title: Accelerating rates of cognitive decline and imaging markers associated with β-amyloid pathology.
abstract: To estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate.
  
  
  
  In 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression.
  
  
  
  Rates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline.
  
  
  
  A considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline.
authors.affiliation: From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA. philipinsel@gmail.com.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Insel
authors.affiliation: From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA.
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.affiliation: From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Mackin
authors.affiliation: From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schöll
authors.affiliation: From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Nosheny
authors.affiliation: From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA.
authors.forename: Duygu
authors.initials: D
authors.lastname: Tosun
authors.affiliation: From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Donohue
authors.affiliation: From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.affiliation: From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
authors.affiliation: From the Center for Imaging of Neurodegenerative Diseases (P.S.I., R.S.M., R.L.N., D.T., M.W.W.), Department of Veterans Affairs Medical Center, San Francisco; Departments of Radiology and Biomedical Imaging (P.S.I., D.T., M.W.W.) and Psychiatry (R.S.M.), University of California, San Francisco; Clinical Memory Research Unit, Faculty of Medicine (P.S.I., N.M.), Lund University; Memory Clinic (N.M.) and Department of Neurology (N.M.), Skåne University Hospital, Lund University; MedTech West and the Department of Clinical Neuroscience and Rehabilitation (M.S.), University of Gothenburg, Sweden; Department of Neurology (M.C.D., P.S.A.), Keck School of Medicine, University of Southern California, Los Angeles; Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley; and Life Sciences Division (M.S., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley CA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000814:Aniline Compounds; D001284:Atrophy; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D003071:Cognition; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging / Q000523:psychology*; D018450:Disease Progression; D005026:Ethylene Glycols; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008609:Mental Status Schedule; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012044:Regression Analysis
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D015415:Biomarkers; D005026:Ethylene Glycols; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C075222:amyloid beta-protein (1-42); D019788:Fluorodeoxyglucose F18; C545186:florbetapir