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Towards understanding cerebral small vessel disease: Innovative, MRI-based, functional markers to discover the terra incognita between large vessels and macroscopic brain lesions

Final Report Summary - SMALLVESSELMRI (Towards understanding cerebral small vessel disease: Innovative, MRI-based, functional markers to discover the terra incognita between large vessels and macroscopic brain lesions)

Cerebral small vessel disease (SVD) causes 25% of all strokes and is a major cause of cognitive decline, dementia and functional disability in the elderly. Two important challenges hamper the development of effective treatments. First, little is known about the mechanism by which SVD leads to brain damage and, thus, to cognitive decline. Second, the current clinical markers and image-based markers of SVD do not reflect SVD itself, but macroscopic brain damage secondary to SVD. Unlike large vessels, small vessels were not visible with conventional imaging techniques, which created a ‘terra incognita’ of small vessel pathology between large vessels on the one hand, and macroscopic brain damage on the other. The aim of this research program was to enter this terra incognita and thus remove the major current obstacle towards developing effective treatments for SVD, by innovative magnetic resonance imaging (MRI) techniques that yield non-invasive markers of small vessel (dys)function in the human brain. To this end two innovative sets of image-based markers have been developed.
The first set enables us, for the first time, to measure blood flow pulsations in the small cerebral arteries and related pulsatile tissue motion and strain (driven by the beating vessels). Mechanical strain plays an important role in cell function, including endothelial cells and neurons, and may be altered in cerebral SVD. Moreover, the tissue pulsations also play an important role in the clearance of waste products from the brain. Impaired clearance of waste products is one of the potential mechanisms that may relate SVD to brain tissue damage and amyloid beta accumulation. A method was successfully developed to measure and quantify blood flow velocity and pulsatility with an MRI scanner with an ultra-high magnetic field strength (7 tesla) in the small penetrating arteries of the cerebral white matter in humans. These vessels have diameters only slightly exceeding the diameter of a human hair. Related to this we can now also measure the minute volume pulsation in the brain tissue due to the wave of blood that passes with each heartbeat. This volume change is of the order one tenth of one percent. With this method, a difference in volume pulsation between gray matter and white matter is observed, which is consistent with both a higher vascularity of gray matter and a higher stiffness of white matter.
The second set of novel markers focuses on brain fluids (cerebrospinal fluid (CSF) and perivascular fluid), the dynamics of which are essential for the maintenance of the brain’s micro-environment. We aimed to obtain quantitative brain fluid markers with MRI that potentially reflect abnormalities in either the blood-brain-barrier (which prevents substances of entering the brain tissue) or waste clearance (“glymphatic system” which ensures effective clearance of potentially harmful waste products within the brain tissue). First, we developed a method to quantitatively map the T2 of CSF, an MRI-specific parameter that depends on fluid composition. We found significant differences in T2 between peripheral CSF and CSF in the ventricles, but future work is needed to disentangle actual fluid composition variation from confounding factors that are intrinsic to the MRI method (partial volume effects, diffusion effects and system imperfections). Second, we evaluated a method to quantify the CSF production rate, and showed that the measured production rate depends on the respiration. Finally, we developed a method to automatically detect perivascular spaces in high resolution brain images.
The developed methods have been evaluated in patients with SVD. In conclusion, this ERC project has shifted the boundaries of the ‘terra incognita’ of SVD, as it allows for new ways to non-invasively assess small vessel (dys)function in the human brain.