In honor of Dysautonomia Awareness Month, we are highlighting a new and trending area of research that could potentially explain some cognitive and fatigue symptoms in relation to dysautonomia in Sjögren's. Below, Dr. Brent Goodman describes the Glymphatic System and its role in nervous system diseases.
By: Brent P. Goodman, M.D.
Chief Medical Officer
Metrodora Institute
Did you know that the brain has its own waste management system called the glymphatic system? This recently described system may play a critical role in brain health and various nervous system diseases and injuries.
Overview
Most people are aware of the lymphatic system, which has important roles in immune function and in the transport of extracellular fluids from the body’s different tissues. The glymphatic system is a recently described system, hypothesized to function as the waste management system for the brain. Interest in this system has exploded in recent years, as investigators have explored its role in brain health, aging, and in various pathological conditions, including neurodegenerative diseases, vascular and traumatic brain injuries, headache disorders, and autoimmune central nervous system conditions.
Up until recently, it has been believed that the lymphatic system did not exist within the brain, and that clearance of debris and metabolites from the brain occurred through other mechanisms. In 2012, a multi-center investigator group reported that cerebrospinal fluid (CSF) entered brain tissue (parenchyma) and mixed with another type of fluid— interstitial fluid— and subsequently drained out of the brain, carrying with it important substances (Iliff 2012). This “waste” fluid ultimately drains into the peripheral lymphatic system. Precise mechanisms responsible for fluid movement through this system are still being elucidated. It has been proposed that the mechanics of respiration, arterial pulsations, and other independent, spontaneous oscillations of blood vessels drives CSF into and through brain tissue, towards the venous system. In 2015 another landmark observation, identified the presence of lymphatic vessels in the meninges (membranes) surrounding the brain (Aspelund 2015; Louveau 2015), and it is now thought that multiple substances drain into these vessels or possibly through cranial or spinal nerves.
Important Components of the Glymphatic System
In order to understand the glymphatic system, it is helpful to understand the fluid components of the brain, brain barriers, and the important structural components of this system (see Figure 1). There are four fluid components in the brain, including: cerebrospinal fluid, interstitial fluid, intracellular fluid, and blood. As noted above, glymphatic system function relies on cerebrospinal fluid entering brain tissue and mixing with interstitial fluid, prior to exiting the brain into the external lymphatics. Interstitial fluid is produced via filtration of plasma in cerebrovascular endothelial cells, while cerebrospinal fluid is continuously produced by choroid plexus lining the ventricles of the brain. In addition to playing a critical role in glymphatic function, cerebrospinal fluid provides protective cushioning for the brain, buffers pH (acidity), maintains important chemical gradients, and distributes neurotrophic growth factors (small proteins that support the growth, survival, and differentiation of neurons). The transport of cerebrospinal fluid into brain parenchyma relies on aquaporin 4 water channels that are attached to astrocytic end feet (see Figure 2).
Figure 1: The cranial meninges, including the dura mater, arachnoid mater, pia mater, and parenchyma. Created in BioRender. Cox, K. (2024) BioRender.com. © Sjögren's Foundation
Figure 2: The glymphatic system flow and mixing of CSF-ISF in the brain parenchyma. Created in BioRender. Cox, K. (2024) BioRender.com. © Sjögren's Foundation
A number of different substances have been demonstrated to be cleared by the glymphatic system. These substances include potassium and lactate, peptides and proteins that cause disease such as amyloid beta and tau, and proteins from damaged neurons. It has also been suggested that the glymphatic system may play a role in the transmission of neuromodulators and diffusion of growth factor through the central nervous system. The glymphatic system may also play a key role in the removal of inflammatory cytokines, which play an important role in immune function. There is increasing interest in the role of the glymphatic system in central nervous system immune surveillance and potential interactions with immune cells and other immune system functioning outside of the nervous system.
Regulation of the Glymphatic System
Glymphatic system function is carefully regulated, with the sleep-wake cycle playing a critical role in glymphatic system processes. Movement of cerebrospinal fluid and clearance of substances through the glymphatic system is significantly increased during sleep. Glymphatic function appears to be most rapid and efficient during slow wave sleep. Mechanisms responsible for differences of glymphatic functioning related to sleep and wakefulness have not yet been fully elucidated, but the sympathetic component of the autonomic nervous system appears to be play an important role. Activation of the sympathetic or “fight or flight” component of the autonomic nervous system is thought to reduce glymphatic function, and less sympathetic nervous system activation during sleep appears to facilitate glymphatic functioning. Additionally, it has been hypothesized that less synchronous neuronal activity characteristic of wakefulness results in a less porous brain that has greater resistance to fluid flow and ultimately, reduced clearance of substances via the glymphatic system. Conversely, synchronous neuronal activity during sleep may be associated with a more porous brain that may be more conducive to fluid movement and clearance of substances from the brain during sleep. Mouse models have demonstrated that extracellular space expands during sleep, facilitating fluid movement through the glymphatic system, while cellular expansion and reduction of the volume of extracellular space during wakefulness is thought to reduce glymphatic function.
Role of the Glymphatic System in Neurological Diseases, Aging, and Brain Injury
The role of the glymphatic system in various neurological diseases is an area of active investigation. Neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, and Dementia with Lewy bodies are characterized pathologically by the accumulation of waste proteins within the brain. Amyloid beta plaques and tau protein aggregate (clump together) and accumulate in Alzheimer’s disease, and alpha-synuclein aggregates in Parkinson’s Disease and Dementia with Lewy Bodies, leading to progressive neurological deterioration. The glymphatic system appears to play an important role in the clearance of these waste proteins, preventing or limiting their aggregation and accumulation. Not surprisingly, potential mechanisms for enhancing glymphatic function to minimize accumulation of these waste proteins and decrease the likelihood of developing these neurodegenerative diseases is an area of active research. Age, for reasons not currently understood, is associated with reduced glymphatic functioning. Mouse models have demonstrated that glymphatic function is reduced 80-90% in old versus young mice. Several factors have hypothesized to account for the reduction of glymphatic function with aging such as, decreased cerebrospinal fluid production with aging, increased arterial stiffness, reduced cerebrospinal fluid pressure, reactive astrocytes, and structural changes to aquaporin 4. Neuroimaging studies have demonstrated a larger amyloid beta burden in individuals with longstanding sleep disruption and shorter sleep duration. Furthermore, cerebrospinal fluid amyloid beta concentration has been demonstrated to be lowest during sleep, and higher during wakefulness. Other studies have also demonstrated higher levels of amyloid beta and tau in individuals with longstanding histories of shorter sleep duration. Mouse models of Parkinson’s disease have demonstrated reduced accumulation of pathogenic alpha-synuclein in animals with pharmacologically-enhanced slow wave sleep (Morawska 2021). There is evidence of disrupted glymphatic function following traumatic brain injury. Traumatic brain injury results in damage to the blood brain barrier, activation of an inflammatory response, activation of excitatory neurotransmitters, accumulation of astrocytes and microglia around the site of injury, and accumulation of the waste proteins amyloid beta and tau. Mouse models of mild traumatic brain injury have demonstrated reduced uptake of gadolinium (a contrast used during an MRI) into the glymphatic system and brain parenchyma and prolonged glymphatic clearance times. Mouse traumatic brain injury models have demonstrated decreased expression of aquaporin-4 along with structural changes to astrocytes. Sleep disruption, known to be common in traumatic brain injury, might also play a role in reduced glymphatic function.
Glymphatic System and Dysautonomia in Sjögren’s
The autonomic nervous system plays a key role in glymphatic system regulation. Sympathetic nervous system activation reduces glymphatic clearance, while parasympathetic activation enhances glymphatic function. Mouse models have demonstrated that blockage of adrenergic (sympathetic) receptors enhances cerebrospinal fluid flow into brain parenchyma, thereby increasing glymphatic function. Vagal nerve stimulator implantation, which activates parasympathetic function, has been shown in mouse models to improve glymphatic function. It is reasonable to hypothesize that various autonomic nervous system disorders or dysautonomia, may result in abnormal glymphatic function. Sjögren’s disease, which has a predilection for causing dysautonomia of varying severity and type, presumably could result in disrupted glymphatic function either through over-activation of sympathetic pathways (hyperadrenergic form of dysautonomia), or impairment of parasympathetic function. Further research is necessary to determine whether these mechanisms have relevance to cognitive symptoms (i.e. “brain fog”) reported by many individuals with Sjögren’s disease.
It is at this point unclear whether or how systemic autoimmune conditions affect the glymphatic system directly, or whether the glymphatic system plays a significant role in the development of systemic autoimmune disorders or their manifestations. The presence of enlarged perivascular spaces (small fluid-filled structures that surround blood vessels in the brain) has been reported to correlate with inflammatory activity in patients with Lupus (Miyata 2017). It has also been demonstrated that peripheral systemic disease can activate inflammatory processes in the brain through activation of neurons in the medulla and hypothalamus via the vagus nerve, and peripheral inflammatory cells may reach the brain directly through a damaged blood brain barrier. It is not known whether disordered (or enhanced) glymphatic function influences peripheral, systemic, autoimmune diseases.
To summarize, the glymphatic system is a recently described system that:
- Is hypothesized to be responsible for clearance of waste substances from the brain; similar to the lymphatic system elsewhere in the body.
- Primarily functions during sleep.
- Declines in function with age.
- Is suppressed by sympathetic nervous system activation.
- Is likely responsible for limiting the aggregation and accumulation of proteins that are responsible for the development of neurodegenerative diseases such as Alzheimer’s disease.
- Is modulated by autonomic nervous system function.
References
- Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., et al. (2012). A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111. doi: 10.1126/scitranslmed.3003748
- Aspelund A, Antila S, Proulx ST, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules J. Exp. Med., 212 (2015), pp. 991-999.
- Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature, 523 (2015), pp. 337-341.
- M.M. Morawska, C.G. Moreira, V.R.Ginde, et al. Slow-wave sleep affects synucleinopathy and regulates proteostatic processes in mouse models of Parkinson’s disease. Sci. Transl. Med., 13 (2021), p. eabe7099,
- Miyata M, Kakeda S, Iwata S, Nakayamada S, Ide S, Watanabe K, Moriya J, Tanaka Y, Korogi Y (2017) Enlarged perivascular spaces are associated with the disease activity in systemic lupus erythematosus. Sci Rep. 7:12566
In honor of Dysautonomia Awareness Month, we are highlighting a new and trending area of research that could potentially explain some cognitive and fatigue symptoms in relation to dysautonomia in Sjögren's. Below, Dr. Brent Goodman describes the Glymphatic System and its role in nervous system diseases.
By: Brent P. Goodman, M.D.
Chief Medical Officer
Metrodora Institute
Did you know that the brain has its own waste management system called the glymphatic system? This recently described system may play a critical role in brain health and various nervous system diseases and injuries.
Overview
Most people are aware of the lymphatic system, which has important roles in immune function and in the transport of extracellular fluids from the body’s different tissues. The glymphatic system is a recently described system, hypothesized to function as the waste management system for the brain. Interest in this system has exploded in recent years, as investigators have explored its role in brain health, aging, and in various pathological conditions, including neurodegenerative diseases, vascular and traumatic brain injuries, headache disorders, and autoimmune central nervous system conditions.
Up until recently, it has been believed that the lymphatic system did not exist within the brain, and that clearance of debris and metabolites from the brain occurred through other mechanisms. In 2012, a multi-center investigator group reported that cerebrospinal fluid (CSF) entered brain tissue (parenchyma) and mixed with another type of fluid— interstitial fluid— and subsequently drained out of the brain, carrying with it important substances (Iliff 2012). This “waste” fluid ultimately drains into the peripheral lymphatic system. Precise mechanisms responsible for fluid movement through this system are still being elucidated. It has been proposed that the mechanics of respiration, arterial pulsations, and other independent, spontaneous oscillations of blood vessels drives CSF into and through brain tissue, towards the venous system. In 2015 another landmark observation, identified the presence of lymphatic vessels in the meninges (membranes) surrounding the brain (Aspelund 2015; Louveau 2015), and it is now thought that multiple substances drain into these vessels or possibly through cranial or spinal nerves.
Important Components of the Glymphatic System
In order to understand the glymphatic system, it is helpful to understand the fluid components of the brain, brain barriers, and the important structural components of this system (see Figure 1). There are four fluid components in the brain, including: cerebrospinal fluid, interstitial fluid, intracellular fluid, and blood. As noted above, glymphatic system function relies on cerebrospinal fluid entering brain tissue and mixing with interstitial fluid, prior to exiting the brain into the external lymphatics. Interstitial fluid is produced via filtration of plasma in cerebrovascular endothelial cells, while cerebrospinal fluid is continuously produced by choroid plexus lining the ventricles of the brain. In addition to playing a critical role in glymphatic function, cerebrospinal fluid provides protective cushioning for the brain, buffers pH (acidity), maintains important chemical gradients, and distributes neurotrophic growth factors (small proteins that support the growth, survival, and differentiation of neurons). The transport of cerebrospinal fluid into brain parenchyma relies on aquaporin 4 water channels that are attached to astrocytic end feet (see Figure 2).
Figure 1: The cranial meninges, including the dura mater, arachnoid mater, pia mater, and parenchyma. Created in BioRender. Cox, K. (2024) BioRender.com. © Sjögren's Foundation
Figure 2: The glymphatic system flow and mixing of CSF-ISF in the brain parenchyma. Created in BioRender. Cox, K. (2024) BioRender.com. © Sjögren's Foundation
A number of different substances have been demonstrated to be cleared by the glymphatic system. These substances include potassium and lactate, peptides and proteins that cause disease such as amyloid beta and tau, and proteins from damaged neurons. It has also been suggested that the glymphatic system may play a role in the transmission of neuromodulators and diffusion of growth factor through the central nervous system. The glymphatic system may also play a key role in the removal of inflammatory cytokines, which play an important role in immune function. There is increasing interest in the role of the glymphatic system in central nervous system immune surveillance and potential interactions with immune cells and other immune system functioning outside of the nervous system.
Regulation of the Glymphatic System
Glymphatic system function is carefully regulated, with the sleep-wake cycle playing a critical role in glymphatic system processes. Movement of cerebrospinal fluid and clearance of substances through the glymphatic system is significantly increased during sleep. Glymphatic function appears to be most rapid and efficient during slow wave sleep. Mechanisms responsible for differences of glymphatic functioning related to sleep and wakefulness have not yet been fully elucidated, but the sympathetic component of the autonomic nervous system appears to be play an important role. Activation of the sympathetic or “fight or flight” component of the autonomic nervous system is thought to reduce glymphatic function, and less sympathetic nervous system activation during sleep appears to facilitate glymphatic functioning. Additionally, it has been hypothesized that less synchronous neuronal activity characteristic of wakefulness results in a less porous brain that has greater resistance to fluid flow and ultimately, reduced clearance of substances via the glymphatic system. Conversely, synchronous neuronal activity during sleep may be associated with a more porous brain that may be more conducive to fluid movement and clearance of substances from the brain during sleep. Mouse models have demonstrated that extracellular space expands during sleep, facilitating fluid movement through the glymphatic system, while cellular expansion and reduction of the volume of extracellular space during wakefulness is thought to reduce glymphatic function.
Role of the Glymphatic System in Neurological Diseases, Aging, and Brain Injury
The role of the glymphatic system in various neurological diseases is an area of active investigation. Neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, and Dementia with Lewy bodies are characterized pathologically by the accumulation of waste proteins within the brain. Amyloid beta plaques and tau protein aggregate (clump together) and accumulate in Alzheimer’s disease, and alpha-synuclein aggregates in Parkinson’s Disease and Dementia with Lewy Bodies, leading to progressive neurological deterioration. The glymphatic system appears to play an important role in the clearance of these waste proteins, preventing or limiting their aggregation and accumulation. Not surprisingly, potential mechanisms for enhancing glymphatic function to minimize accumulation of these waste proteins and decrease the likelihood of developing these neurodegenerative diseases is an area of active research. Age, for reasons not currently understood, is associated with reduced glymphatic functioning. Mouse models have demonstrated that glymphatic function is reduced 80-90% in old versus young mice. Several factors have hypothesized to account for the reduction of glymphatic function with aging such as, decreased cerebrospinal fluid production with aging, increased arterial stiffness, reduced cerebrospinal fluid pressure, reactive astrocytes, and structural changes to aquaporin 4. Neuroimaging studies have demonstrated a larger amyloid beta burden in individuals with longstanding sleep disruption and shorter sleep duration. Furthermore, cerebrospinal fluid amyloid beta concentration has been demonstrated to be lowest during sleep, and higher during wakefulness. Other studies have also demonstrated higher levels of amyloid beta and tau in individuals with longstanding histories of shorter sleep duration. Mouse models of Parkinson’s disease have demonstrated reduced accumulation of pathogenic alpha-synuclein in animals with pharmacologically-enhanced slow wave sleep (Morawska 2021). There is evidence of disrupted glymphatic function following traumatic brain injury. Traumatic brain injury results in damage to the blood brain barrier, activation of an inflammatory response, activation of excitatory neurotransmitters, accumulation of astrocytes and microglia around the site of injury, and accumulation of the waste proteins amyloid beta and tau. Mouse models of mild traumatic brain injury have demonstrated reduced uptake of gadolinium (a contrast used during an MRI) into the glymphatic system and brain parenchyma and prolonged glymphatic clearance times. Mouse traumatic brain injury models have demonstrated decreased expression of aquaporin-4 along with structural changes to astrocytes. Sleep disruption, known to be common in traumatic brain injury, might also play a role in reduced glymphatic function.
Glymphatic System and Dysautonomia in Sjögren’s
The autonomic nervous system plays a key role in glymphatic system regulation. Sympathetic nervous system activation reduces glymphatic clearance, while parasympathetic activation enhances glymphatic function. Mouse models have demonstrated that blockage of adrenergic (sympathetic) receptors enhances cerebrospinal fluid flow into brain parenchyma, thereby increasing glymphatic function. Vagal nerve stimulator implantation, which activates parasympathetic function, has been shown in mouse models to improve glymphatic function. It is reasonable to hypothesize that various autonomic nervous system disorders or dysautonomia, may result in abnormal glymphatic function. Sjögren’s disease, which has a predilection for causing dysautonomia of varying severity and type, presumably could result in disrupted glymphatic function either through over-activation of sympathetic pathways (hyperadrenergic form of dysautonomia), or impairment of parasympathetic function. Further research is necessary to determine whether these mechanisms have relevance to cognitive symptoms (i.e. “brain fog”) reported by many individuals with Sjögren’s disease.
It is at this point unclear whether or how systemic autoimmune conditions affect the glymphatic system directly, or whether the glymphatic system plays a significant role in the development of systemic autoimmune disorders or their manifestations. The presence of enlarged perivascular spaces (small fluid-filled structures that surround blood vessels in the brain) has been reported to correlate with inflammatory activity in patients with Lupus (Miyata 2017). It has also been demonstrated that peripheral systemic disease can activate inflammatory processes in the brain through activation of neurons in the medulla and hypothalamus via the vagus nerve, and peripheral inflammatory cells may reach the brain directly through a damaged blood brain barrier. It is not known whether disordered (or enhanced) glymphatic function influences peripheral, systemic, autoimmune diseases.
To summarize, the glymphatic system is a recently described system that:
References