More Support for Impaired Drainage Theories of Neurodegenerative Disease

There is increasing evidence to suggest that one of the contributing causes of neurodegenerative conditions such as Alzheimer's disease is the failure of drainage of cerebrospinal fluid. Metabolic wastes such as misfolded amyloid and hyperphosphorylated tau are no longer carried from the brain rapidly enough as drainage becomes impaired, and thus build up to cause harm. Leucadia Therapeutics, shepherded by the Methuselah Fund, is focused on relieving the progressive failure of a path through the cribiform plate in the roof of the mouth. Other researchers, such as those here, are investigating drainage through the lymphatic system, which as we well know becomes impaired in a number of characteristic ways with advancing age. These are most likely two ways of looking at the same primary drainage paths.

Our brain swims. It is fully immersed in an aqueous liquid known as cerebrospinal fluid. Every day, the human body produces about half a litre of new cerebrospinal fluid in the cerebral ventricles; this liquid originates from the blood. This same quantity then has to exit the cranial cavity again every day. Researchers have now shown that in mice, the cerebrospinal fluid exits the cranial cavity through the lymph vessels. Past research has inadequately explained how cerebrospinal fluid exits the cranial cavity. Scientists knew that two paths were available - blood vessels and lymphatic vessels, but for a long time, and due due to insufficient research tools, they had assumed that drainage through the veins was by far the predominant pathway.

The researchers have now been able to refute this assumption. They injected tiny fluorescent dye molecules into the ventricles (cavities) of the brain in mice and observed how these molecules exited the cranial cavity. They used a sensitive non-invasive imaging technique to examine the blood vessels in the periphery of the animals' bodies, as well as the lymphatic and blood vessels directly draining the skull. It turned out that the dye molecules appeared after just a few minutes in the lymphatic vessels and lymph nodes outside the brain. The researchers were unable to find any molecules in blood vessels so quickly after the injection.

They were also able to determine the exact path of the dye molecules and thus the cerebrospinal fluid: it leaves the skull along cranial nerve sheaths - in particular around the olfactory and optic nerves. Once in tissue outside the brain, it is removed by the lymphatic vessels. The scientists are not entirely able to rule out whether a small portion of the cerebrospinal fluid also leaves the brain as previously assumed - through the veins. However, based on their research findings, they are convinced that the lion's share travels through the lymphatic system, and that the anatomy textbooks will have to be rewritten.

"The immune system eliminates toxins elsewhere in the body, but the brain is considered to be largely disconnected from this system. Only a few immune cells have access under normal conditions. The cerebrospinal fluid steps into the breach here. By constantly circulating, it flushes the brain and removes unwanted substances." This flushing function could offer a starting point for treatment of neurodegenerative diseases such as Alzheimer's. Alzheimer's is caused by misfolded proteins that accumulate in the brain. Researchers speculate that these misfolded proteins could be eliminated by, for example, drugs that induce lymphatic flow.



It would be interesting to know which, if any, of the seven classes of fundamental damage cause the drop in production of cerebrospinal fluid by cerebral ventricles with age?

With regard to Leucadia Therapeutics testing the hypothesis that Alzhiemers is just (or is largely) due to a decline in drainage, is there any news on their testing? Also, how are they going to test this in mice?

Once anti glucosepane antibodies are available for use as probes to detect glucosepane in vivo, I guess that examination of this part of the lymphatic system around the brain will be one of the first things examined.

Posted by: Jim at November 10th, 2017 11:46 AM

From a quick read of the scientific paper it seems the authors suggest the flow of cerebrospinal fluid drops with age due to a drop in production, not impaired drainage. So maybe the headline of this blog article is a bit misleading?

On the other hand, whatever is causing the drop in CSF production in the cerebral ventricles with age is probably the same underlying damage that could be affecting the lymphatic system and reducing outflow. So targeting the seven SRF damage types should alleviate it.But this situation would suggest that drugs/surgical interventions to improve flow won't do anything if the problem is a lack of CSF production. Maybe alzhiemers is like dry eye disease for the brain? I can't remember off the top of my head why the lactimal gland in the eye stops producing as much fluid with age, leading to dry eye disease.

Posted by: Jim at November 11th, 2017 7:01 AM
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