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August 30, 2022; 99 (9) Research Articles

Relation Between Sex, Menopause, and White Matter Hyperintensities

The Rhineland Study

View ORCID ProfileValerie Lohner, View ORCID ProfileGökhan Pehlivan, View ORCID ProfileGerard Sanroma, Anne Miloschewski, View ORCID ProfileMarkus D. Schirmer, View ORCID ProfileTony Stöcker, View ORCID ProfileMartin Reuter, View ORCID ProfileMonique M.B. Breteler
First published June 29, 2022, DOI: https://doi.org/10.1212/WNL.0000000000200782
Valerie Lohner
From the Population Health Sciences (V.L., G.P., G.S., M.M.B.B.), and Statistics and Machine Learning (A.M.), German Center for Neurodegenerative Diseases (DZNE), Bonn; J. Philip Kistler Stroke Research Center (M.D.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Clinic for Neuroradiology (M.D.S.), University Hospital Bonn, Germany; MR Physics (T.S.), German Center for Neurodegenerative Diseases (DZNE), Bonn; Department of Physics and Astronomy (T.S.), University of Bonn, Germany; Image Analysis (M.R.), German Center for Neurodegenerative Diseases (DZNE), Bonn; A.A. Martinos Center for Biomedical Imaging (M.R.), Massachusetts General Hospital, Boston; Department of Radiology (M.R.), Harvard Medical School, Boston, MA; and Institute for Medical Biometry (M.M.B.B.), Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Germany.
MSc
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Gökhan Pehlivan
From the Population Health Sciences (V.L., G.P., G.S., M.M.B.B.), and Statistics and Machine Learning (A.M.), German Center for Neurodegenerative Diseases (DZNE), Bonn; J. Philip Kistler Stroke Research Center (M.D.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Clinic for Neuroradiology (M.D.S.), University Hospital Bonn, Germany; MR Physics (T.S.), German Center for Neurodegenerative Diseases (DZNE), Bonn; Department of Physics and Astronomy (T.S.), University of Bonn, Germany; Image Analysis (M.R.), German Center for Neurodegenerative Diseases (DZNE), Bonn; A.A. Martinos Center for Biomedical Imaging (M.R.), Massachusetts General Hospital, Boston; Department of Radiology (M.R.), Harvard Medical School, Boston, MA; and Institute for Medical Biometry (M.M.B.B.), Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Germany.
MD
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Gerard Sanroma
From the Population Health Sciences (V.L., G.P., G.S., M.M.B.B.), and Statistics and Machine Learning (A.M.), German Center for Neurodegenerative Diseases (DZNE), Bonn; J. Philip Kistler Stroke Research Center (M.D.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Clinic for Neuroradiology (M.D.S.), University Hospital Bonn, Germany; MR Physics (T.S.), German Center for Neurodegenerative Diseases (DZNE), Bonn; Department of Physics and Astronomy (T.S.), University of Bonn, Germany; Image Analysis (M.R.), German Center for Neurodegenerative Diseases (DZNE), Bonn; A.A. Martinos Center for Biomedical Imaging (M.R.), Massachusetts General Hospital, Boston; Department of Radiology (M.R.), Harvard Medical School, Boston, MA; and Institute for Medical Biometry (M.M.B.B.), Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Germany.
PhD
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Anne Miloschewski
From the Population Health Sciences (V.L., G.P., G.S., M.M.B.B.), and Statistics and Machine Learning (A.M.), German Center for Neurodegenerative Diseases (DZNE), Bonn; J. Philip Kistler Stroke Research Center (M.D.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Clinic for Neuroradiology (M.D.S.), University Hospital Bonn, Germany; MR Physics (T.S.), German Center for Neurodegenerative Diseases (DZNE), Bonn; Department of Physics and Astronomy (T.S.), University of Bonn, Germany; Image Analysis (M.R.), German Center for Neurodegenerative Diseases (DZNE), Bonn; A.A. Martinos Center for Biomedical Imaging (M.R.), Massachusetts General Hospital, Boston; Department of Radiology (M.R.), Harvard Medical School, Boston, MA; and Institute for Medical Biometry (M.M.B.B.), Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Germany.
PhD
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Markus D. Schirmer
From the Population Health Sciences (V.L., G.P., G.S., M.M.B.B.), and Statistics and Machine Learning (A.M.), German Center for Neurodegenerative Diseases (DZNE), Bonn; J. Philip Kistler Stroke Research Center (M.D.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Clinic for Neuroradiology (M.D.S.), University Hospital Bonn, Germany; MR Physics (T.S.), German Center for Neurodegenerative Diseases (DZNE), Bonn; Department of Physics and Astronomy (T.S.), University of Bonn, Germany; Image Analysis (M.R.), German Center for Neurodegenerative Diseases (DZNE), Bonn; A.A. Martinos Center for Biomedical Imaging (M.R.), Massachusetts General Hospital, Boston; Department of Radiology (M.R.), Harvard Medical School, Boston, MA; and Institute for Medical Biometry (M.M.B.B.), Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Germany.
PhD
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Tony Stöcker
From the Population Health Sciences (V.L., G.P., G.S., M.M.B.B.), and Statistics and Machine Learning (A.M.), German Center for Neurodegenerative Diseases (DZNE), Bonn; J. Philip Kistler Stroke Research Center (M.D.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Clinic for Neuroradiology (M.D.S.), University Hospital Bonn, Germany; MR Physics (T.S.), German Center for Neurodegenerative Diseases (DZNE), Bonn; Department of Physics and Astronomy (T.S.), University of Bonn, Germany; Image Analysis (M.R.), German Center for Neurodegenerative Diseases (DZNE), Bonn; A.A. Martinos Center for Biomedical Imaging (M.R.), Massachusetts General Hospital, Boston; Department of Radiology (M.R.), Harvard Medical School, Boston, MA; and Institute for Medical Biometry (M.M.B.B.), Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Germany.
PhD
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Martin Reuter
From the Population Health Sciences (V.L., G.P., G.S., M.M.B.B.), and Statistics and Machine Learning (A.M.), German Center for Neurodegenerative Diseases (DZNE), Bonn; J. Philip Kistler Stroke Research Center (M.D.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Clinic for Neuroradiology (M.D.S.), University Hospital Bonn, Germany; MR Physics (T.S.), German Center for Neurodegenerative Diseases (DZNE), Bonn; Department of Physics and Astronomy (T.S.), University of Bonn, Germany; Image Analysis (M.R.), German Center for Neurodegenerative Diseases (DZNE), Bonn; A.A. Martinos Center for Biomedical Imaging (M.R.), Massachusetts General Hospital, Boston; Department of Radiology (M.R.), Harvard Medical School, Boston, MA; and Institute for Medical Biometry (M.M.B.B.), Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Germany.
PhD
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  • ORCID record for Martin Reuter
Monique M.B. Breteler
From the Population Health Sciences (V.L., G.P., G.S., M.M.B.B.), and Statistics and Machine Learning (A.M.), German Center for Neurodegenerative Diseases (DZNE), Bonn; J. Philip Kistler Stroke Research Center (M.D.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Clinic for Neuroradiology (M.D.S.), University Hospital Bonn, Germany; MR Physics (T.S.), German Center for Neurodegenerative Diseases (DZNE), Bonn; Department of Physics and Astronomy (T.S.), University of Bonn, Germany; Image Analysis (M.R.), German Center for Neurodegenerative Diseases (DZNE), Bonn; A.A. Martinos Center for Biomedical Imaging (M.R.), Massachusetts General Hospital, Boston; Department of Radiology (M.R.), Harvard Medical School, Boston, MA; and Institute for Medical Biometry (M.M.B.B.), Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Germany.
MD, PhD
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Relation Between Sex, Menopause, and White Matter Hyperintensities
The Rhineland Study
Valerie Lohner, Gökhan Pehlivan, Gerard Sanroma, Anne Miloschewski, Markus D. Schirmer, Tony Stöcker, Martin Reuter, Monique M.B. Breteler
Neurology Aug 2022, 99 (9) e935-e943; DOI: 10.1212/WNL.0000000000200782

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Abstract

Background and Objectives Mounting evidence implies that there are sex differences in white matter hyperintensity (WMH) burden in older people. Questions remain regarding possible differences in WMH burden between men and women of younger age, sex-specific age trajectories and effects of (un)controlled hypertension, and the effect of menopause on WMH. Therefore, our aim was to investigate these sex differences and age dependencies in WMH load across the adult life span and to examine the effect of menopause.

Methods This cross-sectional analysis was based on participants of the population-based Rhineland Study (30–95 years) who underwent brain MRI. We automatically quantified WMH using T1-weighted, T2-weighted, and fluid-attenuated inversion recovery images. Menopausal status was self-reported. We examined associations of sex and menopause with WMH load (logit-transformed and z-standardized) using linear regression models while adjusting for age, age-squared, and vascular risk factors. We checked for an age × sex and (un)controlled hypertension × sex interaction and stratified for menopausal status comparing men with premenopausal women (persons aged 59 years or younger), men with postmenopausal women (persons aged 45 years or older), and premenopausal with postmenopausal women (age range 45–59 years).

Results Of 3,410 participants with a mean age of 54.3 years (SD = 13.7), 1,973 (57.9%) were women, of which 1,167 (59.1%) were postmenopausal. We found that the increase in WMH load accelerates with age and in a sex-dependent way. Premenopausal women and men of similar age did not differ in WMH burden. WMH burden was higher and accelerated faster in postmenopausal women compared with men of similar age. In addition, we observed changes related to menopause, in that postmenopausal women had more WMH than premenopausal women of similar age. Women with uncontrolled hypertension had a higher WMH burden compared with men, which was unrelated to menopausal status.

Discussion After menopause, women displayed a higher burden of WMH than contemporary premenopausal women and men and an accelerated increase in WMH. Sex-specific effects of uncontrolled hypertension on WMH were not related to menopause. Further studies are warranted to investigate menopause-related physiologic changes that may inform on causal mechanisms involved in cerebral small vessel disease progression.

Glossary

3D=
3-dimensional;
BMI=
body mass index;
FLAIR=
fluid-attenuated inversion recovery;
FOV=
field-of-view;
HT=
hormone therapy;
IQR=
interquartile range;
TE=
echo time;
TI=
inversion time;
TR=
repetition time;
WMH=
white matter hyperintensities

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.

  • Submitted and externally peer reviewed. The handling editor was José Merino, MD, MPhil, FAAN.

  • CME Course: NPub.org/cmelist

  • Received November 12, 2021.
  • Accepted in final form April 11, 2022.
  • © 2022 American Academy of Neurology
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