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Model-based approaches to characterize cerebral arterial stiffness and CSF transport with MRI
Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
2025 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Modellbaserade metoder för att karakterisera cerebral artärstelhet och CSF-transport med MRI (Swedish)
Abstract [en]

Cerebral small vessel disease (cSVD) is prevalent in the aging population and is believed to be an important contributor to cognitive decline, dementia, and stroke. The underlying mechanisms of cSVD remain largely unknown but are potentially linked to cerebral arterial stiffening. With age and vascular risk factors, the arteries lose their elasticity, facilitating transmission of pulsatile blood flow to the brain which potentially harms the microvasculature through processes involving blood-brain barrier (BBB) disruption. However, the association between cerebral arterial stiffness and cSVD is understudied, likely due to the lack of measurement techniques.

Another potential pathway through which brain health can be affected in aging is via its waste clearance system. It entails flow of cerebrospinal fluid (CSF) from the subarachnoid space (SAS) through the brain via perivascular pathways, enabling clearance of interstitial solutes along the way. Here the CSF production, as well as the cyclic motion of the arterial walls are thought to drive the fluid flow. In line with this, studies have demonstrated that injected contrast agents propagate along the major cerebral arteries, although the separate contributions from diffusion and bulk flow are still to be determined.

The aim of this thesis was to propose methods to assess key parameters believed to influence brain health in the ageing population, specifically stiffness of, and CSF transport along, the major cerebral arteries. Furthermore, the aim was to employ the proposed techniques in relevant cohorts to study physiological and pathological processes.

Using whole-brain 4D flow MRI and leveraging the stiffness-dependent time-delays between blood flow waveforms sampled at increasing depths in the cerebral arterial tree, allowed the quantification of a global cerebral pulse wave velocity (gcPWV). We demonstrated that challenges introduced by low temporal resolution could be handled by utilizing the vast number of potential measurement points along the extent of the cerebrovascular tree (Paper I). We also showed that gcPWV did not critically depend on the included vascular depth (Paper II), or the inclusion of specific arterial branches, and that it demonstrated robustness to large reductions in the amount of input data, as well as the expected sensitivity to age (Paper I).

In a population-based cohort, higher gcPWV was associated with white matter hyperintensity (WMH) volume, the most frequently recognized feature of cSVD (Paper II). gcPWV was also associated to change in WMH volume over a 2.5-year period (Paper III). However, controlling for baseline WMH volume suppressed this relationship, suggesting that the predictive nature of gcPWV at an already old age and over a short time window was limited.

Furthermore, gcPWV showed no association with BBB permeability. Combined with an absence of the previously suggested link between WMH volume and BBB permeability, this finding suggests that increased BBB permeability is unlikely to be a primary pathway for cSVD progression in its early stages (Paper III).

To investigate CSF diffusion and bulk flow, we studied contrast propagation following intrathecal gadolinium injection in patients evaluated for idiopathic normal pressure hydrocephalus (Paper IV). Quantitative MRI was used to measure contrast concentrations at baseline and 3, 5, and 7 hours post-injection. By applying an optimization approach based on the 1D advection-diffusion equation, we identified contributions from both diffusion and bulk flow, with movement occurring in an antegrade direction along the major cerebral arteries in the SAS. The measured diffusivity was significantly higher than that of self-diffusion, indicating enhanced diffusion-like behavior. Notably, the bulk flow component matched the magnitude expected from intrinsic CSF production and absorption.

In conclusion, using 4D flow MRI we developed a robust measurement approach to assess global cerebral arterial stiffness, quantified as gcPWV. Our findings showed that gcPWV was associated with both age and cSVD features, suggesting a role for macrovascular dysfunction in cSVD. However, from a longitudinal perspective, gcPWV had limited predictive value for cSVD development. Additionally, BBB leakage was not associated with gcPWV or WMH volume, indicating that BBB disruption was unlikely to be the primary pathway for disease progression in this cohort. Using a novel approach to assess gadolinium propagation along major arteries in the SAS, we identified an enhanced diffusion behavior and a bulk flow magnitude consistent with intrinsic CSF production and absorption. This highlights the role of classical CSF circulation in delivering fresh CSF for brain clearance.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2025. , p. 68
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2344
Keywords [en]
Magnetic resonance imaging, 4D flow MRI, medical image analysis, pulse wave velocity, contrast enhanced MRI, quantitative MRI, blood-brain barrier, white matter hyperintensities, perivascular spaces, cerebral small vessel disease, arterial stiffness, arteriosclerosis, Atherosclerosis, neurovascular dysfunction, cerebrospinal fluid, CSF circulation, intrathecal contrast injection
National Category
Neurology Radiology, Nuclear Medicine and Medical Imaging Medical Engineering
Research subject
Biomedical Radiation Science; Neurology; radiation physics
Identifiers
URN: urn:nbn:se:umu:diva-234739ISBN: 978-91-8070-607-0 (electronic)ISBN: 978-91-8070-606-3 (print)OAI: oai:DiVA.org:umu-234739DiVA, id: diva2:1932512
Public defence
2025-02-21, Triple Helix, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2025-01-31 Created: 2025-01-29 Last updated: 2025-01-29Bibliographically approved
List of papers
1. Assessing cerebral arterial pulse wave velocity using 4D flow MRI
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2021 (English)In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 41, no 10, p. 2769-2777Article in journal (Refereed) Published
Abstract [en]

Intracranial arterial stiffening is a potential early marker of emerging cerebrovascular dysfunction and could be mechanistically involved in disease processes detrimental to brain function via several pathways. A prominent consequence of arterial wall stiffening is the increased velocity at which the systolic pressure pulse wave propagates through the vasculature. Previous non-invasive measurements of the pulse wave propagation have been performed on the aorta or extracranial arteries with results linking increased pulse wave velocity to brain pathology. However, there is a lack of intracranial “target-organ” measurements. Here we present a 4D flow MRI method to estimate pulse wave velocity in the intracranial vascular tree. The method utilizes the full detectable branching structure of the cerebral vascular tree in an optimization framework that exploits small temporal shifts that exists between waveforms sampled at varying depths in the vasculature. The method is shown to be stable in an internal consistency test, and of sufficient sensitivity to robustly detect age-related increases in intracranial pulse wave velocity.

Place, publisher, year, edition, pages
Sage Publications, 2021
Keywords
arterial stiffness, arteriosclerosis, Atherosclerosis, magnetic resonance imaging, neurovascular dysfunction
National Category
Cardiology and Cardiovascular Disease Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-183012 (URN)10.1177/0271678X211008744 (DOI)000681011400001 ()33853409 (PubMedID)2-s2.0-85104375387 (Scopus ID)
Available from: 2021-05-17 Created: 2021-05-17 Last updated: 2025-02-10Bibliographically approved
2. Cerebral arterial stiffness blood-brain barrier integrity and white matter lesion progression
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(English)Manuscript (preprint) (Other academic)
National Category
Cardiology and Cardiovascular Disease Neurology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-234735 (URN)
Available from: 2025-01-29 Created: 2025-01-29 Last updated: 2025-02-10Bibliographically approved
3. Cerebral arterial stiffness is linked to white matter hyperintensities and perivascular spaces in older adults: a 4D flow MRI study
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2024 (English)In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 44, no 8, p. 1343-1351Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Sage Publications, 2024
Keywords
4D flow MRI, cerebral small vessel disease, perivascular spaces, pulse wave velocity, white matter hyperintensities
National Category
Cardiology and Cardiovascular Disease Neurology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-221120 (URN)10.1177/0271678X241230741 (DOI)001157963000001 ()38315044 (PubMedID)2-s2.0-85184419786 (Scopus ID)
Funder
Swedish Foundation for Strategic Research, RMX18-0152Swedish Heart Lung Foundation, 20180513Swedish Heart Lung Foundation, 20210653The Swedish Brain Foundation, F2022-0216Swedish Research Council, 2017-04949Swedish Research Council, 2022-04263Region Västerbotten
Available from: 2024-02-22 Created: 2024-02-22 Last updated: 2025-02-10Bibliographically approved
4. Diffusion and bulk flow in cerebrospinal fluid along the major cerebral arteries
Open this publication in new window or tab >>Diffusion and bulk flow in cerebrospinal fluid along the major cerebral arteries
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(English)Manuscript (preprint) (Other academic)
National Category
Neurology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-234737 (URN)
Available from: 2025-01-29 Created: 2025-01-29 Last updated: 2025-01-29Bibliographically approved

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