Jul 25, 2019

How well the brain ejects waste may affect disease susceptibility

Photo of meningeal lymphatic vessels around petrosquamous sinus cells

Meningeal lymphatic vessels around petrosquamous sinus at the base of the skull. Photo: Ahn JH and Koh GY/IBS Center for Vascular Research

The brain drains waste fluid via a system of cells that can function incorrectly as they age, potentially leading to neurological issues, according to a preclinical study published in Nature Wednesday.

Why it matters: Researchers think dysfunction in the system of cells could play a role in — and be a potential treatment target for — neurodegenerative disorders like Alzheimer's and multiple sclerosis.

"A build-up of toxic metabolites is strongly associated with age-related neurodegenerative disease ... and our discovery should provide further insights into the role of impaired brain clearance in the development of this disease."
— Study co-author Hyunsoo Cho, of the Institute for Basic Science in South Korea, tells Axios

Background: How the brain and spinal cord drain cerebrospinal fluid (CSF) has been under recent debate, as scientists only recently re-discovered the central nervous system has its own lymphatic system.

  • "The textbook knowledge is that CSF directly drains into veins, however, this is mostly based on knowledge gained from studies performed over 100 years ago," Steven Proulx, of the Theodor Kocher Institute in Switzerland, tells Axios.
  • But studies in recent years, "highlighted the forgotten role" lymphatics play, adds Proulx, who was not part of this study.

Still, the route remains under debate.

  • Proulx says there is evidence CSF can also drain through routes along cranial nerves, like in the nasal or optical region, citing his 2017 study.
  • Others propose the meningeal lymphatic vessels (mLVs) at the top of the skull are most important.

What they did: This research team, over roughly 3 years, used fluorescence microscopy and MRIs to track the function of mLVs in genetically modified mouse and rat models, Cho said.

  • They compared the function of basal (base of skull) and dorsal (top of skull) mLVs between young and older mice.

What they found: MLVs at the base of the skull "provide a direct route for the clearance of large molecules including toxic metabolites from the brain, which is impaired with aging," Cho tells Axios.

  • They found that in the older mice, dorsal mLVs showed faster deterioration and basal mLVs were enlarged and more numerous, but also showed fewer valves and some signs of disintegration.

What they're saying: Taija Mäkinen, of Uppsala University in Sweden, writes in an accompanying News and Views piece...

"[T]he identification of the precise exit routes for fluids leaving the brain is a crucial step towards understanding how waste is cleared from the CNS. This finding might eventually enable the development of therapies that promote CNS drainage to combat pathological processes in neurological diseases."

But, but, but: So far, the experiments have been done in animal models and the findings would have to be tested and confirmed in humans, Proulx says. "Until these studies are performed, I expect that clinicians will remain skeptical of this concept, as it is so radically different from what they have learned in medical school."

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