title: The transitional association between β-amyloid pathology and regional brain atrophy.
abstract: BACKGROUND
  Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) associated with brain atrophy and cognitive decline. The functional form to model the association between Aβ and regional brain atrophy has not been well defined. To determine the relationship between Aβ and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) Aβ to identify subjects as Aβ+ and Aβ- with a trilinear spline model of CSF Aβ.
  
  
  METHODS
  One hundred and eighty-three subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSF Aβ and up to 4 years of longitudinal magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed using mixed-effects regression. Piecewise-linear splines were used to evaluate the nonlinear nature of the association between CSF Aβ and regional atrophy and to identify points of acceleration of atrophy with respect to Aβ. Several parameterizations of CSF Aβ were compared using likelihood ratio tests and the Akaike information criterion. Periods of acceleration of atrophy in which subjects transition from CSF Aβ negativity to CSF Aβ positivity were estimated from the spline models and tested for significance.
  
  
  RESULTS
  Spline models resulted in better fits for many temporal and parietal regions compared with the dichotomous models. The trilinear model showed that periods of acceleration of atrophy varied greatly by region with early changes seen in the insula, amygdala, precuneus, hippocampus, and other temporal regions, occurring before the clinical threshold for CSF Aβ positivity.
  
  
  CONCLUSIONS
  The use of piecewise-linear splines provides an improved model of the nonlinear association between CSF Aβ and regional atrophy in regions implicated in the progression of AD. The important biological finding of this work is that some brain regions show periods of accelerated volume loss well before the CSF Aβ42 threshold. This implies that signs of brain atrophy develop before the current conventional definition of "preclinical AD".
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA. Electronic address: philipinsel@gmail.com.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Insel
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA; Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA; Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.affiliation: Division of Biostatistics & Bioinformatics, Department of Family & Preventive Medicine, University of California, San Diego, CA, USA; Department of Neurosciences, University of California, San Diego, CA, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Donohue
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Mackin
authors.affiliation: Department of Neurosciences, University of California, San Diego, CA, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA; Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D001284:Atrophy; D001921:Brain / Q000473:pathology*; D016022:Case-Control Studies; D060825:Cognitive Dysfunction / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male
chemical_list: D016229:Amyloid beta-Peptides
keywords: ADNI; Alzheimer's disease; Atrophy; Beta amyloid; Trilinear