Quantifying cerebrospinal fluid dynamics: A review of human neuroimaging contributions to CSF physiology and neurodegenerative disease

Abstract

Cerebrospinal fluid (CSF), predominantly produced in the ventricles and circulating throughout the brain and spinal cord, is a key protective mechanism of the central nervous system (CNS). Physical cushioning, nutrient delivery, metabolic waste, including protein clearance, are key functions of the CSF in humans. CSF volume and flow dynamics regulate intracranial pressure and are fundamental to diagnosing disorders including normal pressure hydrocephalus, intracranial hypotension, CSF leaks, and possibly Alzheimer's disease (AD). The ability of CSF to clear normal and pathological proteins, such as amyloid-beta (Aβ), tau, alpha synuclein and others, implicates it production, circulation, and composition, in many neuropathologies. Several neuroimaging modalities have been developed to probe CSF fluid dynamics and better relate CSF volume and flow to anatomy and clinical conditions. Approaches include 2-photon microscopic techniques, MRI (tracer-based, gadolinium contrast, endogenous phase-contrast), and dynamic positron emission tomography (PET) using existing approved radiotracers. Here, we discuss CSF flow neuroimaging, from animal models to recent clinical-research advances, summarizing current endeavors to quantify and map CSF flow with implications towards pathophysiology, new biomarkers, and treatments of neurological diseases.

Keywords: Cerebrospinal fluid; Fluid dynamics; MRI; Modalities; Neuroimaging; PET.

Fig. 1.

Anatomy of the Choroid Plexus. Schematic diagram reproduced with permission from (Lun et al., 2015) highlighting the membrane of epithelial cells composing the choroid plexus (ChP). Steady blood flow, ion and solute exchange, and immune regulation across the stroma allow for secretion of CSF across the epithelium into the ventricles. This figure was originally published in Nat Rev. Neuroscience (DOI: https://doi.org/10.1038/nrn3921).

Fig. 2.

Visualization of the perivascular space (PVS). Schematic diagram from (Abbott et al., 2018) (CC by 4.0) highlighting key features surrounding a penetrating leptomeningeal artery in the subarachnoid space (SAS). The fluid filled perivascular compartment within the outer layers of blood vessels is defined by the astroglial and endothelial basement membranes. Distinct anatomical regions of potential fluid exchange mechanisms are specifically highlighted: 1. Micron-sized pores deemed stomata that allow for communication between the SAS and PVS 2. Fenestrations within pia mater cells providing fluid communication between the subpial space and the SAS.

Fig. 3.

Summary of various proposed CSF clearance pathways. Schematic diagram highlighting strength of scientific evidence from animal and human studies supporting CSF clearance routes across arachnoid granulations, dural lymphatics, cranial nerves, and lumbar nerves from Proulx (2021) (CC by 4.0).