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PLoS One. 2018 May 9;13(5):e0195838. doi: 10.1371/journal.pone.0195838. eCollection 2018.

White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer's disease.

Author information

1
Research Foundation for Mental Hygiene, Inc., New York, NY, United States of America.
2
Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, United States of America.
3
Psychology Department, Fordham University, Bronx, NY, United States of America.
4
Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, United States of America.
5
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, United States of America.
6
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, United States of America.
7
Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States of America.
8
Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States of America.
9
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
10
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States of America.
11
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
12
Centre of Excellence of Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Australia.
13
Indiana Alzheimer Disease Center and Center for Neuroimaging, Department of Radiology and Imaging Science, Indiana University School of Medicine, Indianapolis, IN, United States of America.
14
The Florey Institute, University of Melbourne, Parkville, Australia.
15
Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States of America.
16
German Center for Neurodegenerative Diseases (DZNE) München and Tübingen and Department of Nuclear Medicine, Technische Universität München (TUM), Munich, Germany.
17
Neuroscience Research Australia and University of New South Wales, Sydney, Australia.
18
Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
19
Butler Hospital and Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States of America.
20
Department of Psychiatry & Human Behavior, Alpert Medical School, Brown University, Providence, RI United States of America.
21
Department of Radiology, Mayo Clinic, Rochester, MN, United States of America.
22
Department of Radiology and Biomedical Imaging, Center for Imaging of Neurodegenerative Diseases, San Francisco Veterans Affairs Medical Center and Departments of Psychiatry, Radiology, Medicine, and Neurology, University of California at San Francisco, San Francisco, CA, United States of America.
23
Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, United States of America.

Abstract

INTRODUCTION:

White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer's disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD.

PARTICIPANTS AND METHODS:

Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds.

RESULTS:

Mutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21% of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds.

DISCUSSION:

Although there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid.

PMID:
29742105
PMCID:
PMC5942789
DOI:
10.1371/journal.pone.0195838
[Indexed for MEDLINE]
Free PMC Article

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