| 1. |
- Allentoft, Morten E., et al.
(författare)
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Population genomics of post-glacial western Eurasia
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
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Tidskriftsartikel (refereegranskat)abstract
- Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
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| 2. |
- Björnfot, Cecilia, et al.
(författare)
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Cerebral arterial stiffness is linked to white matter hyperintensities and perivascular spaces in older adults : a 4D flow MRI study
- 2024
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016.
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Tidskriftsartikel (refereegranskat)abstract
- White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66–85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV’s stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.
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| 3. |
- Vikner, Tomas, et al.
(författare)
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5-year associations among cerebral arterial pulsatility, perivascular space dilation, and white matter lesions
- 2022
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Ingår i: Annals of Neurology. - : John Wiley & Sons. - 0364-5134 .- 1531-8249. ; 92:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Objective: High cerebral arterial pulsatility index (PI), white matter lesions (WMLs), enlarged perivascular spaces (PVSs), and lacunar infarcts are common findings in the elderly population, and considered indicators of small vessel disease (SVD). Here, we investigate the potential temporal ordering among these variables, with emphasis on determining whether high PI is an early or delayed manifestation of SVD.Methods: In a population-based cohort, 4D flow MRI data for cerebral arterial pulsatility was collected for 159 participants at baseline (age 64–68), and for 122 participants at follow-up 5 years later. Structural MRI was used for WML and PVS segmentation, and lacune identification. Linear mixed-effects (LME) models were used to model longitudinal changes testing for pairwise associations, and latent change score (LCS) models to model multiple relationships among variables simultaneously.Results: Longitudinal 5-year increases were found for WML, PVS, and PI. Cerebral arterial PI at baseline did not predict changes in WML or PVS volume. However, WML and PVS volume at baseline predicted 5-year increases in PI. This was shown for PI increases in relation to baseline WML and PVS volumes using LME models (R (Formula presented.) 0.24; p < 0.02 and R (Formula presented.) 0.23; p < 0.03, respectively) and LCS models ((Formula presented.) = 0.28; p = 0.015 and (Formula presented.) = 0.28; p = 0.009, respectively). Lacunes at baseline were unrelated to PI.Interpretation: In healthy older adults, indicators of SVD are related in a lead–lag fashion, in which the expression of WML and PVS precedes increases in cerebral arterial PI. Hence, we propose that elevated PI is a relatively late manifestation, rather than a risk factor, for cerebral SVD.
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| 4. |
- Allentoft, Morten E., et al.
(författare)
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100 ancient genomes show repeated population turnovers in Neolithic Denmark
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1–4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5–7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.
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| 5. |
- Birnefeld, Johan, et al.
(författare)
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Cerebral arterial pulsatility is associated with features of small vessel disease in patients with acute stroke and TIA : a 4D flow MRI study
- 2020
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Ingår i: Journal of Neurology. - : Springer. - 0340-5354 .- 1432-1459. ; 267:3, s. 721-730
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Birnefeld, Johan, et al.
(författare)
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Cerebral blood flow assessed with phase-contrast magnetic resonance imaging during blood pressure changes with noradrenaline and labetalol : a trial in healthy volunteers
- 2024
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Ingår i: Anesthesiology. - : Wolters Kluwer. - 0003-3022 .- 1528-1175. ; 140:4, s. 669-678
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Birnefeld, Johan, 1989-
(författare)
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Cerebral hemodynamics in stroke, cerebral small vessel disease and pharmacological interventions : a 4D flow MRI study
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 8. |
- Holmgren, Madelene, 1992-
(författare)
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4D flow MRI and modelling to assess cerebral arterial hemodynamics : method development and evaluation, with implementation in patients with symptomatic carotid stenosis
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blood flow measurements are important for understanding the development of cerebrovascular diseases. With 4D flow magnetic resonance imaging (4D flow MRI), simultaneous velocity measurements are obtained in all cerebral arteries in a scan of about ten minutes. However, 4D flow MRI is a relatively new technique. For usefulness in both clinics and research, detailed knowledge is needed about its accuracy and precision for flow quantification. In patients with stroke or transient ischemic attack (TIA) from a symptomatic carotid stenosis, the stenosis may generate a difference in blood pressure and flow between the left and right cerebral hemispheres. Such a hemispheric pressure difference could be an early marker of to what extent a stenosis is affecting cerebral hemodynamics, which could be useful in the planning of carotid surgery. The overall aim of the thesis was to determine the accuracy of 4D flow MRI to measure cerebral arterial blood flow, and to develop and evaluate an approach combining 4D flow MRI and computational fluid dynamics (CFD) to characterize the cerebral arterial hemodynamics, with implementation in patients with symptomatic carotid stenosis. The thesis is based on four papers, investigating two cohorts.The first cohort consisted of 35 elderly volunteers (mean age 79 years) and was studied in paper I-II. Blood flow rates were measured in nine cerebral arteries with 4D flow MRI and 2D phase-contrast MRI as reference. Three different flow quantification methods for 4D flow MRI were evaluated and optimized: one clustering approach and two threshold-based methods. The proposed new method, based on a locally adapted threshold, outperformed the previously suggested methods in flow rate quantification. For the clustering method, flow rates were systematically underestimated. 4D flow MRI was also evaluated to assess different arterial pulsatility measures, and a Windkessel model was used to estimate reference values for cerebrovascular resistance and cerebral arterial compliance in elderly.The second cohort consisted of 28 stroke and TIA patients (mean age 73 years) with symptomatic carotid stenosis and was studied in paper III-IV. With 4D flow MRI and CFD, the preoperative hemispheric pressure laterality was quantified in the patients. The pressure laterality was compared to hemispheric flow lateralities. Estimating the hemispheric pressure laterality was a promising physiological biomarker for grading the cerebral arterial hemodynamic disturbances in patients with symptomatic carotid stenosis. A CFD model was also developed to predict carotid stump pressure, i.e., the important pressure measured in the clamped carotid artery during surgical removal of the stenosis. The predicted stump pressures were correlated with the pressures measured during surgery. Stump pressure prediction was promising and could be a potential tool in the preoperative planning in order to avoid hypoperfusion during surgery. In summary, post-processing methods were successfully developed and evaluated for accurate assessment of mean and pulsatile cerebral blood flow rates with 4D flow MRI. Thereby, this thesis provided knowledge about possibilities and limitations of how 4D flow MRI can be used with respect to cerebral arterial blood flow rate assessment. By contributing with models combining 4D flow MRI and CFD, specifically developed for analysis of pressure distributions in cerebral arteries, novel methods were proposed for assessing patients with symptomatic carotid stenosis in the planning of carotid surgery.
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| 9. |
- Holmgren, Madelene, et al.
(författare)
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Assessment of Cerebral Blood Flow Pulsatility and Cerebral Arterial Compliance With 4D Flow MRI
- 2020
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Ingår i: Journal of Magnetic Resonance Imaging. - : Wiley-Blackwell. - 1053-1807 .- 1522-2586. ; 51:5, s. 1516-1525
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Four-dimensional flow magnetic resonance imaging (4D flow MRI) enables efficient investigation of cerebral blood flow pulsatility in the cerebral arteries. This is important for exploring hemodynamic mechanisms behind vascular diseases associated with arterial pulsations.PURPOSE: To investigate the feasibility of pulsatility assessments with 4D flow MRI, its agreement with reference two-dimensional phase-contrast MRI (2D PC-MRI) measurements, and to demonstrate how 4D flow MRI can be used to assess cerebral arterial compliance and cerebrovascular resistance in major cerebral arteries.STUDY TYPE: Prospective.SUBJECTS: Thirty-five subjects (20 women, 79 ± 5 years, range 70-91 years).FIELD STRENGTH/SEQUENCE: 4D flow MRI (PC-VIPR) and 2D PC-MRI acquired with a 3T scanner.ASSESSMENT: Time-resolved flow was assessed in nine cerebral arteries. From the pulsatile flow waveform in each artery, amplitude (ΔQ), volume load (ΔV), and pulsatility index (PI) were calculated. To reduce high-frequency noise in the 4D flow MRI data, the flow waveforms were low-pass filtered. From the total cerebral blood flow, total PI (PItot ), total volume load (ΔVtot ), cerebral arterial compliance (C), and cerebrovascular resistance (R) were calculated.STATISTICAL TESTS: Two-tailed paired t-test, intraclass correlation (ICC).RESULTS: There was no difference in ΔQ between 4D flow MRI and the reference (0.00 ± 0.022 ml/s, mean ± SEM, P = 0.97, ICC = 0.95, n = 310) with a cutoff frequency of 1.9 Hz and 15 cut plane long arterial segments. For ΔV, the difference was -0.006 ± 0.003 ml (mean ± SEM, P = 0.07, ICC = 0.93, n = 310) without filtering. Total R was 11.4 ± 2.41 mmHg/(ml/s) (mean ± SD) and C was 0.021 ± 0.009 ml/mmHg (mean ± SD). ΔVtot was 1.21 ± 0.29 ml (mean ± SD) with an ICC of 0.82 compared with the reference. PItot was 1.08 ± 0.21 (mean ± SD).DATA CONCLUSION: We successfully assessed 4D flow MRI cerebral arterial pulsatility, cerebral arterial compliance, and cerebrovascular resistance. Averaging of multiple cut planes and low-pass filtering was necessary to assess accurate peak-to-peak features in the flow rate waveforms.LEVEL OF EVIDENCE: 2Technical Efficacy Stage: 2
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| 10. |
- Holmgren, Madelene, et al.
(författare)
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Diagnostic separation of conventional ⩾50% carotid stenosis and near-occlusion with phase-contrast MRI
- 2024
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Ingår i: European Stroke Journal. - : Sage Publications. - 2396-9873 .- 2396-9881. ; 9:1, s. 135-143
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The aim of this study was to assess sensitivity, specificity and interrater reliability of phase-contrast MRI (PC-MRI) for diagnosing carotid near-occlusion. Patients and methods: Prospective cross-sectional study conducted between 2018 and 2021. We included participants with suspected 50%–100% carotid stenosis on at least one side, all were examined with CT angiography (CTA) and PC-MRI and both ICAs were analyzed. Degree of stenosis on CTA was the reference test. PC-MRI-based blood flow rates in extracranial ICA and intracranial cerebral arteries were assessed. ICA-cerebral blood flow (CBF) ratio was defined as ICA divided by sum of both ICAs and Basilar artery. Results: We included 136 participants. The ICAs were 102 < 50% stenosis, 88 conventional ⩾50% stenosis (31 with ⩾70%), 49 near-occlusion, 12 occlusions, 20 unclear cause of small distal ICA on CTA and one excluded. For separation of near-occlusion and conventional stenoses, ICA flow rate and ICA-CBF ratio had the highest area under the curve (AUC; 0.98–0.99) for near-occlusion. ICA-CBF ratio ⩽0.225 was 90% (45/49) sensitive and 99% (188/190) specific for near-occlusion. Inter-rater reliability for this threshold was excellent (kappa 0.98). Specificity was 94% (29/31) for cases with ⩾70% stenosis. PC-MRI had modest performance for separating <50% and conventional ⩾50% stenosis (highest AUC 0.74), and eight (16%) of near-occlusions were not distinguishable from occlusion (no visible flow). Conclusion: ICA-CBF ratio ⩽0.225 on PC-MRI is an accurate and reliable method to separate conventional ⩾50% stenosis and near-occlusion that is feasible for routine use. PC-MRI should be considered further as a potential standard method for near-occlusion detection, to be used side-by-side with established modalities as PC-MRI cannot separate other degrees of stenosis.
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