Exploring mechanisms of ventricular enlargement in idiopathic normal pressure hydrocephalus: a role of cerebrospinal fluid dynamics and motile cilia.

1 Adams RD, Fisher CM, Hakim S, et al. Symptomatic occult hydrocephalus with normal cerebrospinal-fluid pressure. A treatable syndrome.

N Eng J Med. 1965;273:117–26. https​://doi.org/10.1056/NEJM1​96507​

15273​0301 (published Online First: Epub Date).

2 Marmarou A, Bergsneider M, Relkin N, et al. Development of guidelines

for idiopathic normal-pressure hydrocephalus: introduction. Neurosurgery. 2005;57(3_Suppl):S1–3.

3. Mori E, Ishikawa M, Kato T, et al. Guidelines for management of idiopathic normal pressure hydrocephalus: second edition. Neurologia

medico-chirurgica. 2012;52(11):775–809.

4. Nakajima M, Yamada S, Miyajima M, et al.: Guidelines for Management

of Idiopathic Normal Pressure Hydrocephalus (Third Edition): Endorsed

by the Japanese Society of Normal Pressure Hydrocephalus. Neurologia

medico-chirurgica 2021:(online first) doi: https​://doi.org/10.2176/nmc.

st.2020-0292. (published Online First: Epub Date).

5 Yamada S, Ishikawa M, Iwamuro Y, et al. Choroidal fissure acts as

an overflow device in cerebrospinal fluid drainage: morphological

comparison between idiopathic and secondary normal-pressure hydrocephalus. Sci Rep. 2016;6:39070. https​://doi.org/10.1038/srep3​9070

(published Online First: Epub Date).

6 Yamada S, Ishikawa M, Yamamoto K. Fluid distribution pattern in

adult-onset congenital, idiopathic and secondary normal-pressure

hydrocephalus: implications for clinical care. Front Neurol. 2017;8:583.

https​://doi.org/10.3389/fneur​.2017.00583​ (published Online First: Epub

Date).

7 Yamada S, Ishikawa M, Yamamoto K. Optimal diagnostic indices for idiopathic normal pressure hydrocephalus based on the 3D quantitative

volumetric analysis for the cerebral ventricle and subarachnoid space.

AJNR Am J Neuroradiol. 2015;36(12):2262–9. https​://doi.org/10.3174/

ajnr.A4440​(published Online First: Epub Date).

8 Yamada S, Ishikawa M, Yamamoto K. Comparison of CSF distribution

between idiopathic normal pressure hydrocephalus and Alzheimer

disease. AJNR Am J Neuroradiol. 2016;37(7):1249–55. https​://doi.

org/10.3174/ajnr.A4695​(published Online First: Epub Date).

9 Hashimoto M, Ishikawa M, Mori E, et al. Diagnosis of idiopathic normal

pressure hydrocephalus is supported by MRI-based scheme: a prospective cohort study. Cerebrospinal Fluid Res. 2010;7:18. https​://doi.

org/10.1186/1743-8454-7-18 (published Online First: Epub Date).

10 Baledent O, Gondry-Jouet C, Meyer ME, et al. Relationship between

cerebrospinal fluid and blood dynamics in healthy volunteers and

patients with communicating hydrocephalus. Investigative Radiol.

2004;39(1):45–55. https​://doi.org/10.1097/01.rli.00001​00892​.87214​.49

(published Online First: Epub Date).

11 Bradley WG Jr, Queralt SD, et al. Normal-pressure hydrocephalus: evaluation with cerebrospinal fluid flow measurements at MR imaging. Radiology. 1996;198(2):523–9. https​://doi.org/10.1148/radio​logy.198.2.85968​

61 (published Online First: Epub Date).

12 Bradley WG Jr. CSF flow in the brain in the context of normal pressure

hydrocephalus. AJNR Am J Neuroradiol. 2014;36(5):831–8. https​://doi.

org/10.3174/ajnr.A4124​(published Online First: Epub Date).

13 Lindstrom EK, Ringstad G, Mardal KA, et al. Cerebrospinal fluid volumetric net flow rate and direction in idiopathic normal pressure hydrocephalus. NeuroImage Clin. 2018;20:731–41. https​://doi.org/10.1016/j.

nicl.2018.09.006 (published Online First: Epub Date).

14 Shanks J, Markenroth Bloch K, Laurell K, et al. Aqueductal CSF stroke

volume is increased in patients with idiopathic normal pressure hydrocephalus and decreases after shunt surgery. AJNR Am J Neuroradiol.

2019;40(3):453–9. https​://doi.org/10.3174/ajnr.A5972​ (published Online

First: Epub Date).

15 Yamada S, Miyazaki M, Kanazawa H, et al. Visualization of cerebrospinal

fluid movement with spin labeling at MR imaging: preliminary results in

normal and pathophysiologic conditions. Radiology. 2008;249(2):644–

52. https​://doi.org/10.1148/radio​l.24920​71985​ (published Online First:

Epub Date).

16 Yamada S, Tsuchiya K, Bradley WG, et al. Current and emerging MR

imaging techniques for the diagnosis and management of CSF flow

disorders: a review of phase-contrast and time-spatial labeling inversion pulse. AJNR Am J Neuroradiol. 2015;36(4):623–30. https​://doi.

org/10.3174/ajnr.A4030​(published Online First: Epub Date).

17 Yamada S, Ishikawa M, Ito H, et al. Cerebrospinal fluid dynamics in

idiopathic normal pressure hydrocephalus on four-dimensional flow

imaging. Eur Radiol. 2020;30(8):4454–65. https​://doi.org/10.1007/s0033​

0-020-06825​-6 (published Online First: Epub Date).

18 Yamada S, Ito H, Ishikawa M, et al. Quantification of oscillatory shear

stress from reciprocating CSF motion on 4D flow imaging. AJNR Am

J Neuroradiol. 2021. https​://doi.org/10.3174/ajnr.A6941​ (published

Online First: Epub Date).

19 Bradley WG Jr, Whittemore AR, Kortman KE, et al. Marked cerebrospinal

fluid void: indicator of successful shunt in patients with suspected

normal-pressure hydrocephalus. Radiology. 1991;178(2):459–66. https​://

doi.org/10.1148/radio​logy.178.2.19876​09 (published Online First: Epub

Date).

20 Olstad EW, Ringers C, Hansen JN, et al. Ciliary beating compartmentalizes cerebrospinal fluid flow in the brain and regulates ventricular

development. Curr Biol. 2019;29(2):229-41 e6. https​://doi.org/10.1016/j.

cub.2018.11.059 (published Online First: Epub Date).

21 Ohata S, Nakatani J, Herranz-Perez V, et al. Loss of dishevelleds disrupts

planar polarity in ependymal motile cilia and results in hydrocephalus. Neuron. 2014;83(3):558–71. https​://doi.org/10.1016/j.neuro​

n.2014.06.022 (published Online First: Epub Date).

22 Ohata S, Herranz-Perez V, Nakatani J, et al. Mechanosensory genes Pkd1

and Pkd2 contribute to the planar polarization of brain ventricular

epithelium. J Neurosci. 2015;35(31):11153–68. https​://doi.org/10.1523/

JNEUR​OSCI.0686-15201​52015​.2015 (published Online First: Epub Date).

23 Siyahhan B, Knobloch V, De Zelicourt D, et al. Flow induced by ependymal cilia dominates near-wall cerebrospinal fluid dynamics in the

Yamada et al. Fluids Barriers CNS

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 (2021) 18:20

lateral ventricles. J R Soc Interface. 2014;11(94):20131189. https​://doi.

org/10.1098/rsif.2013.1189 (published Online First: Epub Date).

Cushing H. The third circulation and its channels. Lancet. 1925;2:851–7.

Da Mesquita S, Louveau A, Vaccari A, et al. Functional aspects of

meningeal lymphatics in ageing and Alzheimer’s disease. Nature.

2018;560(7717):185–91. https​://doi.org/10.1038/s4158​6-018-0368-8

(published Online First: Epub Date).

Da Mesquita S, Fu Z, Kipnis J. The meningeal lymphatic system: a new

player in neurophysiology. Neuron. 2018;100(2):375–88. https​://doi.

org/10.1016/j.neuro​n.2018.09.022 (published Online First: Epub Date).

Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow

through the brain parenchyma and the clearance of interstitial solutes,

including amyloid beta. Sci Transl Med. 2012;4(147):147ra11. https​://doi.

org/10.1126/scitr​anslm​ed.30037​48 (published Online First: Epub Date).

Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional

features of central nervous system lymphatic vessels. Nature.

2015;523(7560):337–41. https​://doi.org/10.1038/natur​e1443​2 (published Online First: Epub Date).

Louveau A, Herz J, Alme MN, et al. CNS lymphatic drainage and

neuroinflammation are regulated by meningeal lymphatic vasculature.

Nature Neurosci. 2018;21(10):1380–91. https​://doi.org/10.1038/s4159​

3-018-0227-9 (published Online First: Epub Date).

Mestre H, Tithof J, Du T, et al. Flow of cerebrospinal fluid is driven by

arterial pulsations and is reduced in hypertension. Nat Commun.

2018;9(1):4878. https​://doi.org/10.1038/s4146​7-018-07318​-3 (published

Online First: Epub Date).

Nedergaard M. Neuroscience. Garbage truck of the brain. Science.

2013;340(6140):1529–30. https​://doi.org/10.1126/scien​ce.12405​14

(published Online First: Epub Date).

Ringstad G, Eide PK. Cerebrospinal fluid tracer efflux to parasagittal dura

in humans. Nat Commun. 2020;11(1):354. https​://doi.org/10.1038/s4146​

7-019-14195​-x (published Online First: Epub Date).

Kida S, Pantazis A, Weller RO. CSF drains directly from the subarachnoid

space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol. 1993;19(6):480–8.

Badano JL, Mitsuma N, Beales PL, et al. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genom Hum Genet.

2006;7:125–48. https​://doi.org/10.1146/annur​ev.genom​.7.08050​5.11561​

0 (published Online First: Epub Date).

Furey CG, Zeng X, Dong W, et al. Human genetics and molecular mechanisms of congenital hydrocephalus. World Neurosurg. 2018;119:441–3.

https​://doi.org/10.1016/j.wneu.2018.09.018 (published Online First:

Epub Date).

Zhang J, Williams MA, Rigamonti D. Genetics of human hydrocephalus.

J Neurol. 2006;253(10):1255–66. https​://doi.org/10.1007/s0041​5-0060245-5 (published Online First: Epub Date).

Abdelhamed Z, Vuong SM, Hill L, et al. A mutation in Ccdc39 causes

neonatal hydrocephalus with abnormal motile cilia development in

mice. Development. 2018. https​://doi.org/10.1242/dev.15450​0 (published Online First: Epub Date).

Banizs B, Pike MM, Millican CL, et al. Dysfunctional cilia lead to altered

ependyma and choroid plexus function, and result in the formation

of hydrocephalus. Development. 2005;132(23):5329–39. https​://doi.

org/10.1242/dev.02153​(published Online First: Epub Date).

Dawe HR, Shaw MK, Farr H, et al. The hydrocephalus inducing gene

product, Hydin, positions axonemal central pair microtubules. BMC Biol.

2007;5:33. https​://doi.org/10.1186/1741-7007-5-33 (published Online

First: Epub Date).

Doggett NA, Xie G, Meincke LJ, et al. A 360-kb interchromosomal duplication of the human HYDIN locus. Genomics. 2006;88(6):762–71. https​

://doi.org/10.1016/j.ygeno​.2006.07.012 (published Online First: Epub

Date).

Ibanez-Tallon I, Pagenstecher A, Fliegauf M, et al. Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals

a novel mechanism for hydrocephalus formation. Hum Mol Genetics.

2004;13(18):2133–41. https​://doi.org/10.1093/hmg/ddh21​9 (published

Online First: Epub Date).

Morimoto Y, Yoshida S, Kinoshita A, et al. Nonsense mutation in CFAP43

causes normal-pressure hydrocephalus with ciliary abnormalities.

Neurology. 2019;92(20):e2364–74. https​://doi.org/10.1212/WNL.00000​

00000​00750​5 (published Online First: Epub Date).

Page 9 of 11

43 Kageyama H, Miyajima M, Ogino I, et al. Panventriculomegaly with a

wide foramen of Magendie and large cisterna magna. J Neurosurg.

2016;124(6):1858–66. https​://doi.org/10.3171/2015.6.JNS.15162​

(published Online First: Epub Date).

44 Lechtreck KF, Delmotte P, Robinson ML, et al. Mutations in Hydin impair

ciliary motility in mice. J Cell Biol. 2008;180(3):633–43. https​://doi.

org/10.1083/jcb.20071​0162 (published Online First: Epub Date).

45 Roales-Bujan R, Paez P, Guerra M, et al. Astrocytes acquire morphological and functional characteristics of ependymal cells following disruption of ependyma in hydrocephalus. Acta Neuropathol.

2012;124(4):531–46. https​://doi.org/10.1007/s0040​1-012-0992-6

(published Online First: Epub Date).

46 Tissir F, Qu Y, Montcouquiol M, et al. Lack of cadherins Celsr2 and

Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus. Nat Neurosci. 2010;13(6):700–7. https​://doi.org/10.1038/nn.2555

(published Online First: Epub Date).

47 Wallmeier J, Frank D, Shoemark A, et al. De novo mutations in FOXJ1

result in a motile ciliopathy with hydrocephalus and randomization

of left/right body asymmetry. Am J Hum Genet. 2019;105(5):1030–9.

https​://doi.org/10.1016/j.ajhg.2019.09.022 (published Online First:

Epub Date).

48 Wang X, Zhou Y, Wang J, et al. SNX27 deletion causes hydrocephalus

by impairing ependymal cell differentiation and ciliogenesis. J Neurosci. 2016;36(50):12586–97. https​://doi.org/10.1523/JNEUR​OSCI.162016.2016 (published Online First: Epub Date).

49 Wodarczyk C, Rowe I, Chiaravalli M, et al. A novel mouse model

reveals that polycystin-1 deficiency in ependyma and choroid

plexus results in dysfunctional cilia and hydrocephalus. PloS One.

2009;4(9):e7137. https​://doi.org/10.1371/journ​al.pone.00071​37 (published Online First: Epub Date).

50 Yang HW, Lee S, Yang D, et al. Deletions in CWH43 cause idiopathic

normal pressure hydrocephalus. EMBO Mol Med. 2021. https​://doi.

org/10.15252​/emmm.20201​3249 (published Online First: Epub Date).

51 Ying G, Avasthi P, Irwin M, et al. Centrin 2 is required for

mouse olfactory ciliary trafficking and development of ependymal

cilia planar polarity. J Neurosci. 2014;34(18):6377–88. https​://doi.

org/10.1523/JNEUR​OSCI.0067-14.2014 (published Online First: Epub

Date).

52 Abdi K, Lai CH, Paez-Gonzalez P, et al. Uncovering inherent cellular

plasticity of multiciliated ependyma leading to ventricular wall transformation and hydrocephalus. Nat Commun. 2018;9(1):1655. https​://

doi.org/10.1038/s4146​7-018-03812​-w (published Online First: Epub

Date).

53 Nauli SM, Kawanabe Y, Kaminski JJ, et al. Endothelial cilia are fluid shear

sensors that regulate calcium signaling and nitric oxide production

through polycystin-1. Circulation. 2008;117(9):1161–71. https​://doi.

org/10.1161/CIRCU​LATIO​NAHA.107.71011​1 (published Online First:

Epub Date).

54 Takagishi M, Sawada M, Ohata S, et al. Daple coordinates planar polarized microtubule dynamics in ependymal cells and contributes to

hydrocephalus. Cell Rep. 2017;20(4):960–72. https​://doi.org/10.1016/j.

celre​p.2017.06.089 (published Online First: Epub Date).

55 Drielsma A, Jalas C, Simonis N, et al. Two novel CCDC88C mutations

confirm the role of DAPLE in autosomal recessive congenital hydrocephalus. J Med Genet. 2012;49(11):708–12. https​://doi.org/10.1136/

jmedg​enet-2012-10119​0 (published Online First: Epub Date).

56 Galbreath E, Kim SJ, Park K, et al. Overexpression of TGF-beta 1 in

the central nervous system of transgenic mice results in hydrocephalus. J Neuropathol Exp Neurol. 1995;54(3):339–49. https​://doi.

org/10.1097/00005​072-19950​5000-00007​ (published Online First: Epub

Date).

57 Jimenez AJ, Rodriguez-Perez LM, Dominguez-Pinos MD, et al. Increased

levels of tumour necrosis factor alpha (TNFalpha) but not transforming

growth factor-beta 1 (TGFbeta1) are associated with the severity of

congenital hydrocephalus in the hyh mouse. Neuropathol Appl Neurobiol. 2014;40(7):911–32. https​://doi.org/10.1111/nan.12115​ (published

Online First: Epub Date).

58 Erickson MA, Wilson ML, Banks WA. In vitro modeling of blood-brain

barrier and interface functions in neuroimmune communication. Fluids

Barriers CNS. 2020;17(1):26. https​://doi.org/10.1186/s1298​7-020-00187​

-3 (published Online First: Epub Date).

Yamada et al. Fluids Barriers CNS

(2021) 18:20

59 Kahle KT, Kulkarni AV, Limbrick DD Jr, et al. Hydrocephalus in children.

Lancet. 2016;387(10020):788–99. https​://doi.org/10.1016/S0140​

-6736(15)60694​-8 (published Online First: Epub Date).

60 Sakata-Haga H, Sawada K, Ohnishi T, et al. Hydrocephalus following

prenatal exposure to ethanol. Acta Neuropathol. 2004;108(5):393–8.

https​://doi.org/10.1007/s0040​1-004-0901-8 (published Online First:

Epub Date).

61 Omran AJA, Saternos HC, Althobaiti YS, et al. Alcohol consumption

impairs the ependymal cilia motility in the brain ventricles. Sci Rep.

2017;7(1):13652. https​://doi.org/10.1038/s4159​8-017-13947​-3 (published Online First: Epub Date).

62 Ghaffari-Rafi A, Gorenflo R, Hu H, et al. Role of psychiatric, cardiovascular, socioeconomic, and demographic risk factors on idiopathic

normal pressure hydrocephalus: a retrospective case-control study.

Clin Neurol Neurosurg. 2020;193:105836. https​://doi.org/10.1016/j.cline​

uro.2020.10583​6 (published Online First: Epub Date).

63 Hickman TT, Shuman ME, Johnson TA, et al. Association between shuntresponsive idiopathic normal pressure hydrocephalus and alcohol. J

Neurosurg. 2017;127(2):240–8. https​://doi.org/10.3171/2016.6.JNS16​

496 (published Online First: Epub Date).

64 Hudson M, Nowak C, Garling RJ, et al. Comorbidity of diabetes mellitus

in idiopathic normal pressure hydrocephalus: a systematic literature

review. Fluids Barriers CNS. 2019;16(1):5. https​://doi.org/10.1186/s1298​

7-019-0125-x (published Online First: Epub Date).

65 Jaraj D, Agerskov S, Rabiei K, et al. Vascular factors in suspected normal

pressure hydrocephalus: a population-based study. Neurology. 2016.

https​://doi.org/10.1212/WNL.00000​00000​00236​9 (published Online

First: Epub Date).

66 Rasanen J, Huovinen J, Korhonen VE, et al. Diabetes is associated with

familial idiopathic normal pressure hydrocephalus: a case-control comparison with family members. Fluids Barriers CNS. 2020;17(1):57. https​

://doi.org/10.1186/s1298​7-020-00217​-0 (published Online First: Epub

Date).

67 Fukuda M, Oishi M, Kawaguchi T, et al. Etiopathological factors related

to hydrocephalus associated with vestibular schwannoma. Neurosurgery. 2007;61(6):1186–92. https​://doi.org/10.1227/01.neu.00003​06096​

.61012​.22 (published Online First: Epub Date. discussion 92 – 3).

68 Gerganov VM, Pirayesh A, Nouri M, et al. Hydrocephalus associated

with vestibular schwannomas: management options and factors

predicting the outcome. J Neurosurg. 2011;114(5):1209–15. https​://doi.

org/10.3171/2010.10.JNS.1029 (published Online First: Epub Date).

69 Miyakoshi A, Kohno M, Nagata O, et al. Hydrocephalus associated with

vestibular schwannomas: perioperative changes in cerebrospinal fluid.

Acta Neurochir. 2013;155(7):1271–6. https​://doi.org/10.1007/s0070​

1-013-1742-9 (published Online First: Epub Date).

70 Pirouzmand F, Tator CH, Rutka J. Management of hydrocephalus

associated with vestibular schwannoma and other cerebellopontine angle tumors. Neurosurgery. 2001;48(6):1246–53. https​://doi.

org/10.1097/00006​123-20010​6000-00010​ (published Online First: Epub

Date. discussion 53 – 4).

71 Rogg JM, Ahn SH, Tung GA, et al. Prevalence of hydrocephalus in 157

patients with vestibular schwannoma. Neuroradiology. 2005;47(5):344–

51. https​://doi.org/10.1007/s0023​4-005-1363-y (published Online First:

Epub Date).

72 Tanaka Y, Kobayashi S, Hongo K, et al. Clinical and neuroimaging

characteristics of hydrocephalus associated with vestibular schwannoma. J Neurosurg. 2003;98(6):1188–93. https​://doi.org/10.3171/

jns.2003.98.6..1188 (published Online First: Epub Date).

73 Melkumyants AM, Balashov SA. Effect of blood viscocity on arterial flow

induced dilator response. Cardiovasc Res. 1990;24(2):165–8. https​://doi.

org/10.1093/cvr/24.2.165 (published Online First: Epub Date).

74 Roux E, Bougaran P, Dufourcq P, et al. Fluid shear stress sensing by the

endothelial layer. Front Physiol. 2020;11:861. https​://doi.org/10.3389/

fphys​.2020.00861​ (published Online First: Epub Date).

75 Roman GC, Verma AK, Zhang YJ, et al. Idiopathic normal-pressure

hydrocephalus and obstructive sleep apnea are frequently associated:

a prospective cohort study. J Neurol Sci. 2018;395:164–8. https​://doi.

org/10.1016/j.jns.2018.10.005 (published Online First: Epub Date).

76 Hablitz LM, Pla V, Giannetto M, et al. Circadian control of brain glymphatic and lymphatic fluid flow. Nat Commun. 2020;11(1):4411. https​

Page 10 of 11

77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 ://doi.org/10.1038/s4146​7-020-18115​-2 (published Online First: Epub

Date).

Holth JK, Fritschi SK, Wang C, et al. The sleep-wake cycle regulates

brain interstitial fluid tau in mice and CSF tau in humans. Science.

2019;363(6429):880–4. https​://doi.org/10.1126/scien​ce.aav25​46 (published Online First: Epub Date).

Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the

adult brain. Science. 2013;342(6156):373–7. https​://doi.org/10.1126/

scien​ce.12412​24 (published Online First: Epub Date).

Brown BM, Rainey-Smith SR, Villemagne VL, et al. The relationship between sleep quality and brain amyloid burden. Sleep.

2016;39(5):1063–8. https​://doi.org/10.5665/sleep​.5756 (published

Online First: Epub Date).

Kang JE, Lim MM, Bateman RJ, et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science.

2009;326(5955):1005–7. https​://doi.org/10.1126/scien​ce.11809​62

(published Online First: Epub Date).

Fultz NE, Bonmassar G, Setsompop K, et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep.

Science. 2019;366(6465):628–31. https​://doi.org/10.1126/scien​ce.aax54​

40 (published Online First: Epub Date).

Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in

neurological disorders. Lancet Neurol. 2018;17(11):1016–24. https​://

doi.org/10.1016/S1474​-4422(18)30318​-1 (published Online First: Epub

Date).

Ringstad G, Vatnehol SaS, Eide PK. Glymphatic MRI in idiopathic normal

pressure hydrocephalus. Brain. 2017;140(10):2691–705. https​://doi.

org/10.1093/brain​/awx19​1 (published Online First: Epub Date).

Ringstad G, Valnes LM, Dale AM, et al. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight. 2018.

https​://doi.org/10.1172/jci.insig​ht.12153​7 (published Online First: Epub

Date).

Taoka T, Naganawa S. Glymphatic imaging using MRI. J Magnetic

Resonance Imag. 2020;51(1):11–24. https​://doi.org/10.1002/jmri.26892​

(published Online First: Epub Date).

Ma Q, Ineichen BV, Detmar M, et al. Outflow of cerebrospinal fluid is

predominantly through lymphatic vessels and is reduced in aged mice.

Nat Commun. 2017;8(1):1434. https​://doi.org/10.1038/s4146​7-01701484​-6 (published Online First: Epub Date).

Ohayon MM, Carskadon MA, Guilleminault C, et al. Meta-analysis of

quantitative sleep parameters from childhood to old age in healthy

individuals: developing normative sleep values across the human lifespan. Sleep. 2004;27(7):1255–73. https​://doi.org/10.1093/sleep​/27.7.1255

(published Online First: Epub Date).

Mahuzier A, Shihavuddin A, Fournier C, et al. Ependymal cilia beating

induces an actin network to protect centrioles against shear stress. Nat

Commun. 2018;9(1):2279. https​://doi.org/10.1038/s4146​7-018-04676​-w

(Published Online First: Epub Date).

Liu J, Bi X, Chen T, et al. Shear stress regulates endothelial cell

autophagy via redox regulation and Sirt1 expression. Cell Death Dis.

2015;6:e1827. https​://doi.org/10.1038/cddis​.2015.193 (published Online

First: Epub Date).

Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med. 2009;6(1):16–

26. https​://doi.org/10.1038/ncpca​rdio1​397 (published Online First:

Epub Date).

Shook BA, Lennington JB, Acabchuk RL, et al. Ventriculomegaly associated with ependymal gliosis and declines in barrier integrity in the

aging human and mouse brain. Aging Cell. 2014;13(2):340–50. https​://

doi.org/10.1111/acel.12184​(published Online First: Epub Date).

Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N

Engl J Med. 1994;330(20):1431–8. https​://doi.org/10.1056/NEJM1​99405​

19330​2008 (published Online First: Epub Date).

Hahn C, Schwartz MA. Mechanotransduction in vascular physiology

and atherogenesis. Nat Rev Mol Cell Biol. 2009;10(1):53–62. https​://doi.

org/10.1038/nrm25​96 (published Online First: Epub Date).

Kouzbari K, Hossan MR, Arrizabalaga JH, et al. Oscillatory shear potentiates latent TGF-beta1 activation more than steady shear as demonstrated by a novel force generator. Sci Rep. 2019;9(1):6065. https​://doi.

org/10.1038/s4159​8-019-42302​-x (Published online First: Epub Date).

Yamada et al. Fluids Barriers CNS

(2021) 18:20

95 Ku DN, Giddens DP, Zarins CK, et al. Pulsatile flow and atherosclerosis

in the human carotid bifurcation. Positive correlation between plaque

location and low oscillating shear stress. Arteriosclerosis. 1985;5(3):293–

302. (published Online First: Epub Date).

96 Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in

atherosclerosis. Jama. 1999;282(21):2035–42. https​://doi.org/10.1001/

jama.282.21.2035. (published Online First: Epub Date).

97 Meng H, Tutino VM, Xiang J, et al. High WSS or low WSS? Complex interactions of hemodynamics with intracranial aneurysm initiation, growth,

and rupture: toward a unifying hypothesis. AJNR Am J Neuroradiol.

2014;35(7):1254–62. https​://doi.org/10.3174/ajnr.A3558​. (published

Online First: Epub Date).

98 Luu VZ, Chowdhury B, Al-Omran M, et al. Role of endothelial primary

cilia as fluid mechanosensors on vascular health. Atherosclerosis. 2018;275:196–204. https​://doi.org/10.1016/j.ather​oscle​rosis​

.2018.06.818. (published Online First: Epub Date).

Page 11 of 11

99 Pala R, Jamal M, Alshammari Q, et al. The roles of primary cilia in cardiovascular diseases. Cells. 2018. https​://doi.org/10.3390/cells​71202​33

(published Online First: Epub Date).

100 Nakajima M, Rauramaa T, Makinen PM, et al. Protein tyrosine phosphatase receptor type Q in cerebrospinal fluid reflects ependymal cell

dysfunction and is a potential biomarker for adult chronic hydrocephalus. Eur J Neurol. 2020. https​://doi.org/10.1111/ene.14575​( published

Online First: Epub Date).

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