
Development of a computational approach to predict blood-brain barrier permeability.
Liu Xingrong,Tu Meihua,Kelly Rebecca S,Chen Cuiping,Smith Bill J
Drug metabolism and disposition: the biological fate of chemicals
The objectives of this study were to generate a data set of blood-brain barrier (BBB) permeability values for drug-like compounds and to develop a computational model to predict BBB permeability from structure. The BBB permeability, expressed as permeability-surface area product (PS, quantified as logPS), was determined for 28 structurally diverse drug-like compounds using the in situ rat brain perfusion technique. A linear model containing three descriptors, logD, van der Waals surface area of basic atoms, and polar surface area, was developed based on 23 compounds in our data set, where the penetration across the BBB was assumed to occur primarily by passive diffusion. The correlation coefficient (R(2)) and standard deviation (S.D.) of the model-predicted logPS against the observed are 0.74 and 0.50, respectively. If an outlier was removed from the training data set, the R(2) and S.D. were 0.80 and 0.44, respectively. This new model was tested in two literature data sets, resulting in an R(2) of 0.77 to 0.94 and a S.D. of 0.38 to 0.51. For comparison, four literature models, logP, logD, log(D. MW(-0.5)), and linear free energy relationship, were tested using the set of 23 compounds primarily crossing the BBB by passive diffusion, resulting in an R(2) of 0.33 to 0.61 and a S.D. of 0.59 to 0.76. In summary, we have generated the largest PS data set and developed a robust three-descriptor model that can quantitatively predict BBB permeability. This model may be used in a drug discovery setting to predict the BBB permeability of new chemical entities.
10.1124/dmd.32.1.132
[Evaluation of peritumoral brain edema in intracranial meningiomas using CT perfusion imaging].
Yang Zhi-lin,Ke Yi-quan,Xu Ru-xiang,Peng Ping
Nan fang yi ke da xue xue bao = Journal of Southern Medical University
OBJECTIVE:To evaluate the perfusion characteristics of the peritumoral brain edema of intracranial meningiomas using 16-slice spiral CT perfusion imaging. METHODS:Dynamic contrast-enhanced single-location sequence CT scan was performed in 19 patients with intracranial meningiomas and peritumoral brain edema. The regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV) and the mean transit time (MTT) were calculated for the peritumoral brain edema and the contralateral white matter and comparatively analyzed. RESULTS:The rCBF and rCBV in the peritumoral brain edema were significantly lower than those of the contralateral white matter in patients with meningiomas (rCBF: 14.26-/+7.44 vs 26.92-/+15.71 ml/100 g tissue.min, P<0.05; rCBV: 0.96-/+0.35 vs 2.47-/+1.69 ml/100 g tissue, P<0.05). But the MTT showed no significant difference between the peritumoral brain edema and the contralateral white matter (P>0.05). CONCLUSION:The rCBF and rCBV are significantly lowered in the peritumoral brain edema in comparison with those of the contralateral white matter. Vascular compression by the edema fluid may have a major effect on the tissue blood flow and blood volume.
Quantitative assessment on blood-brain barrier permeability of acute spontaneous intracerebral hemorrhage in basal ganglia: a CT perfusion study.
Xu Haoli,Li Rui,Duan Yuxia,Wang Jincheng,Liu Shuailiang,Zhang Yue,He Wenwen,Qin Xiaotao,Cao Guoquan,Yang Yunjun,Zhuge Qichuan,Yang Jun,Chen Weijian
Neuroradiology
PURPOSE:Blood-brain barrier (BBB) damage aggravates perihematomal edema, and edema volume predicts prognosis independently. But the BBB permeability at the late stage of acute intracerebral hemorrhage (ICH) patients is uncertain. We aimed to assess the BBB permeability of spontaneous basal ganglia ICH using computed tomographic perfusion (CTP) and investigates its relationship with hematoma and perihematomal edema volume. METHODS:We performed CTP on 54 consecutive ICH patients within 24 to 72 h after symptom onset. Permeability-surface area product (PS) derived from CTP imaging was measured in hematoma, "high-PS spot," perihematoma, normal-appearing, hemispheric, and contralateral regions. Hematoma and edema volumes were calculated from non-contrast CT. RESULTS:"High-PS spot" and perihematoma regions had higher PS than the contralateral regions (p < 0.001). Hematoma PS was lower than that in the contralateral regions (p < 0.001). Perihematoma PS of the large-hematoma group was higher than that of the small-hematoma group (p = 0.011). Perihematomal edema volume correlated positively with hematoma volume (β = 0.864, p < 0.001) and perihematoma PS (β = 0.478, p < 0.001). Perihematoma PS correlated positively with hematoma volume (β = 0.373, p = 0.005). CONCLUSIONS:Locally elevated perihematoma PS was found in most spontaneous basal ganglia ICH patients within 24 to 72 h after symptom onset. Perihematoma PS was higher in larger hematomas and was associated with larger edema volume. At this period, BBB leakage is likely to be an important factor in edema formation.
10.1007/s00234-017-1852-9
[Evaluation of cerebral hemodynamics with perfusion CT].
Araki Yuzo,Furuichi Masahiro,Nokura Hiroaki,Sakai Noboru
No to shinkei = Brain and nerve
We report on the evaluation of cerebral ischemic lesions with perfusion CT. Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) of 52 patients mostly with ischemic cerebrovascular disease were analysed using the box-modulation transfer function method with 30 ml of contrast medium intravenously injected at 5 ml/sec. CBF, CBV and MTT of the middle cerebral artery (MCA) territory were 43.5 +/- 4.6 ml/100 g/min, 1.9 +/- 0.2 ml/100 g and 2.9 +/- 0.6 seconds at the unaffected side, and 37.7 +/- 7.3 ml/100 g/min, 2.1 +/- 0.3 ml/100 g, 3.7 +/- 0.9 seconds at the lesion side with stenosis or occlusion in the main MCA trunks or internal carotid artery, respectively. A statistically significant difference was shown in CBF and MTT values. Furthermore, there was a close correlation in CBF values of MCA territories between Xe-CT and perfusion CT (r = 0.645, n = 76, p < 0.0001). MTT showed a positive correlation with CBV in those subjects when MTT was below 4.1 seconds (r = 0.526, p < 0.0001, n = 83). MTT also showed a negative correlation with CBF in those patients when MTT indicated more than 4.1 seconds (r = 0.818, p < 0.001, n = 21). These results suggest that the progression of cerebral ischemia may be classified in 4 stages using perfusion CT. The stages are as follows: stage 0; normal CBF without prolonged MTT and increased CBV, stage 1; relatively increased CBV, stage 2; significantly prolonged MTT, and stage 3; significantly decreased CBF with prolonged MTT.
Evaluation of optimal scan duration and end time in cerebral CT perfusion study.
Hirata Masaaki,Sugawara Yoshifumi,Murase Kenya,Miki Hitoshi,Mochizuki Teruhito
Radiation medicine
PURPOSE:The purpose of this study was to evaluate the optimal end time of scanning and the influence of varying the number of source images adopted for calculation of the parameter values in computerized tomography (CT) perfusion. MATERIALS AND METHODS:Nineteen CT perfusion studies in 14 patients with cerebrovascular disease were retrospectively analyzed. CT perfusion scanning was performed using continuous scans of 1 sec/rotation x60 sec with 5-mm-thick sections. To determine the appropriate end time of scanning, the time-density curves (TDCs) of the anterior cerebral artery (ACA), superior sagittal sinus (SSS), and basal ganglia were analyzed. The functional maps of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were retrospectively generated from various numbers (30, 35, 40, 45, 50, 55, and 60) of source images. Defining the values calculated from the number of source images equal to the end time of the first pass as standard values, the percentage difference between the standard values and the values generated from various numbers of sources were evaluated. RESULTS:The TDCs of SSS showed the latest end time of the first pass (mean, 38.6+/-5.2 sec; range, 32 to 48 sec). Therefore, the values calculated from the number of source images equal to the end time of the first pass of SSS were defined as standard values. Increase and decrease of the number of source images for calculation resulted in increase of the percentage difference in every parameter value. The percentage differences ranged up to 49.6% for CBF, 48.0% for CBV, and 20.0% for MTT. CONCLUSIONS:Scanning until the end time of the first pass of SSS is necessary and sufficient for reliable measurement. Variable scan time based on the TDC of the SSS may be of better utility than use of fixed scan time. Further, the radiation dose could be minimized in many cases by reducing the scan time.
Cerebral Edema in Chronic Mountain Sickness: a New Finding.
Bao Haihua,Wang Duoyao,Zhao Xipeng,Wu Youshen,Yin Guixiu,Meng Li,Wang Fangfang,Ma Lan,Hackett Peter,Ge Ri-Li
Scientific reports
We observed patients with chronic mountain sickness (CMS) in our clinic who developed progressive neurological deterioration (encephalopathy) and we wished to investigate this. We studied nine such CMS patients, and compared them to 21 CMS patients without encephalopathy, and to 15 healthy control subjects without CMS. All 45 subjects lived permanently at 3200-4000 m. Measurements at 2260 m included CMS symptom score, multi-slice CT, perfusion CT, pulse oximetry (SpO%), and hemoglobin concentration (Hb). One patient had MRI imaging but not CT; 5 had CSF pressure measurements. CMS subjects had lower SpO higher Hb, higher brain blood density, lower mean cerebral blood flow (CBF), and significant cerebral circulatory delay compared to controls. The nine CMS subjects with neurological deterioration showed diffuse cerebral edema on imaging and more deranged cerebral hemodynamics. CSF pressure was elevated in those with edema. We conclude that cerebral edema, a previously unrecognized complication, may develop in CMS patients and cause encephalopathy. Contributing factors appear to be exaggerated polycythemia and hypoxemia, and lower and sluggish CBF compared to CMS patients without cerebral edema; but what triggers this complication is unknown. Recognition and treatment of this serious complication will help reduce morbidity and mortality from CMS.
10.1038/srep43224
The importance of CT perfusion for diagnosis and treatment of ischemic stroke in anterior circulation.
Journal of integrative neuroscience
Computed tomography perfusion (CTP) is a functional examination of brain tissue that characterises the state of cerebral perfusion and provides information about the current status of the circulation. CTP can improve diagnostic accuracy of ischemic stroke. Published studies showed that perfusion imaging improves the prognosis of patients with acute ischemic stroke in anterior circulation and allows patients to be referred for treatment outside the time window for administration of intravenous thrombolysis (IVT) or mechanical thrombectomy (MT). In this review we discuss technical aspects of CTP, clinical significance of CTP in anterior circulation stroke (ACS) and its role in diagnostics of stroke mimics.
10.31083/j.jin2103092
Basis and current state of computed tomography perfusion imaging: a review.
Physics in medicine and biology
Computed tomography perfusion (CTP) is a functional imaging that allows for providing capillary-level hemodynamics information of the desired tissue in clinics. In this paper, we aim to offer insight into CTP imaging which covers the basics and current state of CTP imaging, then summarize the technical applications in the CTP imaging as well as the future technological potential. At first, we focus on the fundamentals of CTP imaging including systematically summarized CTP image acquisition and hemodynamic parameter map estimation techniques. A short assessment is presented to outline the clinical applications with CTP imaging, and then a review of radiation dose effect of the CTP imaging on the different applications is presented. We present a categorized methodology review on known and potential solvable challenges of radiation dose reduction in CTP imaging. To evaluate the quality of CTP images, we list various standardized performance metrics. Moreover, we present a review on the determination of infarct and penumbra. Finally, we reveal the popularity and future trend of CTP imaging.
10.1088/1361-6560/ac8717