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Figure legends

Figure 1: Outline of the glymphatic system and concept of “common space” in the brain.

Figure 1a illustrates that perivascular clearance comprises perivascular drainage and the

glymphatic pathways. Cerebrospinal fluid (CSF) flows into the brain parenchyma via the

periarterial space and enters the interstitial space of the brain tissue via AQP4-controlled water

channels, which are localized to the end feet of astrocytes which form the outer wall of the

perivascular space. CSF entering the interstitial space removes waste proteins from the tissue,

then flows into the perivenous space and is discharged outside the brain.

Figure 1b illustrates the concept of “common space” within the brain. The interstitial and CSF

spaces of the brain are regarded as common space, which act not only as supportive structures but

also function as spaces for mass transport, immune function, or intercellular signal transmission.

The common space is filled with “neurofluids”, a term referring to all types of fluids which

comprise the CNS, including CSF, ISF, and blood, and fluid exchange occurs among these

“neurofluid” compartments.

Figure 2: CSF and brain parenchymal contrast enhancement at multiple time points after

intrathecal GBCA administration

Reconstructed T1-weighted images in sagittal (top row), axial (middle row) and coronal (bottom

row) planes from MRI at baseline (before contrast agent administration) and at four subsequent

imaging time points demonstrating time-dependent contrast enhancement of the subarachnoid and

intraventricular spaces in an iNPH patient (a) and a reference subject (b). Reflux of gadobutrol

into the lateral ventricles is a typical feature of iNPH. In the reference subject, retrodural contrast

enhancement can be seen in the sagittal images (top row) at the 1 h, 3 h and 4.5 h time points and

is indicative of CSF leakage.

Used from reference (20) : Public Domain Material.

Figure 3: GBCA leakage from the cortical veins into the cerebrospinal fluid after

intravenous administration

Images from a 49-year-old woman with suspicion of endolymphatic hydrops (a). These images

were obtained 4 h after intravenous administration of a single dose of gadolinium-based contrast

agent. The CSF around the cortical veins shows a high signal intensity on three-dimensional real

inversion recovery (3D-real IR) images (arrows). Images from a 17-year-old woman with a

suspicion of endolymphatic hydrops (b). Enhancement in the CSF around the cortical veins was

not observed in this young patient.

Used from reference (26) : Public Domain Material.

Figure 4: Distribution of GBCA in the perivascular space after intravenous injection

Magnetic resonance cisternography (MRC) from a 71-year-old woman with suspected

endolymphatic hydrops. There is much perivascular space (PVS) in the bilateral basal ganglia (a,

arrows). In the pre-contrast heavily T2-weighted FLAIR (hT2-FL) images (b), the PVS has a lowsignal intensity. In post-contrast hT2-FL images (c), the PVS has an increased signal intensity

(arrows). The CSF also shows an increased signal. Note that some regions of the PVS have a

higher signal than the CSF.

Used from reference (23) : Public Domain Material.

Figure 5: Hypothesized mechanism of gadolinium deposition via the glymphatic system

Schematic illustrating our hypothesis for gadolinium deposition. Compared with GBCA in

systemic circulation, GBCA that is distributed into the CSF cavity via the glymphatic system can

remain in brain tissue for an extended period of time. The authors of this review speculate that

the glymphatic system may contribute to the tissue deposition of gadolinium.

Used from reference (32) : Public Domain Material.

Figure 6: Dynamic curves of relative signals after injection of 17O-labeled water

Dynamic curves of relative signal intensity. A bolus injection of saline or 17O was initiated 120 s

after starting a scan. Significant drops in signal were observed in the cerebral cortex (a), choroid

plexus (d), ventricle (e), and subarachnoid space (f) in the

17

O condition, while only slight

reductions in signal were noted in the basal ganglia/thalamus (b) and white matter (c). In the

cerebral cortex, choroid plexus, and subarachnoid space, the curves are characterized by two

phases: an initial signal drop and a plateau phase. In the ventricle, the signals gradually and

continuously decreased during the acquisition window.

Used from reference (34) : Public Domain Material.

Figure 7: Concept behind the method of diffusion tensor image analysis along the

perivascular space (DTI-ALPS) and outcomes in cases of Alzheimer’s disease

(a) Roentgenogram of an injected coronal brain slice showing parenchymal vessels that run

horizontally within the slice (white box) at the level of the lateral ventricle body. Reproduced with

permission from reference (50). (b) Axial SWI within the slice at the level of the lateral ventricle

body indicates that parenchymal vessels run laterally (x-axis). (c) Superimposed color display of

DTI onto the SWI (b) showing the distribution of projection fibers (z-axis, blue), association

fibers (y-axis, green), and subcortical fibers (x-axis, red). Three ROIs were placed in the area with

the projection fibers (projection area), association fibers (association area) and subcortical fibers

(subcortical area) to measure diffusivities in the three directions (x, y, z). (d) Schematic indicating

the relationship between the orientation of the perivascular space (gray cylinders) and the

directions of the fibers. Note that the orientation of the perivascular space is perpendicular to both

the projection and association fibers. (e-g) Correlation between directional diffusivity and MMSE

scores for the three directions of the three areas (projection, e; association, f; subcortical, g).

Diffusivity of the x-axis is plotted in red, y-axis in green, and z-axis in blue. Regression lines are

also shown in the same colors with the plots, accompanied by values for the correlation coefficient.

Statistically significant correlations are shown as asterisks. In the projection area (e), we found a

significant positive correlation between the diffusivity along the perivascular space (x-axis) and

MMSE scores. In the association area (f), we found a significant positive correlation between the

diffusivity along the perivascular space (x-axis) and MMSE scores. Conversely, there was a

significant negative correlation between the diffusivity along the projection fibers (z-axis) in the

projection area and MMSE scores. There was also a significant negative correlation between the

association fibers (y-axis) in the association area and MMSE scores. These negative correlations

may be explained by white matter degeneration in the projection or association fibers due to AD

or MCI. (h) Correlation between the ALPS-index and MMSE. Correlations between MMSE and

the ALPS-index determined by the following ratio are shown:

ALPS-index = mean (Dxproj, Dxassoc)/mean (Dyproj, Dzassoc).

There was a significant positive correlation (r = 0.46, p = 0.0084) between the ALPS-index and

MMSE scores.

Used from reference (49) with permission.

Arteries

CSF

CSF

Waste

Basement membrane

Veins

AQP4

Basement membrane

Figure 1

Glia cells

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Intravenous administration

Choroid plexus? Cranial nerve endings?

Capillaries surrounding perivascular space?

Venous wall?

Cervical

Lymphatic

system

Cerebrospinal

fluid

Perivascular space

（Artery）

Glymphatic

system

Interstitial

space

Tissue deposition

Perivascular space

（Vein）

Macrocyclic GBCA：Chelate is stable

Linear GBCA: Possibility of de-chelation

Figure 7

Figure 8

Projection area

Subcortical

area

Perivascular space

Association area

1.5

r=0.40*

0.5

r=0.50*

0.5

r=-0.32

r=-0.13

0.5

r=-0.10

r=-0.24

20

ADC(mm2/s)

10

r=-0.35

r=-0.55*

ADC(mm2/s)

ADC(mm2/s)

r=-0.62*

30

10

20

30

10

20

MMSE

MMSE

MMSE

Subcortical area

1.5

1.5

Association area

Association area

Projection area

Projection area

30

Dx

Dy

Dz

Subcortical area

...