brain barrier permeability: dynamic contrast-enhanced magnetic resonance imaging, cerebrospinal fluid / serum albumin quotient and fluorescent dextrans in a human cerebrovascular endothelial cell line. Zonulin did not correlate with blood-brain barrier permeability in vivo or in vitro
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