Cerebrospinal Fluid Flow Dynamics and

The Glymphatic System

Geir Ringstad, MD PhD

Senior Consultant Neuroradiologist Head, Neuroimaging Research Group

Oslo University Hospital, Norway

ECNR 2021

Disclosures / Conflicts of Interest

• Speaker for Bayer

• Chairman and share holder, BrainWideSolutions AS

CSF circulation disorders IIH Chiari CSF leakage Arachnoid cysts Syringomyelia Hydrocephalus

1926: «The third circulation»

Harvey Cushing (1869-1939)

2021: CSF flow is influenced by:

• Cardiac pulsations

• Respiration

• Posture/gravity

• Sleep

• Neuronal activity

• ++ (?)

Cardiac beat related pulsatile CSF flow

Baledent, 2014

Cardiac beat derived effects on CBF and CSF flow

Level Th2

Dreha-Kulaczewski et al. (J Neurosci, 2015) Dreha-Kulaczewski et al. (J Neurosci, 2017)

Aqueduct level

Reversed aqueductal flow in infants ˂ 2 yrs

Bateman and Brown (Childs Nerv Syst, 2012)

Reversed aqueductal flow in iNPH

Ringstad et al. (Brain, 2017)

24 min post ITH 24 hours post ITH

ITH = intrathecal

Cranially directed net CSF flow at CCJ level

Lindstøm et al., 2018

Upward

Combined

Downward

T2 T1 24 hrs after intrathecal contrast

Persistent Blake`s pouch diagnosed at 24 years of age

Lam et al., Sci Rep, 2017

PVS of the spinal cord communicate with SAS

Lawley et al., J Physiol, 2017 PVS = perivascular space SAS = subarachnoid space Roberts et al. (NEJM 2017)

Effects of Spaceflight on Astronaut Brain Structure as Indicated on MRI

~ 6 months in space

CSF inflow at 4th ventricle is coupled to BOLD signal at sleep

Fultz et al. (Science, 2019)

The glia-lymphatic («glymphatic») system

Iliff et al. (Sci Transl Med, 2012))

Arterial pulsatility propels fluid flow in the brain

Nedergaard and Goldman (Science 2020) Mestre et al. (Nat. Comms , 2018)

Nagelhus and Ottersen (Physiol Rev, 2013) From: Wollburg et al.

Aquaporin 4 channels

Iliff et al. Sci Transl (2012)

Reduced Clearance of Amyloid-β in Aqp4-/- mice

WT = Wild Type Aqp4-/- = Aquaporin-4 knockout

Herculano-Houzel, Science 2013 Xie et al, Science 2013

The glymphatic system: Clearing your mind during sleep

Nedergaard and Goldman (Science, 2020)

Causes and effects of glymphatic failure

From: Reeves BC et al. (2020)

gMRI

• Hydrophilic • 604 Da • Hydraulic diameter < 2 nm • Macrocyclic - stable • Not metabolized • No protein binding • Contained outside BBB

Gadobutrol as CSF tracer Gd3+

Is there a perivascular space in human cortex? (Can glymphatic brain enhancement be expected?)

BBrain-wide enhancement of CSF tracer in human subject

Ringstad et al. (JCI Insight, 2018)

% nSU increase

Molecular size of some intrathecally used therapeutic agents

Baclofen: 0,2 kD Cytarabine: 0,3 kD Hydrocortisone: 0,3 kD Methotrexate: 0,4 kD Spinraza: 7,5 kD

Gadobutrol: 0,6 kD (~2 nm hydr diam) PVS diam.: 5-10 μm

T1 “black blood” w/ith gad.

gMRI

Pizzo et al. (J Physiol, 2018)

Brain-wide enhancement in iNPH

Ringstad et al. (JCI Insight, 2018) Ringstad et al. (Brain, 2017)

Science, 2020

Glymphatic failure as common pathway for proteinopathies?

JCI Insight, 2018

Delayed clearance of CSF tracer in iNPH

Ringstad et al. JCI Insight, 2018

Ref, 24h iNPH, 24h

Glymphatic system

Iliff et al. (Sci Transl Med, 2012)

Meningeal lymphatics

Louveau et al. (Nature, 2015)

Da Mesquita et al. (Neuron, 2018)

Glymphatic clearance depends on CSF (lymphatic) clearance

Romanova et al. (bioRxiv, 2019)

Lymphatic ligation accelerates Alzheimer’s pathology in meninges & cognitively important brain regions

+ + + +

3 h 24 h

T1 «black blood» T1 «black blood»

FLAIR

The parasagittal dura (PSD)

From : Fox R et al. Anatomic details of intradural channels in the parasagittal dura: A possible pathway for flow of cerebrospinal fluid

(Neurosurgery, Vol. 39, No.1, July 1996)

C: Intradural channels

T1-BB pre T1-BB 3 h

T1-BB 6 h T1-BB 24 h T1-BB 48 h

0 %

0 %

143 %

250 %

299 %

491 %

414 %

583 %

299 %

491 %

T2-FLAIR

CSF tracer efflux to parasagittal dura

Ringstad and Eide (Nat Comm, 2020)

Kutomi O and Takeda S Microscopy, 2020

Endothelial lined gaps exist in parasagittal dura:

Da Mesquita et al. (Neuron, 2018)

CSF connects brain glymphatics with the immune system

Ringstad and Eide (Nat Comm, 2020) Rustenhoven and Kipnis (Science, 2019)

24 timer post IT 48 timer post IT

Images: Tomas Sakinis, MD

48 timer post IT

Ringstad and Eide (Nat Comm, 2020)

CSF tracer accumulates around parasagittal dura at late time points

In submission, Jan 2021 Jacob et al., Nat Comms 2019

EEvidence of significant spinal CSF clearance

Conclusions:

• The complexity of CSF dynamics is high, our understanding is incomplete

• CSF within the SAS is continuous with all brain regions • Healthy arteries and sleep are important for normal function of the glymphatic system • The glymphatic system and meningeal lymphatics add a metabolic and immunological dimension to CSF flow

MRI markers of CSF tracer dynamics in iNPH

Eide et al. (Brain Comms, 2020)

Future prospect : Extra-vascular CE MRI?

Cuddapah et al. (Nat Reviews Neuroscience, 2014)

?

Kilsdonk et al. (Brain, 2016)

?

Glioma

MS

T2 gMRI

gMRI DIR

Future prospects: Pre-clinical AD diagnosis? Suggested reading: • Nedergaard M and Goldman SA. Glymphatic failure as a final common pathway to dementia (Science, 2020) • Da Mesquita S, Fu Z, Kipnis J. The meningeal lymphatic system: A new player in neurophysiology (Neuron, 2018) • Rustenhoven J and Kipnis J. Bypassing the blood-brain-barrier (Science, 2019)

• Pizzo ME, Wolak DJ, Kumar NN et al. Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery (J Physiol, 2018) • Wardlaw JM, Benveniste H, Nedergaard M et al. Perivascular spaces in the brain: anatomy, physiology and pathology (Nature reviews, 2020)

E-mail: gringsta@ous-hf.no