title: White matter hyperintensities are associated with disproportionate progressive hippocampal atrophy.
abstract: This study investigates relationships between white matter hyperintensity (WMH) volume, cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathology markers, and brain and hippocampal volume loss. Subjects included 198 controls, 345 mild cognitive impairment (MCI), and 154 AD subjects with serial volumetric 1.5-T MRI. CSF Aβ42and total tau were measured (n = 353). Brain and hippocampal loss were quantified from serial MRI using the boundary shift integral (BSI). Multiple linear regression models assessed the relationships between WMHs and hippocampal and brain atrophy rates. Models were refitted adjusting for (a) concurrent brain/hippocampal atrophy rates and (b) CSF Aβ42and tau in subjects with CSF data. WMH burden was positively associated with hippocampal atrophy rate in controls (P = 0.002) and MCI subjects (P = 0.03), and with brain atrophy rate in controls (P = 0.03). The associations with hippocampal atrophy rate remained following adjustment for concurrent brain atrophy rate in controls and MCIs, and for CSF biomarkers in controls (P = 0.007). These novel results suggest that vascular damage alongside AD pathology is associated with disproportionately greater hippocampal atrophy in nondemented older adults. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Cassidy M
authors.initials: CM
authors.lastname: Fiford
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Emily N
authors.initials: EN
authors.lastname: Manning
authors.affiliation: Statistical Innovation Group, Cambridge, AstraZeneca, United Kingdom.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Bartlett
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.|Translational Imaging Group, Centre for Medical Image Computing, University College London, London, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Cash
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Ian B
authors.initials: IB
authors.lastname: Malone
authors.affiliation: Nuffield Department of Clinical Neurosciences, FMRIB Centre, University of Oxford, United Kingdom.|Wellcome Trust Centre for Neuroimaging, London, United Kingdom.
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Ridgway
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Manja
authors.initials: M
authors.lastname: Lehmann
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Kelvin K
authors.initials: KK
authors.lastname: Leung
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.|Translational Imaging Group, Centre for Medical Image Computing, University College London, London, United Kingdom.
authors.forename: Carole H
authors.initials: CH
authors.lastname: Sudre
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.|Translational Imaging Group, Centre for Medical Image Computing, University College London, London, United Kingdom.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Ourselin
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus University Medical Center Utrecht, The Netherlands.
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Biessels
authors.affiliation: Pennington Biomedical Research Center, Baton Rouge, Louisiana.
authors.forename: Owen T
authors.initials: OT
authors.lastname: Carmichael
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.|Translational Imaging Group, Centre for Medical Image Computing, University College London, London, United Kingdom.
authors.forename: M Jorge
authors.initials: MJ
authors.lastname: Cardoso
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Josephine
authors.initials: J
authors.lastname: Barnes
mesh_terms: D000368:Aged; D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001284:Atrophy / Q000000981:diagnostic imaging; D015415:Biomarkers / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006624:Hippocampus / Q000000981:diagnostic imaging*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D016014:Linear Models; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D066127:White Matter / Q000000981:diagnostic imaging*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; hippocampus; mild cognitive impairment; vascular disease; white matter disease; white matter hyperintensity (WMH)