Damage to Lymphatic Vessels Impairs Drainage of Cerebrospinal Fluid with Age

Impaired drainage of cerebrospinal fluid (CSF) with age is a hot topic in the field of neurodegeneration at the moment. In younger individuals, passage of CSF out of the brain via a number of routes is thought to provide a way to maintain normally low levels of metabolic waste, such as the amyloid-β associated with Alzheimer's disease. Reduced fluid flow due to the damage and dysfunction of aging then contributes to the raised levels and aggregation of these waste products, and thus to neurodegenerative conditions. A number of companies are developing therapies based on this vision of brain aging, such as Leucadia Therapeutics. Thus we should expect to see impaired CSF drainage decisively proven or disproven as a major cause of neurodegeneration in clinical trials over the next few years. Even in advance of those trials, the evidence to date is quite compelling, however.

Though the brain drains its waste via the cerebrospinal fluid (CSF), little has been understood about an accurate route for the brain's cleansing mechanism. Scientists have now reported the basal side of the skull as the major route, so called "hotspot" for CSF drainage. They found that basal meningeal lymphatic vessels (mLVs) function as the main plumbing pipes for CSF. They confirmed macromolecules in the CSF mainly runs through the basal mLVs. Notably, the team also revealed that the brain's major drainage system, specifically basal mLVs are impaired with aging.

Throughout our body, excess fluids and waste products are removed from tissues via lymphatic vessels. It was only recently discovered that the brain also has a lymphatic drainage system. mLVs are supposed to carry waste from the brain tissue fluid and the CSF down the deep cervical lymph nodes for disposal. Still scientist are left with one perplexing question - where is the main exit for the CSF? Though mLVs in the upper part of the skull were reported as the brain's clearance pathways in 2014, no substantial drainage mechanism was observed in that section.

The researchers used several techniques to characterize the basal mLVs in detail and verified that specialized morphologic characteristics of basal mLVs indeed facilitate the CSF uptake and drainage. Using CSF contrast-enhanced magnetic resonance imaging in a rat model, they found that CSF is drained preferentially through the basal mLVs. They also utilized a lymphatic-reporter mouse model and discovered that fluorescence-tagged tracer injected into the brain itself or the CSF is cleared mainly through the basal mLVs.

It has long been suggested that CSF turnover and drainage declines with ageing. However, alteration of mLVs associated with ageing is poorly understood. In this study, the researchers observed changes of mLVs in young (3-month-old) and aged (24~27-months-old) mice. They found that the structure of the basal mLVs and their lymphatic valves in aged mice become severely flawed, thus hampering CSF clearance. By mapping out a precise route for the brain's waste clearance system, this study may be able to help find ways to improve the brain's cleansing function, enabling a new strategy for eliminating the buildup of aging-related toxic proteins.

Link: https://www.eurekalert.org/pub_releases/2019-07/ifbs-nim072319.php

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