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Cerebral arterial pulsatility imaging using 4D flow MRI: methodological development and applications in brain aging
Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.ORCID-id: 0000-0003-3181-785X
2022 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

4D flow magnetic resonance imaging (MRI) is increasingly recognizedas a versatile tool to assess arterial and venous hemodynamics. Cerebral arterial pulsatility is typically assessed by analyzing flow waveforms over the cardiac cycle, where flow amplitude is a function of cardiac output, central arterial stiffness, and cerebrovascular resistance and compliance. Excessive pulsatility may propagate to the cerebral microcirculation, and constitute a harmful mechanism for the brain. Indeed, imaging studies have linked arterial pulsatility to hippocampus volume, cerebral small vessel disease (SVD), and Alzheimer’s disease (AD). In animal models, elevated pulsatility leads to blood-brain barrier (BBB) leakage, capillary loss, and cognitive decline. However, associations to cerebrovascular lesions and brain function in the spectrum of normal aging are less investigated. Further, previous 4D flow studies have mainly assessed pulsatility in relatively large cerebral arteries. When exploring links to microvascular damage and brain function, more distal measurements, closer to the microcirculation, are desired. 

This thesis aimed to develop 4D flow MRI post-processing methods to obtain pulsatile waveforms in small, distal cerebral arteries with noisy velocity data and a complex vascular anatomy, and to evaluate pulsatility (primarily assessed by the pulsatility index) in relation to aging, brain function, and other imaging biomarkers of cerebrovascular damage, with particular dedication towards the hippocampus and cerebral SVD. 

To assess pulsatility in distal cerebral arteries, a post-processing method that automatically samples waveforms from numerous small arteries, to obtain a whole-brain representation of the distal arterial waveform, was developed (Paper I). We demonstrated the importance of averaging flow waveforms along multiple vessel segments to avoid overestimations in the pulsatility index, showed agreement with reference methods, and linked distal arterial pulsatility to age. 

To explore links to hippocampal function, we evaluated pulsatility in relation to cognition, hemodynamic low-frequency oscillations (LFOs), perfusion, and hippocampus volume (Paper II). We found that higher pulsatility was linked to worse hippocampus-sensitive episodic memory, weaker hippocampal LFOs, and lower whole-brain perfusion. These findings aligned with models suggesting that hippocampal microvessels could be particularly susceptible to pulsatile stress.

To inform on SVD pathophysiology, we evaluated 5-year associations among pulsatility, white matter lesions (WMLs) and perivascular space (PVS) dilation, using mixed models, factor analysis, and change score models (Paper III). Lead-lag analyses indicated that, while pulsatility at baseline could not predict WML nor PVS progression, WML and PVS volumes at baseline predicted 5-year pulsatility-increases. These findings indicate that individuals with a higher load of cerebrovascular damage are more prone to see increased pulsatility over time, and suggest that high pulsatility is a manifestation, rather a risk factor, for cerebral SVD.   

To shed light on the potential role of BBB leakage in aging and SVD, we used dynamic contrast enhanced (DCE) MRI and intravenous gadolinium injections to quantify BBB permeability (Paper IV). We found stepwise increases in permeability from healthy white matter to WMLs, supporting that BBB leakages are implicated in SVD. However, hippocampal BBB permeability was unrelated to age, indicating that this capillary property is maintained in aging. Finally, arterial pulsatility was unrelated to BBB permeability in WMLs and in the hippocampus, providing no evidence of excessive pulsatility as a trigger of BBB leakage. 

In conclusion, distal arterial pulsatility measurements are reliable when averaging 4D flow waveforms over a large number of vessels. Pulsatility increases with age, and individuals with more cerebrovascular lesions are prone to see larger increases over time. Pulsatility is negatively related to perfusion and hippocampal function. However, the temporal dynamics among the SVD biomarkers, and the absence of pulsatility–permeability associations, challenge the concept of excessive pulsatility as a trigger of microvascular damage. Future studies are needed to understand whether altered cerebral hemodynamics play a causal role in cognitive decline and dementia. Meanwhile, 4D flow hemodynamic parameters could be useful as biomarkers related to vessel properties and cerebrovascular health. 

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University , 2022. , s. 78
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2209
Nyckelord [en]
Magnetic resonance imaging, 4D flow MRI, medical image analysis, cerebral hemodynamics, arterial pulsatility, DCE MRI, blood-brain barrier, white matter lesions, perivascular spaces, cerebral small vessel disease, hippocampus, cognition, aging
Nationell ämneskategori
Neurologi Neurovetenskaper
Forskningsämne
biomedicinsk strålningsvetenskap
Identifikatorer
URN: urn:nbn:se:umu:diva-200458ISBN: 978-91-7855-924-4 (tryckt)ISBN: 978-91-7855-925-1 (digital)OAI: oai:DiVA.org:umu-200458DiVA, id: diva2:1705089
Disputation
2022-11-18, Föreläsningssal A5, Målpunkt R04, Rum 6A5, Norrlands Universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Anmärkning

Ny lokal för disputationen. 

New location for disputation. 

Tillgänglig från: 2022-10-28 Skapad: 2022-10-20 Senast uppdaterad: 2022-11-08Bibliografiskt granskad
Delarbeten
1. Characterizing pulsatility in distal cerebral arteries using 4D flow MRI
Öppna denna publikation i ny flik eller fönster >>Characterizing pulsatility in distal cerebral arteries using 4D flow MRI
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2020 (Engelska)Ingår i: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 40, nr 12, s. 2429-2440Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Recent reports have suggested that age-related arterial stiffening and excessive cerebral arterial pulsatility cause blood-brain barrier breakdown, brain atrophy and cognitive decline. This has spurred interest in developing non-invasive methods to measure pulsatility in distal vessels, closer to the cerebral microcirculation. Here, we report a method based on four-dimensional (4D) flow MRI to estimate a global composite flow waveform of distal cerebral arteries. The method is based on finding and sampling arterial waveforms from thousands of cross sections in numerous small vessels of the brain, originating from cerebral cortical arteries. We demonstrate agreement with internal and external reference methods and show the ability to capture significant increases in distal cerebral arterial pulsatility as a function of age. The proposed approach can be used to advance our understanding regarding excessive arterial pulsatility as a potential trigger of cognitive decline and dementia.

Ort, förlag, år, upplaga, sidor
Sage Publications, 2020
Nyckelord
4D flow MRI, cerebral hemodynamics, arterial pulsatility, cerebral cortical arteries, aging
Nationell ämneskategori
Radiologi och bildbehandling
Identifikatorer
urn:nbn:se:umu:diva-166582 (URN)10.1177/0271678X19886667 (DOI)000497309400001 ()31722598 (PubMedID)2-s2.0-85075164443 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, 2015-05616Vetenskapsrådet, 2017-04949
Tillgänglig från: 2019-12-20 Skapad: 2019-12-20 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
2. Cerebral arterial pulsatility is linked to hippocampal microvascular function and episodic memory in healthy older adults
Öppna denna publikation i ny flik eller fönster >>Cerebral arterial pulsatility is linked to hippocampal microvascular function and episodic memory in healthy older adults
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2021 (Engelska)Ingår i: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 41, nr 7, s. 1778-1790Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Microvascular damage in the hippocampus is emerging as a central cause of cognitive decline and dementia in aging. This could be a consequence of age-related decreases in vascular elasticity, exposing hippocampal capillaries to excessive cardiac-related pulsatile flow that disrupts the blood-brain barrier and the neurovascular unit. Previous studies have found altered intracranial hemodynamics in cognitive impairment and dementia, as well as negative associations between pulsatility and hippocampal volume. However, evidence linking features of the cerebral arterial flow waveform to hippocampal function is lacking. We used a high-resolution 4D flow MRI approach to estimate global representations of the time-resolved flow waveform in distal cortical arteries and in proximal arteries feeding the brain in healthy older adults. Waveform-based clustering revealed a group of individuals featuring steep systolic onset and high amplitude that had poorer hippocampus-sensitive episodic memory (p = 0.003), lower whole-brain perfusion (p = 0.001), and weaker microvascular low-frequency oscillations in the hippocampus (p = 0.035) and parahippocampal gyrus (p = 0.005), potentially indicating compromised neurovascular unit integrity. Our findings suggest that aberrant hemodynamic forces contribute to cerebral microvascular and hippocampal dysfunction in aging.

Ort, förlag, år, upplaga, sidor
Sage Publications, 2021
Nyckelord
4D flow MRI, arterial stiffness, hippocampus, cognition, vasomotion
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:umu:diva-184408 (URN)10.1177/0271678X20980652 (DOI)000664214100024 ()33444091 (PubMedID)2-s2.0-85099415705 (Scopus ID)
Tillgänglig från: 2021-06-14 Skapad: 2021-06-14 Senast uppdaterad: 2023-03-07Bibliografiskt granskad
3. 5-year associations among cerebral arterial pulsatility, perivascular space dilation, and white matter lesions
Öppna denna publikation i ny flik eller fönster >>5-year associations among cerebral arterial pulsatility, perivascular space dilation, and white matter lesions
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2022 (Engelska)Ingår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 92, nr 5, s. 871-881Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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. 

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2022
Nationell ämneskategori
Neurologi
Identifikatorer
urn:nbn:se:umu:diva-199208 (URN)10.1002/ana.26475 (DOI)000843724700001 ()36054261 (PubMedID)2-s2.0-85136905097 (Scopus ID)
Forskningsfinansiär
Stiftelsen för strategisk forskning (SSF)Region Västerbotten, 2017‐04949Knut och Alice Wallenbergs Stiftelse, 2017‐04949Max Planck GesellschaftVetenskapsrådet, 2017‐02217Vetenskapsrådet, 421‐2012‐648
Tillgänglig från: 2022-09-08 Skapad: 2022-09-08 Senast uppdaterad: 2023-05-04Bibliografiskt granskad
4. Blood-brain barrier permeability, vascular density, and cerebral 4D flow MRI hemodynamics in a population-based elderly cohort
Öppna denna publikation i ny flik eller fönster >>Blood-brain barrier permeability, vascular density, and cerebral 4D flow MRI hemodynamics in a population-based elderly cohort
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord
Magnetic resonance imaging, 4D flow MRI, DCE MRI, cerebral, hemodynamics, arterial pulsatility, blood-brain barrier permeability, vascular density, white matter lesions, hippocampus
Nationell ämneskategori
Radiologi och bildbehandling
Identifikatorer
urn:nbn:se:umu:diva-200456 (URN)
Tillgänglig från: 2022-10-20 Skapad: 2022-10-20 Senast uppdaterad: 2023-09-14

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