Allostasis of cerebral water: modelling the transport of cerebrospinal fluid

A validated model of water transport in the cerebral environment is both an ambitious and timely task; many brain diseases relate to imbalances in water regulation. From tumours to strokes, chronic or acute, transport of fluid in the brain plays a crucial role. The importance and complexity of the brain, together with the range of unmet clinical needs that are connected with this organ,make the current research a high-priority.One of the most paradoxical cerebral conditions, hydrocephalus, serves as an excellent metric for judging the success of anymodel developed. In particular, normal pressure hydrocephalus (NPH) is a paradoxical condition with no known cure and existing treatments display unacceptably high failure rates. NPH is considered to be a disease of old age, and like many such diseases, it is related to a change in the transport of fluid in the cerebral environment. This complex system ranges from organ-level transport to cellular membrane channels such as aquaporins; through integrating it in a novel mathematical framework, we suggest that the underlying logic of treatment methods may be misleading.By modelling the transport of cerebrospinal fluid (CSF) between the ventricular system, cerebral tissue and blood networks, we find that changes to the biophysical properties of the brain (rather than structural changes such as aqueduct obstruction) are capable of producing clinically relevant ventriculomegaly in the absence of any obstruction to CSF flowthrough the ventricular system. Specifically, the combination of increased leakiness and compliance of the capillary bed leads to the development of enlarged ventricles with a normal ventricular pressure, replicating clinical features of the presentation of NPH. These results, while needing experimental validation, imply that treatment methods like shunting, that are focussed on structural manipulation, may continue to fail at unacceptably high rates.This thesis is not currently available via ORA