title: β-Amyloid in CSF: Biomarker for preclinical cerebral amyloid angiopathy.
abstract: OBJECTIVE
  To investigate CSF biomarkers in presymptomatic and symptomatic mutation carriers with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a model for sporadic cerebral amyloid angiopathy, and to determine the earliest deposited form of β-amyloid (Aβ).
  
  
  METHODS
  HCHWA-D mutation carriers and controls were enrolled in the cross-sectional EDAN (Early Diagnosis of Amyloid Angiopathy Network) study. The HCHWA-D group was divided into symptomatic carriers with a previous intracerebral hemorrhage and presymptomatic carriers. CSF concentrations of Aβ40, Aβ42, total tau, and phosphorylated tau181proteins were compared to those of controls of a similar age. Correlations between CSF biomarkers, MRI markers, and age were investigated with multivariate linear regression analyses.
  
  
  RESULTS
  We included 10 symptomatic patients with HCHWA-D (mean age 55 ± 6 years), 5 presymptomatic HCHWA-D carriers (mean age 36 ± 13 years), 31 controls <50 years old (mean age 31 ± 7 years), and 50 controls ≥50 years old (mean age 61 ± 8 years). After correction for age, CSF Aβ40and Aβ42were significantly decreased in symptomatic carriers vs controls (median Aβ401,386 vs 3,867 ng/L, p < 0.001; median Aβ42289 vs 839 ng/L, p < 0.001) and in presymptomatic carriers vs controls (median Aβ403,501 vs 4,684 ng/L, p = 0.011; median Aβ42581 vs 1,058 ng/L, p < 0.001). Among mutation carriers, decreasing CSF Aβ40was associated with higher lobar microbleed count (p = 0.010), increasing white matter hyperintensity volume (p = 0.008), and presence of cortical superficial siderosis (p = 0.02).
  
  
  CONCLUSIONS
  Decreased levels of CSF Aβ40and Aβ42occur before HCHWA-D mutation carriers develop clinical symptoms, implicating vascular deposition of both Aβ species as early steps in cerebral amyloid angiopathy pathogenesis. CSF Aβ40and Aβ42may serve as preclinical biomarkers of cerebral amyloid angiopathy pathology.
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston. e.s.van_etten@lumc.nl.
authors.forename: Ellis S
authors.initials: ES
authors.lastname: van Etten
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Verbeek
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van der Grond
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Ronald
authors.initials: R
authors.lastname: Zielman
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Sanneke
authors.initials: S
authors.lastname: van Rooden
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Erik W
authors.initials: EW
authors.lastname: van Zwet
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Anna M
authors.initials: AM
authors.lastname: van Opstal
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Joost
authors.initials: J
authors.lastname: Haan
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Mark A
authors.initials: MA
authors.lastname: van Buchem
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Wermer
authors.affiliation: From the Departments of Neurology (E.S.v.E., R.Z., J.H., M.J.H.W., G.M.T.), Radiology (J.v.d.G., S.v.R., A.M.v.O., M.A.v.B.), and Biostatistics (E.W.v.Z.), Leiden University Medical Center; Departments of Neurology and Laboratory Medicine (M.M.V.), Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen; Department of Neurology (J.H.), Alrijne Hospital, Leiderdorp, the Netherlands; and J. Philip Kistler Stroke Research Center (S.M.G.), Massachusetts General Hospital, Boston.
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Terwindt
mesh_terms: D000328:Adult; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016657:Cerebral Amyloid Angiopathy / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000000981:diagnostic imaging; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)