title: White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY.|Division of Biostatistics, New York State Psychiatric Institute, New York, NY.
authors.forename: Seonjoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY.|Psychology Department, Fordham University, Bronx, NY.
authors.forename: Fawad
authors.initials: F
authors.lastname: Viqar
authors.affiliation: Psychology Department, Fordham University, Bronx, NY.|Department of Neurology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Molly E
authors.initials: ME
authors.lastname: Zimmerman
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Atul
authors.initials: A
authors.lastname: Narkhede
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY.|Department of Neurology, Columbia University Medical Center and the New York Presbyterian Hospital, Columbia University, New York, NY.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tosto
authors.affiliation: Department of Radiology, Washington University School of Medicine, Saint Louis, MO.
authors.forename: Tammie L S
authors.initials: TL
authors.lastname: Benzinger
authors.affiliation: Department of Radiology, Washington University School of Medicine, Saint Louis, MO.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Marcus
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Dementia Research Center, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Virginia
authors.initials: V
authors.lastname: Buckles
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Eric
authors.initials: E
authors.lastname: McDade
authors.affiliation: Center of Excellence of Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Australia.
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
authors.affiliation: Indiana Alzheimer Disease Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
authors.affiliation: The Florey Institute, University of Melbourne, Parkville, Australia.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, CA.
authors.forename: John M
authors.initials: JM
authors.lastname: Ringman
authors.affiliation: Dementia Research Center, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Ryan
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) München and Tübingen and Department of Nuclear Medicine, Technische Universität München (TUM), Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Förster
authors.affiliation: 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.
authors.forename: Christoph
authors.initials: C
authors.lastname: Laske
authors.affiliation: Neuroscience Research Australia and University of New South Wales, Sydney, Australia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
authors.affiliation: Center for Alzheimer Research and Treatment, Brigham and Women's Hospital and Massachusetts General Hospital, Boston, MA.
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
authors.affiliation: Butler Hospital and Department of Neurology, Alpert Medical School, Brown University, Providence, RI.
authors.forename: Stephen
authors.initials: S
authors.lastname: Salloway
authors.affiliation: Department of Psychiatry, Alpert Medical School, Brown University, Providence, RI.
authors.forename: Stephen
authors.initials: S
authors.lastname: Correia
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN.
authors.forename: Clifford
authors.initials: C
authors.lastname: Jack
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Weiner
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Bateman
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY.|Department of Neurology, Columbia University Medical Center and the New York Presbyterian Hospital, Columbia University, New York, NY.|Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY.|Department of Neurology, Columbia University Medical Center and the New York Presbyterian Hospital, Columbia University, New York, NY.|Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Brickman
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D015415:Biomarkers; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D053764:Presenilin-1 / Q000235:genetics; D053766:Presenilin-2 / Q000235:genetics; D066127:White Matter / Q000473:pathology*; D055815:Young Adult; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; C054369:MAPT protein, human; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; C075222:amyloid beta-protein (1-42); D016875:tau Proteins