Prediction of cerebral perfusion pressure during carotid surgery – A computational fluid dynamics approach

Background: Maintaining cerebral perfusion pressure in the brain when a carotid artery is closed during vascular surgery is critical for avoiding intraoperative hypoperfusion and risk of ischemic stroke. Here we propose and evaluate a method based on computational fluid dynamics for predicting patient-specific cerebral perfusion pressures at carotid clamping during carotid endarterectomy. Methods: The study consisted of 22 patients with symptomatic carotid stenosis who underwent carotid endarterectomy (73 ± 5 years, 59–80 years, 17 men). The geometry of the circle of Willis was obtained preoperatively from computed tomography angiography and corresponding flow rates from four-dimensional flow magnetic resonance imaging. The patients were also classified as having a present or absent ipsilateral posterior communicating artery based on computed tomography angiography. The predicted mean stump pressures from computational fluid dynamics were compared with intraoperatively measured stump pressures from carotid endarterectomy. Findings: On group level, there was no difference between the predicted and measured stump pressures (−0.5 ± 13 mmHg, P = 0.86) and the pressures were correlated (r = 0.44, P = 0.039). Omitting two outliers, the correlation increased to r = 0.78 (P < 0.001) (−1.4 ± 8.0 mmHg, P = 0.45). Patients with a present ipsilateral posterior communicating artery (n = 8) had a higher measured stump pressure than those with an absent artery (n = 12) (P < 0.001). Interpretation: The stump pressure agreement indicates that the computational fluid dynamics approach was promising in predicting cerebral perfusion pressures during carotid clamping, which may prove useful in the preoperative planning of vascular interventions.publishedVersio

Cerebralt blodflöde med fokus på blodflödesfördelning, kollateraler och artärpulsationer, hos friska och hos patienter med symtomatisk karotisstenos : en tillämpning med magnetisk resonanstomografi

Background: For the detection and treatment of early cerebral vascular disease it is of paramount importance to first understand the normal physiology of the cerebral vasculature, and subsequently, to understand how and when pathology can develop from that. This is especially important as the population above 65 years of age is increasing and aging itself is an established risk factor for the development of cerebral vascular disease. This, however, is not always an easy task, since there is a subtle balance and overlap between age-related physiological and pathophysiological changes in the arterial system. Atherosclerotic changes that lead to the development of carotid artery stenosis are responsible for about one fifth of all ischemic strokes. Today, the current state of evidence and the algorithm for carotid revascularization is mainly focused on the degree of carotid stenosis and not on its impact on cerebral hemodynamics. One reason for this is the lack of a non-invasive method, that allows for repeated investigations and provides accurate and reliable results to study cerebral hemodynamic changes. The overall aim of this thesis was to explore and develop a comprehensive approach to investigate the cerebral blood flow distribution, collateral function and pulsatility in healthy subjects and in patients with symptomatic carotid stenosis using a phase-contrast magnetic resonance imaging (PCMRI) platform. The thesis is based on four scientific papers (papers I—IV).  Methods: In papers I and II, 49 healthy young (mean 25 years) and 45 healthy elderly (mean 71 years) subjects were included. 2D PCMRI was used to assess cerebral blood flow rate (BFR), pulsatility index (PI) and dampening factor (DF) in 15 cerebral arteries and in the ophthalmic arteries (OA). Thirty-eight patients (mean 72 years) with symptomatic carotid stenosis were included in paper III. Nineteen of these patients (mean 71 years) underwent carotid endarterectomy (CEA) (paper IV). 4D PCMRI was used for BFR assessment in papers III and IV. BFR, its distribution and collateral routes, was measured in 17 cerebral arteries and in the OA. The BFR on ipsilateral side (with symptomatic stenosis) was compared to the contralateral side (papers III and IV). BFR laterality was defined as contralateral BFR minus ipsilateral BFR in paired arteries and, BFR was compared before and after CEA (paper IV). Results: On average, in healthy subjects, 72% of the total cerebral blood flow (tCBF) was distributed through the anterior circulation and 28% through the posterior circulation. The distribution was symmetrical and not affected by age, sex, or brain volume (paper I). Aging resulted in lower BFRs, increased pulsatility and reduced dampening capacity in cerebral arteries. Anatomical variations in the circle of Willis resulted in an asymmetrical distribution of blood flow (papers I and II). In patients with carotid stenosis, a lower BFR was found in the internal carotid artery (ICA) and its branches on the ipsilateral side. The anterior cerebral artery territory was bilaterally, primarily, supplied by the contralateral ICA. In addition to the supply through the ICA, the middle cerebral artery (MCA) territory on the ipsilateral side was secured by collateral supply from the OA and the posterior communicating arteries, seen as retrograde flow in those arteries. Despite these compensations, BFR in ipsilateral side MCA was lower, and this laterality was more pronounced in patients with severe carotid stenosis (≥70%). After CEA, the distribution of BFR going into the cerebral arteries was found to be symmetrically distributed. Total CBF increased postoperatively in patients with collateral recruitment preoperatively (n=9). The BFR laterality in MCA observed prior to CEA, was found only in the group of patients with collateral recruitment preoperatively (paper IV). The degree of stenosis did not differ between the groups with and without collateral recruitment.  Conclusions: This thesis provides a new and comprehensive approach to mapping and quantifying normal cerebral blood flow and pulsatility. By presenting the distribution of tCBF going into cerebral arteries, instead of using absolute values, the effect of age could be neutralized and the results can be applicable when describing healthy cerebral blood flow, regardless of age. 4D PCMRI made it possible to describe the altered blood flow distribution and collateral ranking in patients with carotid stenosis prior to CEA and its normalization after the procedure. Our findings highlight the importance of BFR quantification for understanding cerebral hemodynamics in patients with carotid stenosis. 4D PCMRI technique is a promising clinical tool for investigations of cerebral hemodynamics in patients with stroke

Cerebralt blodflöde med fokus på blodflödesfördelning, kollateraler och artärpulsationer, hos friska och hos patienter med symtomatisk karotisstenos : en tillämpning med magnetisk resonanstomografi

Background: For the detection and treatment of early cerebral vascular disease it is of paramount importance to first understand the normal physiology of the cerebral vasculature, and subsequently, to understand how and when pathology can develop from that. This is especially important as the population above 65 years of age is increasing and aging itself is an established risk factor for the development of cerebral vascular disease. This, however, is not always an easy task, since there is a subtle balance and overlap between age-related physiological and pathophysiological changes in the arterial system. Atherosclerotic changes that lead to the development of carotid artery stenosis are responsible for about one fifth of all ischemic strokes. Today, the current state of evidence and the algorithm for carotid revascularization is mainly focused on the degree of carotid stenosis and not on its impact on cerebral hemodynamics. One reason for this is the lack of a non-invasive method, that allows for repeated investigations and provides accurate and reliable results to study cerebral hemodynamic changes. The overall aim of this thesis was to explore and develop a comprehensive approach to investigate the cerebral blood flow distribution, collateral function and pulsatility in healthy subjects and in patients with symptomatic carotid stenosis using a phase-contrast magnetic resonance imaging (PCMRI) platform. The thesis is based on four scientific papers (papers I—IV).  Methods: In papers I and II, 49 healthy young (mean 25 years) and 45 healthy elderly (mean 71 years) subjects were included. 2D PCMRI was used to assess cerebral blood flow rate (BFR), pulsatility index (PI) and dampening factor (DF) in 15 cerebral arteries and in the ophthalmic arteries (OA). Thirty-eight patients (mean 72 years) with symptomatic carotid stenosis were included in paper III. Nineteen of these patients (mean 71 years) underwent carotid endarterectomy (CEA) (paper IV). 4D PCMRI was used for BFR assessment in papers III and IV. BFR, its distribution and collateral routes, was measured in 17 cerebral arteries and in the OA. The BFR on ipsilateral side (with symptomatic stenosis) was compared to the contralateral side (papers III and IV). BFR laterality was defined as contralateral BFR minus ipsilateral BFR in paired arteries and, BFR was compared before and after CEA (paper IV). Results: On average, in healthy subjects, 72% of the total cerebral blood flow (tCBF) was distributed through the anterior circulation and 28% through the posterior circulation. The distribution was symmetrical and not affected by age, sex, or brain volume (paper I). Aging resulted in lower BFRs, increased pulsatility and reduced dampening capacity in cerebral arteries. Anatomical variations in the circle of Willis resulted in an asymmetrical distribution of blood flow (papers I and II). In patients with carotid stenosis, a lower BFR was found in the internal carotid artery (ICA) and its branches on the ipsilateral side. The anterior cerebral artery territory was bilaterally, primarily, supplied by the contralateral ICA. In addition to the supply through the ICA, the middle cerebral artery (MCA) territory on the ipsilateral side was secured by collateral supply from the OA and the posterior communicating arteries, seen as retrograde flow in those arteries. Despite these compensations, BFR in ipsilateral side MCA was lower, and this laterality was more pronounced in patients with severe carotid stenosis (≥70%). After CEA, the distribution of BFR going into the cerebral arteries was found to be symmetrically distributed. Total CBF increased postoperatively in patients with collateral recruitment preoperatively (n=9). The BFR laterality in MCA observed prior to CEA, was found only in the group of patients with collateral recruitment preoperatively (paper IV). The degree of stenosis did not differ between the groups with and without collateral recruitment.  Conclusions: This thesis provides a new and comprehensive approach to mapping and quantifying normal cerebral blood flow and pulsatility. By presenting the distribution of tCBF going into cerebral arteries, instead of using absolute values, the effect of age could be neutralized and the results can be applicable when describing healthy cerebral blood flow, regardless of age. 4D PCMRI made it possible to describe the altered blood flow distribution and collateral ranking in patients with carotid stenosis prior to CEA and its normalization after the procedure. Our findings highlight the importance of BFR quantification for understanding cerebral hemodynamics in patients with carotid stenosis. 4D PCMRI technique is a promising clinical tool for investigations of cerebral hemodynamics in patients with stroke

4D flow MRI : automatic assessment of blood flow in cerebral arteries

Objective: With a 10-minute 4D flow MRI scan, the distribution of blood flow to individual arteries throughout the brain can be analyzed. This technique has potential to become a biomarker for treatment decisions, and to predict prognosis after stroke. To efficiently analyze and model the large dataset in clinical practice, automatization is needed. We hypothesized that identification of selected arterial regions using an atlas with a priori probability information on their spatial distribution can provide standardized measurements of blood flow in the main cerebral arteries. Approach: A new method for automatic placement of measurement locations in 4D flow MRI was developed based on an existing atlas-based method for arterial labeling, by defining specific regions of interest within the corresponding arterial atlas. The suggested method was evaluated on 38 subjects with carotid artery stenosis, by comparing measurements of blood flow rate at automatically selected locations to reference measurements at manually selected locations. Main results: Automatic and reference measurement ranged from 10 to 580 ml min−1 and were highly correlated (r = 0.99) with a mean flow difference of 0.61 ± 10.7 ml min−1 (p = 0.21). Out of the 559 arterial segments in the manual reference, 489 were correctly labeled, yielding a sensitivity of 88%, a specificity of 85%, and a labeling accuracy of 87%. Significance: This study confirms that atlas-based labeling of 4D flow MRI data is suitable for efficient flow quantification in the major cerebral arteries. The suggested method improves the feasibility of analyzing cerebral 4D flow data, and fills a gap necessary for implementation in clinical use.Originally included in thesis in manuscript form</p

Quantification and mapping of cerebral hemodynamics before and after carotid endarterectomy, using four-dimensional flow magnetic resonance imaging

Background and purpose: A carotid stenosis can have a profound impact on the cerebral hemodynamics that cannot be inferred from the degree of stenosis by itself. We aimed to quantify and map the distribution of blood flow rate (BFR) in cerebral arteries before and after carotid endarterectomy (CEA), using four-dimensional phase-contrast magnetic resonance imaging (4D PCMRI). Methods: Nineteen patients (71±6 years, 2 women) with symptomatic carotid stenosis (≥50%)undergoing CEA were investigated using 4D PCMRI before and after surgery. BFR was measured in 17 cerebral arteries and in the ophthalmic arteries (OA). Collateral recruitment through the anterior and posterior communicating arteries, OA and the leptomeningeal arterial route was identified and quantified. BFR laterality was described as contralateral BFR minus ipsilateral BFR in paired arteries. Results: Total cerebral blood flow increased by 15% (p&lt;0.01) after CEA. On the ipsilateral side, increased BFR was found after CEA in internal carotid artery (ICA) (246±62mL/min vs. 135±80mL/min; p&lt;0.001), anterior cerebral artery (87±mL/min vs. 38±58mL/min; p&lt;0.01) and middle cerebral artery (MCA) (149±43mL/min vs. 119±34mL/min; p&lt;0.01), resulting in a postoperative BFR distribution without signs of laterality. In patients with preoperatively recruited collaterals (n=9), BFR laterality was found in MCA before, but not after, CEA (p&lt;0.01). This laterality was not found in patients without collateral recruitment (n=10) (p=0.2). The degree of stenosis did not differ between the groups with vs. without collateral recruitment (p=0.85).  Conclusion: 4D PCMRI is a useful technique to quantify cerebral hemodynamic changes seen in patients with carotid stenosis before and after CEA. MCA laterality, seen in patients with collateral recruitment before CEA, pointed towards a hemodynamic disturbance in MCA territory for those patients. This study introduces a new and non-invasive way to evaluate cerebral hemodynamics due to carotid stenosis prior to and after CEA.Originally included in thesis in manuscript form with title "Quantification and mapping of cerebral hemodynamics before and after carotid endarterectomy: a 4D PCMRI study"</p

Diagnosing carotid near-occlusion with phase-contrast MRI

Carotid near-occlusion is a frequently overlooked diagnosis when CTA examinations are assessed in routine practice. To evaluate the potential value of phase-contrast MR imaging in identifying near-occlusion, we examined 9 carotid near-occlusions and 20 cases of conventional $50$50% stenosis (198 mL/min, P, .001). ICA flow of #110 mL/min was 100% sensitive and specific for near-occlusion. Phase-contrast MR imaging is a promising tool for diagnosing carotid near-occlusion

Hemodynamic Disturbances in Posterior Circulation Stroke : 4D Flow Magnetic Resonance Imaging Added to Computed Tomography Angiography

Objective: A clinically feasible, non-invasive method to quantify blood flow, hemodynamics, and collateral flow in the vertebrobasilar arterial tree is missing. The objective of this study was to evaluate the feasibility of quantifying blood flow and blood flow patterns using 4D flow magnetic resonance imaging (MRI) in consecutive patients after an ischemic stroke in the posterior circulation. We also explore if 4D-flow, analyzed in conjunction with computed tomography angiography (CTA), has potential as a diagnostic tool in posterior circulation stroke. Methods: Twenty-five patients (mean age 62 years; eight women) with acute ischemic stroke in the posterior circulation were investigated. At admission, all patients were examined with CTA followed by MRI (4D flow MRI and diffusion-weighted sequences) at median 4 days after the presenting event. Based on the classification of Caplan, patients were divided into proximal/middle (n = 16) and distal territory infarcts (n = 9). Absolute and relative blood flow rates were calculated for internal carotid arteries (ICA), vertebral arteries (VA), basilar artery (BA), posterior cerebral arteries (P1 and P2), and the posterior communicating arteries (Pcom). In a control group consisting of healthy elderly, the 90th and 10th percentiles of flow were calculated in order to define normal, increased, or decreased blood flow in each artery. “Major hemodynamic disturbance” was defined as low BA flow and either low P2 flow or high Pcom flow. Various minor hemodynamic disturbances were also defined. Blood flow rates were compared between groups. In addition, a comprehensive analysis of each patient’s blood flow profile was performed by assessing relative blood flow rates in each artery in conjunction with findings from CTA. Results: There was no difference in total cerebral blood flow between patients and controls [604 ± 117 ml/min vs. 587 ± 169 ml/min (mean ± SD), p = 0.39] or in total inflow to the posterior circulation (i.e., the sum of total VA and Pcom flows, 159 ± 63 ml/min vs. 164 ± 52 ml/min, p = 0.98). In individual arteries, there were no significant differences between patients and controls in absolute or relative flow. However, patients had larger interindividual relative flow variance in BA, P1, and P2 (p = 0.01, &lt;0.01, and 0.02, respectively). Out of the 16 patients that had proximal/middle territory infarcts, nine had CTA findings in VA and/or BA generating five with major hemodynamic disturbance identified with 4D flow MRI. For those without CTA findings, seven had no or minor 4D flow MRI hemodynamic disturbance. Among nine patients with distal territory infarcts, one had major hemodynamic disturbances, while the remaining had minor disturbances. Conclusion: 4D flow MRI contributed to the identification of the patients who had major hemodynamic disturbances from the vascular pathologies revealed on CTA. We thus conclude that 4D flow MRI could add valuable hemodynamic information when used in conjunction with CTA

A Stereotactic Probabilistic Atlas for the Major Cerebral Arteries

Improved whole brain angiographic and velocity-sensitive MRI is pushing the boundaries of noninvasively obtained cerebral vascular flow information. The complexity of the information contained in such datasets calls for automated algorithms and pipelines, thus reducing the need of manual analyses by trained radiologists. The objective of this work was to lay the foundation for such automated pipelining by constructing and evaluating a probabilistic atlas describing the shape and location of the major cerebral arteries. Specifically, we investigated how the implementation of a non-linear normalization into Montreal Neurological Institute (MNI) space improved the alignment of individual arterial branches. In a population-based cohort of 167 subjects, age 64-68 years, we performed 4D flow MRI with whole brain volumetric coverage, yielding both angiographic and anatomical data. For each subject, sixteen cerebral arteries were manually labeled to construct the atlas. Angiographic data were normalized to MNI space using both rigid-body and non-linear transformations obtained from anatomical images. The alignment of arterial branches was significantly improved by the non-linear normalization (p &lt; 0.001). Validation of the atlas was based on its applicability in automatic arterial labeling. A leave-one-out validation scheme revealed a labeling accuracy of 96 %. Arterial labeling was also performed in a separate clinical sample (n = 10) with an accuracy of 92.5 %. In conclusion, using non-linear spatial normalization we constructed an artery-specific probabilistic atlas, useful for cerebral arterial labeling

Middle cerebral artery pressure laterality in patients with symptomatic ICA stenosis

An internal carotid artery (ICA) stenosis can potentially decrease the perfusion pressure to the brain. In this study, computational fluid dynamics (CFD) was used to study if there was a hemispheric pressure laterality between the contra- and ipsilateral middle cerebral artery (MCA) in patients with a symptomatic ICA stenosis. We further investigated if this MCA pressure laterality (ΔPMCA) was related to the hemispheric flow laterality (ΔQ) in the anterior circulation, i.e., ICA, proximal MCA and the proximal anterior cerebral artery (ACA). Twenty-eight patients (73±6 years, range 59–80 years, 21 men) with symptomatic ICA stenosis were included. Flow rates were measured using 4D flow MRI data (PC-VIPR) and vessel geometries were obtained from computed tomography angiography. The ΔPMCA was calculated from CFD, where patient-specific flow rates were applied at all input- and output boundaries. The ΔPMCA between the contra- and ipsilateral side was 6.4±8.3 mmHg (p&lt;0.001) (median 3.9 mmHg, range -1.3 to 31.9 mmHg). There was a linear correlation between the ΔPMCA and ΔQICA (r = 0.85, p&lt;0.001) and ΔQACA (r = 0.71, p&lt;0.001), respectively. The correlation to ΔQMCA was weaker (r = 0.47, p = 0.011). In conclusion, the MCA pressure laterality obtained with CFD, is a promising physiological biomarker that can grade the hemodynamic disturbance in patients with a symptomatic ICA stenosis

A Validated RP-HPLC-DAD Method for the Determination of l-Theanine in Tea

BACKGROUND AND PURPOSE: The arterial spin-labeling method for CBF assessment is widely available, but its accuracy is not fully established. We investigated the accuracy of a whole-brain arterial spin-labeling technique for assessing the mean parenchymal CBF and the effect of aging in healthy volunteers. Phase-contrast MR imaging was used as the reference method. MATERIALS AND METHODS: Ninety-two healthy volunteers were included: 49 young (age range, 20-30 years) and 43 elderly (age range, 65-80 years). Arterial spin-labeling parenchymal CBF values were averaged over the whole brain to quantify the mean pCBF(ASL) value. Total. CBF was assessed with phase-contrast MR imaging as the sum of flows in the internal carotid and vertebral arteries, and subsequent division by brain volume returned the pCBF(PCMRI) value. Accuracy was considered as good as that of the reference method if the systematic difference was less than 5 mL/min/100 g of brain tissue and if the 95% confidence intervals were equal to or better than +/- 10 mL/min/100 g. RESULTS: pCBF(ASL) correlated to pCBF(PCMRI) (r = 0.73; P &lt; .001). Significant differences were observed between the pCBF(ASL) and pCBF(PCMRI) values in the young (P = .001) and the elderly (P &lt; .001) volunteers. The systematic differences (mean 2 standard deviations) were -4 +/- 14 mL/min/100 g in the young subjects and 6 +/- 12 mL/min/100 g in the elderly subjects. Young subjects showed higher values than the elderly subjects for pCBF(PCMRI) (young, 57 +/- 8 mL/min/100 g; elderly, 54 +/- 7 mL/min/100 g; P = .05) and pCBF(ASL) (young, 61 +/- 10 mL/min/100 g; elderly, 48 +/- 10 mL/min/100 g; P &lt; .001). CONCLUSIONS: The limits of agreement were too wide for the arterial spin-labeling method to be considered satisfactorily accurate, whereas the systematic overestimation in the young subjects and underestimation in the elderly subjects were close to acceptable. The age-related decrease in parenchymal CBF was augmented in arterial spin-labeling compared with phase-contrast MR imaging