Variability in the circulation of cerebrospinal fluid: causes and clinical implications for intraventricular drug delivery.

Understanding the many factors affecting the circulation of cerebrospinal fluid (CSF) is important for the treatment of neurological diseases, especially when considering macromolecular pharmaceuticals designed to be delivered directly into the ventricles of the brain. CSF production, pressure, flow, and absorption are tightly linked to the maintenance of brain homeostasis and function. Vascular pulsations help propel CSF through the ventricular system and subarachnoid space, with additional contributions made locally from the coordinated beating of ependymal cilia. Along with the anatomic configuration of the CSF pathways, these are critical determinants for moving therapeutic molecules and vectors to specific regions of the central nervous system (CNS) and their eventual clearance. The advent of phase contrast MRI has revolutionized the understanding of fluid flow in the human CNS, which is affected by circadian rhythm, age, molecular factors, and diseases, to name but a few. In this review, the basic principles and recent advances critical for understanding the considerable variability of CSF circulation are examined, considering differences that are encountered between healthy individuals and due to disease states. While the emphasis is on human data, illustrative comparisons with laboratory animals are made to enable translation of preclinical data to clinical use. This literature review is intended to be applicable to a wide variety of therapeutic agents, from drugs and macromolecules to adeno-associated virus (AAV) capsids, that are intended for intraventricular delivery.