Acta Neurochirurgica (2024) 166:274

https://doi.org/10.1007/s00701-024-06161-4

MINI-REVIEW (BY INVITATION)

Neurosurgery and the glymphatic system

Per Kristian Eide1,2,3

Received: 2 May 2024 / Accepted: 5 June 2024

© The Author(s) 2024

Abstract
The discovery of the glymphatic system has fundamentally altered our comprehension of cerebrospinal fluid transport
and the removal of waste from brain metabolism. In the past decade, since its initial characterization, research on the
glymphatic system has surged exponentially. Its potential implications for central nervous system disorders have sparked
significant interest in the field of neurosurgery. Nonetheless, ongoing discussions and debates persist regarding the concept
of the glymphatic system, and our current understanding largely relies on findings from experimental animal studies. This
review aims to address several key inquiries: What methodologies exist for evaluating glymphatic function in humans
today? What is the current evidence supporting the existence of a human glymphatic system? Can the glymphatic system
be considered distinct from the meningeal-lymphatic system? What is the human evidence for glymphatic-meningeal lym-
phatic system failure in neurosurgical diseases? Existing literature indicates a paucity of techniques available for assessing
glymphatic function in humans. Thus far, intrathecal contrast-enhanced magnetic resonance imaging (MRI) has shown
the most promising results and have provided evidence for the presence of a glymphatic system in humans, albeit with
limitations. It is, however, essential to recognize the interconnection between the glymphatic and meningeal lymphatic
systems, as they operate in tandem. There are some human studies demonstrating deteriorations in glymphatic function
associated with neurosurgical disorders, enriching our understanding of their pathophysiology. However, the translation of
this knowledge into clinical practice is hindered by the constraints of current glymphatic imaging modalities.

Keywords Glymphatic system · Meningeal lymphatic vessels · Cerebrospinal fluid · MRI · Neurosurgery

Abbreviations MREG Magnetic resonance encephalography

ACE Arachnoid cuff exits MRI Magnetic resonance imaging
AQP4 Aquaporin-4 PSD Parasagittal dura
CNS Central nervous system PVS Perivascular space
CSF Cerebrospinal fluid PVSAS Perivascular subarachnoid space
DTI-ALPS Diffusion tensor image analysis along the SAH Subarachnoid hemorrhage
perivascular space TBI Traumatic brain injury
GFR Glomerular filtration rate
iNPH Idiopathic normal pressure hydrocephalus
IIH Idiopathic intracranial hypertension Introduction

The discovery of the glymphatic system in 2012 [34]

sparked a significant shift in our understanding of cerebro-
Per Kristian Eide
[email protected] spinal fluid (CSF) dynamics and its crucial role in clear-
ing waste from the brain. Over the past few years, there has
1
Department of Neurosurgery, Oslo University Hospital - been a substantial increase in the literature on experimental
Rikshospitalet, Nydalen Pb 4950 N-0424, Norway studies in animals, particularly rodents, with broad impli-
2
Institute of Clinical Medicine, Faculty of Medicine, cations for the treatment of central nervous system (CNS)
University of Oslo, Oslo, Norway diseases (for review see [57]).
3
KG Jebsen Centre for Brain Fluid Research, University of
Oslo, Oslo, Norway

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The glymphatic system encompasses a brain-wide peri- What methodologies exist for evaluating
vascular transport pathway for fluids and solutes, believed glymphatic function in humans today?
to be pivotal in removing metabolic waste from the brain
[52], while also facilitating the transportation of substances Today, the methods for assessing glymphatic function in
to the brain [44]. In rodents, the glymphatic system is by humans predominantly hinge on magnetic resonance imag-
far most active during sleep [79], but its efficacy diminishes ing (MRI) [40, 70]. More modalities are available in ani-
with aging [41] and in systemic diseases such as experi- mals but are not commented on here. Table 1 provides an
mental arterial hypertension [48] and diabetes [36]. More- overview of the currently used human methods, each with
over, impaired glymphatic function may associate with the its own set of advantages and disadvantages.
accumulation of toxic waste, including amyloid-β, tau, and
α-synuclein in the brain, suggesting a significant role in Intrathecal contrast-enhanced MRI
dementia diseases like Alzheimer’s and Parkinson’s [7, 52].
It has also been proposed to play a crucial role in brain ede- The initial demonstration occurred in a patient investigated
mas resulting from stroke [49] and traumatic brain injury for potential CSF leakage, where intrathecally administered
[33]. gadobutrol (Gadovist, Bayer, GE) enriched brain tissue [15],
The glymphatic system has garnered attention in neuro- indicating the free passage of the contrast agent from the
surgical literature, with expectations regarding its potential subarachnoid space to the cerebral cortex and subcortical
impact on neurosurgical practices [2, 72]. However, critics white matter. Subsequently, it was revealed that intrathecal
highlight unresolved and debated aspects of the glymphatic gadobutrol enriches the entire brain in a centripetal man-
concept [30, 50]. It is worth noting that the bulk of research ner, moving from the cortical surface inward [62, 63, 77].
on the glymphatic system has been conducted in animals, The extent of tracer enrichment heavily relies on the amount
leaving questions unanswered regarding its translation to of tracer in the subarachnoid CSF. Drawbacks include the
humans. From a clinical standpoint, the relevance of the requirement for spinal puncture and the off-label use of
glymphatic system depends on our ability to measure its gadobutrol for intrathecal administration, which raises con-
function or dysfunction, as well as to identify changes in cerns about potential toxic effects and brain deposition.
glymphatic function in response to interventions. However, these concerns may be overstated for several rea-
Against this backdrop, this review critically examines sons: (a) Toxic effects have not been observed in hundreds
the following questions: (1) What methodologies exist for of patients receiving intrathecal gadobutrol in doses of 0.25
evaluating glymphatic function in humans today? (2) What to 0.50 mmol [12, 28, 69]. (b) Gadobutrol retention in the
is the current evidence supporting the existence of a human human brain was not evident after four weeks [64]. (c) Con-
glymphatic system? (3) Can the glymphatic system be con- sidering that the on-label dosage of intravenous gadobutrol
sidered distinct from the meningeal-lymphatic system? (4) is significantly higher than the intrathecal dosage, CSF con-
What is the human evidence for glymphatic-meningeal lym- centrations are comparable following intrathecal and intra-
phatic system failure in neurosurgical diseases? venous injections [74].

Intravenous contrast-enhanced MRI

Due to the necessity of spinal puncture in intrathecal

contrast-enhanced MRI, researchers have explored the

Table 1 Main available MRI methods to assess human glymphatic function

MRI Methodology Advantage Disadvantage
Intrathecal-contrast-enhanced MRI Current gold-standard for Requires spinal puncture.
assessing tracer movement Intrathecal MRI contrast agent used off-label
in human brain
Intravenous contrast-enhanced MRI No spinal puncture required Challenge in defining the glymphatic versus vascular tracer
enrichment.
Diffusion tensor image analysis along Non-invasive Assess events within a small region of deep white matter, not necessar-
the perivascular space (DTI-ALPS) ily representative for glymphatic function.
White matter perivascular spaces (PVS) No need for contrast agents. Limited association between cortical PVS and the PVS of white matter.
Heterogeneity of white matter PVS with unknown communication
towards subarachnoid CSF
Magnetic resonance encephalography Non-invasive method Experimental approach lacking established association with glym-
(MREG) phatic function.

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visualization of glymphatic transport using intravenous Overall, there is currently a scarcity of methods for clini-
contrast agents [81]. The concept is that some contrast cally assessing glymphatic function in humans. Presently,
enters the CSF, allowing for the evaluation of extravascu- intrathecal contrast-enhanced MRI, as developed by the
lar transport. However, a major drawback is the difficulty author and colleagues, is by several considered the gold
in distinguishing between glymphatic and vascular tracer standard for glymphatic imaging in humans [74].
enrichment since contrast may also leak from blood through
the blood-brain-barrier. What is the current evidence supporting the
existence of a human glymphatic system?
MRI diffusion tensor image analysis along the perivascular
space (DTI-ALPS) The current evidence supporting the existence of a human
glymphatic system heavily relies on observations made
A widely used non-invasive MRI method for glymphatic through intrathecal contrast-enhanced MRI, where the con-
visualization is diffusion MRI, particularly the DTI-ALPS trast agent acts as a CSF tracer. Some principal lines of
technique [71]. Despite its increasing popularity, this evidence are depicted in Fig. 1 and can be summarized as
method has significant limitations [58]: (a) It measures follows:
water diffusivity in deep white matter, whereas glymphatic
function pertains to solute and fluid transport rather than Brain-wide distribution of a CSF tracer
water transport alone. (b) Events in deep white matter may
offer limited insight into glymphatic function, which is pri- The glymphatic system functions as a brain-wide perivascu-
marily a cortical phenomenon. (c) The vasculature in deep lar transport network for fluids and solutes, featuring periar-
white matter and cerebral cortex differs. (d) The perivascu- terial influx and perivenous outflux pathways. The contrast
lar spaces encompass less than 1% of the brain volume [4], agent, acting as a CSF tracer, initially enriches the subarach-
and the DTI-ALPS region of interest may not isolate water noid CSF space and subsequently permeates the entire brain
motion in the perivascular space from other directional in a centripetal manner, from the cortical surface to subcorti-
water transport in white matter, for instance along axons. cal regions [63]. Given the typical 1 mm resolution of MRI,
Consequently, there are substantial concerns regarding the the precise route of tracer passage - whether perivascular
use of DTI-ALPS as a measure of glymphatic function. along arteries or veins, along the basement membrane of
capillaries, or across the pia mater into the interstitial tis-
Perivascular spaces (PVS) of deep white matter sue - remains undetermined. Evidence supporting periarte-
rial tracer passage along vessels includes tracer enrichment
Another imaging option involves assessing enlarged white in the cerebral cortex adjacent to major artery trunks of the
matter PVSs as non-invasive measure of glymphatic func- subarachnoid space, such as the anterior cerebral artery,
tion [76]. The burden of enlarged PVS in the centrum middle cerebral artery, and posterior cerebral artery [17,
semiovale and basal ganglia have been proposed as poten- 63]. Importantly, studies administering a CSF tracer to the
tial non-invasive measures of glymphatic function [53]. subarachnoid space of pigs yielded comparable tracer distri-
However, concerns remain regarding the communication bution patterns as observed in humans, with immunohisto-
between white matter PVS and CSF, as well as the relation- chemistry and microscopic examinations confirming tracer
ship between events in white matter and the cerebral cor- confinement to the perivascular spaces [5]. A notable obser-
tex. There may also exist other confounding factors behind vation from human studies is that significant, inter-individ-
enlarged PVS rather than impaired glymphatic function. ual enrichment patterns in brain exist [63] (see Fig. 2).

Magnetic resonance encephalography (MREG) Tracer distribution in the human brain compared with
the pattern of toxic metabolite accumulation in dementia
Another non-invasive approach to evaluate glymphatic func- diseases
tion is ultra-fast MREG [39], which non-invasively assesses
three types of physiological measures affecting brain pul- The glymphatic system is hypothesized to serve as a clear-
sations (cardiac, respiratory and slow waves). While being ance pathway for toxic metabolites like amyloid-β, tau
a promising non-invasive technique, providing for unique in Alzheimer’s disease, and α-synuclein in Parkinson’s
insights into brain pulsations, the primary challenge lies in disease. The pathological aggregation of these metabo-
determining the extent to which alterations observed relate lites in dementia diseases follows a characteristic pattern,
to changes in glymphatic function. which aligns to some degree with the distribution of tracer
observed in human studies [52].

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Fig. 2 The parasagittal dura. An MRI contrast agent utilized as a cere-

brospinal fluid (CSF) tracer enriches the CSF within the subarachnoid
space (SAS) and traverses the arachnoid membrane into the dura mater
along the superior sagittal sinus (SSS), known as the parasagittal dura
(PSD). This phenomenon is depicted here through 3D images gener-
ated from T2-FLAIR images, co-registered with brain segmentation
and CSF tracer enhancement from T1 GRE at 48 h post-intrathecal
tracer injection. (A) The superior sagittal sinus (SSS) is highlighted in
blue, while the parasagittal dura (PSD) is depicted in yellow. (B) The
PSD may extend into the marrow of the skull bone (SB). Additionally,
a vein (V) within the diploic space is shown. CC: Cerebral cortex.
Images by Tomas Sakinis, MD, Department of Radiology, Oslo Uni-
Fig. 1 Glymphatic enrichment of a CSF tracer in a human subject is versity Hospital-Rikshospitalet.
depicted in this figure. Currently, intrathecal contrast-enhanced MRI
is considered the gold standard for glymphatic imaging in humans.
Following the intrathecal injection of a CSF tracer, such as gadobutrol Tracer transport not solely explained by diffusion
(Gadovist, Bayer, GE; 0.50 mmol, total volume 1 ml), tracer enrich-
ment is visualized using standardized MRI T1 acquisitions, as previ-
ously described. The tracer first enriches the subarachnoid spaces (A),
The glymphatic concept suggests that perivascular solute
then progresses to the cerebral cortex and subcortical white matter transport relies on convective forces (i.e., pressure-gradient
(B), as indicated by the percentage increase on the color bars to the forces), with diffusion potentially more prominent in the
right at 7 h. It’s worth noting that the strongest enrichment within the interstitial tissue. In humans, brain-wide tracer transport
subarachnoid space (A) corresponds to the area of strongest enrich-
ment in the cerebral cortex (B). By 24 h, tracer enrichment remained
occurs over hours [63], a prolonged phenomenon not solely
comparable in the subarachnoid space but increased in the cerebral explained by diffusion, indicating the involvement of addi-
ventricles (C), while glymphatic enrichment became brain-wide at this tional forces [73, 75].
time (D; percentage increase in tracer enrichment shown on the color
bars to the right). The tracer gadobutrol is hydrophilic and does not
pass the blood-brain barrier; instead, it remains confined to the extra-
Facilitated solute transport along subarachnoid
vascular compartment when administered intrathecally. It is a neutral perivascular subarachnoid spaces (PVSAS)
compound with a molecular weight of 604 Da. Images provided by
Lars Magnus Valnes, PhD, Department of Neurosurgery, Oslo Univer- Subpial periarterial influx of CSF constitutes a crucial
sity Hospital-Rikshospitalet
aspect of the glymphatic system [34]. In humans, facilitated
tracer transport occurs along major cerebral vessels anterior

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cerebral artery, middle cerebral artery and posterior cerebral flow in mice, without altering the localization of AQP4 to
artery within the subarachnoid space, followed by enrich- astrocytic endfeet [26].
ment of the cerebral cortex where arteries penetrate the
brain [17]. This facilitates the antegrade transport of fresh Evidence of impaired glymphatic clearance in patients
CSF along arteries towards the brain within the PVSAS,
while CSF containing waste products empties perivenously Evidence for a human glymphatic system also relies on
into the subarachnoid space outside PVSAS, to be expelled the in vivo evidence for impaired glymphatic clearance
from the subarachnoid space at arachnoid cuff exit (ACE) in patients with iNPH [16, 63] and idiopathic intracranial
points [68]. hypertension (IIH) [21].
In summary, the evidence supporting the existence and
CSF tracer dynamics from the human brain is sleep- function of the human glymphatic system is multi-faceted,
dependent encompassing various lines of inquiry and observations.

In mice, the glymphatic system primarily operates during Can the glymphatic system be considered distinct
sleep [79], whereas in humans, clearance of tracer from from the meningeal-lymphatic system?
the cerebral cortex and subcortical white matter signifi-
cantly decreases after one night of total sleep deprivation In addition to the discovery of the glymphatic system, the
[20], albeit to a lesser extent than observed in animals. One rediscovery of meningeal lymphatic vessels capable of
night of sleep deprivation also increased accumulation of draining CSF to dural and extra-dural lymphatic structures
amyloid-β in the hippocampus and thalamus of healthy vol- represented a breakthrough [3, 45]. The meningeal lym-
unteers [67]. Modeling studies also suggest a weaker effect phatic pathways may serve as a final common pathway
of sleep deprivation on tracer clearance in humans than for the clearance of substances from both the glymphatic
rodents, though the impact in humans remains demonstrable pathways and the CSF; its function impairs with age [65].
[75]. Furthermore, in patients with chronic impaired sleep While the glymphatic system is a brain-wide clearance sys-
quality, tracer enrichment and clearance in the human brain tem involving the CSF, current understanding indicates that
become altered [23]. clearance primarily occurs to the subarachnoid CSF. The
subsequent step involves clearance from the CSF, a process
Association between markers of glymphatic function and not fully explained by the glymphatic system. Obstruction
plasma biomarkers of dementia of this clearance route may exacerbate waste accumulation
(including amyloid-β, tau and α-synuclein) and dementia
The glymphatic system’s primary function is proposed to disease progression [9, 10, 54]. Therefore, the glymphatic
be the clearance of toxic waste products from brain metabo- system should not be viewed in isolation from the meningeal
lism, with impaired glymphatic clearance hypothesized to lymphatic system. Additionally, the meningeal lymphatic
underlie the abnormal aggregation of toxic waste seen in system plays a crucial role in CNS immunosurveillance,
dementia diseases. In humans, markers of glymphatic func- which may significantly impact the glymphatic system. In
tion derived from CSF tracer assessments correlate with this regard, it is worth noting that perivascular macrophages
plasma biomarkers of neurodegeneration [24]. play an important role in clearing the perivascular pathways
[11].
Role of the water channel aquaporin-4 (AQP4) for In human tracer studies, it was observed that tracer in
glymphatic transport in humans the subarachnoid CSF passed directly to the parasagittal
dura (Fig. 2) through the arachnoid membrane (although the
Indirect evidence suggests a potential role of AQP4 in glym- exact site of transport was not defined) [59], the marrow of
phatic transport in humans. Cortical biopsies from patients skull bone [60], and even to extracranial lymph nodes [18].
with idiopathic normal pressure hydrocephalus (iNPH) A significant observation is that the amount of tracer in the
demonstrate loss of perivascular AQP4 [13, 29]. The iNPH subarachnoid CSF determines the extent of tracer enrich-
patients also show impaired glymphatic enrichment [63]. ment in the parasagittal dura as well as in the brain [59,
However, further investigation is required to determine 62]. Therefore, the CSF in the subarachnoid space seems to
whether the loss of perivascular AQP4 is a causative mech- serve as a reservoir for metabolites, from which substances
anism behind the glymphatic failure. In this regard, it is are transported via lymphatic dural vessels to peripheral
worth noting that a recent study found that acute treatment lymph nodes and blood.
with the AQP4 inhibitor AER-271 inhibited glymphatic However, there has been controversy regarding how sub-
stances within the subarachnoid CSF are transported to the

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dura mater, considering the barrier properties of the arach- Idiopathic normal pressure hydrocephalus (iNPH)
noid barrier cell layer [78]. A recent significant discovery
was the identification of openings in the arachnoid barrier This disease stands out as the most extensively studied
cell layer where bridging veins pass from the cerebral cortex condition to date. In iNPH, the perivascular spaces of the
to the dura mater; these openings were delineated by arach- subarachnoid space (PVSAS) exhibit dysfunction, charac-
noid cuffs, creating arachnoid cuff exit (ACE) points in the terized by widened PVSAS areas and slowed perivascular
arachnoid where cells and substances may pass along the tracer transport [17]. This is accompanied with enhanced
perivenous basement membrane toward the dura mater [68]. tracer enrichment in the brain and slowed clearance, likely
Passage of cells and substances also occurred from outside due to impaired glymphatic transport. Notably, this impair-
to CSF. ment is evident in the entorhinal cortex [16], a region critical
Imaging the capacity of meningeal lymphatic clearance for cognitive function [51], suggesting potential clinical rel-
can pose challenges [61]. Thus, we propose evaluating from evance to the cognitive decline observed in iNPH patients.
plasma samples the CSF-to-blood clearance of an intrathe- Furthermore, this patient group demonstrates pronounced
cal tracer, as a surrogate marker of meningeal lymphatic ventricular tracer enrichment caused by tracer reflux into
clearance capacity [22]. Pharmacokinetic modeling allows the ventricles [19, 62, 63]. These findings indicate marked
for determining individual CSF-to-blood clearance capaci- alterations in solute transport within the CSF in iNPH,
ties, revealing significant inter-individual variability [31]. which may contribute to the accumulation of amyloid-β and
Just as the dose of intravenous drugs can be tailored based tau in the cerebral cortex of these patients [42]. The iNPH
on renal clearance function, as measured by the glomerular disease should be considered a combined neurodegenerative
filtration rate (GFR), so too can the dose of intrathecal drugs and CSF disease where the shunt surgery mainly addresses
be adjusted based on CSF-to-blood clearance function. the CSF component.
It’s worth noting that the primary route for CSF efflux pre-
dominantly takes place at the spinal level. Studies showed Idiopathic intracranial hypertension (IIH)
that peak plasma levels of CSF tracer [31] are observed
several hours prior to the peak enrichment of the tracer in The IIH patients also exhibit evidence of delayed brain-
the PSD [59]. Modeling studies have further suggested that wide tracer clearance [21]. This is of interest given that
approximately two-thirds of the total CSF efflux transpires IIH patients may present with cognitive impairment [80].
from the spinal canal [75]. Additionally, CSF efflux at the Additionally, this patient group presents with an increased
skull base could also be significant, as previously demon- number of enlarged white matter perivascular spaces in the
strated experimentally [1]. centrum semiovale and basal ganglia [37]. While IIH has
In summary, in the context of brain clearance, it may be traditionally been viewed as a CSF or venous obstruction
more useful to consider the glymphatic-meningeal lym- disease, observations of glymphatic failure suggest a more
phatic system as interconnected entities. widespread brain effect, which may be interpreted as consis-
tent with histopathological data [14].
What is the human evidence for glymphatic-
meningeal lymphatic system failure in Subarachnoid hemorrhage (SAH)
neurosurgical diseases?
Following SAH, increased number of enlarged white matter
In the neurosurgical community, there is a growing aware- perivascular spaces in the centrum semiovale was reported
ness of the potential implications of glymphatic failure for [38], which authors attribute to glymphatic failure. A pre-
neurosurgical diseases [2, 72]. This relates to burgeoning vious non-human primate study also provided evidence of
body of experimental literature suggesting a role of glym- glymphatic dysfunction after SAH [27].
phatic dysfunction in conditions such as edema following
subarachnoid hemorrhage [8, 25], traumatic brain injury [6, Traumatic brain injury (TBI)
33, 35], post-stroke edema [49], post-hemicraniectomy fea-
tures [56], subdural hematoma [43, 66], and primary brain Glymphatic function has to a lesser degree been studied in
tumors [32, 46]. TBI patients, but recent experimental evidence suggests a
However, the focus of this review is not on experimental crucial role of glymphatic function for brain edema [33].
animal studies but rather on the human evidence for glym- In patients with traumatic brain injury (TBI), those with
phatic failure in neurological disorders. poor sleep quality exhibit evidence of enlarged white matter
perivascular spaces [53]. Additionally, there was a signifi-
cant positive correlation between the number and volume

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of these spaces and the number of previous mild TBIs, the practice, clinically available tools are required to assess
severity of post-concussive symptoms, and post-traumatic glymphatic and meningeal lymphatic function.
balance issues [55].
Funding Open access funding provided by University of Oslo (incl
Oslo University Hospital)
Diseases affecting the spinal cord

While diseases affecting the spinal cord have not yet been
Declarations
extensively explored, there is evidence of strong glymphatic Ethical approval Not applicable.
enrichment within the spinal cord [47].
Currently, the human evidence for glymphatic altera- Consent to participate Not applicable.
tions in neurosurgical diseases remains limited. However,
it is anticipated that this landscape will evolve with further Consent for publication Not applicable.
research.
Competing interests Not applicable.

Future directions Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
Studies on glymphatic function in neurosurgical diseases adaptation, distribution and reproduction in any medium or format,
have offered new insights into disease mechanisms, yet the as long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons licence, and indicate
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tice has been minimally implemented. To the best of our article are included in the article’s Creative Commons licence, unless
knowledge, the one example is use of intrathecal contrast- indicated otherwise in a credit line to the material. If material is not
enhanced MRI in assessment of iNPH patients in our institu- included in the article’s Creative Commons licence and your intended
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phatic functions before, during, and after interventions. To org/licenses/by/4.0/.
effect change in neurosurgical practice, the evaluation of
glymphatic function must be integrated into treatments or
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