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About The Glymphatic System
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How Does The Glymphatic System Work? How Does MS Affect The Lymphatic System?
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Glymphatic System In Brain Inflammation, Autoimmunity (MS) and Neurodegeneration
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Key Factors That Influence The Glymphatic System
I.About The Glymphatic System
Does brain have lymphatic system? Up until a few years ago, science/modern medicine told us that the brain has not lymphatic vessels. That didn’t make too much sense, considering the facts:
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lymphatic system has three key roles: bring nutrients to the cells, acts as a detox (eliminate excess fluids, toxins and damaged cells) and regulates the immune system
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the brain needs more lymphatics than any other body’s tissue. It uses a lot of energy (a lot more energy compared with other organs), and therefore generates a lot of waste products, too. It also works closely with the immune system (in fact most brain cells are immune cells, not neurons).
Although there were some past experiments supporting the fact that brain may have a lymphatic system, it was officially discovered and described [1] by Dr. Maiken Nedergaard, MD in 2012. The glymphatic system clears waste compounds from the brain, in a similar manner the lymphatic system removes waste from the rest of the body, while bringing more nutrients to the brain cells.
Why is called this way ? “glymphatic” comes from glial cells (the brain cells that support neurons) + the lymphatic system that it mimics.
Pay extra attention to it if you have any brain condition (from depression, to seizures, MS, Parkinson’s or Alzheimer’s disease)- as more damaged cells and waste products are generated compared to a healthy brain. In fact, a dysfunctional glymphatic system may play a key role in the development of these conditions.
How does the glymphatic system work? The glymphatic system works (differently) than the lymphatic system (I wrote about it here and how to improve it naturally here). Are there lymph nodes in the brain? No, the glymphatic system does not have lymph nodes. The brain has no lymph, but has cerebrospinal fluid (CSF) instead. It is connected downstream to an authentic lymphatic system (associated with the meninges, cranial nerves, and large vessels exiting the skull). The waste products are cleared via lymphatic vessels of the neck [2]. For more technical details click here to see how does the glymphatic system work– details about both the glymphatic system and the “conventional” lymphatics in the brain.
II. What does the Glymphatic system do? Glymphatic system functions:
1.Brain detox: helps eliminate waste products from the central nervous system.
2.Helps distribute nutrients (ie glucose, lipids, amino acids), neurotransmitters (and more) to the brain. Also maintains electrolytic environment of the central nervous system and influences systemic acid-base balance.
3. Protective Role
4.Regulates the immune system
1.Waste products elimination. Glymphatic system acts as a self-cleaning, brain detox system. CSF helps remove from the brain a variety of substances: damaged, degenerated cells, metabolic waste products like amyloid beta (Aβ) protein and tau proteins (these two accumulate in excess in neurodegenerative conditions such as Alzheimer’s MS, and Parkinson’s disease [3],[4],[5]). Certain drugs are also eliminated via glymphatic system [6].
2.Nutrient distribution (lipids, proteins, glucose, vitamins and minerals, etc)
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A note on lipids. Lipids are essential to the brain structure and function. The human brain weighs 2% of the body’s total weight yet contains 25% of the cholesterol in the human body. Most of the cholesterol is in the myelin sheaths. Cholesterol is part of the membranes the surround each cell, acts as an antioxidant and also as a raw material to make vitamin D and hormones (ie progesterone, estrogen, testosterone and cortisol). Low cholesterol levels correlate with depression (and even death), while health levels of cholesterol are associated with better memory. Abnormal cholesterol metabolism had been linked with neurological problems, particularly MS and Alzheimer’s disease [7],[8]. One may think that eating healthy fats is enough to keep your brain healthy. However, research shows that the brain synthesizes its own cholesterol [9]. In addition, healthy astrocytes(brain cells) and a healthy glymphatic system is needed to distribute those fats properly in the brain. Technical: Like the liver, brain cells depend on HMG-CoA reductase to produce cholesterol. Astrocytes play a key role in lipid synthesis and lipid distribution by releasing lipid carrier proteins (ie Apolipoprotein E) and in maintaining the highway for distribution, the glymphatic system [10],[11].
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A note on glucose and proteins (amino acids). They are also important for brain health. The insulin resistance in the brain (seen in MS and other neurodegenerative conditions) and neurotransmitter imbalances (seen in MS and other neurodegenerative conditions) could potentially be caused by an impairment along the glymphatics. I wrote about MS-sugar metabolism problems here and many articles on neurotransmitters here. Glymphatic system dysfunctions are seen in MS and other brain conditions Slow lymphatic flow and clearance seems to be a key problem in Alzheimer’s disease as well.[12]The accumulation of waste materials (ie amyloid beta) further aggravate the glymphatic congestion, so it really is a vicious cycle.
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There are other nutrients carried out by the CSF. In addition to glucose, proteins and amino acids, CSF contains micro nutrients (vitamins and minerals) CSF forms a medium through which a diffusion of a various molecules (ie. neurotransmitters, hormones) takes place.
3. Protective role. CSF also has protective roles
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acts as a shock absorber, protecting the brain from sudden changes in pressure or temperature.
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CSF protects against infections as it contains immune cells (ie leukocytes, immunoglobulins). The normal volume of CSF is around 150 mls. The same way the lymph can accumulate and cause lymphedema, CSF can accumulate pathologically and cause hydrocephalus [13].
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Regarding CSF, there are two major changes as we age: its volume and flow. The CSF volume is significantly increased (even more after the 6th decade). The CSF flow, however, is decreased. There is a natural increase in CSF volume as part of the aging process, with a significant increased in volume after the 6th decade. Scientists believe that the CSF volume increases because the brain volume decreases, sort of compensatory mechanism [14]. This concept would support Monroe-Kelly’s doctrine: intracranial space volume remains constant and its individual components (blood, CSF and the nervous tissue) exist in a state of volume equilibrium. An increase in one component will correlate with a decrease in one or the other 2 [15]. I think CSF is doing more than just keeping the volume in balance. The body is trying to compensate the aging process because more CSF means more nutrients and more detox to the brain. The problem is that the CSF flow is decreasing with age, so improving the CSF flow could help prevent and even manage neurodegeneration and inflammation.
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How does MS affect the lymphatic system? The lymphatic flow seems to be decreased in MS and there are more waste (toxic) substances accumulated in the brain. There are changes in the composition of CSF as well, as CSF studies can support a diagnosis of demyelinating disease like MS [16]. Technical: Studies found an increase in Ig concentrations in more than 90% of people with MS. IgG index (a comparison between IgG levels in the CSF and in the serum) is elevated in many with MS. Oligoclonal Immunoglobulin Bands are also identified in the CSF of MS patients (via electrophoresis). The overall protein level is also slightly increased – up to 0.1 g/L. Protein level can be higher during a marked relapse. A slight elevation in cell count (up to 50 per cubic millimeter) can be seen sometimes. Most cells are T-lymphocytes [17].The deep cervical lymph nodes also seem to be affected in MS, and seem to work harder- they are larger compared with the lymph nodes in healthy people [18].
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Regulation of the immune system
It is well-known that the brain is the major organ of the nervous system. But did you know that the brain has more immune cells than neurons? There are neurons and non-neuronal cells (glial cells like microglia and astrocytes, which are immune cells that become overactive in neuroinflammation). The nervous system and the immune system are closely connected. The glymphatic system helps regulate the immune system. CSF contains T cells, which are key cells of the immune system. Recent studies even looked under the microscope to see live the traffic of these immune cells between the CSF and nervous tissue, exploring the role of CSF in MS [19],[20],[21],[22].
source: wikimedia commons
III. Glymphatic system in brain inflammation, autoimmunity (MS) and neurodegeneration
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One study found a significant decrease in glymphatic activity for almost one month following a head trauma (can be repeated injuries such those experienced by athletes, or a single moderate-severe head injury). Beside decreased function of the lymphatic system, there is also scar tissue made up of glial cells. On the other hand, a mild stroke will cause a very short drop in glymphatic activity (resolves within 24 hours) [23].This means that the lymphatic system in the brain is sensitive to acute inflammation as well (not just the low grade chronic inflammation seen in neurodegeneration)
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Decreased activity of the glymphatic system lead to accumulation of toxic waste products and dead cells, etc. One study suggests glymphatic system impairment associated with MS [24].
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Glymphatic system works closely with the blood brain barrier transport- and glymphatic system malfunctions correlate with BBB impairments- as seen in neurodegenerative conditions [25].
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Glymphatic system dysfunction in neurodegenerative diseases.It seems that an impaired lymphatic system in the brain play a role in the accumulation of proteins (sometimes in the form of amyloid plaques and tau tangles characteristic to Alzheimer’s, but overall these abnormal accumulation of proteins is seen in all neurodegenerative conditions). In normal conditions, these proteins are cleared by glymphatic system. Technical: paravascular glymphatic pathway driven by AQP4-dependent bulk flow constitutes a major clearance pathway of interstitial fluid solutes from the brain’s parenchyma [26].
IV. There are many factors that influence the glymphatic system. Some of the most important to consider, in my opinion, are:
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Sleep-awake cycle
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The health of the brain tissue (particularly astrocytes and neurons) and blood vessels
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Stress (emotional, chemical, physical stress)
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Aging process