title: Brain amyloidosis ascertainment from cognitive, imaging, and peripheral blood protein measures.
abstract: BACKGROUND
  The goal of this study was to identify a clinical biomarker signature of brain amyloidosis in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) mild cognitive impairment (MCI) cohort.
  
  
  METHODS
  We developed a multimodal biomarker classifier for predicting brain amyloidosis using cognitive, imaging, and peripheral blood protein ADNI1 MCI data. We used CSF β-amyloid 1-42 (Aβ42) ≤ 192 pg/mL as proxy measure for Pittsburgh compound B (PiB)-PET standard uptake value ratio ≥ 1.5. We trained our classifier in the subcohort with CSF Aβ42 but no PiB-PET data and tested its performance in the subcohort with PiB-PET but no CSF Aβ42 data. We also examined the utility of our biomarker signature for predicting disease progression from MCI to Alzheimer dementia.
  
  
  RESULTS
  The CSF training classifier selected Mini-Mental State Examination, Trails B, Auditory Verbal Learning Test delayed recall, education, APOE genotype, interleukin 6 receptor, clusterin, and ApoE protein, and achieved leave-one-out accuracy of 85% (area under the curve [AUC] = 0.8). The PiB testing classifier achieved an AUC of 0.72, and when classifier self-tuning was allowed, AUC = 0.74. The 36-month disease-progression classifier achieved AUC = 0.75 and accuracy = 71%.
  
  
  CONCLUSIONS
  Automated classifiers based on cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with a modest level of accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.
  
  
  METHODS
  This study provides Class II evidence that a classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy (sensitivity 68%, specificity 78%).
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA. lapostolova@mednet.ucla.edu.
authors.forename: Liana G
authors.initials: LG
authors.lastname: Apostolova
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: Kristy S
authors.initials: KS
authors.lastname: Hwang
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: David
authors.initials: D
authors.lastname: Avila
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: David
authors.initials: D
authors.lastname: Elashoff
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: Omid
authors.initials: O
authors.lastname: Kohannim
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: Edmond
authors.initials: E
authors.lastname: Teng
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Sokolow
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Shaw
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.affiliation: From the Departments of Neurology (L.G.A., K.S.H., D.A., O.K., E.T., P.M.T.), Medicine Statistics Core (D.E.), and School of Nursing (S.S.), David Geffen School of Medicine at University of California, Los Angeles; Institute for Neuroinformatics (P.M.T.), Keck School of Medicine, University of Southern California, Los Angeles; Veterans Affairs Greater Los Angeles Healthcare System (E.T.); Department of Diagnostic Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Public Health and Neuroscience (W.J.J.), University of California, Berkeley; Department of Pathology and Laboratory Medicine (L.S., J.Q.T.), University of Pennsylvania School of Medicine, Philadelphia; Department of Radiology (M.W.W.), University of California, San Francisco; and Department of Veterans Affairs Medical Center (M.W.W.), San Francisco, CA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
mesh_terms: D000368:Aged; D000465:Algorithms; D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D000686:Amyloidosis / Q000175:diagnosis* / Q000473:pathology*; D000814:Aniline Compounds; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000473:pathology*; D003071:Cognition; D060825:Cognitive Dysfunction / Q000097:blood* / Q000235:genetics / Q000473:pathology* / Q000523:psychology; D015331:Cohort Studies; D016208:Databases, Factual; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D010363:Pattern Recognition, Automated; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D049268:Positron-Emission Tomography; D012680:Sensitivity and Specificity; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D015415:Biomarkers; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42)