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Dementia"],"published-print":{"date-parts":[[2015,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Alzheimer's disease (AD) is characterized by the accumulation of \u03b2\u2010amyloid (A\u03b2) associated with brain atrophy and cognitive decline. The functional form to model the association between A\u03b2 and regional brain atrophy has not been well defined. To determine the relationship between A\u03b2 and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) A\u03b2 to identify subjects as A\u03b2+ and A\u03b2\u2212 with a trilinear spline model of CSF A\u03b2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>One hundred and eighty\u2010three subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSF A\u03b2 and up to 4\u00a0years of longitudinal magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed using mixed\u2010effects regression. Piecewise\u2010linear splines were used to evaluate the nonlinear nature of the association between CSF A\u03b2 and regional atrophy and to identify points of acceleration of atrophy with respect to A\u03b2. Several parameterizations of CSF A\u03b2 were compared using likelihood ratio tests and the Akaike information criterion. Periods of acceleration of atrophy in which subjects transition from CSF A\u03b2 negativity to CSF A\u03b2 positivity were estimated from the spline models and tested for significance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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 A\u03b2 positivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The use of piecewise\u2010linear splines provides an improved model of the nonlinear association between CSF A\u03b2 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 A\u03b2<jats:sub>42<\/jats:sub> threshold. This implies that signs of brain atrophy develop before the current conventional definition of \u201cpreclinical AD\u201d.<\/jats:p><\/jats:sec>","DOI":"10.1016\/j.jalz.2014.11.002","type":"journal-article","created":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T18:18:22Z","timestamp":1418149102000},"page":"1171-1179","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["The transitional association between \u03b2\u2010amyloid pathology and regional brain atrophy"],"prefix":"10.1002","volume":"11","author":[{"given":"Philip S.","family":"Insel","sequence":"first","affiliation":[{"name":"Department of Veterans Affairs Medical Center Center for Imaging of Neurodegenerative Diseases  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Mattsson","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Medical Center Center for Imaging of Neurodegenerative Diseases  San Francisco CA USA"},{"name":"Department of Radiology and Biomedical Imaging University of California  San Francisco CA USA"},{"name":"Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy University of Gothenburg  M\u00f6lndal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Donohue","sequence":"additional","affiliation":[{"name":"Division of Biostatistics &amp; Bioinformatics Department of Family &amp; Preventive Medicine University of California  San Diego CA USA"},{"name":"Department of Neurosciences University of California  San Diego CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Scott","family":"Mackin","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Medical Center Center for Imaging of Neurodegenerative Diseases  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"Aisen","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California  San Diego CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Clifford R.","family":"Jack","sequence":"additional","affiliation":[{"name":"Department of Radiology Mayo Clinic  Rochester MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie M.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Q.","family":"Trojanowski","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Weiner","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Medical Center Center for Imaging of Neurodegenerative Diseases  San Francisco CA USA"},{"name":"Department of Radiology and Biomedical Imaging University of California  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Alzheimer's Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,12,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2009.266"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1202753"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp062"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(09)70299-6"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.04.007"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318246d67a"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21955"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2013.1062"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr044"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182a841c6"},{"key":"e_1_2_7_14_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-013-1151-4","article-title":"Longitudinal change in CSF Tau and A\u03b2 biomarkers for up to 48 months in ADNI","volume":"126","author":"Toledo J","year":"2013","journal-title":"Acta Neuropathol"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70044-9"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182840bbe"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181c918b5"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21610"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.1988.10478639"},{"key":"e_1_2_7_20_1","volume-title":"Generalized additive models","author":"Hastie TJ","year":"1990"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.07.012"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp091"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181b16431"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.1993.tb06734.x"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2004.039347"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.21049"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1017\/CBO9780511802843"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000435556.21319.e4"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2014.446"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-0983-7"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt188"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/2051-5960-1-65"}],"container-title":["Alzheimer's &amp; 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