Impaired Glymphatic Transport in Spontaneously Hypertensive Rats

Kristian Nygaard Mortensen; Simon Sanggaard; Humberto Mestre; Hedok Lee; Serhii Kostrikov; Anna L R Xavier; Albert Gjedde; Helene Benveniste; Maiken Nedergaard

doi:10.1523/jneurosci.1974-18.2019

Impaired Glymphatic Transport in Spontaneously Hypertensive Rats

Kristian Nygaard Mortensen, Simon Sanggaard, Humberto Mestre, Hedok Lee, Serhii Kostrikov, Anna L R Xavier, Albert Gjedde, Helene Benveniste, Maiken Nedergaard

Neuropharm and Genetics

30 Citationer (Scopus)

Abstract

The glymphatic system is a brainwide CSF transport system that uses the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna during dynamic contrast-enhanced MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared with WKY rats, regardless of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded glymphatic transport of Gd-DOTA in SHR compared with WKY rats in both age groups, implying that glymphatic transport, including solute clearance from brain parenchyma, is impaired during evolving hypertension in young SHR, an effect that worsens in states of chronic hypertension. The study demonstrates the suppression of glymphatic clearance in SHR rats and thus offers new insight into the coexistence of hypertension and concomitant vascular pathologies in Alzheimer’s disease. The study further highlights the importance of considering the distribution of tracers in the CSF compartment in the analysis of the glymphatic system.

Originalsprog	Engelsk
Tidsskrift	The Journal of neuroscience : the official journal of the Society for Neuroscience
Vol/bind	39
Udgave nummer	32
Sider (fra-til)	6365-6377
Antal sider	23
ISSN	0270-6474
DOI	https://doi.org/10.1523/jneurosci.1974-18.2019
Status	Udgivet - 7 aug. 2019

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10.1523/jneurosci.1974-18.2019

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abstract = "The glymphatic system is a brainwide CSF transport system that uses the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna during dynamic contrast-enhanced MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared with WKY rats, regardless of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded glymphatic transport of Gd-DOTA in SHR compared with WKY rats in both age groups, implying that glymphatic transport, including solute clearance from brain parenchyma, is impaired during evolving hypertension in young SHR, an effect that worsens in states of chronic hypertension. The study demonstrates the suppression of glymphatic clearance in SHR rats and thus offers new insight into the coexistence of hypertension and concomitant vascular pathologies in Alzheimer{\textquoteright}s disease. The study further highlights the importance of considering the distribution of tracers in the CSF compartment in the analysis of the glymphatic system.",

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AU - Sanggaard, Simon

AU - Mestre, Humberto

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AU - Kostrikov, Serhii

AU - Xavier, Anna L R

AU - Gjedde, Albert

AU - Benveniste, Helene

AU - Nedergaard, Maiken

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AB - The glymphatic system is a brainwide CSF transport system that uses the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna during dynamic contrast-enhanced MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared with WKY rats, regardless of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded glymphatic transport of Gd-DOTA in SHR compared with WKY rats in both age groups, implying that glymphatic transport, including solute clearance from brain parenchyma, is impaired during evolving hypertension in young SHR, an effect that worsens in states of chronic hypertension. The study demonstrates the suppression of glymphatic clearance in SHR rats and thus offers new insight into the coexistence of hypertension and concomitant vascular pathologies in Alzheimer’s disease. The study further highlights the importance of considering the distribution of tracers in the CSF compartment in the analysis of the glymphatic system.

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JO - The Journal of neuroscience : the official journal of the Society for Neuroscience

JF - The Journal of neuroscience : the official journal of the Society for Neuroscience

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ER -

Impaired Glymphatic Transport in Spontaneously Hypertensive Rats

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