Abstract

We mapped the distribution of atrophy in Parkinson's Disease (PD) using MRI and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation.

Article and author information

Author details

  1. Yashar Zeighami

    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Miguel Ulla

    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Yasser Iturria-Medina

    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Mahsa Dadar

    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Yu Zhang

    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Kevin Michel-Herve Larcher

    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Vladimir Fonov

    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Alan C Evans

    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Douglas Louis Collins

    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Alain Dagher

    McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
    For correspondence
    alain.dagher@mcgill.ca
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Human subjects: For the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data)Each participating PPMI site received approval from a local research ethics committee before study initiation, and obtained written informed consent from all subjects participating in the study.For the resting state fMRI data collected in our lab, We acquired resting state fMRI in 51 healthy, right-handed volunteers.The experimental protocol was reviewed and approved by Research Ethics Board of Montreal Neurological Institute. All subjects gave informed consent.

Copyright

© 2015, Zeighami 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

  • 6,995
    views
  • 1,380
    downloads
  • 201
    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. Yashar Zeighami
  2. Miguel Ulla
  3. Yasser Iturria-Medina
  4. Mahsa Dadar
  5. Yu Zhang
  6. Kevin Michel-Herve Larcher
  7. Vladimir Fonov
  8. Alan C Evans
  9. Douglas Louis Collins
  10. Alain Dagher
(2015)
Network structure of brain atrophy in de novo Parkinson's Disease
eLife 4:e08440.
https://doi.org/10.7554/eLife.08440

Share this article

https://doi.org/10.7554/eLife.08440

Further reading

    1. Neuroscience
    Yi-Yun Ho, Qiuwei Yang ... Melissa R Warden
    Research Article

    The infralimbic cortex (IL) is essential for flexible behavioral responses to threatening environmental events. Reactive behaviors such as freezing or flight are adaptive in some contexts, but in others a strategic avoidance behavior may be more advantageous. IL has been implicated in avoidance, but the contribution of distinct IL neural subtypes with differing molecular identities and wiring patterns is poorly understood. Here, we study IL parvalbumin (PV) interneurons in mice as they engage in active avoidance behavior, a behavior in which mice must suppress freezing in order to move to safety. We find that activity in inhibitory PV neurons increases during movement to avoid the shock in this behavioral paradigm, and that PV activity during movement emerges after mice have experienced a single shock, prior to learning avoidance. PV neural activity does not change during movement toward cued rewards or during general locomotion in the open field, behavioral paradigms where freezing does not need to be suppressed to enable movement. Optogenetic suppression of PV neurons increases the duration of freezing and delays the onset of avoidance behavior, but does not affect movement toward rewards or general locomotion. These data provide evidence that IL PV neurons support strategic avoidance behavior by suppressing freezing.

    1. Neuroscience
    Brian C Ruyle, Sarah Masud ... Jose A Morón
    Research Article

    Millions of Americans suffering from Opioid Use Disorders face a high risk of fatal overdose due to opioid-induced respiratory depression (OIRD). Fentanyl, a powerful synthetic opioid, is a major contributor to the rising rates of overdose deaths. Reversing fentanyl overdoses has proved challenging due to its high potency and the rapid onset of OIRD. We assessed the contributions of central and peripheral mu opioid receptors (MORs) in mediating fentanyl-induced physiological responses. The peripherally restricted MOR antagonist naloxone methiodide (NLXM) both prevented and reversed OIRD to a degree comparable to that of naloxone (NLX), indicating substantial involvement of peripheral MORs to OIRD. Interestingly, NLXM-mediated OIRD reversal did not produce aversive behaviors observed after NLX. We show that neurons in the nucleus of the solitary tract (nTS), the first central synapse of peripheral afferents, exhibit a biphasic activity profile following fentanyl exposure. NLXM pretreatment attenuates this activity, suggesting that these responses are mediated by peripheral MORs. Together, these findings establish a critical role for peripheral MORs, including ascending inputs to the nTS, as sites of dysfunction during OIRD. Furthermore, selective peripheral MOR antagonism could be a promising therapeutic strategy for managing OIRD by sparing CNS-driven acute opioid-associated withdrawal and aversion observed after NLX.