Nasopharyngeal lymphatic vessels discovered to be critical for cerebrospinal fluid outflow

A new study finds that the "lymphatic plexus" behind the nose that drains cerebrospinal fluid from the brain may have an impact on neurodegenerative diseases.

In a groundbreaking study (cover article) recently published in the journal Nature, researchers led by KOH Gou Young, director of the Vascular Research Center at the Institute for Basic Science (IBS) in Korea, found that , there is a unique lymphatic network in the back of the nose, which plays a key role in draining cerebrospinal fluid (CSF). The study reveals a previously unknown pathway for cerebrospinal fluid outflow, potentially opening new avenues for understanding and treating neurodegenerative diseases.

The research was published in the magazine "Nature" on January 10, 2024 (latest impact factor: 64.8)

In our brains, waste products from metabolic activity are excreted through the cerebrospinal fluid. Waste products that accumulate in the brain, if not removed properly, can damage nerve cells, leading to impaired cognitive function, dementia, and other neurodegenerative diseases. Therefore, the regulation of cerebrospinal fluid production, circulation and drainage has been a focus of scientific attention, especially in relation to age-related diseases such as Alzheimer's disease and other neurodegenerative diseases.

The brain produces approximately 500 ml of this fluid every day, which drains from the subarachnoid space. Among the known drainage pathways are the lymphatic vessels surrounding the cranial nerves and the upper nasal cavity area. Although there is good evidence that lymphatics contribute to cerebrospinal fluid clearance, determining the exact anatomical connection between the subarachnoid space and extracranial lymphatics remains a challenge due to their extremely complex structure.

Koh's team addressed this problem by using genetically modified mice with fluorescent markers for lymphocytes, microsurgery, and advanced imaging techniques. Their efforts revealed a detailed network of lymphatic vessels in the back of the nose, which is a major hub for the outflow of cerebrospinal fluid to deep cervical lymph nodes. These lymphatic vessels have unique characteristics, including abnormally shaped valves and short lymphatic vessels.

Lead researcher JIN Hokyung emphasized: "Our study identified the nasopharyngeal lymphatic plexus as a hub for cerebrospinal fluid outflow. cerebrospinal fluid from specific cranial regions flows to deep cervical lymph nodes in the neck through these lymphatic vessels. This finding may have important implications for the understanding and treatment of cerebrospinal fluid outflow. Blockage-related diseases have important implications."

The study also showed that drug activation of deep cervical lymph nodes enhanced cerebrospinal fluid drainage in mice. The researchers were able to successfully modulate cervical lymphatics using either phenylephrine (which activates α1-adrenergic receptors, causing smooth muscle contraction) or sodium nitroprusside (which releases nitric oxide, causing muscle relaxation and blood vessel dilation). Importantly, this feature is preserved during aging, even in the presence of atrophy and functional impairment of the nasopharyngeal lymphatic plexus.

"Deep cervical lymphatic vessels remain intact with age, providing a potential target for therapeutic intervention aimed at improving CSF outflow in individuals with compromised brain health," said YOON Jin-Hui, co-first author of the study. "

However, this effort also faces some challenges. To expose lymphatic vessels in mice, deep anesthesia and removal of neck muscles are required. These delicate surgeries themselves alter the physiological dynamics of cerebrospinal fluid drainage, because cerebral blood flow and blood pulsations in blood vessels contribute to cerebrospinal fluid circulation, which in turn affects cerebrospinal fluid outflow.

Additionally, while the imaging techniques used were informative, the researchers believe that more advanced imaging methods in live animals, such as synchrotron X-ray imaging, may reveal more dynamic features of cerebrospinal fluid drainage under physiological conditions.

Three-dimensional morphological characteristics of the nasopharynx and retronasal lymphatic plexus

"We plan to validate all findings obtained from mice in primates, including monkeys and humans," said KOH Gou Young, director of the IBS Vascular Research Center. "We aim to study in reliable animal models whether by pharmacological or mechanical means Activating lymphatic vessels in the neck to see if Alzheimer's disease progression can be prevented by improving cerebrospinal fluid clearance."

Korea Institute of Basic Science founded in 2011