Cerebral Arterial Pulsation Drives Paravascular CSF–Interstitial Fluid Exchange in the Murine Brain

By Jeffrey J. Iliff, Minghuan Wang, Douglas M. Zeppenfeld, A. Venkataraman, Benjamin A. Plog, Yonghong Liao, R. Deane, Maiken Nedergaard. Journal of Neuroscience, 2013

1,117 citations recorded by the source corpus.

CSF from the subarachnoid space moves rapidly into the brain along paravascular routes surrounding penetrating cerebral arteries, exchanging with brain interstitial fluid (ISF) and facilitating the clearance of interstitial solutes, such as amyloid β, in a pathway that we have termed the “glymphatic” system. Prior reports have suggested that paravascular bulk flow of CSF or ISF may be driven by arterial pulsation. However, cerebral arterial pulsation could not be directly assessed. In the present study, we use in vivo two-photon microscopy in mice to visualize vascular wall pulsatility in penetrating intracortical arteries. We observed that unilateral ligation of the internal carotid artery significantly reduced arterial pulsatility by ∼50%, while systemic administration of the adrenergic agonist dobutamine increased pulsatility of penetrating arteries by ∼60%. When paravascular CSF–ISF exchange was evaluated in real time using in vivo two-photon and ex vivo fluorescence imaging, we observed that internal carotid artery ligation slowed the rate of paravascular CSF–ISF exchange, while dobutamine increased the rate of paravascular CSF–ISF exchange. These findings demonstrate that cerebral arterial pulsatility is a key driver of paravascular CSF influx into and through the brain parenchyma, and suggest that changes in arterial pulsatility may contribute to accumulation and deposition of toxic solutes, including amyloid β, in the aging brain.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/3ef98c6deec90f15b4cd87118056f98d69e2513e

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Citations in the corpus

Vascular Contributions to Cognitive Impairment and Dementia Including Alzheimer’s Disease (2014, background): “An emerging area of interest in cerebrovascular circulation in health and disease that may help identify novel drug targets is clearance of parenchymal waste, including Ab, into the CSF via perivascular circulation (also referred to as the glymphatic system [56,57]).”
Impairment of paravascular clearance pathways in the aging brain (2014, methodology): “Impairment of glymphatic pathway function was accompanied by a 27% reduction in cerebral arterial wall pulsatility, which is an important contributor to paravascular flux along the glymphatic pathway.(7,17,26) In addition, we show that impairment of paravascular CSF–ISF exchange is similarly associa”
Revisiting the concept of CNS immune privilege (2015, background): “Both the efficiency of tracer infiltration into the brain parenchyma and its clearance from the brain are dependent on the maintenance of arteriole pulsatility [39] and CSF pressure [40,41].”
The Glymphatic System – A Beginner's Guide (2015, positive): “Other factors perhaps contributing to the reduction of glymphatic activity with aging are the decline in CSF production by 66% and CSF pressure by 27% percent [70, 87, 88].”
Glymphatic MRI in idiopathic normal pressure hydrocephalus (2017, methodology): “REF = reference subject; SU = signal unit. subarachnoid space (Iliff et al., 2012, 2013a; Bedussi et al., 2017), but contradictory to studies where intraparenchymal injection of tracers has been used (Carare et al., 2008; Bakker et al., 2016), where it was concluded with retrograde flow.”
Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury (2014, background): “We have defined a brain-wide paravascular pathway that facilitates the efficient clearance of interstitial proteins and peptides, including amyloid- , from the brain parenchyma (Iliff et al., 2012, 2013a,b; Xie et al., 2013).”