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March 05, 2019; 92 (10) Article

Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine

Clara Domínguez, Ana López, Pedro Ramos-Cabrer, Alba Vieites-Prado, Maria Pérez-Mato, Carmen Villalba, Tomás Sobrino, Xiana Rodriguez-Osorio, Francisco Campos, José Castillo, Rogelio Leira
First published February 1, 2019, DOI: https://doi.org/10.1212/WNL.0000000000007047
Clara Domínguez
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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Ana López
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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Pedro Ramos-Cabrer
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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Alba Vieites-Prado
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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Maria Pérez-Mato
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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Carmen Villalba
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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Tomás Sobrino
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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Xiana Rodriguez-Osorio
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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Francisco Campos
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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José Castillo
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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Rogelio Leira
From the Departments of Neurology (C.D., A.L., X.R.-O., R.L.) and Radiology (C.V.), Hospital Clinico Universitario, Universidade de Santiago de Compostela; Clinical Neurosciences Research Laboratory (A.V.-P., M.P.-M., T.S., F.C., J.C., R.L.), Health Research Institute of Santiago de Compostela; Magnetic Resonance Imaging (P.R.-C.), Molecular Imaging Unit, CIC biomaGUNE, Donostia–San Sebastian; and Ikerbasque (P.R.-C.), The Basque Foundation for Science, Bilbao, Spain.
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Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine
Clara Domínguez, Ana López, Pedro Ramos-Cabrer, Alba Vieites-Prado, Maria Pérez-Mato, Carmen Villalba, Tomás Sobrino, Xiana Rodriguez-Osorio, Francisco Campos, José Castillo, Rogelio Leira
Neurology Mar 2019, 92 (10) e1076-e1085; DOI: 10.1212/WNL.0000000000007047

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This article has a correction. Please see:

  • Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine - September 24, 2019
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Abstract

Objective To study iron deposition in red nucleus (RN), globus pallidus (GP), and periaqueductal gray matter (PAG) as a potential biomarker of chronic migraine (CM) and its association with levels of biomarkers related to migraine pathophysiology.

Methods This case-control study included 112 patients with migraine (55 CM, 57 episodic migraine [EM]) and 25 headache-free controls. We analyzed iron deposition using 3T MRI and the NIH software platform ImageJ; we analyzed serum levels of markers of inflammation, endothelial dysfunction, and blood-brain barrier (BBB) disruption by ELISA in peripheral blood during interictal periods.

Results Patients with CM showed larger iron grounds volume in RN compared to patients with EM (70.2 ± 6.8 vs 25.5 ± 7.3 μL, p < 0.001) and controls (70.2 ± 6.8 vs 15.1 ± 10.8 μL, p < 0.001), as well as larger iron deposits in PAG compared to patients with EM (360.3 ± 6.5 vs 249.7 ± 6.9 μL, p < 0.001) and controls (360.3 ± 6.5 vs 168.6 ± 10.3 μL, p < 0.001). In PAG, differences were also significant between patients with EM and controls. No significant differences were obtained for GP. Receiver operating characteristic curves showed that the optimal threshold for iron volume was 15 μL in RN (80% sensitivity, 71% specificity) and 240 μL in PAG (93% sensitivity, 97% specificity). Iron grounds volume in PAG was correlated with higher plasma levels of soluble tumor necrosis factor–like WEAK (r = 0.395, p = 0.005) and cellular fibronectin (r = 0.294, p = 0.040).

Conclusions Patients with CM showed increased iron deposition in RN and PAG compared to patients with EM and controls. Iron grounds volume in PAG identified correctly patients with CM and was associated with elevated biomarkers of endothelial dysfunction and BBB disruption.

Glossary

BBB=
blood-brain barrier;
BG=
basal ganglia;
CAMERA=
Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis;
cFn=
cellular fibronectin;
CGRP=
calcitonin gene-related peptide;
EM=
episodic migraine;
GP=
globus pallidus;
hs-CRP=
high-sensitivity C-reactive protein;
IL=
interleukin;
PAG=
periaqueductal gray matter;
PTX3=
pentraxin 3;
RN=
red nucleus;
ROI=
region of interest;
sTWEAK=
soluble tumor necrosis factor–like WEAK;
TGV=
trigeminovascular;
TNF-α=
tumor necrosis factor-α

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.

  • CME Course: NPub.org/cmelist

  • Received August 27, 2018.
  • Accepted in final form October 31, 2018.
  • © 2019 American Academy of Neurology
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Letters: Rapid online correspondence

  • Author response: Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine
    • Clara Domínguez, MD, Hospital Clínico Universitario de Santiago de Compostela
    • Rogelio Leira, MD, PhD, Hospital Clínico Universitario de Santiago de Compostela
    Submitted May 17, 2019
  • Author response: Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine
    • Rogelio Leira, MD, PhD, Hospital Clínico Universitario de Santiago de Compostela
    • Clara Dominguez, MD, Hospital Clínico Universitario de Santiago de Compostela
    Submitted April 21, 2019
  • Author response: Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine
    • Rogelio Leira, PhD, MD, Hospital Clínico Universitario de Santiago de Compostela
    • Clara Domínguez, MD, Hospital Clínico Universitario de Santiago de Compostela
    Submitted April 13, 2019
  • Reader response: Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine
    • Kenneth M.A. Welch, Professor Emeritus, Division of Clinical Sciences,, Chicago Medical School, Rosalind Franklin University
    Submitted April 06, 2019
  • Reader response: Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine
    • Vinod Gupta, Physician, Migraine-Headache Institute, Gupta Medical Centre (New Delhi, India)
    Submitted March 08, 2019
  • Reader response: Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine
    • Khichar Shubhakaran, Neurology Professor, Dr. Sampurnanand Medical College (Jodhpur, India)
    Submitted March 05, 2019
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