Seonjoo Lee1,2, Fawad Viqar3,4, Molly E Zimmerman4,5, Atul Narkhede3, Giuseppe Tosto3,6, Tammie L S Benzinger7, Daniel S Marcus7, Anne M Fagan8, Alison Goate9, Nick C Fox10, Nigel J Cairns11, David M Holtzman8, Virginia Buckles8, Bernardino Ghetti12, Eric McDade8, Ralph N Martins13, Andrew J Saykin14, Colin L Masters15, John M Ringman16, Natalie S Ryan10, Stefan Förster17, Christoph Laske18, Peter R Schofield19, Reisa A Sperling20, Stephen Salloway21, Stephen Correia22, Clifford Jack23, Michael Weiner24, Randall J Bateman8, John C Morris8, Richard Mayeux3,6,25, Adam M Brickman3,6,25. 1. Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY. 2. Division of Biostatistics, New York State Psychiatric Institute, New York, NY. 3. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY. 4. Psychology Department, Fordham University, Bronx, NY. 5. Department of Neurology, Albert Einstein College of Medicine, Bronx, NY. 6. Department of Neurology, Columbia University Medical Center and the New York Presbyterian Hospital, Columbia University, New York, NY. 7. Department of Radiology, Washington University School of Medicine, Saint Louis, MO. 8. Department of Neurology, Washington University School of Medicine, St. Louis, MO. 9. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY. 10. Dementia Research Center, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom. 11. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO. 12. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN. 13. Center of Excellence of Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Australia. 14. Indiana Alzheimer Disease Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN. 15. The Florey Institute, University of Melbourne, Parkville, Australia. 16. Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, CA. 17. German Center for Neurodegenerative Diseases (DZNE) München and Tübingen and Department of Nuclear Medicine, Technische Universität München (TUM), Munich, Germany. 18. German Center for Neurodegenerative Diseases (DZNE) and the Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany. 19. Neuroscience Research Australia and University of New South Wales, Sydney, Australia. 20. Center for Alzheimer Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital, Boston, MA. 21. Butler Hospital and Department of Neurology, Alpert Medical School, Brown University, Providence, RI. 22. Department of Psychiatry, Alpert Medical School, Brown University, Providence, RI. 23. Department of Radiology, Mayo Clinic, Rochester, MN. 24. 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. 25. Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY.
Abstract
OBJECTIVE: White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD. METHODS: The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO. RESULTS: Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset. INTERPRETATION: Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939.
OBJECTIVE: White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD. METHODS: The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO. RESULTS: Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset. INTERPRETATION: Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939.
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