title: Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease.
abstract: Familial Alzheimer's disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid beta coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on magnetic resonance imaging, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 precodon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (5 precodon 200) had postmortem examination. Increased WMH were observed in the PSEN1 postcodon 200 group and in the single APP patient with an amyloid beta coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The precodon 200 group had younger ages at onset, decreased axonal density and/or integrity, and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD.
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK. Electronic address: natalie.ryan@ucl.ac.uk.
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Ryan
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Biessels
authors.affiliation: Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Lois
authors.initials: L
authors.lastname: Kim
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK; Department of Medical Statistics, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Nicholas
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Barber
authors.affiliation: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, London, UK.
authors.forename: Phoebe
authors.initials: P
authors.lastname: Walsh
authors.affiliation: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, London, UK.
authors.forename: Priya
authors.initials: P
authors.lastname: Gami
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Huw R
authors.initials: HR
authors.lastname: Morris
authors.affiliation: Department of Medical Imaging, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: António J
authors.initials: AJ
authors.lastname: Bastos-Leite
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Beck
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: VIB Center for the Biology of Disease, Leuven, Belgium; Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Lucia
authors.initials: L
authors.lastname: Chavez-Gutierrez
authors.affiliation: VIB Center for the Biology of Disease, Leuven, Belgium; Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: de Strooper
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
authors.forename: Martin N
authors.initials: MN
authors.lastname: Rossor
authors.affiliation: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, London, UK.
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.affiliation: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, London, UK.
authors.forename: Tammaryn
authors.initials: T
authors.lastname: Lashley
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics* / Q000473:pathology*; D003062:Codon / Q000235:genetics; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics; D012189:Retrospective Studies; D066127:White Matter / Q000473:pathology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D003062:Codon; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Amyloid precursor protein (APP); Cerebral amyloid angiopathy; Familial Alzheimer's disease; Presenilin 1 (PSEN1, PS1); White matter hyperintensities