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Purpose: Cerebrospinal fluid (CSF) flow oscillations have emerged as a potentially important marker related to brain clearance, but their acquisition often relies on specialized imaging MRI sequences. The purpose of this work was to enable quantitative assessment of CSF flow associated with cardiac, respiratory, and low-frequency cycles using widely available functional magnetic resonance imaging (fMRI) acquisitions.

Methods: A method was developed to translate fMRI-derived CSF inflow signals into quantitative flow rates. This approach modeled the spin-history of an oscillating ensemble of molecules. Validation was performed using phantom experiments with cardiac-, respiratory-, and low-frequency-like oscillatory flow. The method was further applied to resting-state data from 48 older adults (68–82 years, 19 women) to characterize CSF flow at the foramen magnum.

Results: Phantom experiments demonstrated excellent correlations between estimated and true velocities for cardiac- and respiratory-like frequencies (r = 0.94 and 0.97, respectively) and moderate correlation for the low-frequency-like oscillation (r = 0.58). In the population cohort, median CSF stroke volumes were 0.77 [0.57, 1.09] mL for the cardiac cycle, 0.38 [0.26, 0.88] mL for the respiratory cycle, and 0.26 [0.14, 0.39] mL for the low-frequency cycle.

Conclusion: The proposed spin-history modeling method enabled quantitative estimation of CSF flow components using a conventional fMRI dataset and showed that the cardiac cycle dominates CSF motion at the foramen magnum.

According to glymphatic system theory, cerebrospinal fluid (CSF) perfuses the brain’s interstitial space to support waste clearance, but the magnitude of this flow and the outflow pathway of interstitial fluid (ISF) in humans remain uncertain. To achieve flow quantification, we applied a compartment-model approach applied in conjunction with serial quantitative MRI data acquired after intrathecal gadolinium administration. Using the method, we estimated CSF-to-ISF inflow to 45 ± 20 mL/h, in patients with suspected idiopathic normal pressure hydrocephalus. Tissue-specific contributions were 34 ± 14 mL/h in cortical gray matter, 11±6 mL/h in white matter, and 0.4 ± 0.3 mL/h in subcortical gray matter, suggesting that CSF perfusion occurs primarily in superficial regions near the subarachnoid space. A lack of correlation between inflow and total craniospinal system outflow (r = 0.03, P = 0.91) suggested that ISF recirculates back into CSF rather than exiting the craniospinal system via a separate route. Independent experiments in healthy older individuals using intravenous gadolinium administration supported ISF-to-CSF recirculation, where contrast material that presumably crossed the blood–brain barrier subsequently appeared in the subarachnoid space, allowing ISF-to-CSF flow quantification. These findings provide a quantitative framework for studying brain clearance in humans and support subarachnoid space recirculation as an important efflux route.

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.

Background: White matter lesions (WML) and dilated perivascular spaces (PVS) are features of small vessel disease (SVD), commonly observed in aging and dementia, with unknown pathophysiology. Human studies have documented contrast accumulation within and in proximity of SVD-lesions. However, whether such observations mainly reflect excessive blood-brain barrier (BBB) leakage, or altered microvascular density in the investigated regions, remains unclear.

Methods: To evaluate the roles of BBB leakage and vascular density in aging and SVD, dynamic contrast enhanced (DCE) MRI was used to estimate the permeability-surface area product (PS) and fractional plasma volume () in normal-appearing brain tissue and in proximity of and within WML and PVS in a population-based cohort (N = 56; 34/22 m/f; age 64 to 84 years). Analysis of variance (ANOVA) was used to assess regional differences in PS and and analysis of covariance (ANCOVA) was used to assess regional differences in PS with and vascular risk as covariates.

Results: Pronounced increases in PS and were observed from normal-appearing white matter (NAWM) to WML peripheries to WMLs. Similar PS and increases were observed from basal ganglia (BG) to BG-PVS. Further, PS in NAWM and white matter (WM) PVS were found to increase with cortex-to-ventricular depth. However, ANCOVA models with as a covariate showed that variance in PS was mainly explained by vp (η2=0.17 to η2=0.35; all p < 10− 3), whereas the effect of region was only borderline-significant when comparing NAWM, WML peripheries and WML (p = 0.03) and non-significant for the other comparisons (p > 0.29).

Conclusions: Our findings support the notion that contrast leakage across the BBB accumulates within and in proximity of SVD-related lesions. However, high contrast accumulation may mainly reflect high vascularization, and to a lesser degree than previously recognized BBB dysfunction.

Blood-brain barrier (BBB) disruption may contribute to cognitive decline, but questions remain whether this association is more pronounced for certain brain regions, such as the hippocampus, or represents a whole-brain mechanism. Further, whether human BBB leakage is triggered by excessive vascular pulsatility, as suggested by animal studies, remains unknown. In a prospective cohort (N = 50; 68-84 years), we used contrast-enhanced MRI to estimate the permeability-surface area product (PS) and fractional plasma volume ( formula presented ), and 4D flow MRI to assess cerebral arterial pulsatility. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) score. We hypothesized that high PS would be associated with high arterial pulsatility, and that links to cognition would be specific to hippocampal PS. For 15 brain regions, PS ranged from 0.38 to 0.85 (·10-3 min-1) and formula presented from 0.79 to 1.78%. Cognition was related to PS (·10-3 min-1) in hippocampus (β = - 2.9; p = 0.006), basal ganglia (β = - 2.3; p = 0.04), white matter (β = - 2.6; p = 0.04), whole-brain (β = - 2.7; p = 0.04) and borderline-related for cortex (β = - 2.7; p = 0.076). Pulsatility was unrelated to PS for all regions (p > 0.19). Our findings suggest PS-cognition links mainly reflect a whole-brain phenomenon with only slightly more pronounced links for the hippocampus, and provide no evidence of excessive pulsatility as a trigger of BBB disruption.

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.

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.