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February 25, 2020; 94 (8) Article

Unique white matter structural connectivity in early-stage drug-naive Parkinson disease

View ORCID ProfileVirendra R. Mishra, Karthik R. Sreenivasan, Zhengshi Yang, Xiaowei Zhuang, Dietmar Cordes, Zoltan Mari, Irene Litvan, Hubert H. Fernandez, David Eidelberg, Aaron Ritter, Jeffrey L. Cummings, Ryan R. Walsh
First published December 27, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008867
Virendra R. Mishra
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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  • ORCID record for Virendra R. Mishra
Karthik R. Sreenivasan
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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Zhengshi Yang
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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Xiaowei Zhuang
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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Dietmar Cordes
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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Zoltan Mari
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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Irene Litvan
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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Hubert H. Fernandez
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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David Eidelberg
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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Aaron Ritter
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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Jeffrey L. Cummings
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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Ryan R. Walsh
From Imaging Research (V.R.M., K.R.S., Z.Y., X.Z., D.C.), Lou Ruvo Center for Brain Health (Z.M., A.R., J.L.C.), Cleveland Clinic Foundation, Las Vegas, NV; Departments of Psychology and Neuroscience (D.C.), University of Colorado at Boulder; Department of Neurosciences (I.L.), University of California San Diego, La Jolla; Center for Neurological Restoration (H.H.F.), Cleveland Clinic, OH; Center for Neurosciences (D.E.), Feinstein Institute for Medical Research, Manhasset, NY; UNLV Department of Brain Health (J.L.C.), School of Integrated Health Sciences, Las Vegas, NV; and Muhammad Ali Parkinson Center (R.R.W.), Barrow Neurological Institute, Phoenix, AZ.
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Citation
Unique white matter structural connectivity in early-stage drug-naive Parkinson disease
Virendra R. Mishra, Karthik R. Sreenivasan, Zhengshi Yang, Xiaowei Zhuang, Dietmar Cordes, Zoltan Mari, Irene Litvan, Hubert H. Fernandez, David Eidelberg, Aaron Ritter, Jeffrey L. Cummings, Ryan R. Walsh
Neurology Feb 2020, 94 (8) e774-e784; DOI: 10.1212/WNL.0000000000008867

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Abstract

Objective To investigate the topographic arrangement and strength of whole-brain white matter (WM) structural connectivity in patients with early-stage drug-naive Parkinson disease (PD).

Methods We employed a model-free data-driven approach for computing whole-brain WM topologic arrangement and connectivity strength between brain regions by utilizing diffusion MRI of 70 participants with early-stage drug-naive PD and 41 healthy controls. Subsequently, we generated a novel group-specific WM anatomical network by minimizing variance in anatomical connectivity of each group. Global WM connectivity strength and network measures were computed on this group-specific WM anatomical network and were compared between the groups. We tested correlations of these network measures with clinical measures in PD to assess their pathophysiologic relevance.

Results PD-relevant cortical and subcortical regions were identified in the novel PD-specific WM anatomical network. Impaired modular organization accompanied by a correlation of network measures with multiple clinical variables in early PD were revealed. Furthermore, disease duration was negatively correlated with global connectivity strength of the PD-specific WM anatomical network.

Conclusion By minimizing variance in anatomical connectivity, this study found the presence of a novel WM structural connectome in early PD that correlated with clinical symptoms, despite the lack of a priori analytic assumptions. This included the novel finding of increased structural connectivity between known PD-relevant brain regions. The current study provides a framework for further investigation of WM structural changes underlying the clinical and pathologic heterogeneity of PD.

Glossary

AD=
Alzheimer disease;
DaT=
dopamine uptake transporter;
dMRI=
diffusion MRI;
FA=
fractional anisotropy;
FW=
free-water;
HC=
healthy controls;
Inf-Fron-Tri-Left=
left frontal inferior triangularis;
MDS-UPDRS-III=
Movement Disorder Society–sponsored Unified Parkinson's Disease Rating Scale Part III;
MNI=
Montreal Neurological Institute;
MoCA=
Montreal Cognitive Assessment;
NBS=
network-based statistic;
PALM=
permutation analysis of linear models;
PD=
Parkinson disease;
PPMI=
Parkinson's Progression Markers Initiative;
ROI=
region of interest;
SMA=
supplementary motor area;
WM=
white matter

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received April 29, 2019.
  • Accepted in final form August 28, 2019.
  • © 2019 American Academy of Neurology
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