Interstitial Fluidopathy of the Central Nervous System: An Umbrella Term for Disorders with Impaired Neurofluid Dynamics

Abstract

Interest in interstitial fluid dynamics has increased since the proposal of the glymphatic system hypothesis. Abnormal dynamics of the interstitial fluid have been pointed out to be an important factor in various pathological statuses. In this article, we propose the concept of central nervous system interstitial fluidopathy as a disease or condition in which abnormal interstitial fluid dynamics is one of the important factors for the development of a pathological condition. We discuss the aspects of interstitial fluidopathy in various diseases, including Alzheimer’s disease, Parkinson’s disease, normal pressure hydrocephalus, and cerebral small vessel disease. We also discuss a method called “diffusion tensor image analysis along the perivascular space” using MR diffusion images, which is used to evaluate the degree of interstitial fluidopathy or the activity of the glymphatic system.

Dynamics of Cerebral Interstitial Fluid (ISF) and Cerebrospinal Fluid (CSF)

The term “last 1 mile” was originally used in the telecommunications industry to refer to “the last section of a telecommunications connection.” Today, it is often used in the logistics and transportation industries to refer to the last point of contact at which goods and services reach customers. In the brain, oxygen and glucose, which are necessary for tissue metabolism, are transported to the tissues by the blood. However, transportation in the last 100 micrometers between the blood-brain barrier (BBB) and the cells is made by the ISF. ISF is not only responsible for the supply of substances to tissues but also for the removal of waste products from tissues. The lymphatic system, which is the waste removal system in the body, is absent in the brain. In recent years, ISF in the brain has been considered to play a role similar to the lymphatic system. The glymphatic system hypothesis proposes the involvement of ISF and CSF in the elimination of waste products from tissues.¹ The glymphatic system is a term coined from a combination of glial cells and the lymphatic system. The glymphatic system hypothesis indicates that the CSF flows into the brain parenchyma through the perivascular space around the arteries and enters the interstitium of the brain tissue through water channels controlled by aquaporin 4 (AQP4). In the interstitium, the fluid washes away the waste products from the tissue, flows into the perivascular space around the veins, and finally drains out of the brain. Regarding the drainage of waste from tissues, another pathway via the arterial wall has been proposed and recently termed intramural periarterial drainage (iPAD) system.^2,3 Although there have been several arguments against the glymphatic system hypothesis, it is important to consider that ISF and CSF play important roles in maintaining brain function and homeostasis.

With the growing interest in the dynamics of ISF and CSF, there has been a movement to refer to all types of fluid in the intracranial space, including CSF, ISF, and blood, collectively as neurofluids and to evaluate their dynamics.⁴ In addition, the classical concept of CSF circulation, such as its production in the choroid plexus and absorption in the arachnoid granule, is being questioned. Although a new common agreement to replace it has not yet been established, several theories have been proposed. A recent hypothesis of CSF production is that it is predominantly produced by hydrostatic pressure from capillaries in the brain parenchyma as ISF.⁵ In addition to capillaries in the brain parenchyma, water migration from the ependymal tissue of the ventricles, the pia mater of the brain surface, and the perivascular space has been shown.^5,6 Figure 1 summarizes the anatomical structures related to the dynamics of CSF and ISF, the dynamics of water molecules as solvents in CSF and ISF, and the dynamics of solutes in CSF and ISF based on recent papers.^7–11

Fig. 1.

Structure and dynamics related to CSF and ISF. a. Structures associated with CSF and ISF. The perivascular space is a continuous space along blood vessels, with the basement membrane as the inner wall and glia limitans as the outer wall. The basement membrane and glia limitans, together with vascular endothelial cells and astrocyte peduncles, form the BBB, which protects the brain microenvironment by controlling the transport of molecules. b. Dynamics of water molecules as solvents in CSF and ISF. It has been suggested that CSF is mainly produced by capillaries in the brain, in addition to water movement from the ependymal tissue of the ventricles or pia mater of the brain surface. Cerebral ISF is integral to the CSF. These are thought to be the sources of CSF supply to the ventricles and cisterns.^5,6 There are no tight junctions in the pia mater, and water molecules and low-molecular-weight substances can easily move in both directions. The ependymal cells of the ventricles have tight junctions, but water molecules and other substances of low molecular weight can move in both directions.¹¹⁴ The choroid plexus, which is regarded as the main site of CSF production in classical CSF theory, is also involved in the production of CSF to some extent but its volume is approximately 1/100 of that produced by capillaries.¹¹⁵ CSF drains into venous and lymphatic systems. The passage of water in the venous system is bidirectional in both the ventricular walls and surface pia mater, and there is a rapid transfer of ISF and CSF, suggesting an indirect drainage pathway to the venous system through the ISF and capillary walls.⁶ c. Drainage pathways of solutes in CSF and ISF. According to the glymphatic system hypothesis, waste products produced in the brain tissue migrate toward the venous side of the capillaries and enter the perivascular space through the gap in the endfeet of astrocytes. The perivascular space is thought to be connected to the dural lymphatic system through the perivascular space of bridging veins.¹¹ A pathway via the arterial wall has been proposed, which is now known as the iPAD system.^2,3 In this pathway, soluble amyloid-β from the brain interstitium, along with ISF, enters the capillary artery wall and is transported up the artery through the basement membrane between the vascular smooth muscle cells. BBB, blood-brain barrier; CSF, cerebrospinal fluid; iPAD, intramural periarterial drainage; ISF, interstitial fluid.

The perivascular space is an important structure in the glymphatic system. The perivascular space is a continuous space along the blood vessels, with the basement membrane of the vessels as the inner wall and glia limitans as the outer wall. Among the elements associated with the perivascular space, the basement membrane and glia limitans form the BBB, along with vascular endothelial cells and the endfeet of astrocytes. Various immune cells migrate through the BBB into the interstitial space.¹² In other words, the perivascular space and CSF serve not only as a structure for the exchange of molecules but also as a structure for immune responses in brain tissue.¹³ The interstitial space of the brain accounts for 15%–20% of the total brain volume and contains ISF and extracellular matrix.¹⁴ ISF in the central nervous system (CNS) is produced by the BBB and serves as a medium for nutrient supply, waste removal, and intercellular communication.^8,14 The extracellular matrix, a component of the interstitial space, is a complex of polysaccharides and proteins found in the basement membrane and intercellular spaces.¹⁵ The basement membrane is composed of extracellular matrix proteins, including collagen IV, proteoglycans, and glycoproteins such as laminin; thus, disruption of these structures leads to abnormalities in ISF dynamics.

Central Nervous System Interstitial Fluidopathy

All the structures shown in Fig. 1 are related to the dynamics of the ISF. In particular, the function of various barriers, including the BBB, is important for maintaining tissue homeostasis in the brain. In general, the function of a membrane structure as a barrier is to allow essential substances to pass through quickly and to block other substances, such as large molecules. Impairment of this function results in protein leakage into the interstitium and impaired efflux of waste products. This leads to the accumulation of waste products, tissue dysfunction, and eventually conditions such as neuroinflammation. We have proposed the term “CNS interstitial fluidopathy” to describe diseases or conditions in which abnormalities in ISF dynamics are one of the important factors in the pathological process.¹⁶ The term “-pathy” is often used as an umbrella term for a group of diseases or as a concept that encompasses multiple diseases with a common mechanism or cause. Various diseases and conditions have been found to cause disturbances in ISF dynamics. Considering the aspects of ISF dynamics, it will facilitate the development of imaging and examination methods to elucidate pathophysiological mechanisms and aid in the development of novel methods to treat or prevent diseases. Alzheimer’s disease, Parkinson’s disease, stroke, small vessel disease (SVD), normal pressure hydrocephalus, and head trauma are diseases or conditions in which abnormalities in ISF dynamics have been reported to be important aspects of the pathogenesis.^1,17–20 Even in the absence of pathological conditions, imaging findings suggest that the barrier function of the vascular wall may be impaired owing to aging (Fig. 2)^9,21,22 which suggests that deterioration in ISF dynamics may be associated with aging.

Fig. 2.

Extravascular leakage of GBCA. Heavily T2-weighted FLAIR 4h after administration of GBCA (a: 40s, b: teens). Contrast leakage from veins on the surface of the brain into the surrounding CSF space is observed in most patients over 40 yrs of age but is not seen in younger patients, suggesting that the permeability of the vein wall changes with age. Reprinted by permission from reference #22. CSF, cerebrospinal fluid; FLAIR, fluid attenuated inversion recovery; GBCA, gadolinium-based contrast agent.

There is a controversy over whether abnormalities in ISF dynamics are a cause or a consequence of various disorders. Many researchers have considered this debate, and the general consensus is that the accumulation of abnormal waste products and ISF dynamics form a vicious cycle. One study suggested that the clearance of extracellular tau by ISF is a regulatory mechanism whose impairment contributes to tau aggregation and neurodegeneration.²³ Alzheimer’s disease is also thought to generate a vicious cycle in which amyloid β accumulation along the blood vessels impairs ISF dynamics, resulting in even more severe parenchymal accumulation of amyloid β and neuronal death.²⁴ Nedergaard, a proponent of the glymphatic system hypothesis, also states that waste proteins aggregate and obstruct flow, further promoting fibril polymerization through a vicious positive feedback cycle that inhibits glymphatic function and inflammation.²⁵

Evaluation Method for CNS Interstitial Fluid Dynamics

Several attempts have been made to evaluate and image the function of the glymphatic system. The first evaluation of the glymphatic system was carried out by a tracer study using two-photon laser microscopy of fluorescent tracers administered into the CSF space.¹ An early tracer study in animals using an MRI, which is a cross-sectional imaging technique, involves injecting a gadolinium-based contrast agent (GBCA) into the CSF space through the foramen magnum to observe signal changes in the brain parenchyma.^26,27 The evaluation of MRI using an intrathecally administered GBCA as a tracer has been reported in humans. Clinical findings have been reported in which relatively high doses of GBCA were intrathecally injected by accident,²⁸ or small doses of GBCA were systematically intrathecally injected for diagnostic purposes.^29,30 Each report showed GBCA penetration and influx from the surface of the brain to the cortex and deep brain parenchyma. There have been reports evaluating the decreased activity of the glymphatic system in normal pressure hydrocephalus using intrathecal GBCA as a tracer.^19,31 Intrathecal administration of GBCA is a direct method for evaluating glymphatic system dynamics. However, intrathecal administration of GBCA has not been approved in humans, making their use in clinical cases practically impossible.

Studies of intravenously injected GBCA have also been conducted. Heavily T2-weighted 3D-fluid attenuated inversion recovery (FLAIR) imaging approximately 4h after intravenous contrast injection can detect very small amounts of GBCA and is useful for the diagnosis of endolymphatic hydrops in Meniere’s disease.³² This technique simultaneously depicts the distribution of GBCA in other intracranial tissues. In a study, imaging of normal volunteers over time after intravenous GBCA administration was reported. In addition, contrast enhancement was detected using heavily T2-weighted 3D-FLAIR in the anterior eye segment, optic nerve sheath, Meckel’s cave, perilymph, CSF in the internal auditory canal, and CSF in the ambient cistern. The timing of maximum enhancement differed among locations.³³ The enhancement of the perivascular space at 4 h after intravenous GBCA administration was confirmed in human participants without renal insufficiency.³⁴ Tracer studies have also reported using T1-weighted contrast-enhanced MRI to evaluate intraparenchymal GBCA.³⁵ In this study, the Patlak method was applied to evaluate the BBB leakage rate, local blood plasma volume, and global BBB leakage in patients with early Alzheimer’s disease. Another study utilized serial intravenous contrast-enhanced T1 mapping.³⁶ In this study, T1 maps were acquired at baseline and several times until 12h after intravenous contrast material injection in healthy volunteers in day and night cycles. This study showed that clearance of a GBCA was greater after sleep than during daytime wakefulness.³⁶

Assessments using diffusion images have been attempted to evaluate the activity of the glymphatic system. The above-mentioned tracer studies attempted to evaluate the behavior of tracers after administration in an integral manner. In contrast, evaluation by diffusion imaging is different from tracer stidies because it evaluates the movement of water molecules in the tissue at the time of imaging. It may be possible to assess glymphatic system activity at any given time point. In 2017, diffusion tensor image analysis along the perivascular space (DTI-ALPS) was proposed as a method to assess water molecule movement in the deep white matter by using diffusion tensor images, assuming that diffusivity limited to the direction of the perivascular space reflects the function of the glymphatic system (Fig. 3).³⁷ This method calculates an index called the ALPS index, which evaluates the relative ratio of diffusivity in the direction of the perivascular space. In a test-retest study of normal volunteers, the ALPS index was robust under a fixed imaging protocol, even when different scanners from different vendors were used.³⁸ Because of the non-invasive nature of this technique, many studies have employed it as a method that can reflect the state of the interstitial fluid dynamics or glymphatic system.^37–78

Fig. 3.

Evaluation of ISF dynamics in AD by the DTI-ALPS method. Diffusion tensor images were taken from normal patients, patients with mild cognitive impairment, and patients with Alzheimer’s disease. The diffusivities in the x, y, and z directions (a–d) were measured in the regions of interest located in the projection fiber region (e), association fiber region (f), and subcortical region (g), respectively. In the projection and association fiber regions, diffusivity in the direction of the projection fibers (blue in the z-direction) and in the direction of the association fibers (green in the y-direction) were inversely correlated with the MMSE score and increased with the severity of Alzheimer’s disease. Whereas diffusivity in the direction of the perivascular space (red in the x-direction) correlated with the MMSE score and increased with the severity of Alzheimer’s disease. Assuming that diffusivity limited to the direction of the perivascular space reflects the function of the glymphatic system, the diffusivity in the direction of the perivascular space was evaluated by the ratio of the diffusivity in the perivascular space to the diffusivity in the direction orthogonal to the direction of travel of the perivascular space and main white matter fibers (ALPS index). “ALPS index” = “mean (Dxxproj, Dxxassoc)”/“mean (Dyyproj, Dzzassoc). The ALPS index was significantly inversely correlated with the MMSE score (h), suggesting that the ALPS index may be an indicator of glymphatic system function. Reprinted by permission from reference #37. AD, Alzheimer’s disease; DTI-ALPS, diffusion tensor image analysis along the perivascular space; ISF, interstitial fluid.

Alzheimer’s Disease as a CNS Interstitial Fluidopathy

Amyloid beta is an abnormal protein associated with Alzheimer’s disease. Aggregates of amyloid-β form amyloid plaques between cells and contribute to disease progression. The first paper to propose the glymphatic system hypothesis by Iliff et al.¹ also evaluated disorders in amyloid-β efflux in healthy and AQP4 knockout mice. Evaluation of the time course of amyloid-β efflux after direct injection into brain tissue showed delayed efflux in AQP4 knockout mice. This suggests that the glymphatic system, including the AQP4 water channels, is involved in amyloid-β efflux. It was also reported that intrathecal amyloid-β administration delayed the migration of amyloid-β in the brain of a mouse model of Alzheimer’s disease.⁷⁹ Accumulation of amyloid-β may lead to dysfunction of the glymphatic system that in turn leads to further accumulation of amyloid-β, and this vicious cycle may occur in tissues. It has also been reported that administration of TGN-020, an inhibitor of AQP4, also inhibits tau protein efflux.⁸⁰

Fewer studies have examined the relationship between Alzheimer’s disease and the glymphatic system in humans. Evaluation of positron emission tomography imaging using 11C-Pittsburgh Compound-B (PiB), an amyloid imaging tracer, has shown that patients with Alzheimer’s disease have altered CSF dynamics. The altered CSF dynamics suggests a possible imbalance between amyloid-β production and efflux, which may cause an imbalance in amyloid-β production and discharge.⁸¹ Amyloid imaging in humans using 18F-florbetaben as a tracer showed an increased accumulation of amyloid-β after a night of sleep deprivation.⁸² As discussed above, GBCA are often used to evaluate the glymphatic system in animal studies. However, in humans, intrathecal administration of GBCA has not been approved because of its potential for serious side effects. Therefore, there are only a few reports of intrathecal tracer studies of intrathecal administration and no studies on its use in Alzheimer’s disease. As an alternative to invasive evaluation using intrathecal tracers, which is particularly difficult in clinical practice, non-invasive evaluation methods, such as diffusion imaging, are being explored. As mentioned above, the DTI-ALPS method has been proposed as a non-invasive method for glymphatic system evaluation. The ALPS index was significantly inversely correlated with the Mini Mental State Examination (MMSE) score. In addition, the ALPS index was significantly correlated with age in evaluations of normal participants, mildly cognitively impaired patients, and patients with Alzheimer’s disease.³⁷

Parkinson’s Disease as a CNS Interstitial Fluidopathy

Parkinson’s disease is known as α-synucleinopathy. Previously, abnormal protein accumulation has been thought to occur independently in individual cells. Recently, a pathological mechanism has been proposed in which abnormal proteins propagate along nerve fibers in a prion-like manner and spread to the surrounding cells (α-synuclein propagation). α-synuclein pathology may spread from the gastrointestinal tract and olfactory bulb via the vagus nerve to the ventral mesencephalon and ascend to the brainstem, limbic system, and neocortex.⁸³ Abnormalities in ISF dynamics have also been suggested as a potential pathogenesis of Parkinson’s disease. In a tracer experiment using A53T mice, a model of Parkinson’s disease that overexpresses mutant α-synuclein, the migration of intrathecally injected fluorescent tracers into the brain parenchyma or glymphatic influx was significantly reduced in A53T mice compared to that in controls. Additionally, A53T mice showed a significant reduction in cervical inflammation. Furthermore, it has been shown that cervical lymph node strangulation in A53T mice further exacerbates glymphatic influx. Possible mechanisms include increased α-synuclein deposition, glial activation, exacerbated neuroinflammation, and the loss of dopaminergic neurons.⁸⁴ In humans, a study evaluating signal changes in meningeal lymphatic vessels after GBCA administration in patients with Parkinson’s disease has been reported. The report showed that visualization of meningeal lymphatic vessels was delayed in patients with Parkinson’s disease. This is thought to be due to the accumulation of α-synuclein caused by impaired drainage of the meningeal lymphatics, resulting in degeneration associated with Parkinson’s disease.⁸⁵ Hypotheses have also been put forward regarding the antecedents of Parkinson’s disease onset in relation to ISF dynamics. These hypotheses propose that glymphatic function may be compromised by the combined neurotoxic effects of α-synuclein protein aggregates and deteriorated dopaminergic neurons that are linked to altered rapid eye movement (REM) sleep, circadian rhythms, and clock gene dysfunction.¹⁷ Such Parkinson-related impairment of interstitial dynamics may be a consequence of α-synuclein pathology, which is thought to be the primary pathophysiology. However, it is worth noting that Parkinson’s disease is associated with interstitial fluidopathy.

Evaluation of Parkinson’s disease using the DTI-ALPS method has also been reported. In a report comparing normal controls and patients with Parkinson’s disease of various severities, a decrease in the ALPS index was observed in Parkinson’s disease cases with cognitive symptoms, and a correlation between the severity of Parkinson’s disease and ALPS index was observed (Fig. 4).⁴³ In a study on Parkinson’s disease by stage, there was no significant difference in the ALPS index between normal controls and patients with early Parkinson’s disease, but a significant decrease in the ALPS index was reported in the late Parkinson’s disease group.⁴⁹ In a comparative study with essential tremor, the ALPS index was lower in Parkinson’s disease cases than in essential tremor cases but was not associated with cognitive symptoms. In this study, the ALPS index was also shown to be inversely correlated with age and the Fazekas scale on MRI.⁵⁰

Fig. 4.

Evaluation of ISF dynamics in PD by the DTI-ALPS method. The DTI-ALPS method was used to evaluate the ALPS index in patients with Parkinson’s disease without cognitive impairment, patients with PD-MCI, and patients with PDD. The ALPS and unified PD rating scale, a measure of the severity of PD, showed a significant inverse correlation (a). The ALPS indices of the PD-MCI and PDD groups were significantly lower than those of the normal control group (b). Reprinted by permission from reference #43. DTI-ALPS, diffusion tensor image analysis along the perivascular space; ISF, interstitial fluid; PD, Parkinson’s disease; PDD, Parkinson’s disease experiencing dementia; PD-MCI, Parkinson’s disease experiencing mild cognitive impairment; PDN, Parkinson’s disease patients with normal cognition.

Idiopathic Normal Pressure Hydrocephalus as a CNS Interstitial Fluidopathy

Idiopathic normal pressure hydrocephalus (iNPH) is one of the most common forms of communicating hydrocephalus, in which intracranial pressure is often maintained in the normal range despite the presence of enlarged ventricles. iNPH shows characteristic imaging findings, including enlargement of the Sylvian fissure, narrowing of the parietal CSF space, and narrowing of the corpus callosum angle.^86,87 However, its pathophysiology, including spinal fluid dynamics, remains unclear. A recent study of AQP4 immunostaining in cortical brain biopsies showed a significant decrease in the density of AQP4 water channels in the endoplasmic reticulum of astrocytes along cortical microvessels in patients with iNPH. It has also been postulated that impaired ISF dynamics, impaired waste drainage, and associated neurodegeneration are important factors in the pathogenesis of iNPH.⁸⁸ In other words, iNPH is not only caused by abnormal CSF dynamics but also by a disturbance in ISF dynamics. In this respect, the role of iNPH as a CNS interstitial fluidopathy is becoming clear.

According to a report on the intrathecal injection of GBCA as a tracer and MRI observation over time, backflow of contrast medium into the ventricles of the brain was noticeable in the iNPH group. In addition, both the iNPH and control groups showed enhancement of the CSF space and brain parenchyma over time, but the staining of the brain parenchyma tended to be prolonged in the iNPH group after 4 h of observation.⁸⁹ However, as mentioned previously, intrathecal injection of a GBCA was not approved because it is highly invasive. Therefore, it is virtually impossible to perform such procedures in clinical practice. On the other hand, various attempts have been made to evaluate abnormal ISF dynamics in iNPH by using non-invasive imaging techniques. In addition to evaluation by diffusion imaging (DTI-ALPS), which is discussed below, evaluation by MR spectroscopy (MRS) has also been reported.⁹⁰ The MRS study showed that the peaks of macromolecules were increased in patients with iNPH who had gait disturbance and cognitive symptoms compared to controls. These macromolecule peaks decreased after shunt surgery, indicating that normal pressure hydrocephalus causes impaired elimination of waste proteins, which can be evaluated by MRS.

Studies of iNPH using the DTI-ALPS method have also been reported. Yokota et al. compared iNPH cases with non-iNPH ventricular dilatation to normal controls.⁵⁹ The iNPH group showed a significantly lower ALPS index than the non-iNPH ventricular dilatation group (Fig. 5). Regarding the discrimination between the two groups, the area under the receiver operating characteristic (ROC) curve was 1.0, showing an extremely high discrimination ability. In addition, another report showed a significant decrease in the ALPS index in the iNPH group in response to the tap test. Moreover, this report also showed a correlation between the callosal angle and APLS index.⁴²

Fig. 5.

Evaluation of ISF dynamics in idiopathic normal pressure hydrocephalus by the DTI-ALPS method. Comparison of ALPS indices in the Control, piNPH, and iNPH. The results of manual placement of the ROI (a) and atlas-based placement (b) are shown. Both methods showed a significantly lower ALPS index in the normal pressure hydrocephalus group than in the normal controls or ventricular enlargement alone. Reprinted by permission from reference #59. Control, normal control group; DTI-ALPS, diffusion tensor image analysis along the perivascular space; iNPH, normal pressure hydrocephalus group; ISF, interstitial fluid; piNPH, ventricular enlargement only group.

Mechanical Injuries and Pressure Changes as a CNS Interstitial Fluidopathy

An association between mechanical injury to the head and impaired ISF dynamics was reported by Iliff et al. in mice with head trauma.⁹¹ In an experiment where a fluorescent tracer was intrathecally injected after mechanical injury to one side of the rat brain, tracer migration into the brain was poor beginning the day after trauma, and this finding persisted for 4 w after trauma. The post-traumatic brain is vulnerable to tau protein accumulation and degeneration. Impairment of ISF dynamics owing to the trauma, as described above, may be a reason for this. Repeated mild traumatic brain injuries in young athletes are becoming increasingly prevalent, and animal experiments have been conducted to address this problem. The kinetics of intrathecally administered GBCA was evaluated in an experiment in which adolescent rats were repeatedly subjected to mild traumatic brain injury. The results showed that the washout of GBCA was delayed in the limbic system and olfactory bulb, which suggested an abnormal ISF dynamics in these regions.⁹² Damage to the medullary veins can also be seen in high-energy head trauma,⁹³ which may contribute to abnormal ISF dynamics.

Changes in cerebral ISF dynamics owing to mechanical forces in the cranium have also been observed, even in conditions without traumatic brain injury. One experiment compared ISF dynamics between rats undergoing craniectomy and those undergoing cranioplasty. Craniectomy, in which pressure is released, results in decreased penetration of intrathecally injected GBCA into the brain interstitium, whereas cranioplasty, in which the skull is closed again, results in better penetration into the brain interstitium.⁹⁴ These findings suggest that mechanical factors such as intracranial pressure may be involved in cerebral ISF dynamics. In an experiment, GBCA was injected into macaque monkeys under conditions of CSF leakage. The GBCA penetrated from the brain surface to the brain parenchyma within 20 min after administration in the control group and penetrated deep into the brain over time. In contrast, in monkeys with CSF leakage, the GBCA remained in the basal cistern and did not penetrate the brain parenchyma.⁹⁵ These results indicated that the abnormalities in ISF dynamics can be caused not only by abnormalities in the membrane structure of the CNS (including the BBB), but also by mechanical factors such as pressure. This is one of the reasons why we did not name our concept of CNS interstitial fluidopathy as, for example, menblenopathy or barriopathy.

Cerebral Small Vessel Disease as an Interstitial Fluidopathy

Capillaries in the cerebral interstitium have various functions, including the BBB and drainage of waste products via the vessel walls, as mentioned above. Cerebral SVD, a disorder of the capillaries or small vessels, presents a wide range of disorders. Many hereditary cerebral SVDs have been shown to cause smooth muscle cell loss and tunica media degeneration, resulting in impaired ISF drainage and capillary dysfunction owing to pericyte damage.⁹⁶ In some SVDs, experiments have demonstrated impaired ISF dynamics. A compartmental analysis of changes in the distribution of large amounts of intrathecally injected GBCA over time was performed to analyze ISF dynamics in hypertensive SVD using a hypertensive rat model. In this experiment, the influx and efflux rates of GBCA were significantly lower in hypertensive rats than in controls, both for flow into and out of tissues, which indicated impaired ISF dynamics in hypertensive SVD.⁹⁷ Moreover, in a study of interstitial changes associated with hypertensive SVDs in humans, the DTI-ALPS method was used to evaluate hypertensive SVD and impaired ISF dynamics. In addition, a cohort study of 126 patients showed a significant decrease in the ALPS index in the hypertensive group.⁹⁸ Autopsy tissue studies of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have also been reported. In CADASIL cases, the perivascular space was significantly larger than that of the controls. Furthermore, higher proportion of degenerated myelin basic protein was observed in CADASIL cases compared to that of the controls, indicating myelin degeneration. In addition, hyalinization of the vessels significantly increased. These results suggest that the high signal in the temporal pole on T2-weighted images in CADASIL cases is not because of lacunar infarction but owing to myelin degeneration and perivascular space enlargement related to impaired drainage of ISF.⁹⁹

Glaucoma and Meniere’s Disease as Interstitial Fluidopathies

The optic nerve, like the brain, is surrounded by the pia mater, arachnoid membrane, and dura mater. CSF pressure within the optic nerve sheath is equivalent to intracranial pressure. Therefore, the optic nerve is affected by both intraocular and intracranial pressures. A structure in the sclera of the eye called the cribriform plate serves as a barrier between the two regions of intraocular pressure and intracranial pressure.¹⁰⁰ Glaucoma is a major cause of blindness. Glaucoma results in the progressive degeneration of retinal ganglion cells and eventually in irreversible retinal ganglion cell death. The development of glaucoma is correlated with intraocular pressure. Control of intraocular pressure is a means of controlling the development of glaucoma. However, the exact mechanism underlying glaucoma development remains unclear. Wostyn et al. reported a hypothesis for the pathogenesis of glaucoma.¹⁰¹ According to their hypothesis, CSF normally flows into the perivascular space within the retina from the central retinal artery periphery and subsequently drains out from the central retinal vein periphery. However, in glaucoma cases, the above interstitial flow is mechanically impaired owing to the deformation of cribriform plate in the optic nerve. COL4A1 mutation-related SVD, a hereditary SVD mentioned above, is also associated with glaucoma.^102,103 COL4A1 is a gene that encodes type 4 collagen, which is an essential component of the basement membrane of blood vessels. COL4A1 mutation-related SVD is associated with cerebral ischemia and cerebral hemorrhage owing to cerebral vascular vulnerability and various other disorders, including congenital porencephaly. The fact that this systematic abnormality of the basement membrane is associated with glaucoma suggests that some kind of membrane damage may be involved in addition to the above-mentioned mechanical cause, as hypothesized by Wostyn et al.¹⁰⁴

Meniere’s disease is a complex disorder with many underlying factors, but it is believed to be caused by an excess of endolymphatic fluid, resulting in damage to ganglion cells.^105,106 Abnormal fluid dynamics in the labyrinth and various types of aquaporin expression are thought to cause endolymphatic hydrops. Similar factors that cause interstitial fluidopathy were described in this study, suggesting that abnormalities in ISF dynamics may play an important role in the development and progression of Meniere’s disease.

Aging and Interstitial Fluid Dynamics

Although aging is not a pathological condition, age-related changes in the cerebral ISF dynamics and waste excretory systems have been reported, which suggests that interstitial fluidopathy may be associated with aging. In an animal study that reported the relationship between age-related changes in the expression of astrocytic AQP4 and changes in glymphatic pathway function, aging was associated with a decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma and widespread loss of perivascular AQP4 polarization.¹⁰⁷ In a study of intrathecal administration of contrast media in human participants, the clearance of the glymphatic pathway was related to aging.¹⁰⁸ In the studies by intravenous administration of contrast media in the human participant, as introduced in Fig. 2, the degree of leakage of contrast media from the subpial space around the cortical veins to the surrounding subarachnoid space was reported to be significantly accelerated by aging, especially in > 40 age groups.^21,22 ALPS studies have also shown that alteration of ISF dynamics progresses with age beginning from the 40s.³⁹ Cerebral SVD is a common accompaniment of aging; MRI features include dilated perivascular spaces.¹⁰⁹ Dilated perivascular spaces are also commonly observed in MR images in clinical practice, even in healthy elderly participants. Enlargement of the perivascular space has been suggested as an important finding in SVD, possibly involving impaired ISF dynamics and perivascular pathology.¹⁸ However, further work is necessary to fully describe the relationship between aging and impairment of ISF dynamics.

Conclusion

We propose the term “interstitial fluidopathy” as an umbrella term to describe a series of diseases in which abnormalities in ISF dynamics occurring in the CNS are one of the important factors. Umbrella terms such as tauopathy, TDP-43 proteinopathy, or α-synucleinopathy, in which the causative agent related to the disease is the key, have clear definitions. In contrast, umbrella terms that are related to causative structure or function are more difficult to define. For example, ciliopathy is a general term for diseases caused by abnormalities in primary cilia, and many genetic abnormalities have been identified.¹¹⁰ However, the pathways by which genetic abnormalities cause phenotypic abnormalities have not been fully elucidated, and the boundaries between syndromes are often vague, making it difficult to distinguish them accurately. The term “interstitial fluidopathy” is an umbrella term that is as difficult to define as the above. Although the existence of diseases related to ISF dynamics is currently recognized, there are many unknowns regarding the diseases and mechanisms involved. These unknowns need to be addressed in future studies.

There is a paper that describes the ideal form of the umbrella term. This paper discusses what global health is, but apart from the main topic of the paper, it also discusses how the umbrella term should be defined.¹¹¹ This paper points out that the penumbra, or the half-shadow caused by the umbrella, and the main shadow vary depending on the distance between the light source and the umbrella. It is pointed out that if the definition of a term is too strict, important elements may not be included in the term penumbra, while if the scope of the term is too broad, the definition of the term itself, including the penumbra, may become thin and diluted. The definition of interstitial fluidopathy also includes the main shadow and the penumbra. For example, in the case of iNPH, ISF dynamics are closely associated with the pathogenesis of the disease. Contrastingly, in Parkinson’s disease, although various studies have been reported, there is no conclusive evidence, and it must be stated that it corresponds to the penumbra. However, we do not believe that it is advisable to limit the discussion to what is or is not included in the terminology, which is, black and white. We believe that acknowledging the existence of the gray area of the penumbra and conducting research, discussion, and thinking that includes the nature of its boundaries will contribute to the elucidation of disease mechanisms and the development of treatment methods in a comprehensive sense.

Although the interstitial space has numerous functions, including mass transport, immune function, and intercellular signal transduction, it may be possible to develop common therapeutic and preventive strategies, at least in part because various diseases that result in interstitial fluidopathy share similar pathological mechanisms. For example, cilostazol treatment has been tested in Alzheimer’s disease to improve the ISF dynamics.¹¹² In addition, in animal experiments, a combination of microbubbles and focused ultrasound has been tested to promote the drainage of amyloid-β into the CSF space.¹¹³ The concept of fluidopathy is useful in drug-based or the above-mentioned therapies. Moreover, assessing the effects of activities such as exercise and sleep on cerebral ISF dynamics may help ameliorate or delay the progression of diseases that have aspects of interstitial fluidopathy. This perspective on ISF dynamics is important for understanding and diagnosing the pathogenesis of various CNS diseases and ultimately for developing therapeutic strategies.

Fig. 6.

Umbrella term and penumbra. The main shadow and half-shadow, or penumbra, caused by the umbrella, vary depending on the distance between the light source and the umbrella (a–c). When if the scope of the term is too strict, as in a, important elements may not be included in the term penumbra, whereas if the scope of the term is too broad, as in c, the definition of the term itself, including penumbra, becomes thin and diluted. Reprinted by permission from reference #111.

Funding Statement

The current study was supported by KAKENHI (21K07563).