title: Cerebral amyloid angiopathy with and without hemorrhage: evidence for different disease phenotypes.
abstract: OBJECTIVE
  To gain insight into different cerebral amyloid angiopathy (CAA) phenotypes and mechanisms, we investigated cortical superficial siderosis (CSS), a new imaging marker of the disease, and its relation with APOE genotype in patients with pathologically proven CAA, who presented with and without intracerebral hemorrhage (ICH).
  
  
  METHODS
  MRI scans of 105 patients with CAA pathologic confirmation and MRI were analyzed for CSS (focal, ≤3 sulci; disseminates, ≥4 sulci) and other imaging markers. We compared pathologic, imaging, and APOE genotype data between subjects with vs without ICH, and investigated associations between CSS and APOE genotype.
  
  
  RESULTS
  Our cohort consisted of 54 patients with CAA with symptomatic lobar ICH and 51 without ICH. APOE genotype was available in 53 patients. More than 90% of pathology samples in both groups had neuritic plaques, whereas neurofibrillary tangles were more commonly present in the patients without ICH (87% vs 42%, p < 0.0001). There was a trend for patients with CAA with ICH to more commonly have APOE ε2 (48.7% vs 21.4%, p = 0.075), whereas patients without ICH were more likely to be APOE ε4 carriers (85.7% vs 53.9%, p = 0.035). Disseminated CSS was considerably commoner in patients with ICH (33.3% vs 5.9%, p < 0.0001). In logistic regression, disseminated CSS was associated with APOE ε2 (but not APOE ε4) (odds ratio 5.83; 95% confidence interval 1.49-22.82, p = 0.011).
  
  
  CONCLUSIONS
  This neuropathologically defined CAA cohort suggests that CSS and APOE ε2 are related to the hemorrhagic expression of the disease; APOE ε4 is enriched in nonhemorrhagic CAA. Our study emphasizes the concept of different CAA phenotypes, suggesting divergent pathophysiologic mechanisms.
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston. acharidimou@mgh.harvard.edu.
authors.forename: Andreas
authors.initials: A
authors.lastname: Charidimou
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Sergi
authors.initials: S
authors.lastname: Martinez-Ramirez
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Ashkan
authors.initials: A
authors.lastname: Shoamanesh
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Jamary
authors.initials: J
authors.lastname: Oliveira-Filho
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Matthew
authors.initials: M
authors.lastname: Frosch
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Vashkevich
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Alison
authors.initials: A
authors.lastname: Ayres
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosand
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Mahmut Edip
authors.initials: ME
authors.lastname: Gurol
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.affiliation: From the Department of Brain Repair and Rehabilitation (A.C.), UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; and the Hemorrhagic Stroke Research Program, Stroke Research Center, Department of Neurology (A.C., S.M.-R., A.S., J.O.-F., A. Vashkevich, A.A., J.R., M.E.G., S.M.G., A. Viswanathan), C.S. Kubik Laboratory for Neuropathology (M.F.), Division of Neurocritical Care and Emergency Neurology (J.R.), and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Anand
authors.initials: A
authors.lastname: Viswanathan
mesh_terms: D000368:Aged; D053329:Apolipoprotein E2 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D016657:Cerebral Amyloid Angiopathy / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism*; D002543:Cerebral Hemorrhage / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005838:Genotype; D006486:Hemosiderosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype
chemical_list: D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D015415:Biomarkers