Adult Hydrocephalus and the Glymphatic System

Adult hydrocephalus, especially idiopathic normal pressure hydrocephalus (iNPH), involves cerebrospinal fluid (CSF) dysfunction that is associated with impaired waste clearance in the brain, potentially causing toxic protein buildup. This condition shares features with neurodegenerative diseases like Alzheimer’s, where amyloid-β and tau proteins accumulate. Recent discoveries in the glymphatic and meningeal lymphatic systems, key in CSF and metabolic waste clearance, provide insights into these protein imbalances. However, altered CSF flow in iNPH may disrupt glymphatic transport, exacerbating protein deposits. This review proposes reframing iNPH as a cerebral “CSF-proteinopathy” disorder, although its full relationship with glymphatic impairment needs further exploration.

Key points

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Adult hydrocephalus includes various cerebrospinal fluid (CSF) disorders, with idiopathic normal pressure hydrocephalus (iNPH) as the most prevalent type.
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Discoveries of the glymphatic-meningeal lymphatic systems have transformed our understanding of CSF dynamics, revealing new pathways for waste clearance and fluid transport, important for hydrocephalus.
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The glymphatic system functions as a “brainwashing” pathway, clearing metabolic waste through perivascular spaces.
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Impaired glymphatic function is associated with neurodegenerative diseases and may contribute to toxic protein accumulation in hydrocephalus.
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The iNPH subtype of adult hydrocephalus may be redefined as a “CSF-proteinopathy,” reflecting both CSF dysfunction and protein buildup, akin to proteinopathies in dementia.

Introduction

Adult hydrocephalus encompasses a group of disorders linked by cerebrospinal fluid (CSF) abnormalities. This review will primarily focus on idiopathic normal pressure hydrocephalus (iNPH), more recently also denoted Hakim’s disease, named after the researcher who first described it. ^, iNPH is the most common form of adult hydrocephalus, and its prevalence has been significantly underestimated. Recently, studies have shown a prevalence of probable or possible iNPH in approximately 2% of individuals aged 70 years and around 5% in those aged over 80 years. ^, The disease is progressive, leading to clinical deterioration over time, and can eventually result in dependency and the need for nursing care, as well as increased mortality. Notably, patients with iNPH may experience substantial clinical improvement following CSF diversion (shunt) surgery.

The year 2025 marks several important anniversaries in CSF research. In 1825, François Magendie first described and named cerebrospinal fluid , following his research on fluid flow and function within the brain and spinal cord; he observed its passage through the foramen of Magendie, an opening in the fourth ventricle that now bears his name. In 1875, Swedish anatomists Axel Key and Gustaf Retzius made pioneering discoveries in the anatomy and physiology of CSF and the meningeal system. They provided a detailed anatomic description of the meningeal layers—dura mater, arachnoid mater, and pia mater—and mapped the circulation of CSF, demonstrating its flow through the subarachnoid space (SAS) and its role in cushioning the brain and spinal cord. They also presented evidence that CSF is absorbed into the venous system, primarily through the arachnoid granulations. In 1925, Harvey Cushing, the father of modern neurosurgery, introduced the concept of the Third Circulation to describe the unique movement and role of CSF within the central nervous system (CNS), highlighting that CSF circulation functions independently from the circulatory (blood) and lymphatic systems. Key aspects of Cushing’s Third Circulation concept include (1) continuous production of CSF within the choroid plexuses of the brain ventricles; (2) CSF circulation through the ventricles, the SAS, and around the spinal cord; and (3) CSF absorption into the venous system, primarily through arachnoid granulations. Cushing further proposed that CSF plays a crucial role in protecting the brain from mechanical injury by acting as a cushion, regulating intracranial pressure (ICP), and maintaining a stable environment for the CNS. Although he did not fully explain the metabolic functions of CSF, he suggested that it might aid in nutrient delivery and waste removal within the CNS. This latter hypothesis is notable, considering the recent discoveries about the role of CSF in clearing metabolic waste.

Traditionally, hydrocephalus has been viewed as an imbalance between CSF production and absorption. Early neurosurgical pioneer Walter E. Dandy introduced the differentiation between noncommunicating and communicating hydrocephalus, based on the location of CSF obstruction within the pathways.

Over the last decade, the traditional Third Circulation model has been increasingly questioned. The discoveries of the glymphatic system in 2012 and the meningeal lymphatic system in 2015 ^, have generated substantial interest among both basic and clinical neuroscientists.

The Glymphatic System

The glymphatic system was first described through experiments on the distribution of CSF tracers within the rodent brain (for review, see Rasmussen and colleagues ). Following the injection of tracers into the cisterna magna, the authors visualized the tracer’s movement in vivo using 2 photon microscopy, along with ex vivo assessments in brain sections. They observed that CSF tracers traveled along the outer surfaces of blood vessels (perivascular spaces [PVS]) within the subpial region, demonstrating direct CSF passage from the SAS into brain tissue. While CSF influx appeared to follow periarterial pathways, efflux was proposed to occur perivenously. This study provided evidence that periarterial CSF influx mixes with ISF, facilitating the clearance of metabolic waste, such as amyloid proteins, via perivenous routes, essentially functioning as a “brain washing” system. The primary driving forces behind glymphatic transport are arterial pulsations, which create pressure gradients (convective forces) that enable the forward transport of substances along arteries. The main pathway for this transport is the perivascular space, known as Virchow–Robin perivascular spaces (VRS), which extends into the microvessels surrounded by astrocytic end-feet enriched with the water channel protein aquaporin-4 (AQP4).

Further experimental research has shown that glymphatic function deteriorates with age, in systemic conditions like arterial hypertension and diabetes, and following trauma or hemorrhage. In rodents, glymphatic transport is largely active during sleep.

Various aspects with the glymphatic system are a topic of ongoing debate. Key questions include whether there is a directional CSF flow from periarterial to perivenous spaces via the interstitial space, the roles of convective versus diffusive forces, and the specific function of AQP4 in fluid transport. Competing theories include the intramural periarterial drainage (IPAD) concept, which suggests that substances like amyloid move retrogradely along arteries, contrasting with the glymphatic model that proposes forward (antegrade) transport along arteries.

Despite these debates, growing evidence supports the existence of a brain-wide perivascular pathway for the movement of fluids and solutes antegrade along vessels at the arterial side, relevant for neurosurgical diseases. The glymphatic system seems essential for delivering substances needed for normal brain function and may serve as a waste clearance mechanism, though the exact efflux pathways are still debated. Effective clearance is critical for the brain, an organ with high energy demands that produces approximately 3 to 4 g of proteins daily, much more than skeletal muscle.

Since the glymphatic system was first identified in rodents, it was questioned whether a similar system exists in humans. While there are various methods to study glymphatic function in animals, methods for human glymphatic imaging are limited.

Intrathecal contrast-enhanced MRI, first described in 2015, has thus far provided the strongest evidence for a glymphatic system in human ^, ; this modality is from here referred to as glymphatic MRI (gMRI). It may be considered the current gold standard. This technique involves intrathecal administration of an MRI contrast agent followed by sequential MRI scans, and estimation over time of extravascular tracer enrichment from changes T1 signal or T1 time. Results from using this method are shown in Fig. 1 A–C. However, this method has limitations, such as the need for spinal puncture and the off-label use of intrathecal MRI contrast agents. Most studies have used gadobutrol at a dose of 0.5 mmol or lower (0.10 or 0.25 mmol), with no reported adverse events or evidence of brain deposition in safety studies. In clinical practice, gadobutrol is administered intravenous in higher doses; notably, the concentrations of gadolinium in brain are comparable after intrathecal and intravenous administration. Based on tracer studies using an MRI contrast agent as CSF tracer conducted by our group, we present evidence supporting the existence of a glymphatic system in humans; key findings include

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An intrathecal tracer disperses across the brain from the cortical surface inward (see Fig. 1 A–C), mainly along the major arteries (anterior, middle, and posterior cerebral arteries). ^,
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Tracer distribution is sleep-dependent. In patients with total sleep deprivation for 1 night, glymphatic clearance was delayed, and poor sleep quality correlated with altered tracer distribution ( Fig. 1 D, E).
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Within the SAS, tracer moves antegrade along PVS of the arteries before distributing in the SAS and cortical regions ( Fig. 2 A–H).

Fig. 2

Following an intrathecal injection of an MRI contrast agent, early consecutive MRI acquisitions demonstrate antegrade perivascular transport along branches of the anterior cerebral artery (ACA, A–F ). A 3 dimensional (3D) image shows tracer enrichment in the subarachnoid space (SAS) and along the PVSAS of the pericallosal artery ( G ). Tracer transport confined to the PVSAS ( H ), moving in an antegrade direction ( arrow ). Asterics in B and E refers to first-time tracer appearance.

( From Eide PK, Ringstad G, in Nature Communications, 2024, reprinted by permission under the terms of the Creative Commons Attribution 4.0 International License. Illustration: Øystein Horgmo, University of Oslo.)
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Tracer transport cannot be fully explained by diffusion alone; while diffusion dominates within interstitial spaces, convective forces (driven by pressure gradients) contribute along blood vessels.
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The pattern of CSF tracer distribution mirrors that of waste product buildup seen in neurodegenerative diseases like Alzheimer’s and Parkinson’s. Delayed glymphatic clearance could potentially be linked to abnormal protein deposits in the brain.
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Additionally, the distribution and clearance of tracers are associated with levels of waste products like amyloid-β and tau in the blood.

A noninvasive method that recently has gained attention is the diffusion tensor image analysis along the perivascular space (DTI-ALPS) technique. However, this modality primarily measures water diffusivity in a small white matter region rather than glymphatic function. While an increasing body of literature refers to DTI-ALPS results as measures of glymphatic function, this method does not assess the transport of larger molecules, a hallmark of glymphatic function.

Another approach involves studying PVS in subcortical white matter that are visible on MRI, typically in the basal ganglia and centrum semiovale. The function of PVS remains less understood, though recent research has focused on studying PVS size and volume as potential markers of glymphatic function. A recent study suggested a direct tracer pathway from the SAS to the PVS, indicating that PVS visible on MRI might reflect glymphatic function. However, further research is needed to clarify whether this is a useful approach.

The term perivascular space is used for various anatomic structures: (1) The perivascular subarachnoid spaces (PVSAS) represent a compartment within the SAS that facilitates transport along major arteries. This space lies between the outer layer of the arterial wall and a perivascular membrane. (2) The VRS is located in the subpial space and are extensions of the SAS, surrounding blood vessels as they penetrate the brain tissue from the pia mater. (3) The PVS seen on MRI, especially in T2-weighted images, appear as small, round, or linear hyperintensities following the course of vessels in the white matter. They are most frequently observed in the basal ganglia, centrum semiovale, and subcortical regions near the lateral ventricles.

Meningeal Lymphatic System

While the presence of lymphatic vessels within the meninges had long been recognized, it was not until 2015 that 2 independent research groups provided evidence of meningeal vessels in the dura mater near the superior sagittal sinus, capable of draining CSF to extradural lymphatic structures. ^, In recent years, experimental research has further supported the passage of cells and solutes across the meninges, providing a foundation for immunologic cross talk. ^, Perivascular border macrophages appear to help maintain open perivascular pathways, suggesting that the immune system influences perivascular (glymphatic) transport. More recently, efflux routes have been identified along veins that enter the dura mater via structures known as arachnoid cuff exit points.

Our human studies demonstrated direct tracer passage from the SAS to the parasagittal dura (PSD), with a distribution pattern unlikely to be restricted solely to the sites of bridging veins ( Fig. 3 A–D). Tracer further distributed to the skull bone marrow.

How should meningeal lymphatic clearance capacity be measured in humans? Imaging approaches alone may not reliably assess clearance capacity. Therefore, we developed a blood test to measure CSF-to-blood clearance capacity. ^, Clearance varies widely among individuals, even within the same disease categories. It represents total clearance capacity from the CSF to the bloodstream. Based on our experience, the most pronounced clearance appears to occur from the spinal compartment.

How have the discoveries of the glymphatic and meningeal-lymphatic systems impacted our understanding of hydrocephalus?

Adult Hydrocephalus: a Cerebral Cerebrospinal Fluid-Proteinopathy Disease

The term “hydrocephalus” implies that the condition is solely a disorder of CSF (or water). It may be more accurate to describe adult hydrocephalus, at least iNPH, as a cerebral “CSF-proteinopathy” disease, reflecting both CSF dysfunction and the accumulation of toxic proteins, such as amyloid-β and tau peptides. These 2 factors are closely interlinked with CSF serving as the common pathway for both glymphatic function and clearance through meningeal-lymphatic pathways. Fully understanding the role of the glymphatic system in hydrocephalus requires recognizing that adult hydrocephalus encompasses both a CSF disturbance and a neurodegenerative aspect.

Cerebrospinal fluid flow alterations in adult hydrocephalus

Adult hydrocephalus is indeed a CSF disorder, as evidenced by patients’ clinical improvement following CSF drainage through tap tests or extended lumbar drainage, and sustained improvement after CSF diversion surgery. Moreover, a hallmark of hydrocephalus is the morphologic alteration of CSF spaces, though it remains an ongoing debate, which measures and tests that best predict the clinical response to shunting. ^,

In recent years, a growing body of data has shown that CSF flow patterns are significantly altered in adult hydrocephalus. Two imaging techniques to study these patterns are phase-contrast MRI (PC-MRI) and tracer distribution assessments after intrathecal injection. At the cranio–cervical junction, CSF flow typically moves from the spinal canal upward to cranial cavity ( Fig. 4 A). ^, Moreover, CSF flow in the Sylvian aqueduct is frequently reversed in adult hydrocephalus, with reflux directed toward the ventricles ( Fig. 4 B), ^, ^, indicating lower intraventricular pressure that enables reversed flow. These net CSF flow directions and the volumes of net flow differ considerably from the traditional values of ventricular CSF production of about 0.3 to 0.4 mL/min (see Fig. 4 A, B). In comparison, tracer studies further support this by demonstrating tracer reflux into the ventricles; in cases with grade 3 to 4 reflux, tracer remains in the ventricles until the following day ( Fig. 5 A–E). ^,