Page 72 - TI Journal 18-1

66 HUFFMAN ET. AL

clearance from the interstitium, the glymphatic retrograde to blood flow occur within the vessel walls
flow hypothesis offers an alternative explanation. of arteries and capillaries, enabling the movement of
Expanding prior research on perivascular flow solutes and waste along the basement membrane of
(33,63,64,71,83), Iliff and colleagues employed in the vascular smooth muscle (4,10,11,53). On the other
vivo two-photon microscopy to visualize the flow of hand, glymphatic flow utilizes the space between the
CSF from the SAS into the parenchyma via periarte- basement membrane of the vascular smooth muscle
rial spaces in real time (36). Their findings revealed a and astrocyte endfeet and is involved with CSF-ISF
pathway of bulk flow allowing CSF to directly interact exchange (36). Such models may help explain these
with ISF in the interstitium (36). seemingly opposing mechanisms; however, more
The exchange of CSF-ISF is a core aspect of the research is required to understand whether inconsis-
glymphatic hypothesis and is grounded by the flow of tent results (4,8,36) stem from anatomical differences
subarachnoid CSF into the parenchyma along periar- (31,53) or unknown physiological conditions (31,66).
terial pathways, across astrocyte endfeet, and into the
interstitium (Figure 1). As CSF interacts with ISF, bulk Meningeal Lymphatic Vessels
flow facilitates the movement of solutes and metabolic The anatomical pathways by which CSF-ISF efflux
waste toward perivenous pathways surrounding large from glymphatic flow reaches the cervical lymphatics
draining veins and white matter tracks (36). Fluids remain controversial but are thought to drain into
entering these perivenous pathways drain from the and spread from the SAS (66). Recent research has
parenchyma to the SAS and eventually to the cervical revealed novel meningeal lymphatic vessels associated
lymphatics. with the dural sinuses of mice that may redefine the
CSF-ISF exchange in the brain interstitium is immunological basis of CNS function (5,50).
heavily reliant on the protein aquaporin-4 (AQP4), Fluorescent tracers injected into the cisterna
a water channel present on astrocyte endfeet that magna and parenchyma drain along the lymphatic
aids the movement of fluid in and out of perivascular vessels of the meninges to the deep cervical lymph
spaces (36). Earlier studies have shown that basic nodes (5,50). Of these lymphatic vessels identified so
diffusion is not sufficient for moving large molecular far, all have been shown to exit the base of the skull
weight tracers over distances suitable for clearing the along draining veins, cranial nerves, and the ptery-
interstitial space, thus a system of ISF bulk flow must gopalatine artery connected to the internal carotid
exist (1). According to the glymphatic hypothesis, the artery (5). Others have also used the technique of in
convective flow of CSF into the interstitial space is vivo hyperspectral imaging to show that quantum
a key mechanism involved in the removal of solutes dot fluorescent nanoparticles injected into the cis-
and metabolic waste from the interstitium. When terna magna drain to the cervical lymph nodes (51).
Iliff and colleagues utilized AQP4 knockout mice Although unable to identify specific efflux pathways,
to examine the relation between this water channel hyperspectral imaging with quantum dots may prove
and solute clearance, their observations revealed that to be a uniquely noninvasive technique for gauging
the removal of soluble Aβ was reduced by ~65% (36). lymphatic drainage of the brain. Taken together, these
Thus, the AQP4 water channel is a main facilitator of findings provide convincing evidence that the CNS
CSF-ISF exchange. is far more connected to the peripheral environment
Although the glymphatic hypothesis may simply than previously considered.
be an extension to the retrograde flow of ISF, it is The meningeal lymphatic vessels have been recog-
again important to note that scenarios permitting nized as a main route for CSF-ISF efflux from the SAS
the efflux of ISF along periarterial pathways over (35). As reviewed in Simon and Iliff, glymphatic flow
glymphatic flow, or vice versa, remain to be deter- drains parenchymal fluid along perivenous tracks to
mined. Figure 1 represents both mechanisms and how cisterns and may enable the communication between
these different models may be associated with fluid these lymphatic vessels and perivascular drainage
movement and waste clearance. Pathways of ISF efflux (66). Such models have claimed that dural lymphatic