Umeå University's logo

umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Cerebral arterial pulsatility imaging using 4D flow MRI: methodological development and applications in brain aging
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.ORCID iD: 0000-0003-3181-785X
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
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. 

Place, publisher, year, edition, pages
Umeå: Umeå University , 2022. , p. 78
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2209
Keywords [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
National Category
Neurology Neurosciences
Research subject
Biomedical Radiation Science
Identifiers
URN: urn:nbn:se:umu:diva-200458ISBN: 978-91-7855-924-4 (print)ISBN: 978-91-7855-925-1 (electronic)OAI: oai:DiVA.org:umu-200458DiVA, id: diva2:1705089
Public defence
2022-11-18, Föreläsningssal A5, Målpunkt R04, Rum 6A5, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Note

Ny lokal för disputationen. 

New location for disputation. 

Available from: 2022-10-28 Created: 2022-10-20 Last updated: 2022-11-08Bibliographically approved
List of papers
1. Characterizing pulsatility in distal cerebral arteries using 4D flow MRI
Open this publication in new window or tab >>Characterizing pulsatility in distal cerebral arteries using 4D flow MRI
Show others...
2020 (English)In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 40, no 12, p. 2429-2440Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Sage Publications, 2020
Keywords
4D flow MRI, cerebral hemodynamics, arterial pulsatility, cerebral cortical arteries, aging
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-166582 (URN)10.1177/0271678X19886667 (DOI)000497309400001 ()31722598 (PubMedID)2-s2.0-85075164443 (Scopus ID)
Funder
Swedish Research Council, 2015-05616Swedish Research Council, 2017-04949
Available from: 2019-12-20 Created: 2019-12-20 Last updated: 2023-03-24Bibliographically approved
2. Cerebral arterial pulsatility is linked to hippocampal microvascular function and episodic memory in healthy older adults
Open this publication in new window or tab >>Cerebral arterial pulsatility is linked to hippocampal microvascular function and episodic memory in healthy older adults
Show others...
2021 (English)In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 41, no 7, p. 1778-1790Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Sage Publications, 2021
Keywords
4D flow MRI, arterial stiffness, hippocampus, cognition, vasomotion
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-184408 (URN)10.1177/0271678X20980652 (DOI)000664214100024 ()33444091 (PubMedID)2-s2.0-85099415705 (Scopus ID)
Available from: 2021-06-14 Created: 2021-06-14 Last updated: 2023-03-07Bibliographically approved
3. 5-year associations among cerebral arterial pulsatility, perivascular space dilation, and white matter lesions
Open this publication in new window or tab >>5-year associations among cerebral arterial pulsatility, perivascular space dilation, and white matter lesions
Show others...
2022 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 92, no 5, p. 871-881Article in journal (Refereed) 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. 

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-199208 (URN)10.1002/ana.26475 (DOI)000843724700001 ()36054261 (PubMedID)2-s2.0-85136905097 (Scopus ID)
Funder
Swedish Foundation for Strategic ResearchRegion Västerbotten, 2017‐04949Knut and Alice Wallenberg Foundation, 2017‐04949Max Planck SocietySwedish Research Council, 2017‐02217Swedish Research Council, 421‐2012‐648
Available from: 2022-09-08 Created: 2022-09-08 Last updated: 2023-05-04Bibliographically approved
4. Blood-brain barrier permeability, vascular density, and cerebral 4D flow MRI hemodynamics in a population-based elderly cohort
Open this publication in new window or tab >>Blood-brain barrier permeability, vascular density, and cerebral 4D flow MRI hemodynamics in a population-based elderly cohort
Show others...
(English)Manuscript (preprint) (Other academic)
Keywords
Magnetic resonance imaging, 4D flow MRI, DCE MRI, cerebral, hemodynamics, arterial pulsatility, blood-brain barrier permeability, vascular density, white matter lesions, hippocampus
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-200456 (URN)
Available from: 2022-10-20 Created: 2022-10-20 Last updated: 2023-09-14

Open Access in DiVA

fulltext(11349 kB)192 downloads
File information
File name FULLTEXT01.pdfFile size 11349 kBChecksum SHA-512
83f4545b3495de54f9d0768bc6624d66a27edcf9ec77299858805117f80f7e1adf5d7fa84ccaf91b8ab354e8a322ba99fa9a0de443795eeb58e6097a892900eb
Type fulltextMimetype application/pdf
spikblad(102 kB)21 downloads
File information
File name SPIKBLAD02.pdfFile size 102 kBChecksum SHA-512
c631fdf91987aa5c9bb9c06c6972e7a69f4ae4ce2caddb7eadc85db0e8f28da582c4efcf4f641a3549824b8f7c651486b5bcf1efc113882c07130e36fb419200
Type spikbladMimetype application/pdf

Authority records

Vikner, Tomas

Search in DiVA

By author/editor
Vikner, Tomas
By organisation
Radiation Physics
NeurologyNeurosciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 192 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1025 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf