Science - USA (2020-10-02)

unappreciated role in the clearance of neuro-
toxic waste from the brain. In particular, we have
found that the brain’s fluid transport system is
designed to take advantage of cardiac pulsa-
tility to drive CSF transport in the neuropil ( 28 ).
The ejection pressure of blood from the left ven-
tricle is partly absorbed by the elastic arterial
wall of the aorta. As the ejected blood transits
the arteries, it enlarges the arterial diameter as
its pulse wave propagates downstream ( 28 ).
About 20 to 25% of the total ejected blood vol-
ume enters the CNS via the paired internal
carotid and posterior cerebral arteries. Pulsa-
tility in these large-caliber arteries constantly
transmits pressure waves along the axis of the
major vessels, as well as through the soft brain
tissue (Fig. 4). The motion of the brain is lo-
cally supplemented by the pulsatility of the
penetrating arteries, as they enter the brain
from the CSF-filled subarachnoid space, there-
by driving CSF into the neuropil along the
periarterial spaces ( 24 ). It should not be sur-
prising that heart diseases associated with
reduced cardiac output, including congestive
heart failure and atrial dysrhythmias ( 95 ), are
also associated with diminished glymphatic
flow, because the pulsatility of the cerebral ar-
teries and hence the driving forces within the
glymphatic system are reduced. Indeed, the cog-
nitive decline frequently noted in patients with a
low cardiac ejection fraction, often attributed to
low cerebral perfusion, may also reflect poor glym-
phatic flow and incomplete waste clearance, as
well as a consequent predisposition to aggregate
formation and still-slower glymphatic flow ( 95 ).
Small vessel disease (SVD) is a vascular
disorder that targets the small cerebral vessels,
in which penetrating arterioles undergo pro-
gressive thickening of their walls ( 96 ). Deteri-
oration of the vascular bed may occur alone or
in combination with other pathologies ( 97 ),
leading to progressive demyelination and loss
of white matter ( 98 ). SVD is common in pa-
tients with hypertension, many of whom are
concurrently diabetic or smokers, and it pro-
gresses silently for years before dementia is
clinically evident ( 99 ). Hypertension induces
hypertrophy of vascular smooth muscle cells,
with a stiffening of the arterial wall that damp-
ens arterial wall pulsatility and compliance,
thus reducing convective perivascular flow
( 94 , 100 ). The stiffening of the perivascular
glycocalyx of diabetic patients has a similar ef-
fect ( 101 ), and the two disorders are in frequent
combination as the incidence of obesity, a pre-
disposing factor and comorbidity to both, in-
creases worldwide. SVD is linked to glymphatic
dysfunction in experimental models ( 91 ) and
may potentiate the progression of neurodegene-
rative dementias in the same patients at risk for
SVD-associated vascular dementia. It is not sur-
prising, then, that the clinical distinctions be-
tween AD and the vascular dementias are often
blurred by their frequent co-association ( 102 ).

Outlook

Fundamentally, the studies discussed here

highlight the benefits of a good night’s sleep.

Sleep is an evolutionarily conserved mechanism

that serves multiple purposes, with benefits

to the homeostatic support of the cardiovas-

cular system, immune system, and memory

( 103 – 105 ). Yet the most fundamental incen-

tive for the brain to sleep lies in its own self-

preservation: Only the sleeping brain is capable

of efficiently clearing the waste products gen-

erated during active wakefulness. Amyloid-b,

tau, anda-synuclein are all present in the brain

extracellular fluid and CSF at higher concen-

trations during wakefulness than during sleep,

and sleep deprivation further increases these

levels ( 106 – 108 ). Indeed, positron emission

tomography imaging has shown that a single

night of sleep deprivation resulted in a significant

increase in amyloid-bburden in the hippocampus

and thalamus ( 109 ). Humans need sleep to clear

proteins from the brain extracellular space, or

these proteins will aggregate, impede fluid flow,

and potentiate further fibril polymerization.

Together with local inflammation, this pro-

cess may be expected to progressively suppress

glymphatic flow in the most affected regions.

Overall, these observations suggest a causal

linkage between the sleep-wake cycle and its

regulation of fluid flow via the glymphatic sys-

tem, and thereby the modulation of the balance

between protein clearance and aggregation.

As such, the observations suggest a basis for the

increased incidence of protein aggregation–

related disorders that occur with aging, the

appearance of which tracks age-related declines

in both vascular health and glymphatic pat-

ency. The neurodegenerative dementias may

thus be viewed as the products of a final com-

mon pathway that integrates the dysfunction

of any and all of these closely interdependent

upstream mechanisms (Fig. 3). These various

processes are linked in their regulation by the

brain’s glymphatic system, the directed regu-

lation of which may, in turn, present new

therapeutic opportunities for the disease-

modifying treatment of patients with these

disorders ( 75 ). In particular, the development

of small-molecule agonists of glymphatic efflux

might present opportunities to slow disease

progression in the aggregation disorders, just

as the optimization of cardiovascular health

might be expected to delay disease onset. These

systems are intimately connected such that

modulation of glymphatic flow, and hence

protein clearance from the brain, will ulti-

mately require a deeper understanding of the

dependence of both glymphatic and lymphatic

flow on intracardiac pressures.

Recent advances in neuroimaging have pro-

vided multiple approaches to map the human

glymphatic system and to assess its functional

competence in the context of disease, as well as

the effects thereof on sleep-dependent glymphatic

cycling ( 72 , 73 , 108 , 110 ). The diagnostic neuroim-

aging of glymphatic function via such“glympho-

grams”may provide both a means to predict the

risk of developing proteinopathies and an ap-

proach by which to evaluate the efficacy of

glymphatic flow–directed treatments as they

are developed. Until then, the most assured means

of preserving effective glymphatic clearance is

to get a good night’s sleep.

REFERENCESANDNOTES

1. B. A. Manderet al.,Nat. Neurosci. 16 , 357–364 (2013).


2. K. Spiegelhalder, W. Regen, S. Nanovska, C. Baglioni,
   D. Riemann,Curr. Psychiatry Rep. 15 , 364 (2013).


3. A. P. Spira, L. P. Chen-Edinboro, M. N. Wu, K. Yaffe,
   Curr. Opin. Psychiatry 27 , 478–483 (2014).


4. L. Leigh, I. L. Hudson, J. E. Byles,J. Sleep Res. 24 , 648–657 (2015).


5. E. Aserinsky, N. Kleitman,Science 118 , 273–274 (1953).


6. J. A. Hobson,Nature 437 , 1254–1256 (2005).


7. A. A. Borbély,Hum. Neurobiol. 1 , 195–204 (1982).


8. A. V. Rodriguezet al.,J. Neurosci. 36 , 12436–12447 (2016).


9. M. Massimini, R. Huber, F. Ferrarelli, S. Hill, G. Tononi,
   J. Neurosci. 24 , 6862–6870 (2004).


10. S. M. Rajaratnam, M. E. Howard, R. R. Grunstein,Med. J. Aust.
    199 , S11–S15 (2013).


11. G. Kecklund, J. Axelsson,BMJ 355 , i5210 (2016).


12. O. Itaniet al.,Sleep Med. 39 , 87–94 (2017).


13. K. Bokenbergeret al.,Eur. J. Epidemiol. 33 , 977–987 (2018).


14. G. Tononi, C. Cirelli,Neuron 81 , 12–34 (2014).


15. V. V. Vyazovskiy, C. Cirelli, M. Pfister-Genskow, U. Faraguna,
    G. Tononi,Nat. Neurosci. 11 , 200–208 (2008).


16. R. Huberet al.,Cereb. Cortex 23 , 332–338 (2013).


17. J. Logothetis, I. Milonas, S. Bostantzopoulou,Eur. Neurol. 25
    (suppl. 2), 134–140 (1986).


18. L. de Vivoet al.,Science 355 , 507–510 (2017).


19. S. B. Noyaet al.,Science 366 , eaav2642 (2019).


20. F. Brüninget al.,Science 366 , eaav3617 (2019).


21. D. C. Rubinsztein,Nature 443 , 780–786 (2006).


22. P. Ballabh, A. Braun, M. Nedergaard,Neurobiol. Dis. 16 ,1–13 (2004).


23. T. A. Thibaudeau, R. T. Anderson, D. M. Smith,Nat. Commun.
    9 , 1097 (2018).


24. J. J. Iliffet al.,Sci. Transl. Med. 4 , 147ra111 (2012).


25. M. Nedergaard,Science 340 , 1529–1530 (2013).


26. M. Simard, G. Arcuino, T. Takano, Q. S. Liu, M. Nedergaard,
    J. Neurosci. 23 , 9254–9262 (2003).


27. J. Tithof, D. H. Kelley, H. Mestre, M. Nedergaard,
    J. H. Thomas,Fluids Barriers CNS 16 , 19 (2019).


28. H. Mestreet al.,Nat. Commun. 9 , 4878 (2018).


29. E. A. Nagelhus, O. P. Ottersen,Physiol. Rev. 93 , 1543–1562 (2013).


30. H. Mestreet al.,eLife 7 , e40070 (2018).


31. H. Mestreet al.,Science 367 , eaax7171 (2020).


32. M. Braun, J. J. Iliff,Int. Rev. Neurobiol. 154 , 413–436 (2020).


33. X. Wanget al.,Sci. Transl. Med. 12 , eaaw3210 (2020).


34. H. Mestre, Y. Mori, M. Nedergaard,Trends Neurosci. 43 , 458–466 (2020).


35. L. Xieet al.,Science 342 , 373–377 (2013).


36. L. M. Hablitzet al.,Sci. Adv. 5 , eaav5447 (2019).


37. L. Hauglund, C. Pavan, M. Nedergaard,Curr. Opin. Physiol. 15 ,
    1 – 6 (2020).


38. L. Hablitzet al.,Nat. Commun. 11 , 4411 (2020).


39. A. Louveauet al.,Nature 523 , 337–341 (2015).


40. A. Aspelundet al.,J. Exp. Med. 212 , 991–999 (2015).


41. C. B. Brøchner, C. B. Holst, K. Møllgård,Front. Neurosci. 9 , 75 (2015).


42. J. H. Ahnet al.,Nature 572 , 62–66 (2019).


43. Q. Maet al.,Acta Neuropathol. 137 , 151–165 (2019).


44. Q. Ma, Y. Decker, A. Müller, B. V. Ineichen, S. T. Proulx,
    J. Exp. Med. 216 , 2492–2502 (2019).


45. L. Jacobet al.,Nat. Commun. 10 , 4594 (2019).


46. A. Louveauet al.,J. Clin. Invest. 127 , 3210–3219 (2017).


47. M. Pappollaet al.,Neurobiol. Dis. 71 , 215–219 (2014).


48. J. P. Scallan, S. D. Zawieja, J. A. Castorena-Gonzalez,
    M. J. Davis,J. Physiol. 594 , 5749–5768 (2016).


49. B. Jakic, D. Kerjaschki, G. Wick,Gerontology10.1159/000508459 (2020).


50. S. Da Mesquitaet al.,Nature 560 , 185–191 (2018).


51. L. Wanget al.,Brain Pathol. 29 , 176–192 (2019).


52. B. T. Kresset al.,Ann. Neurol. 76 , 845–861 (2014).


53. H. Benvenisteet al.,Gerontology 65 , 106–119 (2019).


54. Y. Zhouet al.,Ann. Neurol. 87 , 357–369 (2020).


55. W. Penget al.,Neurobiol. Dis. 93 , 215–225 (2016).


56. J. J. Iliffet al.,J. Neurosci. 34 , 16180–16193 (2014).


57. W. Zouet al.,Transl. Neurodegener. 8 , 7 (2019).


58. S. Sundaramet al.,Neurosci. Biobehav. Rev. 103 , 305–315 (2019).

SCIENCEsciencemag.org 2 OCTOBER 2020•VOL 370 ISSUE 6512 55