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5-year associations among cerebral arterial pulsatility, perivascular space dilation, and white matter lesions
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.ORCID iD: 0000-0003-3181-785X
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).ORCID iD: 0000-0002-8603-9453
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).ORCID iD: 0000-0002-2031-722X
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0001-6451-1940
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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. Vol. 92, no 5, p. 871-881
National Category
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-199208DOI: 10.1002/ana.26475ISI: 000843724700001PubMedID: 36054261Scopus ID: 2-s2.0-85136905097OAI: oai:DiVA.org:umu-199208DiVA, id: diva2:1694204
Funder
Swedish Foundation for Strategic ResearchRegion Västerbotten, 2017‐04949Knut and Alice Wallenberg Foundation, 2017‐04949Max Planck SocietySwedish Research Council, 2017‐02217Swedish Research Council, 421‐2012‐648Available from: 2022-09-08 Created: 2022-09-08 Last updated: 2023-05-04Bibliographically approved
In thesis
1. Cerebral arterial pulsatility imaging using 4D flow MRI: methodological development and applications in brain aging
Open this publication in new window or tab >>Cerebral arterial pulsatility imaging using 4D flow MRI: methodological development and applications in brain aging
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
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:nbn:se:umu:diva-200458 (URN)978-91-7855-924-4 (ISBN)978-91-7855-925-1 (ISBN)
Public defence
2022-11-18, Föreläsningssal A5, Målpunkt R04, Rum 6A5, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
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Note

Ny lokal för disputationen. 

New location for disputation. 

Available from: 2022-10-28 Created: 2022-10-20 Last updated: 2022-11-08Bibliographically approved

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Vikner, TomasKaralija, NinaEklund, AndersMalm, JanLundquist, AndersRiklund, KatrineNyberg, LarsWåhlin, Anders

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Radiation PhysicsDiagnostic RadiologyUmeå Centre for Functional Brain Imaging (UFBI)NeurosciencesStatisticsDepartment of Radiation SciencesDepartment of Integrative Medical Biology (IMB)Department of Applied Physics and Electronics
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