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Cerebral hemodynamics in stroke, cerebral small vessel disease and pharmacological interventions: a 4D flow MRI study
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.ORCID iD: 0000-0001-6331-4283
2024 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Cerebral hemodynamik vid stroke, cerebral småkärlssjukdom och farmakologiska interventioner : en 4D flow MRI-studie (Swedish)
Abstract [en]

Background and aim: Current cerebrovascular imaging techniques provide important information on arterial anatomy and structural pathologies, such as stenoses and occlusions, but physicians are left to infer how the blood flow is affected. In addition, the relationship between blood pressure and cerebral blood flow is complex and poorly understood. Increased transmission of cardiac pulsatility to the cerebral microvasculature has been suggested as a causative factor of cerebral small vessel disease (CSVD) but previous research have yielded conflicting results regarding this relationship. 4D flow magnetic resonance imaging (MRI) is a novel and promising technique enabling time-resolved blood flow quantification with whole-brain coverage and relatively short scan times. However, despite its obvious potential, there is not yet an evidence-based application for the use of 4D flow MRI within stroke or CSVD. This dissertation aimed to apply 4D flow MRI to describe blood flow patterns in posterior circulation stroke and cerebral blood flow responses to common pharmacological agents used to alter arterial blood pressure as well as to examine the relationship between cerebral arterial pulsatility and CSVD.

Methods and Results: This doctoral dissertation consisted of four papers, referred to by roman numerals. 4D flow MRI and computed tomography angiography (CTA) were applied in 25 patients with acute ischemic stroke in the posterior circulation and a reference population of 15 healthy elderly (paper I). Individual flow profiles were created for each stroke patient and hemodynamic disturbances as well as collateral compensation were described. We show that hemodynamic findings were related to structural findings from CTA.

The cross-sectional relationship between cerebral arterial pulsatility (quantified using 4D flow MRI as pulsatility index [PI] and flow volume pulsatility [FVP]) and features of CSVD were examined using regression analysis in 89 patients with acute ischemic stroke (paper II) and a population-based sample of 862 elderly (paper III). Internal carotid artery FVP was associated with increasing white matter hyperintensity (WMH) volume in patients with stroke and TIA (paper II). In addition, increasing middle cerebral artery FVP and PI were associated with worse cognitive function. In the population sample, high FVP and PI were associated with increasing WMH volume, lower brain volume and the presence of lacunes, but not the composite MRI-CSVD (paper III). Among subjects with MRI-CSVD, displaying symptoms consistent with cerebral small vessel disease was associated with higher WMH volume, lower brain volume and active smoking, but not any measure of pulsatility.

Eighteen healthy volunteers were administered noradrenaline to increase mean arterial pressure by 20% above baseline, and labetalol to decrease mean arterial pressure to 15% below baseline (paper IV). Cerebral blood flow was measured using phase-contrast MRI at each blood pressure level and compared to baseline. Despite a marked increase in blood pressure, noradrenaline administration caused a reduction in cerebral blood flow and cardiac output. Meanwhile, labetalol administration caused no change in cerebral blood flow but an increased cardiac output.

Conclusions: 4D flow MRI can detect hemodynamic disturbances and discriminate between hemodynamic disturbances and normal flow in patients with structural vascular pathologies. This additional information compared to structural imaging alone could potentially be used for prognosis and selection for procedures in clinical care. Cerebral arterial pulsatility is modestly associated with several MRI and clinical features of CSVD but not all. Cerebral arterial pulsatility as the main risk factor of CSVD seems unlikely but its involvement in the pathophysiology cannot be ruled out. Raising the blood pressure with noradrenaline decreases cerebral blood flow and cardiac output without any redistribution from peripheral to cerebral flow. This highlights the pitfalls of using blood pressure as a surrogate for cerebral blood flow and questions the validity of our understanding of cerebral autoregulation. Lowering the blood pressure with labetalol does not affect cerebral blood flow, reassuring its use in clinical routine. 4D flow MRI can be integrated into an in-patient work-up in selected cases of acute ischemic stroke and into the workflow of large epidemiological studies.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. , p. 79
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2304
Keywords [en]
4D flow MRI, cerebral blood flow, cerebral arterial pulsatility, pulsatility index, stroke, cerebral small vessel disease, noradrenaline, labetalol, white matter hyperintensities, lacunes, perivascular spaces
National Category
Neurology
Research subject
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-223865ISBN: 978-91-8070-391-8 (print)ISBN: 978-91-8070-392-5 (electronic)OAI: oai:DiVA.org:umu-223865DiVA, id: diva2:1855079
Public defence
2024-05-31, Betula, målpunkt L0, byggnad 6M, Norrlands universitetssjukhus, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2024-05-08 Created: 2024-04-29 Last updated: 2024-04-30Bibliographically approved
List of papers
1. Hemodynamic Disturbances in Posterior Circulation Stroke: 4D Flow Magnetic Resonance Imaging Added to Computed Tomography Angiography
Open this publication in new window or tab >>Hemodynamic Disturbances in Posterior Circulation Stroke: 4D Flow Magnetic Resonance Imaging Added to Computed Tomography Angiography
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2021 (English)In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 15, article id 656769Article in journal (Refereed) Published
Abstract [en]

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, <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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021
Keywords
basilar artery, blood flow, brain infarction, hemodynamics, magnetic resonance imaging, posterior cerebral artery, stroke, vertebral artery
National Category
Radiology, Nuclear Medicine and Medical Imaging Neurology
Research subject
Radiology
Identifiers
urn:nbn:se:umu:diva-188871 (URN)10.3389/fnins.2021.656769 (DOI)000707751700001 ()34658752 (PubMedID)2-s2.0-85117091785 (Scopus ID)
Funder
Swedish Research Council, 2015-05616Swedish Heart Lung Foundation, 20140592Swedish Heart Lung Foundation, 20180513
Available from: 2021-11-01 Created: 2021-11-01 Last updated: 2024-04-29Bibliographically approved
2. Cerebral arterial pulsatility is associated with features of small vessel disease in patients with acute stroke and TIA: a 4D flow MRI study
Open this publication in new window or tab >>Cerebral arterial pulsatility is associated with features of small vessel disease in patients with acute stroke and TIA: a 4D flow MRI study
2020 (English)In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 267, no 3, p. 721-730Article in journal (Refereed) Published
Abstract [en]

Cerebral small vessel disease (SVD) is a major cause of stroke and cognitive impairment. However, the underlying mechanisms behind SVD are still poorly understood. High cerebral arterial pulsatility has been suggested as a possible cause of SVD. In population studies, arterial pulsatility has been linked to white matter hyperintensities (WMH), cerebral atrophy, and cognitive impairment, all features of SVD. In stroke, pulsatility data are scarce and contradictory. The aim of this study was to investigate the relationship between arterial pulsatility and SVD in stroke patients. With a cross-sectional design, 89 patients with acute ischemic stroke or TIA were examined with MRI. A neuropsychological assessment was performed 1 year later. Using 4D flow MRI, pulsatile indices (PI) were calculated for the internal carotid artery (ICA) and middle cerebral artery (M1, M3). Flow volume pulsatility (FVP), a measure corresponding to the cyclic expansion of the arterial tree, was calculated for the same locations. These parameters were assessed for associations with WMH volume, brain volume and cognitive function. ICA-FVP was associated with WMH volume (β = 1.67, 95% CI: [0.1, 3.24], p = 0.037). M1-PI and M1-FVP were associated with decreasing cognitive function (β = - 4.4, 95% CI: [- 7.7, - 1.1], p = 0.009 and β = - 13.15, 95% CI: [- 24.26, - 2.04], p = 0.02 respectively). In summary, this supports an association between arterial pulsatility and SVD in stroke patients, and provides a potential target for further research and preventative treatment. FVP may become a useful biomarker for assessing pulsatile stress with PCMRI and 4D flow MRI.

Place, publisher, year, edition, pages
Springer, 2020
Keywords
4D flow MRI, Pulsatile index, Pulsatility, Small vessel disease, White matter hyperintensities
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-167287 (URN)10.1007/s00415-019-09620-6 (DOI)000515353700019 ()31728712 (PubMedID)2-s2.0-85075255985 (Scopus ID)
Funder
Swedish Research Council, 2015-05616Swedish Research Council, 2017-04949Swedish Heart Lung Foundation, 20110383Swedish Heart Lung Foundation, 20140592The Swedish Brain Foundation
Available from: 2020-01-15 Created: 2020-01-15 Last updated: 2024-04-29Bibliographically approved
3. Associations of cerebral arterial pulsatility, clinical symptoms and imaging features of cerebral small vessel disease
Open this publication in new window or tab >>Associations of cerebral arterial pulsatility, clinical symptoms and imaging features of cerebral small vessel disease
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(English)Manuscript (preprint) (Other academic)
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-223864 (URN)
Available from: 2024-04-29 Created: 2024-04-29 Last updated: 2024-04-29
4. Cerebral blood flow assessed with phase-contrast magnetic resonance imaging during blood pressure changes with noradrenaline and labetalol: a trial in healthy volunteers 
Open this publication in new window or tab >>Cerebral blood flow assessed with phase-contrast magnetic resonance imaging during blood pressure changes with noradrenaline and labetalol: a trial in healthy volunteers 
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2024 (English)In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 140, no 4, p. 669-678Article in journal (Refereed) Published
Abstract [en]

Background: Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on MAP as a surrogate even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase contrast MRI to characterize blood flow responses in healthy volunteers to commonly used pharmacological agents that increase or decrease arterial blood pressure.

Methods: Eighteen healthy volunteers aged 30-50 years were investigated with phase contrast MRI. Intraarterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase contrast MRI and defined as the sum of flow in the internal carotid arteries and vertebral arteries. CO was defined as the flow in the ascending aorta.

Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg−1 · h−1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03).

Conclusion: In healthy awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. This data does not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

Place, publisher, year, edition, pages
Wolters Kluwer, 2024
National Category
Neurology Radiology, Nuclear Medicine and Medical Imaging Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-220047 (URN)10.1097/ALN.0000000000004775 (DOI)37756527 (PubMedID)2-s2.0-85187724522 (Scopus ID)
Funder
Region Västerbotten
Available from: 2024-01-26 Created: 2024-01-26 Last updated: 2024-04-29Bibliographically approved

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67891011129 of 18
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