Non-invasive imaging of CSF-mediated brain clearance pathways via assessment of perivascular fluid movement with DTI MRI

Abstract

The glymphatics system describes a CSF-mediated clearance pathway for the removal of potentially harmful molecules, such as amyloid beta, from the brain. As such, its components may represent new therapeutic targets to alleviate aberrant protein accumulation that defines the most prevalent neurodegenerative conditions. Currently, however, the absence of any non-invasive measurement technique prohibits detailed understanding of glymphatic function in the human brain and in turn, it's role in pathology. Here, we present the first non-invasive technique for the assessment of glymphatic inflow by using an ultra-long echo time, low b-value, multi-direction diffusion weighted MRI sequence to assess perivascular fluid movement (which represents a critical component of the glymphatic pathway) in the rat brain. This novel, quantitative and non-invasive approach may represent a valuable biomarker of CSF-mediated brain clearance, working towards the clinical need for reliable and early diagnostic indicators of neurodegenerative conditions such as Alzheimer's disease.

Data availability

All the data has been deposited on Dryad (https://dx.doi.org/10.5061/dryad.121hs31).

The following data sets were generated

Article and author information

Author details

  1. Ian F Harrison

    UCL Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1250-4911
  2. Bernard Siow

    UCL Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Aisha B Akilo

    UCL Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Phoebe G Evans

    UCL Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Ozama Ismail

    UCL Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Yolanda Ohene

    UCL Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Payam Nahavandi

    UCL Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. David L Thomas

    Department of Brain Repair and Rehabilitation, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1491-1641
  9. Mark F Lythgoe

    UCL Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Jack A Wells

    UCL Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom
    For correspondence
    jack.wells@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4171-3539

Funding

Wellcome (Sir Henry Dale Fellowship 204624/Z/16/Z)

  • Phoebe G Evans
  • Jack A Wells

Royal Society (Sir Henry Dale Fellowship 204624/Z/16/Z)

  • Phoebe G Evans
  • Jack A Wells

Engineering and Physical Sciences Research Council (EP/N034864/1)

  • Ian F Harrison
  • David L Thomas
  • Mark F Lythgoe

National Institute for Health Research

  • Mark F Lythgoe

Medical Research Council (MR/K026739/1)

  • Mark F Lythgoe

Department of Health

  • Mark F Lythgoe

Leonard Wolfson Experimental Neurology Centre (PR/ylr/18575)

  • David L Thomas

Engineering and Physical Sciences Research Council (UCL Centre for Doctoral Training in Medical Imaging (EP/L016478/1)

  • Yolanda Ohene
  • Payam Nahavandi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were performed in accordance with the UK Home Office's Animals (Scientific Procedures) Act (1986). All procedures were minimally invasive and with a relatively high level of isoflurane for deep anesthesia throughout imaging.

Copyright

© 2018, Harrison et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,807
    views
  • 1,033
    downloads
  • 123
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ian F Harrison
  2. Bernard Siow
  3. Aisha B Akilo
  4. Phoebe G Evans
  5. Ozama Ismail
  6. Yolanda Ohene
  7. Payam Nahavandi
  8. David L Thomas
  9. Mark F Lythgoe
  10. Jack A Wells
(2018)
Non-invasive imaging of CSF-mediated brain clearance pathways via assessment of perivascular fluid movement with DTI MRI
eLife 7:e34028.
https://doi.org/10.7554/eLife.34028

Share this article

https://doi.org/10.7554/eLife.34028

Further reading

    1. Neuroscience
    Moritz F Wurm, Doruk Yiğit Erigüç
    Research Article

    Recognizing goal-directed actions is a computationally challenging task, requiring not only the visual analysis of body movements, but also analysis of how these movements causally impact, and thereby induce a change in, those objects targeted by an action. We tested the hypothesis that the analysis of body movements and the effects they induce relies on distinct neural representations in superior and anterior inferior parietal lobe (SPL and aIPL). In four fMRI sessions, participants observed videos of actions (e.g. breaking stick, squashing plastic bottle) along with corresponding point-light-display (PLD) stick figures, pantomimes, and abstract animations of agent–object interactions (e.g. dividing or compressing a circle). Cross-decoding between actions and animations revealed that aIPL encodes abstract representations of action effect structures independent of motion and object identity. By contrast, cross-decoding between actions and PLDs revealed that SPL is disproportionally tuned to body movements independent of visible interactions with objects. Lateral occipitotemporal cortex (LOTC) was sensitive to both action effects and body movements. These results demonstrate that parietal cortex and LOTC are tuned to physical action features, such as how body parts move in space relative to each other and how body parts interact with objects to induce a change (e.g. in position or shape/configuration). The high level of abstraction revealed by cross-decoding suggests a general neural code supporting mechanical reasoning about how entities interact with, and have effects on, each other.

    1. Neuroscience
    Gyeong Hee Pyeon, Hyewon Cho ... Yong Sang Jo
    Research Article Updated

    Recent studies suggest that calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) represent aversive information and signal a general alarm to the forebrain. If CGRP neurons serve as a true general alarm, their activation would modulate both passive nad active defensive behaviors depending on the magnitude and context of the threat. However, most prior research has focused on the role of CGRP neurons in passive freezing responses, with limited exploration of their involvement in active defensive behaviors. To address this, we examined the role of CGRP neurons in active defensive behavior using a predator-like robot programmed to chase mice. Our electrophysiological results revealed that CGRP neurons encode the intensity of aversive stimuli through variations in firing durations and amplitudes. Optogenetic activation of CGRP neurons during robot chasing elevated flight responses in both conditioning and retention tests, presumably by amplifying the perception of the threat as more imminent and dangerous. In contrast, animals with inactivated CGRP neurons exhibited reduced flight responses, even when the robot was programmed to appear highly threatening during conditioning. These findings expand the understanding of CGRP neurons in the PBN as a critical alarm system, capable of dynamically regulating active defensive behaviors by amplifying threat perception, and ensuring adaptive responses to varying levels of danger.