Merel M. van der Thiel

Interstitial fluid (ISF) refers to the fluid between the parenchymal cells and along the perivascular spaces (PVS). ISF plays a crucial role in delivering nutrients and clearing waste products from the brain. This narrative review focuses on the use of MRI techniques to measure various ISF characteristics in humans. The complementary value of contrast‐enhanced and noncontrast‐enhanced techniques is highlighted. While contrast‐enhanced MRI methods allow measurement of ISF transport and flow, they lack quantitative assessment of ISF properties. Noninvasive MRI techniques, including multi‐ b ‐value diffusion imaging, free‐water‐imaging, T 2 ‐decay imaging, and DTI along the PVS, offer promising alternatives to derive ISF measures, such as ISF volume and diffusivity. The emerging role of these MRI techniques in investigating ISF alterations in neurodegenerative diseases (eg, Alzheimer's disease and Parkinson's disease) and cerebrovascular diseases (eg, cerebral small vessel disease and stroke) is discussed. This review also emphasizes current challenges of ISF imaging, such as the microscopic scale at which ISF has to be measured, and discusses potential focus points for future research to overcome these challenges, for example, the use of high‐resolution imaging techniques. Noninvasive MRI methods for measuring ISF characteristics hold significant potential and may have a high clinical impact in understanding the pathophysiology of neurodegenerative and cerebrovascular disorders, as well as in evaluating the efficacy of ISF‐targeted therapies in clinical trials. Level of Evidence 3 Technical Efficacy Stage 2

Perivascular spaces (PVS) and blood–brain barrier (BBB) disruption are two key features of cerebral small vessel disease (cSVD) and neurodegenerative diseases that have been linked to cognitive impairment and are involved in the cerebral waste clearance system. Magnetic resonance imaging (MRI) offers the possibility to study these pathophysiological processes noninvasively in vivo. This educational review provides an overview of the MRI techniques used to assess PVS functionality and BBB disruption. MRI‐visible PVS can be scored on structural images by either (subjectively) counting or (automatically) delineating the PVS. We highlight emerging (diffusion) techniques to measure proxies of perivascular fluid and its movement, which may provide a more comprehensive understanding of the role of PVS in diseases. For the measurement of BBB disruption, we explain the most commonly used MRI technique, dynamic contrast‐enhanced (DCE) MRI, as well as a more recently developed technique based on arterial spin labeling (ASL). DCE MRI and ASL are thought to measure complementary characteristics of the BBB. Furthermore, we describe clinical studies that have utilized these MRI techniques in cSVD and neurodegenerative diseases, particularly Alzheimer's disease (AD). These studies demonstrate the role of PVS and BBB dysfunction in these diseases and provide insight into the large overlap, but also into the differences between cSVD and AD. Overall, MRI techniques may provide valuable insights into the pathophysiological mechanisms underlying these diseases and have the potential to be used as markers for disease progression and treatment response. Level of Evidence 3 Technical Efficacy Stage 2