Philip S Insel1, Niklas Mattsson2, R Scott Mackin2, Michael Schöll2, Rachel L Nosheny2, Duygu Tosun2, Michael C Donohue2, Paul S Aisen2, William J Jagust2, Michael W Weiner2. 1. 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. 2. 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.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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